**+**

Control Elective Acute

**\*\*\* \*\*\***

**3.1.4.3 SOD activity** 

the whole study (Figure 7.)

**0**

**Before surgery**

**\*\*\* +**

**200**

**400**

**600**

**SOD (U/l)**

#=p<0,05 vs. before surgery

the intervention.

**3.1.5 Investigation of prooxidants** 

**3.1.5.1 PMA induced free radical production** 

**800**

**1000**

**1200**

production corrected to the WBC numbers, 3. the Slope: the rate of rise of the ascending part of the free radical generation curves and the WBC numbers (Figure 8.).

Fig. 8. Upper left panel: white blood cell numbers, upper right panel: lag time, bottom left panel: slope of free radical curve, bottom right panel: maximal free radical production. \*\*\*=<0.001 vs. control, +++=p<0.001 vs. elective, #= p< 0.01 vs. before surgery).

In Acute group WBC numbers were significantly higher (upper left panel) and Lag time was significantly shorter (upper right panel) before and one week after the surgery, than the similar values in Elective and Control Groups (\*=p<0.05 vs. Control, # = p<0.05 vs. Elective groups). Slope of the free radical producing curves became steeper in acute and elective groups, signing that more and more active WBC are present before and one week after the surgery, but in Acute group this free radical generation was significantly higher, than in the other two groups. The maximum of free radical production continuously elevated both in acute and in elective groups, but these elevation in acute group was several times higher than it was measured in elective group (figure 8.).

#### **3.1.5.2 Investigation of lipid peroxidation due to measurement of MDA in plasma and in red blood cell haemolysate**

It is a well known fact, that one of the main consequence of long-lasting atherosclerosis is the significant decrease in the polyunsaturated fatty acid (PUFA) content of the membranes, due to saturation of the membrane lipids which responsible for the rigidity of the membranes. MDA is one of the lipid peroxydation end products, generated in the course of

Investigation of the Oxidative Stress, the Altered Function

mode of intervention, surgery or application of thrombolytics.

**3.1.5.4 Conclusion of the first series of the experiments** 

response to aggregation inductors.

**3.2.1 Clinical chemistry data** 

**3.2 Results of the second series of experiments** 

dilatation of collateral arteries (Brennan ML et al 2010).

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 75

(Brennan ML et al 2003). MPO is a hydrogen peroxide oxidoreductase, specifically found on mammalian polymorphonuclear leukocytes (PMN), responsible for the bactericidal capability of these cells. PMN activation and mediator release are partially responsible for the morbidity and mortality of revascularization of ischemic lower limb, regardless of the

Ischemia/reperfusion injury, accompanied by revascularization surgeries of lower limb, was in the focus of the present study. This problem has great importance in the clinical practice because of its poor outcome (postoperative mortality is 15-60%). Tissue injury appears not only under ischemia, but after restoration of the blood flow in the formerly ischemic areas, due to the reperfusion injury, as well (Yasin) NM et al. 2002), (Arato et al 2009). Ischemia reperfusion injury of lower limb is accompanied by muscle changes with progressive micro-vascular damage, and affects all circulating cells (RBC, WBC, and PLT), as well. These cells are in connection with each other and with cells of the vessel walls, too. Inflammatory response following reperfusion varies greatly, and depends on the time and severity of ischemia. According to our results in accordance with several other studies, the duration and severity of ischemia is proportional to the damage occurred after it. Studying thrombocyte function and antioxidant prooxidant status of our unique patient groups, several new aspects of ischemia reperfusion injury were revealed. Peripheral arterial disease is a common progressive disorder that attaches the circulation of the legs, particularly in people over 55 years, strengthening in these patients the greatly increased risk of heart attack or stroke, and of dying within a decade. Several aspects of the problem were intensively studied, but platelet function during the restoration of the circulation of ischemic lower limb was hardly investigated before. It was revealed in this study that an effective antiaggregating therapy was applied in these patients, and effectively reduced the aggregation induced by ADP and collagen in PRP, but this reduction in whole blood was completely disappeared, both in ADP and collagen induced aggregation in Acute and Elective groups too. Above this a highly significant increase in platelet aggregation was measured in whole blood, in response to both types of inductors, one week after the surgery in Acute group. We concluded on the basis of our result that the long-lasting hypoxia is responsible for the increased PLT aggregation in whole blood, as the consequence of the shift of the antioxidant-prooxidant balance to the prooxidant direction lead to the increased

Monitoring thrombocyte function and antioxidant prooxidant status of diabetic patients with peripheral arterial disease is inevitably important, because of the increased risk of complication. Patients suffering from both diabetes and PAD are at risk of developing critical limb ischemia, ulceration and potentially requiring limb amputation. In addition, diabetes complicates surgical treatment of PAD and impairs vascular functions. The presence of diabetes increases the frequency of intermittent claudication. The relative risk of amputation in diabetic population is 12,4-fold higher compared to the non diabetic patients (95%, 10,9-14,9), and this value doubles above 65 years. Diabetes increases the sensing of shear stress and the response to vasoconstrictor stimuli, reducing the recruitment and

free radical induced peroxydation of PUFA. MDA is frequently used as a lipid peroxydation marker in biological tissues.

Fig. 9. MDA level in red blood cell (RBC) hemolysate (left panel) and in plasma (right panel), \*= p<0.05 vs. Control, \*\*= p<0.01 vs. Control, \*\*\*= p<0.0051 vs. Control +=p<0.05 vs. Elective, #=p<0.05 vs. before surgery

Surprisingly, in our case MDA concentration of erythrocyte membrane remained in a standard, relatively low level during the whole study, in the Acute group. We speculated about the background of this phenomenon, and finally we concluded that the long-lasting hypoxia preceeded the surgery may exhausted of the PUFA contents of the lipidmembranes. At the same time, plasma MDA of Acute group (right panel) were significantly higher than in Elective and Control groups, and elevated further 24 hours after the surgery, and returned to the baseline one week after the surgery. In Elective group a bell-shaped elevation appeared which peaked 2 hours after surgery (Figure 9. right panel).

#### **3.1.5.3 Changes in MPO**

In spite of MPO have not been evaluated in routine clinical chemistry studies, according to a recent study of Brevetti and coworkers its elevated level, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease (Brevetti G , 2008). According to an other study it is a marker of myocardial infarction too. The base-line myeloperoxidase level independently predicts the risk of major adverse coronary events within 30 days.

Fig. 10. **Myeloperoxidase level in Control, Elective and Acute groups.** MPO level both in Elective and Acute groups were significantly higher than in Control before surgery, than after a transient decrease in the postoperative period returned to the preoperative level.

(Brennan ML et al 2003). MPO is a hydrogen peroxide oxidoreductase, specifically found on mammalian polymorphonuclear leukocytes (PMN), responsible for the bactericidal capability of these cells. PMN activation and mediator release are partially responsible for the morbidity and mortality of revascularization of ischemic lower limb, regardless of the mode of intervention, surgery or application of thrombolytics.

#### **3.1.5.4 Conclusion of the first series of the experiments**

Angioplasty, Various Techniques and Challenges in 74 Treatment of Congenital and Acquired Vascular Stenoses

free radical induced peroxydation of PUFA. MDA is frequently used as a lipid peroxydation

**0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 1,1 1,2 1,3**

Fig. 9. MDA level in red blood cell (RBC) hemolysate (left panel) and in plasma (right panel), \*= p<0.05 vs. Control, \*\*= p<0.01 vs. Control, \*\*\*= p<0.0051 vs. Control +=p<0.05 vs.

elevation appeared which peaked 2 hours after surgery (Figure 9. right panel).

**0,00 0,20 0,40 0,60 0,80 1,00 1,20 1,40**

**Myeloperoxidase**

**Before surgery**

**\*\*\***

**After surgery 24 hours later 1 week later**

**\*\***

Control Elective Acute **\***

Surprisingly, in our case MDA concentration of erythrocyte membrane remained in a standard, relatively low level during the whole study, in the Acute group. We speculated about the background of this phenomenon, and finally we concluded that the long-lasting hypoxia preceeded the surgery may exhausted of the PUFA contents of the lipidmembranes. At the same time, plasma MDA of Acute group (right panel) were significantly higher than in Elective and Control groups, and elevated further 24 hours after the surgery, and returned to the baseline one week after the surgery. In Elective group a bell-shaped

In spite of MPO have not been evaluated in routine clinical chemistry studies, according to a recent study of Brevetti and coworkers its elevated level, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease (Brevetti G , 2008). According to an other study it is a marker of myocardial infarction too. The base-line myeloperoxidase level independently predicts the risk of major adverse coronary events within 30 days.

**\*\*\***

Fig. 10. **Myeloperoxidase level in Control, Elective and Acute groups.** MPO level both in Elective and Acute groups were significantly higher than in Control before surgery, than after a transient decrease in the postoperative period returned to the preoperative level.

**# \*\*\* \*\***

**Plasma MDA (nmol/ml**

**Before surgery After surgery 24 hours later 1 week later**

**\*\***

**\*\*\* #** <sup>+</sup> +

**\*\***

**Control Elective Acute**

**\*\***

+

**\*\***

**\*\***

**#**

marker in biological tissues.

**Before surgery After surgery 24 hours later 1 week later**

Elective, #=p<0.05 vs. before surgery

**3.1.5.3 Changes in MPO** 

**<sup>+</sup> ++ + ++**

**\* \***

**#**

**Control Elective Acute**

**MDA in RBC haemolysate (nmol/ml)**

Ischemia/reperfusion injury, accompanied by revascularization surgeries of lower limb, was in the focus of the present study. This problem has great importance in the clinical practice because of its poor outcome (postoperative mortality is 15-60%). Tissue injury appears not only under ischemia, but after restoration of the blood flow in the formerly ischemic areas, due to the reperfusion injury, as well (Yasin) NM et al. 2002), (Arato et al 2009). Ischemia reperfusion injury of lower limb is accompanied by muscle changes with progressive micro-vascular damage, and affects all circulating cells (RBC, WBC, and PLT), as well. These cells are in connection with each other and with cells of the vessel walls, too. Inflammatory response following reperfusion varies greatly, and depends on the time and severity of ischemia. According to our results in accordance with several other studies, the duration and severity of ischemia is proportional to the damage occurred after it. Studying thrombocyte function and antioxidant prooxidant status of our unique patient groups, several new aspects of ischemia reperfusion injury were revealed. Peripheral arterial disease is a common progressive disorder that attaches the circulation of the legs, particularly in people over 55 years, strengthening in these patients the greatly increased risk of heart attack or stroke, and of dying within a decade. Several aspects of the problem were intensively studied, but platelet function during the restoration of the circulation of ischemic lower limb was hardly investigated before. It was revealed in this study that an effective antiaggregating therapy was applied in these patients, and effectively reduced the aggregation induced by ADP and collagen in PRP, but this reduction in whole blood was completely disappeared, both in ADP and collagen induced aggregation in Acute and Elective groups too. Above this a highly significant increase in platelet aggregation was measured in whole blood, in response to both types of inductors, one week after the surgery in Acute group. We concluded on the basis of our result that the long-lasting hypoxia is responsible for the increased PLT aggregation in whole blood, as the consequence of the shift of the antioxidant-prooxidant balance to the prooxidant direction lead to the increased response to aggregation inductors.

#### **3.2 Results of the second series of experiments**

#### **3.2.1 Clinical chemistry data**

Monitoring thrombocyte function and antioxidant prooxidant status of diabetic patients with peripheral arterial disease is inevitably important, because of the increased risk of complication. Patients suffering from both diabetes and PAD are at risk of developing critical limb ischemia, ulceration and potentially requiring limb amputation. In addition, diabetes complicates surgical treatment of PAD and impairs vascular functions. The presence of diabetes increases the frequency of intermittent claudication. The relative risk of amputation in diabetic population is 12,4-fold higher compared to the non diabetic patients (95%, 10,9-14,9), and this value doubles above 65 years. Diabetes increases the sensing of shear stress and the response to vasoconstrictor stimuli, reducing the recruitment and dilatation of collateral arteries (Brennan ML et al 2010).

Investigation of the Oxidative Stress, the Altered Function

**%**

**diabetic patients with PAD** 

with PAD were significantly higher (p<0.05), than that of Control

**AUC kollagen** 

**Impedance (Ohm) ADP**

Control, significant difference can't be detected.

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 77

**Collagen-induced aggregation (2 µgml) in PRP**

**<sup>+</sup> \*\***

**Max (%) Final (%) Slope**

**3.2.2.2 Investigation of ADP induce platelet aggregation in whole blood in control and** 

**01234567**

**Control DM1 DM2**

Fig. 14. Area under the ADP induced platelet aggregation curves (AUC). AUC of patients

\*

Fig. 13. ADP induced platelet aggregation of healthy and diabetic patients with PAD in the function of time. However patient's data were higher in every time points compared to

Fig. 12. Collagen induced platelet aggregation in PRP of diabetic patients with PAD.

**Control DM1 DM2**

**\*\* \*\* \*\***

**(%/min)**

**\*\* \*\***

> **Lag time (sec)**

**time (min)**

**Controll DM1 DM2**


Table 4. Clinical Chemistry of Control subjects and DM1 and DM2 patients.

Glucose and triglyceride levels of diabetic patients were higher than the normal values. The mean value of cholesterol level was within the normal range, but individually high values were measured, as well.

#### **3.2.2 Investigation of platelet aggregation**

#### **3.2.2.1 Investigation of PLT function in platelet rich plasma**

Investigation of platelet function by turbidimetric method in PRP is a more frequently used method, than impedance measurement in whole blood. Our own investigations focused our attention on the usefulness of the parallel measurements. There are several advantages using both methods parallel, e.g. in PRP platelet function can be measured independently from other circulating cells. It is very advantageous if we investigate the effect of antiplatelet drug in a specific direction. Contrary, in whole blood the effects of the other components of circulating cells of blood (leukocytes, red blood cells) can be studied together.

Fig. 11. ADP induced platelet aggregation in PRP of diabetic patients with PAD.

All parameter were measured in DM1 and DM2 Patients were reduced, compared to Control. In DM2 patients Slope of the aggregation curve was significantly higher compared to Elective groups.

.

Angioplasty, Various Techniques and Challenges in 76 Treatment of Congenital and Acquired Vascular Stenoses

Glucose and triglyceride levels of diabetic patients were higher than the normal values. The mean value of cholesterol level was within the normal range, but individually high values

Investigation of platelet function by turbidimetric method in PRP is a more frequently used method, than impedance measurement in whole blood. Our own investigations focused our attention on the usefulness of the parallel measurements. There are several advantages using both methods parallel, e.g. in PRP platelet function can be measured independently from other circulating cells. It is very advantageous if we investigate the effect of antiplatelet drug in a specific direction. Contrary, in whole blood the effects of the other components of circulating cells of blood (leukocytes, red blood cells) can be

**5µM ADP-induced aggregation in PRP**

**Max (%) Final (%) Slope**

Fig. 11. ADP induced platelet aggregation in PRP of diabetic patients with PAD.

All parameter were measured in DM1 and DM2 Patients were reduced, compared to Control. In DM2 patients Slope of the aggregation curve was significantly higher compared

**\*\* \*\* \*\***

**\*\* \*\* \*\* \*\***

**(%/min)**

**Lag time (sec)**

.

**Control DM1 DM2**

**patients Glucose Triglyceride Cholesterol**  DM1 11.4 ±1.6 1.9 ± 0.3 4.3±0.6 DM2 7.3 ±0.7 4.3 ±1.4 5.2 ±0.7 Healty 4.82 ±0.27 1.1±0.15 4.2 ±0.5 Normal values 4.2-6.1 mmol/l 0.4-1.7 mmol/l 3.7-5.2 mmol/l

Table 4. Clinical Chemistry of Control subjects and DM1 and DM2 patients.

**Group of** 

were measured, as well.

studied together.

to Elective groups.

**3.2.2 Investigation of platelet aggregation** 

**3.2.2.1 Investigation of PLT function in platelet rich plasma** 

**%**

Fig. 12. Collagen induced platelet aggregation in PRP of diabetic patients with PAD.

Fig. 13. ADP induced platelet aggregation of healthy and diabetic patients with PAD in the function of time. However patient's data were higher in every time points compared to Control, significant difference can't be detected.

Fig. 14. Area under the ADP induced platelet aggregation curves (AUC). AUC of patients with PAD were significantly higher (p<0.05), than that of Control

Investigation of the Oxidative Stress, the Altered Function

**AU/103 WBC cells**

µU/ml of insulin, considering 100% of AUC without insulin

**AUC Collagen induced aggregation** 

presence of 80 µU/ml of insulin

**Collagen impedanceHealthy (Ohm)**

Fig. 18. PMA induced ROS production was higher in patients then in Control

**3.2.4.1 In vitro effect of actrapid insulin on collagen induced platelet aggregation in whole blood of healthy volunteers, DM1 and DM2 patients with PAD was investigated**  Actrapid insulin exerts its effect within a short time in patients too, that was the reason why we chose this. Platelet aggregation was expressed in Ohm, and area under the curves was calculated as well, and we expressed in %. AUC without insulin was considered as 100%.

**3.2.4 In vitro effects on insulin on platelet aggregation in whole blood** 

0 µU/ml Ins 40 µU/ml Ins 80 µU/ml Ins 160 µU/ml Ins

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 79

**\*\***

**Control DM1 DM2**

01234567

**0 µU/ml 40 µU/ml 80 µU/ml 160 µU/ml**

Fig. 20. AUC in healthy subjects. Significant decrease was detected in the presence of 80

\*\* **\***

Fig. 19. Collagen induced aggregation in healthy volunteer's whole blood in the function of time, in the presence or absence of Actrapid insulin. A significant decrease occurred in the

**\*\***

**id (perc)**

**insulin**

**\* \* \***

**#**

**3.2.2.3 Investigation of PLT function in whole blood in control and diabetic patients collagen induce platelet aggregation in whole blood** 

Fig. 15. Collagen induced platelet aggregation in whole blood of healthy and diabetic subjects with PAD in the function of time. Platelet aggregation of diabetic patients was higher in each point of times, but significant difference has not been observed among the groups.

Fig. 16. AUC of the platelet aggregation curves of healthy and diabetic patients. Significant differences were measured among DM1 and DM2 groups, compared to each other (#)., and between DM1 and Control.

#### **3.2.3 Antioxidant and prooxidant levels**

Plasma GHS levels were similar in the three groups, however SOD activity was significantly lower in both patients groups, compared to Control (Figure 17). WBC numbers in the DM1 group was the double and ROS production/103 WBC was 20 times higher in DM1 group than in Control and was double of the DM2 (Fig.18)

Fig. 17. SOD activity was significantly lower in patients groups than in Control.

Angioplasty, Various Techniques and Challenges in 78 Treatment of Congenital and Acquired Vascular Stenoses

**0123456**

**ontrol DM1 DM2**

Fig. 16. AUC of the platelet aggregation curves of healthy and diabetic patients. Significant differences were measured among DM1 and DM2 groups, compared to each other (#)., and

Plasma GHS levels were similar in the three groups, however SOD activity was significantly lower in both patients groups, compared to Control (Figure 17). WBC numbers in the DM1 group was the double and ROS production/103 WBC was 20 times higher in DM1 group

**Control DM1 DM2**

**\*\***

**\***

**\***#

Fig. 15. Collagen induced platelet aggregation in whole blood of healthy and diabetic subjects with PAD in the function of time. Platelet aggregation of diabetic patients was higher in each

point of times, but significant difference has not been observed among the groups.

**Time (min)**

**3.2.2.3 Investigation of PLT function in whole blood in control and diabetic patients** 

**collagen induce platelet aggregation in whole blood** 

**Control DM1 DM2**

**iImpedance (Ohm) Collagén**

**AUC impedance AUC (Ohm)**

between DM1 and Control.

**3.2.3 Antioxidant and prooxidant levels** 

than in Control and was double of the DM2 (Fig.18)

**SOD (µU/ml)**

Fig. 17. SOD activity was significantly lower in patients groups than in Control.

Fig. 18. PMA induced ROS production was higher in patients then in Control

#### **3.2.4 In vitro effects on insulin on platelet aggregation in whole blood**

#### **3.2.4.1 In vitro effect of actrapid insulin on collagen induced platelet aggregation in whole blood of healthy volunteers, DM1 and DM2 patients with PAD was investigated**

Actrapid insulin exerts its effect within a short time in patients too, that was the reason why we chose this. Platelet aggregation was expressed in Ohm, and area under the curves was calculated as well, and we expressed in %. AUC without insulin was considered as 100%.

Fig. 19. Collagen induced aggregation in healthy volunteer's whole blood in the function of time, in the presence or absence of Actrapid insulin. A significant decrease occurred in the presence of 80 µU/ml of insulin

Fig. 20. AUC in healthy subjects. Significant decrease was detected in the presence of 80 µU/ml of insulin, considering 100% of AUC without insulin

Investigation of the Oxidative Stress, the Altered Function

patients (Figure 24.)

samples of patients with DM2.

platelet aggregation and PMA induced ROS generation.

**AU/103 cellt/µl**

and CM2 patients' whole blood, in vitro.

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 81

**3.2.5 Effect of exogenous insulin on PMA induced ROS production in whole blood**  Insulin effect on the maximum of PMA induced ROS production was investigated, as well. The presence of insulin in whole blood was able to reduce PMA induced ROS production in whole blood in healthy subjects and that of DM1 patients' blood too, but not in DM 2

Fig. 24. Insulin was not able to reduce area under platelet aggregation curve in blood

**\*\*\***

**\*\*\***

**0 µU/ml 40 µU/ml 80 µU/ml 160 µU/ml insulin**

**\*\*\***

Fig. 25. Effect of insulin on PMA induced ROS production on whole blood of Control, DM1

The presence of DM1 or DM2 diabetes differently influenced the thrombocyte function and antioxidant status of PAD patients, and the in vitro effects of insulin on collagen induced

**3.3 Summary of data obtained from investigation of diabetic patients blood** 

**\*\*\***

**#**

**\*\*\***

**\*\*\***

Controll DM1 GM2

**\*\*\***

**#**

Fig. 21. Collagen induced platelet aggregation in the function of time on whole blood in DM1 patients. DM1 patient's blood was sensitive to each concentration of insulin, without any significant difference among the groups.

Fig. 22. AUC of collagen induced platelet aggregation curves in DM1. The three insulin concentration caused similar, but significant decrease in the aggregation.

Fig. 23. Collagen induced platelet aggregation in DM2 patients. Insulin was ineffective on collagen induced platelet aggregation.

Angioplasty, Various Techniques and Challenges in 80 Treatment of Congenital and Acquired Vascular Stenoses

01234567

\*\*

0 µU/ml 40 µU/ml 80 µU/ml 160 µU/ml

Fig. 22. AUC of collagen induced platelet aggregation curves in DM1. The three insulin

Fig. 23. Collagen induced platelet aggregation in DM2 patients. Insulin was ineffective on

\*\* \*\* \*\*

\*\*

\*\*

Fig. 21. Collagen induced platelet aggregation in the function of time on whole blood in DM1 patients. DM1 patient's blood was sensitive to each concentration of insulin, without

\*\*

Time (min)

inzulin

\*\* \*\*

\*\*

\*\*

0

concentration caused similar, but significant decrease in the aggregation.

20

**C o llag en im p ed an ce A U C** 

collagen induced platelet aggregation.

40 60 80

**DM1**

100 120

C o llag e n, Im p e d ance, (O hm

any significant difference among the groups.

) DM1

0 µU/ml 40 µU/ml 80 µU/ml 1600 µU/ml

#### **3.2.5 Effect of exogenous insulin on PMA induced ROS production in whole blood**

Insulin effect on the maximum of PMA induced ROS production was investigated, as well. The presence of insulin in whole blood was able to reduce PMA induced ROS production in whole blood in healthy subjects and that of DM1 patients' blood too, but not in DM 2 patients (Figure 24.)

Fig. 24. Insulin was not able to reduce area under platelet aggregation curve in blood samples of patients with DM2.

Fig. 25. Effect of insulin on PMA induced ROS production on whole blood of Control, DM1 and CM2 patients' whole blood, in vitro.

#### **3.3 Summary of data obtained from investigation of diabetic patients blood**

The presence of DM1 or DM2 diabetes differently influenced the thrombocyte function and antioxidant status of PAD patients, and the in vitro effects of insulin on collagen induced platelet aggregation and PMA induced ROS generation.

Investigation of the Oxidative Stress, the Altered Function

extensive way in Elective group too.

induced micro-vascular alterations.

antioxidants have important role in tissue protection.

of Platelets and Neutrophils, in the Patients with Peripheral Arterial Disease 83

prooxidants, while antioxidant capacity decreases especially in Acute group and in a less

It has to be mentioned that SOD deficiency is a highly important determinant of the increased ROS production and the increase in platelet aggregation one week after the surgery. Pipinos and co-workers published that, the SOD enzyme mutation of gastrocnemius muscle of rats is a risk factor of PAD, (Pipinos II and Swanson SA 2008). Intracellular GSH and the plasma –SH groups possess remarkable antioxidant capacities. Before the surgery their levels were almost equal in the three groups, but after surgery a small but significant transient reduction was measured in their levels, mainly in the Acute group. Conflicting results are published about the effects of volatile anaesthetics on oxidative stress, and some local anaesthetics can cause transient decrease in GSH level in skeletal muscles (Jia-Li Luo, et al 1996). It can be supposed that transient decrease in GSH level is partially caused by the surgical intervention. Further alterations are caused by the disease itself, due to the sclerotic vessels, and/or the presence of hypertension, and other disturbances. These states also complicated by increased free radical generation, which usually increased further by the surgical intervention. Activated platelets play definitive role in the development of atherosclerosis and increase of the risk of surgical interventions. In spite of these there are only few data which can highlight the background of the poor prognosis of PAD and the role of thrombocytes in these processes. Other risk-factors which have definitive role, the activated complement system (Beinrohr L), leukocyte-thrombocyte interaction, and the increased endothelin release. The consequences of IR affect not only the great conduit vessels, but microcirculation is also affected (Kaszaki et al 2006). In the course of the animal studies they improved the protective effects of endothelin-A receptor antagonists and preconditioning against IR

Diabetes is also a well defined risk factor which worsens the outcome the surgical intervention. In the second series of our study thrombocyte function and antioxidant prooxidant status of diabetic patients with peripheral arterial disease were investigated and effects of exogenous insulin were tested. Platelet aggregation of PRP in diabetic patients was reduced compared to healthy blood donors signing the efficacy of their antiplatelet treatment. This difference failed to appear in whole blood. Free radical productions were significantly higher and SOD enzyme activities were significantly lower in diabetic patients compared to control. Low concentrations of insulin reduced the aggregation and free radical production in healthy and Type 1 diabetic patient's blood but failed to induce such effects in Type 2 diabetic ones. Insulin resistance is developed against not only the metabolic effects of insulin, but against other activities of this important hormone, as well. Revealing the alterations caused by surgical intervention in the function of circulating cells is inevitably important to improve the outcome of these procedures and reduce the complication of surgical intervention and facilitate recovery. Insulin is a vital hormone which essential for the glucose uptake of skeletal muscle and the heart. Insulin resistance increases the harmful effect of IR. Insulin effect can be improved and free radical production can be decreased by antioxidant, signing the important roles of free radicals in the pathogenesis of IR. Mice overexpressing extracellular SOD are less sensitive to IR (Sheng H et al 1999), signing that endogenous

Investigating platelet aggregation in whole blood of patients neither in ADP, nor in collagen induced aggregation curves differed significantly from each other or the control. Calculating area under curves (AUC), significant differences were revealed, showing that platelets of DM1 patients was more sensitive to both inductors than that of in other two groups (Figure 13-16). This increased sensitivity was accompanied by lower SOD activity (Figure 17.) and highly significant increase in PMA induced ROS generation (Figure 18.).

In vitro effects of insulin on collagen induced platelet aggregation, and PMA induced ROS generation were also investigated in the presence of 0, 40, 80, 160 U/ml insulin in the whole blood. A U-shaped inhibition in collagen induced aggregation was detected in healthy subjects, a constant decrease in DM1 patients, without dose dependence, but insulin was ineffective in DM2 patients blood (figure 19-25). The maximum values of PMA induced ROS generation was significantly higher than in other two groups, but insulin pre-treatment was able to reduce it. Insulin was able to reduce the low ROS levels were induced by PMA in the blood donor's blood, but not in DM2 patient's blood.

#### **4. Conclusion**

Reconstruction of blood flow in the formerly ischemic tissues induces chain reactions, which affect not only the tissues are involved, but threats the integrity of the whole organism, causing multiorgan failure and death. The irreversible muscle cell damage begins 3 hour after ischemia and completed about within 6 hours (Blaisdell W. 2002). Tissue damage induced by the revascularization surgery of lower limbs had been in the focus of our studies. Our main aims were to study and characterize the role of the duration of the hypoxia on the thrombocyte function, and on the other circulating cells, especially on the leukocytes. ADP and collagen were used as platelet aggregation inductors. ADP is able to potentate the effects of other inductors, such as thrombin, due to stimulate and stabilize the thrombus. Collagen appears in the blood steam in the course of the injury of endothelial lineage. Collagen directly acts due to GPIIbIIIa receptors, and indirectly by Von-Willebrand factor, induces platelet aggregation and increases the adherence of platelet to the vessel wall, too.

Our studies can be considered new, in the respects of the parallel measurement of aggregation in platelet rich plasma and in whole blood within the same samples, at the same time. We revealed significant differences using the two methods. In isolated thrombocyte the effectiveness of antiplatelet therapy can be tested directly on the thrombocyte itself, during the hospitalization. In whole blood, the modulating effects of other cellular and non cellular components of blood can be studied. The disturbances in antioxidant/prooxidant balance are in the background of this phenomenon. The most surprising results were in our studies, that in PRP a satisfactory aggregation inhibition was detected in both the Acute and Elective groups (Figure1 and 3), but in whole blood (Figure 3., 4.,5., 6.) a highly significant elevation in ADP and collagen induced aggregation were revealed in the Acute group, compared to the Elective and Control ones. We concluded that the increased leukocyte numbers, the elevated free radical production of the individual leukocytes, and the exhausted antioxidant capacity, mainly the significant reduction in SOD activity, had important role (Figure 7. and 8). We pointed out the importance of the increase of Angioplasty, Various Techniques and Challenges in 82 Treatment of Congenital and Acquired Vascular Stenoses

Investigating platelet aggregation in whole blood of patients neither in ADP, nor in collagen induced aggregation curves differed significantly from each other or the control. Calculating area under curves (AUC), significant differences were revealed, showing that platelets of DM1 patients was more sensitive to both inductors than that of in other two groups (Figure 13-16). This increased sensitivity was accompanied by lower SOD activity (Figure 17.) and highly significant increase in PMA induced ROS generation

In vitro effects of insulin on collagen induced platelet aggregation, and PMA induced ROS generation were also investigated in the presence of 0, 40, 80, 160 U/ml insulin in the whole blood. A U-shaped inhibition in collagen induced aggregation was detected in healthy subjects, a constant decrease in DM1 patients, without dose dependence, but insulin was ineffective in DM2 patients blood (figure 19-25). The maximum values of PMA induced ROS generation was significantly higher than in other two groups, but insulin pre-treatment was able to reduce it. Insulin was able to reduce the low ROS levels were induced by PMA

Reconstruction of blood flow in the formerly ischemic tissues induces chain reactions, which affect not only the tissues are involved, but threats the integrity of the whole organism, causing multiorgan failure and death. The irreversible muscle cell damage begins 3 hour after ischemia and completed about within 6 hours (Blaisdell W. 2002). Tissue damage induced by the revascularization surgery of lower limbs had been in the focus of our studies. Our main aims were to study and characterize the role of the duration of the hypoxia on the thrombocyte function, and on the other circulating cells, especially on the leukocytes. ADP and collagen were used as platelet aggregation inductors. ADP is able to potentate the effects of other inductors, such as thrombin, due to stimulate and stabilize the thrombus. Collagen appears in the blood steam in the course of the injury of endothelial lineage. Collagen directly acts due to GPIIbIIIa receptors, and indirectly by Von-Willebrand factor, induces platelet aggregation and increases the adherence of platelet to the vessel

Our studies can be considered new, in the respects of the parallel measurement of aggregation in platelet rich plasma and in whole blood within the same samples, at the same time. We revealed significant differences using the two methods. In isolated thrombocyte the effectiveness of antiplatelet therapy can be tested directly on the thrombocyte itself, during the hospitalization. In whole blood, the modulating effects of other cellular and non cellular components of blood can be studied. The disturbances in antioxidant/prooxidant balance are in the background of this phenomenon. The most surprising results were in our studies, that in PRP a satisfactory aggregation inhibition was detected in both the Acute and Elective groups (Figure1 and 3), but in whole blood (Figure 3., 4.,5., 6.) a highly significant elevation in ADP and collagen induced aggregation were revealed in the Acute group, compared to the Elective and Control ones. We concluded that the increased leukocyte numbers, the elevated free radical production of the individual leukocytes, and the exhausted antioxidant capacity, mainly the significant reduction in SOD activity, had important role (Figure 7. and 8). We pointed out the importance of the increase of

in the blood donor's blood, but not in DM2 patient's blood.

(Figure 18.).

**4. Conclusion** 

wall, too.

prooxidants, while antioxidant capacity decreases especially in Acute group and in a less extensive way in Elective group too.

It has to be mentioned that SOD deficiency is a highly important determinant of the increased ROS production and the increase in platelet aggregation one week after the surgery. Pipinos and co-workers published that, the SOD enzyme mutation of gastrocnemius muscle of rats is a risk factor of PAD, (Pipinos II and Swanson SA 2008). Intracellular GSH and the plasma –SH groups possess remarkable antioxidant capacities. Before the surgery their levels were almost equal in the three groups, but after surgery a small but significant transient reduction was measured in their levels, mainly in the Acute group. Conflicting results are published about the effects of volatile anaesthetics on oxidative stress, and some local anaesthetics can cause transient decrease in GSH level in skeletal muscles (Jia-Li Luo, et al 1996). It can be supposed that transient decrease in GSH level is partially caused by the surgical intervention. Further alterations are caused by the disease itself, due to the sclerotic vessels, and/or the presence of hypertension, and other disturbances. These states also complicated by increased free radical generation, which usually increased further by the surgical intervention. Activated platelets play definitive role in the development of atherosclerosis and increase of the risk of surgical interventions. In spite of these there are only few data which can highlight the background of the poor prognosis of PAD and the role of thrombocytes in these processes. Other risk-factors which have definitive role, the activated complement system (Beinrohr L), leukocyte-thrombocyte interaction, and the increased endothelin release. The consequences of IR affect not only the great conduit vessels, but microcirculation is also affected (Kaszaki et al 2006). In the course of the animal studies they improved the protective effects of endothelin-A receptor antagonists and preconditioning against IR induced micro-vascular alterations.

Diabetes is also a well defined risk factor which worsens the outcome the surgical intervention. In the second series of our study thrombocyte function and antioxidant prooxidant status of diabetic patients with peripheral arterial disease were investigated and effects of exogenous insulin were tested. Platelet aggregation of PRP in diabetic patients was reduced compared to healthy blood donors signing the efficacy of their antiplatelet treatment. This difference failed to appear in whole blood. Free radical productions were significantly higher and SOD enzyme activities were significantly lower in diabetic patients compared to control. Low concentrations of insulin reduced the aggregation and free radical production in healthy and Type 1 diabetic patient's blood but failed to induce such effects in Type 2 diabetic ones. Insulin resistance is developed against not only the metabolic effects of insulin, but against other activities of this important hormone, as well. Revealing the alterations caused by surgical intervention in the function of circulating cells is inevitably important to improve the outcome of these procedures and reduce the complication of surgical intervention and facilitate recovery. Insulin is a vital hormone which essential for the glucose uptake of skeletal muscle and the heart. Insulin resistance increases the harmful effect of IR. Insulin effect can be improved and free radical production can be decreased by antioxidant, signing the important roles of free radicals in the pathogenesis of IR. Mice overexpressing extracellular SOD are less sensitive to IR (Sheng H et al 1999), signing that endogenous antioxidants have important role in tissue protection.

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**5** 

*Italy* 

**Antithrombotic Therapy After** 

Beniamino Zalunardo1, Diego Tonello1, Fabio Busato1, Laura Zotta1, Sandro Irsara2 and Adriana Visonà1

*1Angiology Unit, San Giacomo Hospital, Castelfranco Veneto (TV) 2Vascular Surgery, San Giacomo Hospital, Castelfranco Veneto (TV)* 

Peripheral arterial disease affects approximately 12% of adults and 20% of adults over 70 years (Hiatt et al., 1995). This disease results from one or more lesions in the arterial system of the lower extremity that restrict blood flow. The restriction of blood flow during ambulation may cause intermittent claudication, i.e. muscular pain due to lack of blood supply. About one fifth of people with peripheral arterial disease have intermittent claudication. About half of people with peripheral arterial disease are asymptomatic. A small part of people with peripheral arterial disease (< 10%) have critical limb ischemia, i.e. rest muscular pain and/or ischemic ulceration or gangrene of toes. Based on the severity of symptoms, the stages of the disease are classified as Fontaine stages I-IV, where stage I is asymptomatic, stage IIa is the occurrence of intermittent claudication after a pain-free walking distance of more than 200 m, stage IIb is intermittent claudication after less than 200

Patients with peripheral arterial disease, which is an expression of systemic atherosclerosis,

Medical therapy should include modification or elimination of atherosclerotic risk factors (cigarette smoking, diabetes mellitus, hypertension, hyperlipidemia), and antiplatelet therapies to decrease the risk of cardiovascular events and to improve survival. Moreover, the initial approach to the treatment of limb symptoms should focus to relieve discomfort, to improve exercise performance, and daily functional abilities by means of structured exercise and, in selected patients, pharmacotherapies to treat the exercise limitation of claudication (Norgren et al, 2007). Lower extremity revascularization is indicated for patients with a lifestyle-limiting disability due to intermittens claudication or with chronic critical limb

There are two types of revascularization procedure: endovascular or surgical. Percutaneous transluminal angioplasty with or without stenting is an endovascular technique for revascularizing obstructed arteries. It was first introduced by Dotter and Judkins (Dotter &

In peripheral transluminal angioplasty the recanalization of obstructed arteries is obtained by dilatation of a stenosis (i.e. a narrowing of the vessel diameter) or recanalization of a total occlusion, using a wire-guided inatable balloon catheter. Usually the femoral artery in the

Judkins, 1964), and subsequently improved by Grüntzig (Grüntzig & Hopff, 1974).

m, stage III is rest pain, and stage IV is the presence of ischemic ulcers.

have an increased risk of cardiovascular events (Hankey et al., 2006).

ischemia (Hirsch et al., 2006; Norgren et al., 2007).

**1. Introduction** 

**Peripheral Angioplasty** 


### **Antithrombotic Therapy After Peripheral Angioplasty**

Beniamino Zalunardo1, Diego Tonello1, Fabio Busato1, Laura Zotta1, Sandro Irsara2 and Adriana Visonà1 *1Angiology Unit, San Giacomo Hospital, Castelfranco Veneto (TV) 2Vascular Surgery, San Giacomo Hospital, Castelfranco Veneto (TV) Italy* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 88 Treatment of Congenital and Acquired Vascular Stenoses

Yassin MM, Harkin DW, Barros D'Sa AA, Halliday MI, Rowlands BJ. Lower limb ischemia-

Sheng H, Bart RD, Oury TD, Pearlstein RD, Crapo JD, Warner DS. Mice overexpressing

dysfunction. World J Surg. 6(1):115-21.2002.

ischemia. Neuroscience. 88. (1): 185-91.199

reperfusion injury triggers a systemic inflammatory response and multiple organ

extracellular superoxide dismutase have increased resistance to focal cerebral

Peripheral arterial disease affects approximately 12% of adults and 20% of adults over 70 years (Hiatt et al., 1995). This disease results from one or more lesions in the arterial system of the lower extremity that restrict blood flow. The restriction of blood flow during ambulation may cause intermittent claudication, i.e. muscular pain due to lack of blood supply. About one fifth of people with peripheral arterial disease have intermittent claudication. About half of people with peripheral arterial disease are asymptomatic. A small part of people with peripheral arterial disease (< 10%) have critical limb ischemia, i.e. rest muscular pain and/or ischemic ulceration or gangrene of toes. Based on the severity of symptoms, the stages of the disease are classified as Fontaine stages I-IV, where stage I is asymptomatic, stage IIa is the occurrence of intermittent claudication after a pain-free walking distance of more than 200 m, stage IIb is intermittent claudication after less than 200 m, stage III is rest pain, and stage IV is the presence of ischemic ulcers.

Patients with peripheral arterial disease, which is an expression of systemic atherosclerosis, have an increased risk of cardiovascular events (Hankey et al., 2006).

Medical therapy should include modification or elimination of atherosclerotic risk factors (cigarette smoking, diabetes mellitus, hypertension, hyperlipidemia), and antiplatelet therapies to decrease the risk of cardiovascular events and to improve survival. Moreover, the initial approach to the treatment of limb symptoms should focus to relieve discomfort, to improve exercise performance, and daily functional abilities by means of structured exercise and, in selected patients, pharmacotherapies to treat the exercise limitation of claudication (Norgren et al, 2007). Lower extremity revascularization is indicated for patients with a lifestyle-limiting disability due to intermittens claudication or with chronic critical limb ischemia (Hirsch et al., 2006; Norgren et al., 2007).

There are two types of revascularization procedure: endovascular or surgical. Percutaneous transluminal angioplasty with or without stenting is an endovascular technique for revascularizing obstructed arteries. It was first introduced by Dotter and Judkins (Dotter & Judkins, 1964), and subsequently improved by Grüntzig (Grüntzig & Hopff, 1974).

In peripheral transluminal angioplasty the recanalization of obstructed arteries is obtained by dilatation of a stenosis (i.e. a narrowing of the vessel diameter) or recanalization of a total occlusion, using a wire-guided inatable balloon catheter. Usually the femoral artery in the

Antithrombotic Therapy After Peripheral Angioplasty 91

Risk factors for restenosis/reocclusion include severity of atherosclerosis in run-off arteries, length of diseased segments, number of treated lesions, stage of disease, and presence of cardiovascular risk factors (Norgren et al., 2007). Female gender may be an independent predictor of decreased primary patency of external iliac artery stents (Timaran et al., 2001). Inflammation, revealed by an elevated C-reactive protein, was also considered as a risk factor for restenosis at six months after successful femoropopliteal angioplasty (Schillinger

The rate of restenosis/reocclusion of suprainguinal (iliac) arteries after peripheral transluminal angioplasty ranges from 14% after one year to 29% after 5 years, while the rate of restenosis/reocclusion of infrainguinal (femoropopliteal) arteries after peripheral transluminal angioplasty with or without stenting ranges from 23-35% after one year to 45-58% after 5 years (Norgren et al., 2007). Patients with stenoses or occlusions of infrainguinal arteries of less than 3 cm had a favourable long-term patency rate of 74%

Patients subjected to local thrombolysis show higher incidences of restenosis/reocclusion

It is important to define the lesion suitable for balloon angioplasty in both the suprainguinal

Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) redefined the indications for endovascular or surgical revascularization on the basis of anatomical characteristics of the lesions. Endovascular interventions are recommended for: i) unilateral or bilateral stenosis of common iliac artery; unilateral or bilateral single short ( 3 cm) stenosis of external iliac artery; ii) single stenosis 10 cm in length of femoropopliteal arteries; single occlusion 5 cm in length of femoropopliteal arteries (TASC

Endovascular interventions are the preferred treatments for: i) short ( 3 cm) stenosis of infrarenal aorta; unilateral common iliac artery occlusion; single or multiple stenosis totaling 3-10 cm involving the external iliac artery not extending into the common femoral artery; unilateral external iliac artery occlusion not involving the origin of internal iliac or common femoral artery; ii) multiple lesions (stenoses or occlusions), each 5 cm of femoropopliteal segment; single stenosis or occlusion 15 cm not involving the infra geniculate popliteal artery; single or multiple lesions in the absence of continuous tibial vessels to improve inow for a distal bypass; heavily calcied occlusion 5 cm in length; single popliteal

Provisional stent placement is indicated for iliac arteries as salvage therapy for a suboptimal or failed result from balloon dilatation (persistent translesional gradient, residual stenosis greater than 50%, flow-limiting dissection). Stenting is effective as primary therapy for common and external iliac artery stenoses and occlusions. Moreover, stents can be useful in the femoral, popliteal and tibial arteries as a salvage therapy for suboptimal or failed results

As mentioned above, the implantation of drug-eluting stents, nitinol stents, paclitaxelcoated angioplasty balloons, or treatment by intravascular brachytherapy following peripheral angioplasty have been considered as interventions with the capacity of reducing the occurrence of restenosis/reocclusion. A study by Schillinger et al. showed better results at one year with self-expanding nitinol stent in femoropopliteal segments (Schillinger et al., 2006). Use of paclitaxel-coated angioplasty balloons during percutaneous treatment of

et al., 2002).

(Gallino et al., 1984).

(Decrinis et al., 1993).

and infrainguinal districts.

Type A lesions) (Norgren et al., 2007).

stenosis (TASC Type B lesions) (Norgren et al., 2007).

from balloon dilatation (Hirsch et al., 2006).

groin is cannulated and a deflated balloon catheter is inserted and pushed forward along the guide-wire to the sites of obstruction. Stenting is usually added to reduce the risk of reocclusion, especially if there is a major endothelial damage, arterial dissection or nonsatisfactory dilatation with relevant residual stenosis. Self-expanding metallic stents are mainly applied at the aortic bifurcation or iliac segments, whereas the femoropopliteal level, until recently, was associated with a higher risk for reocclusion due to smaller vessel diameters in distal arteries (Do et al., 1992; Mahler et al., 1999; Palmaz et al., 1985; Strecker et al., 1988).

The implantation of drug-eluting stents, nitinol stents, paclitaxel-coated angioplasty balloons, or treatment by intravascular brachytherapy following peripheral angioplasty of the femoropopliteal arteries have been considered as interventions with the capacity of reducing the occurrence of restenosis/reocclusion (Schillinger et al., 2006; Gray et al., 2008). In patients with peripheral arterial disease endovascular procedures are generally the treatment of choice for short-segment iliac or femoral-popliteal artery lesions (TASC-A, single stenosis less than 3 cm long). Longer segment iliac or femoral-popliteal artery lesions (TASC-B, single iliac stenosis 5-10 cm long, two iliac lesions 3-5 cm long, single occlusion of an iliac artery, tandem femoral-popliteal stenoses less than 3 cm long, single femoralpopliteal lesion 3-5 cm in length) are frequently treated by endovascular techniques (Norgren et al., 2007).

Restenosis (or reocclusion) is the main complication of peripheral transluminal angioplasty. Balloon angioplasty has been shown to induce endothelial injury and oxidative stress with subsequent endothelial dysfunction, platelet aggregation, macrophage activation, and smooth muscle cell proliferation (McBride et al., 1988; Taniyama & Griendling, 2003). Peripheral transluminal angioplasty induces a prothrombotic condition: atherosclerotic plaques are disrupted and platelets aggregate at the site of the damaged arterial wall (Fuster et al., 1995). Thus, as a result of platelet aggregation, activated blood clotting in the damaged atheromatous artery and low shear stress, restenosis (or reocclusion) is frequent (Schwartz, 1998; Wentzel et al., 2003).

In particular, the effects of balloon angioplasty on the platelet activation have been studied previously in vitro and in vivo. Peripheral transluminal angioplasty has been shown to result in significant imbalance between the production of prostacyclin, an effective vasodilatator and platelet antiaggregator produced in endothelial cells, and thromboxane A2, a potent smooth muscle constrictor and platelet aggregator formed in platelets, with shift more toward increased thromboxane A2 production. This finding is suggestive of significant platelet activation and may have implication for future failure of peripheral angioplasty (Parmar et al., 2010). An increased formation of thromboxane A2 was also seen in other two studies, one in patients undergoing peripheral angioplasty and one in patients after coronary angioplasty (Rossi et al., 1997; Peterson et al., 1986).

In addition, in the initial phase after balloon and stent procedures, coagulation system is activated, as demonstrated by increased serum levels of thrombin-antithrombin complexes, D-dimer and fibrinopeptide A. This condition favours early thrombotic occlusion, where 'early' is usually defined as a period covering the first 4 weeks after the intervention (Tsakiris et al., 1999; Tschöpl et al., 1997). Subsequently, intimal hyperplasia, a redundant healing of the arterial wall, which is responsible for restenosis and reocclusion in the midand long-term, may follow. Intimal hyperplasia occurs as a result of denudation (tearing off of the inner lining) of the endothelium caused by damage to the vessel wall with the catheter. Smooth muscle cells in the medial layer are stimulated to grow and migrate into the intimal layer (Haudenschild, 1995; Jørgensen et al., 1990).

Angioplasty, Various Techniques and Challenges in 90 Treatment of Congenital and Acquired Vascular Stenoses

groin is cannulated and a deflated balloon catheter is inserted and pushed forward along the guide-wire to the sites of obstruction. Stenting is usually added to reduce the risk of reocclusion, especially if there is a major endothelial damage, arterial dissection or nonsatisfactory dilatation with relevant residual stenosis. Self-expanding metallic stents are mainly applied at the aortic bifurcation or iliac segments, whereas the femoropopliteal level, until recently, was associated with a higher risk for reocclusion due to smaller vessel diameters in distal arteries (Do et al., 1992; Mahler et al., 1999; Palmaz et al., 1985; Strecker et al., 1988). The implantation of drug-eluting stents, nitinol stents, paclitaxel-coated angioplasty balloons, or treatment by intravascular brachytherapy following peripheral angioplasty of the femoropopliteal arteries have been considered as interventions with the capacity of reducing the occurrence of restenosis/reocclusion (Schillinger et al., 2006; Gray et al., 2008). In patients with peripheral arterial disease endovascular procedures are generally the treatment of choice for short-segment iliac or femoral-popliteal artery lesions (TASC-A, single stenosis less than 3 cm long). Longer segment iliac or femoral-popliteal artery lesions (TASC-B, single iliac stenosis 5-10 cm long, two iliac lesions 3-5 cm long, single occlusion of an iliac artery, tandem femoral-popliteal stenoses less than 3 cm long, single femoralpopliteal lesion 3-5 cm in length) are frequently treated by endovascular techniques

Restenosis (or reocclusion) is the main complication of peripheral transluminal angioplasty. Balloon angioplasty has been shown to induce endothelial injury and oxidative stress with subsequent endothelial dysfunction, platelet aggregation, macrophage activation, and smooth muscle cell proliferation (McBride et al., 1988; Taniyama & Griendling, 2003). Peripheral transluminal angioplasty induces a prothrombotic condition: atherosclerotic plaques are disrupted and platelets aggregate at the site of the damaged arterial wall (Fuster et al., 1995). Thus, as a result of platelet aggregation, activated blood clotting in the damaged atheromatous artery and low shear stress, restenosis (or reocclusion) is frequent (Schwartz,

In particular, the effects of balloon angioplasty on the platelet activation have been studied previously in vitro and in vivo. Peripheral transluminal angioplasty has been shown to result in significant imbalance between the production of prostacyclin, an effective vasodilatator and platelet antiaggregator produced in endothelial cells, and thromboxane A2, a potent smooth muscle constrictor and platelet aggregator formed in platelets, with shift more toward increased thromboxane A2 production. This finding is suggestive of significant platelet activation and may have implication for future failure of peripheral angioplasty (Parmar et al., 2010). An increased formation of thromboxane A2 was also seen in other two studies, one in patients undergoing peripheral angioplasty and one in patients

In addition, in the initial phase after balloon and stent procedures, coagulation system is activated, as demonstrated by increased serum levels of thrombin-antithrombin complexes, D-dimer and fibrinopeptide A. This condition favours early thrombotic occlusion, where 'early' is usually defined as a period covering the first 4 weeks after the intervention (Tsakiris et al., 1999; Tschöpl et al., 1997). Subsequently, intimal hyperplasia, a redundant healing of the arterial wall, which is responsible for restenosis and reocclusion in the midand long-term, may follow. Intimal hyperplasia occurs as a result of denudation (tearing off of the inner lining) of the endothelium caused by damage to the vessel wall with the catheter. Smooth muscle cells in the medial layer are stimulated to grow and migrate into

after coronary angioplasty (Rossi et al., 1997; Peterson et al., 1986).

the intimal layer (Haudenschild, 1995; Jørgensen et al., 1990).

(Norgren et al., 2007).

1998; Wentzel et al., 2003).

Risk factors for restenosis/reocclusion include severity of atherosclerosis in run-off arteries, length of diseased segments, number of treated lesions, stage of disease, and presence of cardiovascular risk factors (Norgren et al., 2007). Female gender may be an independent predictor of decreased primary patency of external iliac artery stents (Timaran et al., 2001). Inflammation, revealed by an elevated C-reactive protein, was also considered as a risk factor for restenosis at six months after successful femoropopliteal angioplasty (Schillinger et al., 2002).

The rate of restenosis/reocclusion of suprainguinal (iliac) arteries after peripheral transluminal angioplasty ranges from 14% after one year to 29% after 5 years, while the rate of restenosis/reocclusion of infrainguinal (femoropopliteal) arteries after peripheral transluminal angioplasty with or without stenting ranges from 23-35% after one year to 45-58% after 5 years (Norgren et al., 2007). Patients with stenoses or occlusions of infrainguinal arteries of less than 3 cm had a favourable long-term patency rate of 74% (Gallino et al., 1984).

Patients subjected to local thrombolysis show higher incidences of restenosis/reocclusion (Decrinis et al., 1993).

It is important to define the lesion suitable for balloon angioplasty in both the suprainguinal and infrainguinal districts.

Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) redefined the indications for endovascular or surgical revascularization on the basis of anatomical characteristics of the lesions. Endovascular interventions are recommended for: i) unilateral or bilateral stenosis of common iliac artery; unilateral or bilateral single short ( 3 cm) stenosis of external iliac artery; ii) single stenosis 10 cm in length of femoropopliteal arteries; single occlusion 5 cm in length of femoropopliteal arteries (TASC Type A lesions) (Norgren et al., 2007).

Endovascular interventions are the preferred treatments for: i) short ( 3 cm) stenosis of infrarenal aorta; unilateral common iliac artery occlusion; single or multiple stenosis totaling 3-10 cm involving the external iliac artery not extending into the common femoral artery; unilateral external iliac artery occlusion not involving the origin of internal iliac or common femoral artery; ii) multiple lesions (stenoses or occlusions), each 5 cm of femoropopliteal segment; single stenosis or occlusion 15 cm not involving the infra geniculate popliteal artery; single or multiple lesions in the absence of continuous tibial vessels to improve inow for a distal bypass; heavily calcied occlusion 5 cm in length; single popliteal stenosis (TASC Type B lesions) (Norgren et al., 2007).

Provisional stent placement is indicated for iliac arteries as salvage therapy for a suboptimal or failed result from balloon dilatation (persistent translesional gradient, residual stenosis greater than 50%, flow-limiting dissection). Stenting is effective as primary therapy for common and external iliac artery stenoses and occlusions. Moreover, stents can be useful in the femoral, popliteal and tibial arteries as a salvage therapy for suboptimal or failed results from balloon dilatation (Hirsch et al., 2006).

As mentioned above, the implantation of drug-eluting stents, nitinol stents, paclitaxelcoated angioplasty balloons, or treatment by intravascular brachytherapy following peripheral angioplasty have been considered as interventions with the capacity of reducing the occurrence of restenosis/reocclusion. A study by Schillinger et al. showed better results at one year with self-expanding nitinol stent in femoropopliteal segments (Schillinger et al., 2006). Use of paclitaxel-coated angioplasty balloons during percutaneous treatment of

Antithrombotic Therapy After Peripheral Angioplasty 93

The second meta-analysis is a Cochrane review of 14 randomized trials comparing different antithrombotic drugs (anticoagulants, antiplatelet agents and others) with no treatment or placebo to prevent restenosis/reocclusion following peripheral vascular treatment. The trials included patients with symptomatic peripheral arterial disease treated by endovascular revascularization of the iliac or femoropopliteal arteries. Various pharmacological interventions were analysed: anticoagulants, antiplatelet agents and other vasoactive drugs were compared with no treatment, placebo, or any other vasoactive drug. Clinical endpoints were reocclusion, amputation, death, myocardial infarction, stroke and major bleeding. The efficacy and safety of acetylsalcylic acid and low molecular weight heparins have been shown. Aspirin (50-300 mg daily) started prior to femoropopliteal peripheral transluminal angioplasty has been shown to be the most effective prophylactic treatment. Low molecular weight heparins seem to be more effective in preventing

restenosis or reocclusion than unfractionated heparin (Dörfer-Melly et al., 2005).

after balloon angioplasty of femoropopliteal lesions (Watson & Bergqvist, 2000).

We analyse the studies identified in the following paragraphs (Table 1).

angioplasty (Visonà et al., 2009).

Study Group, 1994).

1990).

Group, 1994).

**3.1 Aspirin with or without dipyridamole** 

was not significant (Do & Mahler, 1994; Pilger et al. 1991).

Watson and Bergqvist identified eleven randomized trials with antithrombotic agents, but they didn't clarify their usefulness in reducing the likelihood of restenosis or reocclusion

Our group recently conducted a review on antithrombotic therapy after peripheral

Two studies compared aspirin combined with dipyridamole to placebo (Heiss et al., 1990;

In a single-center trial 199 patients undergoing balloon angioplasty of femoropopliteal arteries were randomized to high dose aspirin (990 mg) combined with dipyridamole (225 mg), low dose aspirin (300 mg) plus dipyridamole (225 mg), or placebo. Clinical and angiographic improvement was observed in both treatment groups in comparison with placebo, but this was statistically significant only in the high-dose aspirin group (Heiss et al.,

A multicenter study randomized 223 patients undergoing balloon angioplasty of iliac or femoropopliteal arteries to receive either placebo or aspirin (50 mg) plus dipyridamole (400 mg). No difference was observed between the two groups. A possible explanation of this result may be a higher percentage of patients with more favourable iliac lesions in the placebo group (65% versus 51%). Moreover, use of metallic stents was not performed (Study

According the conclusions of the Cochrane review, a 60% reduction of restenosis/ reocclusion was found with aspirin 330 mg combined with dipyridamole as compared to placebo up to 12 months after angioplasty of femoropopliteal arteries. A similar positive effect on patency was found with aspirin 50 to 100 mg combined with dipyridamole as compared to placebo at 6 months, but this was not significant (Dörfer-Melly et al., 2005). Aspirin/dipyridamole showed a superior effect on patency after femoropopliteal angioplasty compared to vitamin K antagonists at 3, 6, and 12 months, but even this effect

Aspirin 50 to 330 mg, with or without dipyridamole, started before femoropopliteal endovascular treatment, appeared to be the most effective and safest strategy, and reduced the incidence of restenosis/reocclusion at 6 and 12 months when compared with no therapy or vitamin K antagonists. Three trials compared the efficacy and safety of different doses of

femoropopliteal disease has been shown to be associated with significant reductions in late lumen loss (Tepe et al., 2008). Endovascular brachytherapy has been proposed as a promising treatment modality to reduce restenosis after angioplasty (Minar et al., 2000). However, the phenomenon of late acute thrombotic occlusion in patients receiving endovascular brachytherapy after stenting of the femoropopliteal arteries may compromise the benets of endovascular radiation. The fact that late acute thrombotic occlusions occurs concomitantly with stopping clopidogrel in patients treated with a double antiplatelet regimen (aspirin 100 mg / day and clopidogrel 75 mg / day) suggests an intensive and prolonged antithrombotic prevention in these patients (Bonvini et al., 2003).

There are much few data concerning antithrombotic therapy after peripheral arterial revascularization, and patients with peripheral arterial disease are often treated on the basis of experiences extrapolated from coronary arteries (Visonà et al., 2009).

Antithrombotic therapy has been shown to lower the incidence of associated cardiovascular events (Sobel & Verhaeghe, 2008). A meta-analysis of 42 trials has shown a statistically significant 23% reduction of vascular events (vascular death, nonfatal myocardial infarction or stroke) in 9,214 patients with peripheral arterial disease treated with antiplatelet therapy. Even patients having peripheral angioplasty benefited to a similar degree (Antithrombotic Trialists' Collaboration, 2002). Clopidogrel seems to be superior to aspirin in reducing cardiovascular events, particularly in patients with peripheral arterial disease (relative risk reduction of 23%) (CAPRIE Steering Committee, 1996), but this advantage is minimal. Lifelong antiplatelet therapy is usually recommended for all patients with peripheral arterial disease to prevent death and disability from stroke and myocardial infarction.

Antithrombotic drugs to prevent restenosis would make an important contribution to the sustained success of endovascular treatment. The main questions concern the most effective and safe antithrombotic therapy and its duration.

#### **2. Methods**

We performed a Medline search of English language studies published between 1976 and 2010 with the keywords "antithrombotic therapy, peripheral angioplasty". We also considered the reviews and meta-analyses. We selected two meta-analyses, two reviews, and fifteen original articles.

#### **3. Results**

Two meta-analyses and two reviews evaluated the efficacy and safety of antithrombotic agents for the prevention of restenosis after balloon angioplasty in patients with peripheral arterial disease (Girolami et al., 2000; Dörfer-Melly et al., 2005; Watson & Bergqvist, 2000; Visonà et al. 2009).

The first meta-analysis evaluated the efficacy of conservative adjuvant therapy after endovascular or surgical revascularization procedures. The meta-analysis, including thirtytwo studies, showed that, compared to non-active control, aspirin (100-300 mg daily) with dipyridamole (225-450 mg daily) improves patency (odds ratio 0.69) and mortality (odds ratio 0.57). Similarly, ticlopidine has been shown to improve patency and amputation rates (odds ratio 0.53 and 1.01, respectively), and therefore may be used when aspirin is contraindicated. Data on the effectiveness of vitamin K inhibitors were not conclusive (Girolami et al., 2000).

Angioplasty, Various Techniques and Challenges in 92 Treatment of Congenital and Acquired Vascular Stenoses

femoropopliteal disease has been shown to be associated with significant reductions in late lumen loss (Tepe et al., 2008). Endovascular brachytherapy has been proposed as a promising treatment modality to reduce restenosis after angioplasty (Minar et al., 2000). However, the phenomenon of late acute thrombotic occlusion in patients receiving endovascular brachytherapy after stenting of the femoropopliteal arteries may compromise the benets of endovascular radiation. The fact that late acute thrombotic occlusions occurs concomitantly with stopping clopidogrel in patients treated with a double antiplatelet regimen (aspirin 100 mg / day and clopidogrel 75 mg / day) suggests an intensive and

There are much few data concerning antithrombotic therapy after peripheral arterial revascularization, and patients with peripheral arterial disease are often treated on the basis

Antithrombotic therapy has been shown to lower the incidence of associated cardiovascular events (Sobel & Verhaeghe, 2008). A meta-analysis of 42 trials has shown a statistically significant 23% reduction of vascular events (vascular death, nonfatal myocardial infarction or stroke) in 9,214 patients with peripheral arterial disease treated with antiplatelet therapy. Even patients having peripheral angioplasty benefited to a similar degree (Antithrombotic Trialists' Collaboration, 2002). Clopidogrel seems to be superior to aspirin in reducing cardiovascular events, particularly in patients with peripheral arterial disease (relative risk reduction of 23%) (CAPRIE Steering Committee, 1996), but this advantage is minimal. Lifelong antiplatelet therapy is usually recommended for all patients with peripheral arterial

Antithrombotic drugs to prevent restenosis would make an important contribution to the sustained success of endovascular treatment. The main questions concern the most effective

We performed a Medline search of English language studies published between 1976 and 2010 with the keywords "antithrombotic therapy, peripheral angioplasty". We also considered the reviews and meta-analyses. We selected two meta-analyses, two reviews,

Two meta-analyses and two reviews evaluated the efficacy and safety of antithrombotic agents for the prevention of restenosis after balloon angioplasty in patients with peripheral arterial disease (Girolami et al., 2000; Dörfer-Melly et al., 2005; Watson & Bergqvist, 2000;

The first meta-analysis evaluated the efficacy of conservative adjuvant therapy after endovascular or surgical revascularization procedures. The meta-analysis, including thirtytwo studies, showed that, compared to non-active control, aspirin (100-300 mg daily) with dipyridamole (225-450 mg daily) improves patency (odds ratio 0.69) and mortality (odds ratio 0.57). Similarly, ticlopidine has been shown to improve patency and amputation rates (odds ratio 0.53 and 1.01, respectively), and therefore may be used when aspirin is contraindicated. Data on the effectiveness of vitamin K inhibitors were not conclusive

prolonged antithrombotic prevention in these patients (Bonvini et al., 2003).

disease to prevent death and disability from stroke and myocardial infarction.

and safe antithrombotic therapy and its duration.

**2. Methods** 

**3. Results** 

Visonà et al. 2009).

(Girolami et al., 2000).

and fifteen original articles.

of experiences extrapolated from coronary arteries (Visonà et al., 2009).

The second meta-analysis is a Cochrane review of 14 randomized trials comparing different antithrombotic drugs (anticoagulants, antiplatelet agents and others) with no treatment or placebo to prevent restenosis/reocclusion following peripheral vascular treatment. The trials included patients with symptomatic peripheral arterial disease treated by endovascular revascularization of the iliac or femoropopliteal arteries. Various pharmacological interventions were analysed: anticoagulants, antiplatelet agents and other vasoactive drugs were compared with no treatment, placebo, or any other vasoactive drug. Clinical endpoints were reocclusion, amputation, death, myocardial infarction, stroke and major bleeding. The efficacy and safety of acetylsalcylic acid and low molecular weight heparins have been shown. Aspirin (50-300 mg daily) started prior to femoropopliteal peripheral transluminal angioplasty has been shown to be the most effective prophylactic treatment. Low molecular weight heparins seem to be more effective in preventing restenosis or reocclusion than unfractionated heparin (Dörfer-Melly et al., 2005).

Watson and Bergqvist identified eleven randomized trials with antithrombotic agents, but they didn't clarify their usefulness in reducing the likelihood of restenosis or reocclusion after balloon angioplasty of femoropopliteal lesions (Watson & Bergqvist, 2000).

Our group recently conducted a review on antithrombotic therapy after peripheral angioplasty (Visonà et al., 2009).

We analyse the studies identified in the following paragraphs (Table 1).

#### **3.1 Aspirin with or without dipyridamole**

Two studies compared aspirin combined with dipyridamole to placebo (Heiss et al., 1990; Study Group, 1994).

In a single-center trial 199 patients undergoing balloon angioplasty of femoropopliteal arteries were randomized to high dose aspirin (990 mg) combined with dipyridamole (225 mg), low dose aspirin (300 mg) plus dipyridamole (225 mg), or placebo. Clinical and angiographic improvement was observed in both treatment groups in comparison with placebo, but this was statistically significant only in the high-dose aspirin group (Heiss et al., 1990).

A multicenter study randomized 223 patients undergoing balloon angioplasty of iliac or femoropopliteal arteries to receive either placebo or aspirin (50 mg) plus dipyridamole (400 mg). No difference was observed between the two groups. A possible explanation of this result may be a higher percentage of patients with more favourable iliac lesions in the placebo group (65% versus 51%). Moreover, use of metallic stents was not performed (Study Group, 1994).

According the conclusions of the Cochrane review, a 60% reduction of restenosis/ reocclusion was found with aspirin 330 mg combined with dipyridamole as compared to placebo up to 12 months after angioplasty of femoropopliteal arteries. A similar positive effect on patency was found with aspirin 50 to 100 mg combined with dipyridamole as compared to placebo at 6 months, but this was not significant (Dörfer-Melly et al., 2005).

Aspirin/dipyridamole showed a superior effect on patency after femoropopliteal angioplasty compared to vitamin K antagonists at 3, 6, and 12 months, but even this effect was not significant (Do & Mahler, 1994; Pilger et al. 1991).

Aspirin 50 to 330 mg, with or without dipyridamole, started before femoropopliteal endovascular treatment, appeared to be the most effective and safest strategy, and reduced the incidence of restenosis/reocclusion at 6 and 12 months when compared with no therapy or vitamin K antagonists. Three trials compared the efficacy and safety of different doses of

Antithrombotic Therapy After Peripheral Angioplasty 95

tolerated, and might be combined with aspirin, when increased risk factors for

In one study ticlopidine was compared to vitamin K inhibitors. No significant difference in efficacy was found between the two drugs (Schneider et al., 1987, as cited in Sobel &

The administration of clopidogrel and aspirin leads to a potent platelet inhibition, whose benefits have been demonstrated for patients with acute coronary syndrome, symptomatic vascular disease, and presence of multiple cardiovascular risk factors. A randomized doubleblind trial showed that the administration of clopidogrel and aspirin significantly suppresses platelet function up to 30 days after lower limb angioplasty, compared to aspirin and placebo (Cassar et al., 2005a). On the other hand, addition of clopidogrel to the standard antithrombotic therapy with aspirin had no effect on the levels of markers of coagulation activation, such as D-dimer and thrombin-antithrombin III, in patients with intermittent claudication before or after endovascular intervention (Cassar et al., 2005b). Moreover, therapy with clopidogrel and aspirin had no significant effect on markers of vascular smooth muscle

Dual antiplatelet therapy (clopidogrel plus aspirin), leading to a potent platelet inhibition, has been shown to be more effective than aspirin alone in reducing cardiovascular events in patients with acute non-ST coronary syndrome. This finding has not been confirmed in patients at high cardiovascular risk but not in the acute phase, where risk-benefit ratio is less favourable (Keller et al., 2007). A potential benefit of clopidogrel and aspirin versus aspirin alone in patients with symptomatic vascular disease has been suggested by the CHARISMA trial, which enrolled more than 15,000 patients with either evident clinical cardiovascular

The benefit of more potent platelet inhibition with dual therapy, aspirin and clopidogrel, has been shown in a trial on acute coronary syndromes (CURE) (Fox et al., 2004). However, the efficacy and safety of this dual antiplatelet therapy after peripheral angioplasty have not been evaluated in a randomized controlled trial. The Clopidogrel and Aspirin in the Management of Peripheral Endovascular Revascularization study (CAMPER) was designed to evaluate this outcome after femoropopliteal angioplasty, but it was stopped, due to difficulties of randomization, perhaps because many patients were already treated off-label

The administration of ticlopidine and acetylsalicylic acid has been shown to improve neurological outcome after carotid stenting without an additional increase in bleeding complications in patients undergoing carotid stenting, compared to acetylsalicylic acid alone

Aspirin and clopidogrel were used as standard therapy in two major randomized controlled trials of carotid stenting (preprocedure and at least for 30 days) (SPACE Collaborative

Although it is questionable to extrapolate experience from one anatomic region to another, in the absence of data on peripheral interventions, dual antiplatelet therapy seems to be a reasonable approach to reduce thrombotic complications after lower extremity balloon angioplasty and stenting, especially in the femoropopliteal and tibial districts. In fact, many physicians in the world use dual antiplatelet therapy with aspirin (100 mg / day) and clopidogrel (75 mg / day) before and after peripheral transluminal angioplasty and stenting of peripheral arteries. Dual antiplatelet therapy is continued for 4 weeks after the intervention.

restenosis/reocclusion are detected, although specific data are lacking.

cell proliferation before and after peripheral angioplasty (Wilson et al., 2009).

Verhaeghe, 2008).

**3.4.3 Dual antiplatelet therapy** 

(Dalainas et al., 2006).

Group, 2006; Mas et al., 2006).

disease or multiple risk factors (Bhatt et al., 2006).

with clopidogrel and aspirin (Patrono et al., 2004).

aspirin after peripheral angioplasty. The doses tested ranged from 50 mg / day to 1000 mg / day. The three studies showed that higher doses of aspirin had no advantage on early reocclusion (within one month) and were more likely to cause gastrointestinal side effects including peptic ulcer (Weichert et al., 1994; Minar et al., 1995; Ranke et al., 1994).

#### **3.2 Oral anticoagulants**

Anticoagulation is frequently combined with antiplatelet therapy after femoropopliteal or tibial artery balloon angioplasty, although the results of three randomized controlled trials do not support this practice (Schneider et al., 1987, as cited in Sobel & Verhaeghe, 2008; Pilger et al., 1991; Do & Mahler, 1994). In fact, in all three studies no significant difference was observed in arterial patency rate between the anticoagulation groups and the antiplatelet therapy groups (only slightly lower patency rate and more bleeding complications in the anticoagulation groups).

#### **3.3 Low molecular weight heparins**

Intimal hyperplasia is responsible for restenosis and reocclusion after angioplasty in the mid- and long-term. Low molecular weight heparins have been shown in experimental studies to have antiproliferative effects in addition to their antithrombotic properties (Wilson et al., 1991). Their potential to reduce restenosis remains to be established. The hypothesis that low molecular weight heparins plus aspirin are more effective than aspirin alone in reducing incidence of restenosis after peripheral transluminal angioplasty was tested in two trials. Nadroparin, administered at a dose adjusted to weight for 7 days after femoropopliteal angioplasty, has been shown to be more effective to prevent reocclusion at 6 months than unfractionated heparin, without causing increased bleeding (Schweizer et al., 2001). Despite this interesting result, dalteparin 2500 UI, administered for 3 months after femoropopliteal angioplasty plus aspirin 100 mg/day versus aspirin alone, failed to reduce incidence of restenosis/reocclusion at 12 months. However, dalteparin appeared to be beneficial at the 12-month follow-up in the subgroup of patients with critical limb ischemia (Koppensteiner et al., 2006).

#### **3.4 New antiplatelet drugs (abciximab, thienopyridines)**

There are few studies available on potent new antiplatelet drugs such as abciximab and thienopyridines.

#### **3.4.1 Abciximab**

In one study in high-risk patients with long segmental femoropopliteal interventions adjunctive administration of abciximab had a favorable effect on patency and clinical outcome in patients undergoing complex femoropopliteal catheter interventions not hampered by serious bleeding. Treatment effect of abciximab observed at 30 days was maintained at 6 months (Dörfer-Melly et al., 2005).

In another study adjunctive abciximab after nitinol stenting of the superficial femoral artery did not appear to demonstrate any identifiable effect on functional outcomes at 9 months (Ansel et al., 2006).

#### **3.4.2 Thienopyridines**

The thienopyridines, ticlopidine and clopidogrel, interfere with the adenosine diphosphate (ADP) pathway. They might represent a useful alternative to aspirin, when it is not Angioplasty, Various Techniques and Challenges in 94 Treatment of Congenital and Acquired Vascular Stenoses

aspirin after peripheral angioplasty. The doses tested ranged from 50 mg / day to 1000 mg / day. The three studies showed that higher doses of aspirin had no advantage on early reocclusion (within one month) and were more likely to cause gastrointestinal side effects

Anticoagulation is frequently combined with antiplatelet therapy after femoropopliteal or tibial artery balloon angioplasty, although the results of three randomized controlled trials do not support this practice (Schneider et al., 1987, as cited in Sobel & Verhaeghe, 2008; Pilger et al., 1991; Do & Mahler, 1994). In fact, in all three studies no significant difference was observed in arterial patency rate between the anticoagulation groups and the antiplatelet therapy groups (only slightly lower patency rate and more bleeding

Intimal hyperplasia is responsible for restenosis and reocclusion after angioplasty in the mid- and long-term. Low molecular weight heparins have been shown in experimental studies to have antiproliferative effects in addition to their antithrombotic properties (Wilson et al., 1991). Their potential to reduce restenosis remains to be established. The hypothesis that low molecular weight heparins plus aspirin are more effective than aspirin alone in reducing incidence of restenosis after peripheral transluminal angioplasty was tested in two trials. Nadroparin, administered at a dose adjusted to weight for 7 days after femoropopliteal angioplasty, has been shown to be more effective to prevent reocclusion at 6 months than unfractionated heparin, without causing increased bleeding (Schweizer et al., 2001). Despite this interesting result, dalteparin 2500 UI, administered for 3 months after femoropopliteal angioplasty plus aspirin 100 mg/day versus aspirin alone, failed to reduce incidence of restenosis/reocclusion at 12 months. However, dalteparin appeared to be beneficial at the 12-month follow-up in the subgroup of patients with critical limb ischemia

There are few studies available on potent new antiplatelet drugs such as abciximab and

In one study in high-risk patients with long segmental femoropopliteal interventions adjunctive administration of abciximab had a favorable effect on patency and clinical outcome in patients undergoing complex femoropopliteal catheter interventions not hampered by serious bleeding. Treatment effect of abciximab observed at 30 days was

In another study adjunctive abciximab after nitinol stenting of the superficial femoral artery did not appear to demonstrate any identifiable effect on functional outcomes at 9 months

The thienopyridines, ticlopidine and clopidogrel, interfere with the adenosine diphosphate (ADP) pathway. They might represent a useful alternative to aspirin, when it is not

including peptic ulcer (Weichert et al., 1994; Minar et al., 1995; Ranke et al., 1994).

**3.2 Oral anticoagulants** 

complications in the anticoagulation groups).

**3.3 Low molecular weight heparins** 

(Koppensteiner et al., 2006).

thienopyridines.

**3.4.1 Abciximab** 

(Ansel et al., 2006).

**3.4.2 Thienopyridines** 

**3.4 New antiplatelet drugs (abciximab, thienopyridines)** 

maintained at 6 months (Dörfer-Melly et al., 2005).

tolerated, and might be combined with aspirin, when increased risk factors for restenosis/reocclusion are detected, although specific data are lacking.

In one study ticlopidine was compared to vitamin K inhibitors. No significant difference in efficacy was found between the two drugs (Schneider et al., 1987, as cited in Sobel & Verhaeghe, 2008).

The administration of clopidogrel and aspirin leads to a potent platelet inhibition, whose benefits have been demonstrated for patients with acute coronary syndrome, symptomatic vascular disease, and presence of multiple cardiovascular risk factors. A randomized doubleblind trial showed that the administration of clopidogrel and aspirin significantly suppresses platelet function up to 30 days after lower limb angioplasty, compared to aspirin and placebo (Cassar et al., 2005a). On the other hand, addition of clopidogrel to the standard antithrombotic therapy with aspirin had no effect on the levels of markers of coagulation activation, such as D-dimer and thrombin-antithrombin III, in patients with intermittent claudication before or after endovascular intervention (Cassar et al., 2005b). Moreover, therapy with clopidogrel and aspirin had no significant effect on markers of vascular smooth muscle cell proliferation before and after peripheral angioplasty (Wilson et al., 2009).

#### **3.4.3 Dual antiplatelet therapy**

Dual antiplatelet therapy (clopidogrel plus aspirin), leading to a potent platelet inhibition, has been shown to be more effective than aspirin alone in reducing cardiovascular events in patients with acute non-ST coronary syndrome. This finding has not been confirmed in patients at high cardiovascular risk but not in the acute phase, where risk-benefit ratio is less favourable (Keller et al., 2007). A potential benefit of clopidogrel and aspirin versus aspirin alone in patients with symptomatic vascular disease has been suggested by the CHARISMA trial, which enrolled more than 15,000 patients with either evident clinical cardiovascular disease or multiple risk factors (Bhatt et al., 2006).

The benefit of more potent platelet inhibition with dual therapy, aspirin and clopidogrel, has been shown in a trial on acute coronary syndromes (CURE) (Fox et al., 2004). However, the efficacy and safety of this dual antiplatelet therapy after peripheral angioplasty have not been evaluated in a randomized controlled trial. The Clopidogrel and Aspirin in the Management of Peripheral Endovascular Revascularization study (CAMPER) was designed to evaluate this outcome after femoropopliteal angioplasty, but it was stopped, due to difficulties of randomization, perhaps because many patients were already treated off-label with clopidogrel and aspirin (Patrono et al., 2004).

The administration of ticlopidine and acetylsalicylic acid has been shown to improve neurological outcome after carotid stenting without an additional increase in bleeding complications in patients undergoing carotid stenting, compared to acetylsalicylic acid alone (Dalainas et al., 2006).

Aspirin and clopidogrel were used as standard therapy in two major randomized controlled trials of carotid stenting (preprocedure and at least for 30 days) (SPACE Collaborative Group, 2006; Mas et al., 2006).

Although it is questionable to extrapolate experience from one anatomic region to another, in the absence of data on peripheral interventions, dual antiplatelet therapy seems to be a reasonable approach to reduce thrombotic complications after lower extremity balloon angioplasty and stenting, especially in the femoropopliteal and tibial districts. In fact, many physicians in the world use dual antiplatelet therapy with aspirin (100 mg / day) and clopidogrel (75 mg / day) before and after peripheral transluminal angioplasty and stenting of peripheral arteries. Dual antiplatelet therapy is continued for 4 weeks after the intervention.

Antithrombotic Therapy After Peripheral Angioplasty 97

Currently, for patients undergoing lower extremity balloon angioplasty (with or without stenting), the American College of Chest Physicians (ACCP) recommends long-term aspirin (75-100 mg / day) (grade 1C), and recommends against anticoagulation with heparin or

Randomized, prospective studies with dual therapy are needed for resolving some issues, such as real efficacy of dual therapy in peripheral district, the optimal loading dose in patients undergoing endovascular revascularization, and the optimal duration of dual therapy following peripheral angioplasty and stenting (Plosker & Lyseng-Williamson, 2007).

Some drugs have interesting vasoactive properties, that may improve outcome after peripheral angioplasty. Iloprost, the prostacyclin analogue, and cilostazol, a phosphodiesterase type 3 inhibitor, have multiple effects, such as inhibition of platelet activation, vasodilation, antiproliferation of vascular smooth muscle cells, and improvement of endothelial cell function. These effects may lead to the inhibition of neointimal

Iloprost was investigated in a small study in conjunction with aspirin. A 3-day periinterventional intravenous infusion of iloprost plus long-term aspirin didn't reduce

Cilostazol after endovascular therapy for femoropopliteal lesions was more effective in

Patients with peripheral arterial disease benefit from receiving life-long aspirin at a daily dose of 75 mg to 100 mg or clopidogrel at a daily dose of 75 mg. Patients undergoing peripheral transluminal angioplasty should receive aspirin at a daily dose of 75 mg to 100 mg, started before the intervention and continued life-long. Thienopyridines, e.g. clopidogrel, might represent a useful alternative to aspirin in cases of intolerance to aspirin. Although randomized clinical trials are lacking, it is reasonable to consider short-term dual antiplatelet therapy with aspirin and thienopyridines for infrainguinal stenting, given the relatively high rate of restenosis/reocclusion after interventions. It is reasonable to administer a 300-600 mg loading dose 6-24 hours before angioplasty, and to continue dual therapy for 4 weeks. If a drug-eluting peripheral stent was placed, dual therapy is maintained for 6-12 months. Use of low molecular weight heparins may be reserved for patients with critical limb iischemia. Abciximab may be useful after extended

femoropopliteal interventions in patients at high risk of restenosis/reocclusion.

(February 2006), pp. 288-297, ISSN 1522-1946

Ansel, G.M.; Silver, M.J.; Botti, C.F. Jr; Rocha-Singh, K.; Bates, M.C.; Rosenfield, K.;

Schainfeld, R.M.; Laster, S.B. & Zander, C. (2006). Functional and clinical outcomes of nitinol stenting with and without abciximab for complex superficial femoral artery disease: a randomized trial. *Catheter Cardiovasc Interv*, Vol.67, No.2,

incidence of restenosis, compared to aspirin alone (Horrocks et al., 1997).

reducing restenosis than ticlopidine (Iida et al., 2008).

vitamin K inhibitors (grade 1A) (Sobel & Verhaeghe, 2008).

**3.5 Vasoactive drugs** 

hyperplasia after stenting.

Further studies are needed.

**4. Conclusion** 

**5. References** 

Then aspirin is continued indefinitely (Visonà et al., 2009). Treatment with a loading dose of clopidogrel 6-24 hours before angioplasty seems to improve the clinical outcome (Verheugt et al., 2007), and a 600 mg loading dose versus 300 mg at least 12 hours before the procedure provides greater benefit in coronary syndromes (Cuisset et al., 2006). In addition, an intraarterial bolus of heparin (3000 to 5000 U) is often administered at the time of the procedure.


Pts= patients; ASA=acetylsalicylic acid; LMWHs=low molecular weight heparins; R=randomized; DB=double blind; O=open; nC=number of centres

Table 1. Drugs, studies published, patients analysed and study designs

Currently, for patients undergoing lower extremity balloon angioplasty (with or without stenting), the American College of Chest Physicians (ACCP) recommends long-term aspirin (75-100 mg / day) (grade 1C), and recommends against anticoagulation with heparin or vitamin K inhibitors (grade 1A) (Sobel & Verhaeghe, 2008).

Randomized, prospective studies with dual therapy are needed for resolving some issues, such as real efficacy of dual therapy in peripheral district, the optimal loading dose in patients undergoing endovascular revascularization, and the optimal duration of dual therapy following peripheral angioplasty and stenting (Plosker & Lyseng-Williamson, 2007).

#### **3.5 Vasoactive drugs**

Angioplasty, Various Techniques and Challenges in 96 Treatment of Congenital and Acquired Vascular Stenoses

Then aspirin is continued indefinitely (Visonà et al., 2009). Treatment with a loading dose of clopidogrel 6-24 hours before angioplasty seems to improve the clinical outcome (Verheugt et al., 2007), and a 600 mg loading dose versus 300 mg at least 12 hours before the procedure provides greater benefit in coronary syndromes (Cuisset et al., 2006). In addition, an intraarterial bolus of heparin (3000 to 5000 U) is often administered at the time of the procedure.

> ASA 300 mg / dipyridamole 225 mg ASA 990 mg / dipyridamole 225 mg

103 94

> 11 13 14

> 63 64

R, DB, 1C

R, DB, 12C

R, DB, 1C

R, DB, 2C

R, DB, 2C

R, O, 1C

R, O, 1C

R, O, 1C

R, O, 1C

R, O, 1C

R, O, 3C

R, DB, 1C

R, O, 1C

R, O, 2C

R, O, 1C

ASA 50 mg / dipyridamole 400 mg

ASA 990 mg / dipirydamole 225 mg

ASA 50 mg / dipyridamole 400 mg

ASA 500 mg / dipirydamole 225 mg

Weight adjusted nadroparin + ASA

Unfractionated heparin + ASA 100 mg Dalteparin 2500 IU + ASA 100 mg

Iloprost 72 h + ASA 300 mg after 72 h

None 72 h + ASA 300 mg after 72 h

Drugs Author, year Treatments Pts Design

Placebo

Placebo ASA 990 mg

ASA 50 mg ASA 900 mg ASA 300 mg ASA 1000 mg ASA 100 mg ASA 1000 mg

Anticoagulant

Anticoagulant

ASA 100 mg

Ticlopidine Anticoagulant

Abciximab Placebo

ASA 300 mg

Table 1. Drugs, studies published, patients analysed and study designs

Ticlopidine 200 mg

Pts= patients; ASA=acetylsalicylic acid; LMWHs=low molecular weight heparins; R=randomized;

Abciximab + ASA 100 mg Placebo + ASA 100 mg

100 mg

ASA ± dipyridamole

Oral

anticoagulants

LMWHs

Abciximab

Iloprost

Heiss, 1990

Study Group, 1994 Hess, 1978

Ranke, 1992

Weichert, 1994

Minar, 1995

Pilger, 1991

Schweizer, 2001

2006

1987

Dörfer-Melly, 2005 Ansel, 2006

Horrocks, 1997

Cilostazol Iida, 2008 Cilostazol 200 mg

DB=double blind; O=open; nC=number of centres

Ticlopidine Schneider,

Koppensteiner,

Do, 1994

Some drugs have interesting vasoactive properties, that may improve outcome after peripheral angioplasty. Iloprost, the prostacyclin analogue, and cilostazol, a phosphodiesterase type 3 inhibitor, have multiple effects, such as inhibition of platelet activation, vasodilation, antiproliferation of vascular smooth muscle cells, and improvement of endothelial cell function. These effects may lead to the inhibition of neointimal hyperplasia after stenting.

Iloprost was investigated in a small study in conjunction with aspirin. A 3-day periinterventional intravenous infusion of iloprost plus long-term aspirin didn't reduce incidence of restenosis, compared to aspirin alone (Horrocks et al., 1997).

Cilostazol after endovascular therapy for femoropopliteal lesions was more effective in reducing restenosis than ticlopidine (Iida et al., 2008).

Further studies are needed.

#### **4. Conclusion**

Patients with peripheral arterial disease benefit from receiving life-long aspirin at a daily dose of 75 mg to 100 mg or clopidogrel at a daily dose of 75 mg. Patients undergoing peripheral transluminal angioplasty should receive aspirin at a daily dose of 75 mg to 100 mg, started before the intervention and continued life-long. Thienopyridines, e.g. clopidogrel, might represent a useful alternative to aspirin in cases of intolerance to aspirin. Although randomized clinical trials are lacking, it is reasonable to consider short-term dual antiplatelet therapy with aspirin and thienopyridines for infrainguinal stenting, given the relatively high rate of restenosis/reocclusion after interventions. It is reasonable to administer a 300-600 mg loading dose 6-24 hours before angioplasty, and to continue dual therapy for 4 weeks. If a drug-eluting peripheral stent was placed, dual therapy is maintained for 6-12 months. Use of low molecular weight heparins may be reserved for patients with critical limb iischemia. Abciximab may be useful after extended femoropopliteal interventions in patients at high risk of restenosis/reocclusion.

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**6** 

*USA* 

**Evidence-Based Invasive Treatments** 

**Aneurysmal Subarachnoid Hemorrhage** 

*1Postdoctoral Research Scientist, Department of Neurological Surgery* 

Starting in 1984, the technique of angioplasty was no longer confined to only the treatment of peripheral and coronary arteries. In the original paper investigating the technique of angioplasty in cerebral arteries after cerebral vasospasm from aneurysmal subarachnoid hemorrhage (aSAH) , Zubkov et al. found an overall decrease in headaches and focal neurological deficits after the procedure (Zubkov et al, 1984). Despite advances in both medical and endovascular treatment of cerebral vasospasm since then, vasospasm remains a prominent source of morbidity and mortality for patients in the Neuro-Intensive Care Unit. At an estimated incidence rate of 10-28/100000 people, aSAH is associated with a 20% to 40% risk of development of symptomatic, cerebral vasospasm. Of these patients experiencing symptomatic vasospasm, an estimated 10-15% will die before medical therapy while the other 85-90% will have an overall mortality rate of 32-67% (Weant et al, 2010;

In a review of the literature investigating endovascular treatment of cerebral vasospasm, an absence of standardization is present across these studies. Starting from the basics, the literature has not produced a "gold standard" definition of vasospasm. While some groups define vasospasm by a clinical ,neurological deterioration (Andaluz et al, 2002), others use a variety of diagnostic modalities, such as Transcranial Doppler Velocities (Oskouian et al, 2002), digital subtraction angiography (Frontera et al, 2009), and narrowing of vessel diameter via CT angiography (Coenen et al, 1998), to make the same diagnosis. Therefore, assessing the overall efficacy of angioplasty for cerebral vasospasm is difficult when the

Once a diagnosis of cerebral vasospasm is confirmed, a lack of standardization continues throughout its treatment. While some groups have associated a good neurological grade

literature provides different indications for the same treatment.

**1. Introduction** 

Frontera et al, 2009).

**for Cerebral Vasospasm Following** 

Geoffrey Appelboom1, Adam Jacoby2, Matthew Piazza2 and E. Sander Connolly3

*2Research Fellow, Department of Neurological Surgery* 

*3Bennett M. Stein Professor of Neurological Surgery* 

*Columbia University, New York, NY* 

*Columbia University, New York, NY* 

*Columbia University, New York, NY* 


### **Evidence-Based Invasive Treatments for Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage**

Geoffrey Appelboom1, Adam Jacoby2, Matthew Piazza2 and E. Sander Connolly3 *1Postdoctoral Research Scientist, Department of Neurological Surgery Columbia University, New York, NY 2Research Fellow, Department of Neurological Surgery Columbia University, New York, NY 3Bennett M. Stein Professor of Neurological Surgery Columbia University, New York, NY USA* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 104 Treatment of Congenital and Acquired Vascular Stenoses

Wentzel, J.J.; Gijsen, F.J.; Stergiopulos, N.; Serruys, P.W.; Slager, C.J. & Krams, R. (2003).

Wilson, N.V.; Salisbury, J.R. & Kakkar, V.V. (1991). Effect of low molecular weight heparin

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1383, ISSN 0007-1323

Shear stress, vascular remodeling and neointimal formation. *Journal of Biomechanics*,

on myointimal hyperplasia. *Brit J Surg*, Vol.78, No.11, (November 1991), pp. 1381-

controlled trial of aspirin and clopidogrel versus aspirin and placebo on markers of smooth muscle proliferation before and after peripheral angioplasty. *J Vasc Surg*,

> Starting in 1984, the technique of angioplasty was no longer confined to only the treatment of peripheral and coronary arteries. In the original paper investigating the technique of angioplasty in cerebral arteries after cerebral vasospasm from aneurysmal subarachnoid hemorrhage (aSAH) , Zubkov et al. found an overall decrease in headaches and focal neurological deficits after the procedure (Zubkov et al, 1984). Despite advances in both medical and endovascular treatment of cerebral vasospasm since then, vasospasm remains a prominent source of morbidity and mortality for patients in the Neuro-Intensive Care Unit. At an estimated incidence rate of 10-28/100000 people, aSAH is associated with a 20% to 40% risk of development of symptomatic, cerebral vasospasm. Of these patients experiencing symptomatic vasospasm, an estimated 10-15% will die before medical therapy while the other 85-90% will have an overall mortality rate of 32-67% (Weant et al, 2010; Frontera et al, 2009).

> In a review of the literature investigating endovascular treatment of cerebral vasospasm, an absence of standardization is present across these studies. Starting from the basics, the literature has not produced a "gold standard" definition of vasospasm. While some groups define vasospasm by a clinical ,neurological deterioration (Andaluz et al, 2002), others use a variety of diagnostic modalities, such as Transcranial Doppler Velocities (Oskouian et al, 2002), digital subtraction angiography (Frontera et al, 2009), and narrowing of vessel diameter via CT angiography (Coenen et al, 1998), to make the same diagnosis. Therefore, assessing the overall efficacy of angioplasty for cerebral vasospasm is difficult when the literature provides different indications for the same treatment.

> Once a diagnosis of cerebral vasospasm is confirmed, a lack of standardization continues throughout its treatment. While some groups have associated a good neurological grade

Evidence-Based Invasive Treatments for Cerebral

Coenen

Oskouian

Eskridge 1998,

Jestaedt 2008,

Zweinenberg

Frontera 2011, Acta

Muizelaar 2001, Acta

Katoh 1999, Neurological Focus

Fujii 1995, Neurosurg Rev

Choi 2011, J Korean

Murai 2005, Surgical

Santillan 2011,

Table 1.

Neurosurg

Neurology

Neurosurgery

1998,

2002,

Neurosurgical Focus

Neurosurgical Focus

Neurosurgery

Neurochir Suppl

Neurochir Suppl

**First Author Date/Journal Definition of Vasospasm** 

Vasospasm Following Aneurysmal Subarachnoid Hemorrhage 107

Keuskamp 2008, J Neurosurg Angiographic CT 0, no vasospasm. Mild <20%, Mild Moderate 21-40%,

Firlik 1997, J Neurosurg Angiographic CT 0, no vasospasm. Mild, <50% stenosis. Moderate 50% stenosis. Severe >50% stenosis. Kaku 1992, J Neurosurg Symptomatic (new neurological deficit not attributable to other causes) and TCD velocity >100 cm/sec Elliott 1998, J Neurosurg TCD > 120 cm/sec and vessel diameter via CT; >25% narrowing

was 50%, severe was 75%;

Neurosurgery TCD and Angiography, unclear scales used

TCD > 120 cm/s

angiography


Kassell 1992, J Neurosurg Angiographic >50% reduction in diameter

VMCA/VEC-ICA of more than 3.

Beck 2006, J Neurosurg TCD velocity >120 cm/s in presence of Lindegaard index of>3 and

moderate and >250 severe

moderate, and over 60% severe Jun 2010, AJNR Angiographic; decrease in 50% or more in diameter of vessel segment

more decrease on GCS

severe vasospasm recorded was >200 cm/s

moderate 41-60%, moderate-severe 61-80%. Severe >81% constriction

25% decrease in the vessel diameter was defined as mild, moderate

Retrospective CT angiography 0 , no vasospasm; 1, vessel narrowing less than 70%; 2, vessel narrowing greater than 70%; or 3, subtotal

Symptomatic (50% decrease in somatosensory evoked potential amplitutde, increase in somatosensory evoked potential latency or increase of greater than 150 cm/second, or clinical vasospasm by new neurological deficit or loss of two points on GCS), decrease to less than 15 mmHg in tissue oxygenation; also verified via digital subtraction

on TCD measurements alone, VMCA >120 cm/s and HR

occlusion with high-grade hemodynamic compromise

Symptomatic (delayed neuronal deficits not explained by hydrocephalus, cerebral edema, infection, or other causes)

moderate = 50% reduction, severe >50% reduction

hematoma, brain edema, or hydrocephalus)

constriction of vessel for angiographic)

TCD velocities; between 150 and 200 cm/s mild vasospasm and >200

Angiographic (mild vasospasm <50% reduction in vessel diameter,

Angiographic; <30% luminal narrowing mild, between 30 and 60%

Symptomatic (new focal neurological deficit not attributable to seizure,

Symptomatic and Angiographic (clinical, not defined greater than 50%

Symptomatic defined by onset of delayed neurological deficit with 2 or

upon admission to the hospital and an early, clinical response to initial treatment for vasospasm with improved outcomes, a treatment regimen for vasospasm is far from standardized (Charpentier et al, 1999; Frontera et al, 2010). Although treatment for vasospasm differs from hospital to hospital, most studies examining the management of vasospasm use a combination of hypervolemia, hemodilution, and hypertension (triple-H) therapy as well as the calcium channel blocker nimodipine as their first-line treatments (Frontera et al, 2009). Besides applying these two "core" therapies, recent studies have tried various combinations of endovascular therapies, such as intra-arterial papaverine and verapamil, as well as transluminal balloon angioplasty, first described by Zubkov in 1984 (Frontera et al, 2009; Zubkov et al, 1984). Despite evidence of improved outcomes from papaverine, verapamil, and angioplasty therapies, the absence of a large, prospective, multi-center, randomized, controlled trial, evaluating these treatments has prevented the creation of a gold standard protocol for treatment of vasospasm (Frontera et al, 2009; Zubkov et al, 1984).

#### **2. Definition of vasospasm**

Zubkov set the stage for investigating the endovascular treatments of vasospasm after aneurysmal subarachnoid hemorrhage. Epidemiologically, aneurysms are estimated to be present in between 1% and 9% of the population; the incidence of aSAH is around 1 per 10,000 people and increases with age and female sex (Dupont et al, 2010). While the cause of aneurysms and subsequent ruptures are not completely elucidated, risk factors for aSAH include smoking, alcohol use, cocaine use, and hypertension (Dupont et al, 2010).

Cerebral vasospasm after aSAH, macroscopically, is a contraction of smooth muscle in cerebral arteries (Al-Tamimi et al, 2010). This contraction, however, is difficult to measure and define from direct observation. From the articles reviewed, vasospasm definitions can be divided into three categories; groups have defined vasospasm by either clinical indications, Transcranial Doppler Velocity measurements, or by angiographic vessel diameter evidence. While Kaku et al. define vasospasm as a Transcranial Doppler mean flow velocity greater than 100 cm/sec or an increase of more than 30 cm/sec (Kaku et al, 1992) , Firlik et al. report vasospasm by measuring percentage stenosis through angiogram analysis (Firlik et al, 1997). Frontera et al. include a definition for vasospasm, which is defined by the development of new focal neurological symptoms or deficits after other causes have been excluded (Frontera et al, 2011). Below, Table 1 reports the variation in definitions of vasospasm used by different studies in this literature review.

#### **3. Pharmaceutical, non-endovascular treatments of vasospasm**

While studies investigating endovascular therapy for cerebral vasospasm are mostly retrospective with a small sample size, a group of prospective, randomized, controlled trials on the efficacy of non-endovascular, pharmaceutical treatment of vasospasm does exist. Recent trials have investigated the efficacy of statins, calcium channel blockers, a nonglucocorticoid aminosteroid, recombinant tissue plasminogen activator, and an endothelin receptor antagonist in vasospasm therapy. Although this review focuses on endovascular treatments for vasospasm, the future of vasospasm therapy also involves nonendovascular treatments.

Angioplasty, Various Techniques and Challenges in 106 Treatment of Congenital and Acquired Vascular Stenoses

upon admission to the hospital and an early, clinical response to initial treatment for vasospasm with improved outcomes, a treatment regimen for vasospasm is far from standardized (Charpentier et al, 1999; Frontera et al, 2010). Although treatment for vasospasm differs from hospital to hospital, most studies examining the management of vasospasm use a combination of hypervolemia, hemodilution, and hypertension (triple-H) therapy as well as the calcium channel blocker nimodipine as their first-line treatments (Frontera et al, 2009). Besides applying these two "core" therapies, recent studies have tried various combinations of endovascular therapies, such as intra-arterial papaverine and verapamil, as well as transluminal balloon angioplasty, first described by Zubkov in 1984 (Frontera et al, 2009; Zubkov et al, 1984). Despite evidence of improved outcomes from papaverine, verapamil, and angioplasty therapies, the absence of a large, prospective, multi-center, randomized, controlled trial, evaluating these treatments has prevented the creation of a gold standard protocol for treatment of vasospasm (Frontera

Zubkov set the stage for investigating the endovascular treatments of vasospasm after aneurysmal subarachnoid hemorrhage. Epidemiologically, aneurysms are estimated to be present in between 1% and 9% of the population; the incidence of aSAH is around 1 per 10,000 people and increases with age and female sex (Dupont et al, 2010). While the cause of aneurysms and subsequent ruptures are not completely elucidated, risk factors for aSAH

Cerebral vasospasm after aSAH, macroscopically, is a contraction of smooth muscle in cerebral arteries (Al-Tamimi et al, 2010). This contraction, however, is difficult to measure and define from direct observation. From the articles reviewed, vasospasm definitions can be divided into three categories; groups have defined vasospasm by either clinical indications, Transcranial Doppler Velocity measurements, or by angiographic vessel diameter evidence. While Kaku et al. define vasospasm as a Transcranial Doppler mean flow velocity greater than 100 cm/sec or an increase of more than 30 cm/sec (Kaku et al, 1992) , Firlik et al. report vasospasm by measuring percentage stenosis through angiogram analysis (Firlik et al, 1997). Frontera et al. include a definition for vasospasm, which is defined by the development of new focal neurological symptoms or deficits after other causes have been excluded (Frontera et al, 2011). Below, Table 1 reports the variation in

While studies investigating endovascular therapy for cerebral vasospasm are mostly retrospective with a small sample size, a group of prospective, randomized, controlled trials on the efficacy of non-endovascular, pharmaceutical treatment of vasospasm does exist. Recent trials have investigated the efficacy of statins, calcium channel blockers, a nonglucocorticoid aminosteroid, recombinant tissue plasminogen activator, and an endothelin receptor antagonist in vasospasm therapy. Although this review focuses on endovascular treatments for vasospasm, the future of vasospasm therapy also involves non-

include smoking, alcohol use, cocaine use, and hypertension (Dupont et al, 2010).

definitions of vasospasm used by different studies in this literature review.

**3. Pharmaceutical, non-endovascular treatments of vasospasm** 

et al, 2009; Zubkov et al, 1984).

**2. Definition of vasospasm** 

endovascular treatments.


Table 1.

Evidence-Based Invasive Treatments for Cerebral

**e. Fibrinolytic therapy** 

cerebral vasospasm.

Vasospasm Following Aneurysmal Subarachnoid Hemorrhage 109

vasoconstrictor possibly increased after aSAH (Macdonald et al, 2008) and its pathway to vasoconstriction have been investigated for possible targets in the treatment of vasospasm. Specifically, Macdonald et al. looked at the efficacy of the endothelin receptor antagonist, clazosentan, in the prospective, randomized, double-blind, placebo-controlled CONSCIOUS-1 trial. While Macdonald et al. report no significant difference between the treatment and control groups with respect to morbidity and mortality, they find a reduction of moderate or severe vasospasm from 66% in the placebo group to 23% in the highest dosage treatment group (Macdonald et al, 2008). Complications associated with clazosentan administration included anemia, hypotension and pulmonary issues including pneumonia, pleural effusions, pulmonary edema, and acute respiratory distress syndrome. The results of the CONSCIOUS-1 trial point to the disconnect between vasospasm and clinical outcome. While Macdonald et al. report a decrease in vasospasm from digital subtraction angiography after treatment, they find no effect on morbidity and mortality (Macdonald et al, 2008). Like other studies in this review of the literature, this trial calls for further

exploration in the connection between vasospasm and clinical consequences.

The correlation between subarachnoid clot thickness and degree of vasospasm led to the possibility of fibrinolytic therapy in the treatment of cerebral vasospasm. In a prospective, randomized, blinded, placebo-controlled trial by Findlay, the efficacy of intracisternal, recombinant tissue plasminogen activator for prevention of vasospasm was investigated with angiographic vasospasm serving as the primary endpoint (Findlay, 1995) Although Findlay reports angiographic vasospasm in 74.4% of placebo patients and 64.6% of treatment patients, the difference between the two groups was not statistically significant (P=.31) An interesting, significant finding from the same study comes from the treatment of patients with thick subarachnoid clots. In this group, Findlay finds a 56% relative risk reduction of severe vasospasm in the treatment group, suggesting a very specific indication for treatment with recombinant tissue plasminogen activator. While Findlay also reports a pattern of lower mean velocities on transcranial Doppler, reduced delayed neurological worsening, a lower 14 day mortality rate, and improved 3 month outcome in the treatment group, none of these findings was statistically significant (Findlay, 1995). As with all fibrinolytic treatment, the possibility of treatment associated hemorrhage presents as a risk. While these studies, investigating the efficacy of pharmaceutical, non-endovascular treatments of vasospasm, are well-designed and have promising results, future larger scale, multi-center trials, with mortality serving as a primary outcome measure, would help determine which therapies should be added to the standard protocol for treatment of

**4. Current institutional protocols for treatment of aSAH and vasospasm** 

While a standard of care has not been completely established for the treatment of cerebral vasospasm, common themes are ubiquitous throughout a review of the literature. After diagnosis of aSAH, the following treatment can be divided into two sections, common to most recent studies. The first part of therapy involves stabilizing the patient's aSAH while the second focuses on the prevention or management of cerebral vasospasm. Before cerebral vasospasm is even considered, the aSAH is ideally treated surgically by either endovascular coiling or clipping. However, the timing of surgery, similar to the definition of cerebral vasospasm, has not been completely standardized. While Choi et al.'s protocol (Choi et al,

#### **a. Statin therapy**

The statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, have been theorized to have a protective role in the development of cerebral vasospasm. In addition to inhibiting the synthesis of cholesterol, statins are also thought to regulate endothelial and nitric oxide synthase function (Al-Tamimi et al, 2010), and therefore might affect the spasticity of the cerebral vasculature. Two statins, specifically simvastatin and pravastatin, have been investigated in randomized, placebo-controlled, trials. The results on simvastatin treatment of cerebral vasospasm have been mixed. While Vergouwen et al. find that simvastatin treatment provided no improvement on TCD-defined vasospasm (Vergouwen et al, 2009), Chou et al. report that angiographic vasospasm was present in 5/19 patients treated with simvastatin compared with 8/20 patients given a placebo (Chou et al, 2008). No differences, however, are statistically significant. In their meta-analysis, Etminan et al. include only 190 patients and find this number to be too small to make conclusions about the efficacy of statin therapy (Etminan et al, 2011).

#### **b. Calcium antagonist therapy**

Nimodipine, a calcium antagonist and part of the current standard of care for treatment of cerebral vasospasm, inhibits calcium entry. However, other pathways exist within the cell that affect calcium utilization and also serve as possible targets for the treatment of vasospasm. In a prospective, randomized, placebo-controlled, double-blind trial, Shibuya et al. investigated the efficacy of AT877, an inhibitor of myosin light-chain kinase, of protein kinases A,G, and C, and of the actions of free intracellular calcium ions (Shibuya et al, 1992). With intravenous therapy of AT877, Shibuya et al. report a statistically significant reduction of angiographic vasospasm by 38% as well as a reduction in symptomatic vasospasm by 30%. Clinically, Shibuya et al. find AT877's effect on outcomes to be similar to nimodipine's; the article reports a significant reduction in poor outcomes associated with vasospasm by 54% and finds no significant adverse side effects (Shibuya et al, 1992). A possible downside of treatment with AT877 is its short half-life. Although Shibuya et al. report that AT877's metabolite still shows spasmolytic qualities, the parent compound has an estimated half-life of under fifteen minutes.

#### **c. Treatment with tirilizad mesylate**

In response to the possible connection between free radical-induced lipid peroxidation and vasospasm, the 21 aminosteroid, tirilazad meslyate, was created to inhibit this pathway (Kassell et al, 1996). In a prospective, randomized, double-blind, controlled trial of 1023 patients, Kassell et al. investigated the efficacy of tirilazad mesylate, using symptomatic vasospasm and Glasgow Outcome Scale scores at three months as outcome measures. Although Kassell et al. do not report a statistically significant reduction in symptomatic vasospasm with aSAH after treatment with tirilazad mesylate, they argue for the presence (p=.048) of a decrease in vasospasm at higher doses of tirilazad mesylate. The most promising statistics from this article, however, concern the three month outcomes for patients in the treatment group. Kassell et al. report in the highest dosage of tirilazad mesylate, 63% of patients had a good recovery, compared to 53% of the vehicle treated group (Kassell et al, 1996). This difference was statistically significant. Despite minor injection site phlebitis, tirilazad mesylate was not associated with life-threatening or adverse medical events.

#### **d. Endothelin receptor antagonist therapy**

Systemic vasoconstriction is controlled by many physiological hormones, including adrenergic agonists, angiotensin II, and antidiuretic hormone. Endothelin, a powerful vasoconstrictor possibly increased after aSAH (Macdonald et al, 2008) and its pathway to vasoconstriction have been investigated for possible targets in the treatment of vasospasm. Specifically, Macdonald et al. looked at the efficacy of the endothelin receptor antagonist, clazosentan, in the prospective, randomized, double-blind, placebo-controlled CONSCIOUS-1 trial. While Macdonald et al. report no significant difference between the treatment and control groups with respect to morbidity and mortality, they find a reduction of moderate or severe vasospasm from 66% in the placebo group to 23% in the highest dosage treatment group (Macdonald et al, 2008). Complications associated with clazosentan administration included anemia, hypotension and pulmonary issues including pneumonia, pleural effusions, pulmonary edema, and acute respiratory distress syndrome. The results of the CONSCIOUS-1 trial point to the disconnect between vasospasm and clinical outcome. While Macdonald et al. report a decrease in vasospasm from digital subtraction angiography after treatment, they find no effect on morbidity and mortality (Macdonald et al, 2008). Like other studies in this review of the literature, this trial calls for further exploration in the connection between vasospasm and clinical consequences.

#### **e. Fibrinolytic therapy**

Angioplasty, Various Techniques and Challenges in 108 Treatment of Congenital and Acquired Vascular Stenoses

The statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, have been theorized to have a protective role in the development of cerebral vasospasm. In addition to inhibiting the synthesis of cholesterol, statins are also thought to regulate endothelial and nitric oxide synthase function (Al-Tamimi et al, 2010), and therefore might affect the spasticity of the cerebral vasculature. Two statins, specifically simvastatin and pravastatin, have been investigated in randomized, placebo-controlled, trials. The results on simvastatin treatment of cerebral vasospasm have been mixed. While Vergouwen et al. find that simvastatin treatment provided no improvement on TCD-defined vasospasm (Vergouwen et al, 2009), Chou et al. report that angiographic vasospasm was present in 5/19 patients treated with simvastatin compared with 8/20 patients given a placebo (Chou et al, 2008). No differences, however, are statistically significant. In their meta-analysis, Etminan et al. include only 190 patients and find this number to be too small to make

Nimodipine, a calcium antagonist and part of the current standard of care for treatment of cerebral vasospasm, inhibits calcium entry. However, other pathways exist within the cell that affect calcium utilization and also serve as possible targets for the treatment of vasospasm. In a prospective, randomized, placebo-controlled, double-blind trial, Shibuya et al. investigated the efficacy of AT877, an inhibitor of myosin light-chain kinase, of protein kinases A,G, and C, and of the actions of free intracellular calcium ions (Shibuya et al, 1992). With intravenous therapy of AT877, Shibuya et al. report a statistically significant reduction of angiographic vasospasm by 38% as well as a reduction in symptomatic vasospasm by 30%. Clinically, Shibuya et al. find AT877's effect on outcomes to be similar to nimodipine's; the article reports a significant reduction in poor outcomes associated with vasospasm by 54% and finds no significant adverse side effects (Shibuya et al, 1992). A possible downside of treatment with AT877 is its short half-life. Although Shibuya et al. report that AT877's metabolite still shows spasmolytic qualities, the parent compound has an estimated half-life

In response to the possible connection between free radical-induced lipid peroxidation and vasospasm, the 21 aminosteroid, tirilazad meslyate, was created to inhibit this pathway (Kassell et al, 1996). In a prospective, randomized, double-blind, controlled trial of 1023 patients, Kassell et al. investigated the efficacy of tirilazad mesylate, using symptomatic vasospasm and Glasgow Outcome Scale scores at three months as outcome measures. Although Kassell et al. do not report a statistically significant reduction in symptomatic vasospasm with aSAH after treatment with tirilazad mesylate, they argue for the presence (p=.048) of a decrease in vasospasm at higher doses of tirilazad mesylate. The most promising statistics from this article, however, concern the three month outcomes for patients in the treatment group. Kassell et al. report in the highest dosage of tirilazad mesylate, 63% of patients had a good recovery, compared to 53% of the vehicle treated group (Kassell et al, 1996). This difference was statistically significant. Despite minor injection site phlebitis, tirilazad mesylate was not associated with life-threatening or adverse

Systemic vasoconstriction is controlled by many physiological hormones, including adrenergic agonists, angiotensin II, and antidiuretic hormone. Endothelin, a powerful

conclusions about the efficacy of statin therapy (Etminan et al, 2011).

**a. Statin therapy** 

**b. Calcium antagonist therapy** 

of under fifteen minutes.

medical events.

**c. Treatment with tirilizad mesylate** 

**d. Endothelin receptor antagonist therapy** 

The correlation between subarachnoid clot thickness and degree of vasospasm led to the possibility of fibrinolytic therapy in the treatment of cerebral vasospasm. In a prospective, randomized, blinded, placebo-controlled trial by Findlay, the efficacy of intracisternal, recombinant tissue plasminogen activator for prevention of vasospasm was investigated with angiographic vasospasm serving as the primary endpoint (Findlay, 1995) Although Findlay reports angiographic vasospasm in 74.4% of placebo patients and 64.6% of treatment patients, the difference between the two groups was not statistically significant (P=.31) An interesting, significant finding from the same study comes from the treatment of patients with thick subarachnoid clots. In this group, Findlay finds a 56% relative risk reduction of severe vasospasm in the treatment group, suggesting a very specific indication for treatment with recombinant tissue plasminogen activator. While Findlay also reports a pattern of lower mean velocities on transcranial Doppler, reduced delayed neurological worsening, a lower 14 day mortality rate, and improved 3 month outcome in the treatment group, none of these findings was statistically significant (Findlay, 1995). As with all fibrinolytic treatment, the possibility of treatment associated hemorrhage presents as a risk. While these studies, investigating the efficacy of pharmaceutical, non-endovascular treatments of vasospasm, are well-designed and have promising results, future larger scale,

multi-center trials, with mortality serving as a primary outcome measure, would help determine which therapies should be added to the standard protocol for treatment of cerebral vasospasm.

#### **4. Current institutional protocols for treatment of aSAH and vasospasm**

While a standard of care has not been completely established for the treatment of cerebral vasospasm, common themes are ubiquitous throughout a review of the literature. After diagnosis of aSAH, the following treatment can be divided into two sections, common to most recent studies. The first part of therapy involves stabilizing the patient's aSAH while the second focuses on the prevention or management of cerebral vasospasm. Before cerebral vasospasm is even considered, the aSAH is ideally treated surgically by either endovascular coiling or clipping. However, the timing of surgery, similar to the definition of cerebral vasospasm, has not been completely standardized. While Choi et al.'s protocol (Choi et al,

Evidence-Based Invasive Treatments for Cerebral

**5. Experimental endovascular treatments for vasospasm** 

papaverine, or transluminal balloon angioplasty of the affected vessels.

the ACA and MCA to deliver medical therapy (Jun et al, 2010).

dosage protocols across studies in this literature review.

papaverine use is widely accepted as treatment for vasospasm. **b. Angioplasty for cerebral vasospasm and its efficacy** 

**a. Intra-arterial medical treatment and its efficacy** 

Vasospasm Following Aneurysmal Subarachnoid Hemorrhage 111

Besides medical therapy with intravenous or oral nimodipine and Triple-H therapy, cerebral vasospasm after aSAH, has been experimentally treated with methods that are theoretically sound. While nitric oxide donors, phosphodiesterase inhibitors, endothelin antogonists, statins, and magnesium (Weant et al, 2010; Fathi et al, 2001; Shankar et al, 2011) have all been investigated for treating cerebral vasospasm through expected vasodilatory effects, the focus of current endovascular studies has predominantly remained on intra-arterial medical therapy with the calcium channel antagonist ,verapamil ,or the posphodiesterase inhibtor,

The methods of administering intra-arterial medical therapy differ slightly from group to group and depend on the specific article from the review of the literature. A representative technique, however, is described by Feng et al . A 5F or 6F guiding catheter is used to infuse the specified drug in the internal carotid or vertebral arteries. With this technique, the physician hopes to deliver medical therapy to the spastic vessels (Feng et al, 2002). Some groups, such as Jun et al., report a slightly different protocol if severe vasospasm is present in the ACA or MCA.; they describe using a microcatheter to reach the spastic portions of

Although most studies evaluating the efficacy of intra-arterial medical therapy and angioplasty are retrospective with a relatively small sample size, they do show some promise in the treatment of cerebral vasospasm. While Kaku et al. report an improvement in neurological function in 80% of patients treated with intra-arterial papaverine (Kaku et al, 1992), Keuskamp et al. describe a median reduction of 2 units on their vasospasm scale after treatment with intra-arterial verapamil (Keuskamp et al, 2008). However, the data on intraarterial medical treatment of cerebral vasospasm are not completely straightforward; Coenen et al. report that the benefits from intra-arterial papaverine administration are neither reliable nor sustained. Another problem that arises in comparing studies, evaluating the efficacy of intra-arterial medical treatment, is the dosage of drug administered (Coenen et al, 1998). While Kassell et. al use 100-300 mg of papaverine in their protocol (Kassell et al, 1992) , Firlik et al. report using between 300 and 600 mg of the same drug (Firlik et al, 1997). It is difficult to generalize the efficacy of intra-arterial medical therapy given the variety of

However, intra-arterial treatment of cerebral vasospasm does not come without risk. Investigating the risks of intra-arterial verapamil infusion and papaverine therapy respectively, Feng et al. and Keuskamp et al. find no significant changes in intracranial pressure, heart rate, or hemodynamic parameters after intra-arterial treatment (Feng et al, 2002; Keuskamp et al, 2008). These are not the only parameters, however, by which safety of intra-arterial therapies should be assessed. Intra-arterial administration of papaverine and verapamil have both been associated with case reports of seizures (Zubkov et al, 1984) while papaverine alone has been linked to aphasia, mental status changes, and even respiratory arrest. On the cellular level, papaverine might also adversely affect neuronal mitochondrial respiration (Weant et al, 2010). Although Feng et al. and Keuskamp et al. report that intraarterial therapy is safe, further research should be conducted before verapamil or

Beginning in 1984, the treatment of cerebral vasospasm after aSAH came to include the physical dilation of cerebral arteries using transluminal balloon angioplasty. The original

2011) calls for surgery within twenty four hours of the aSAH, Murai et al. include patients whose aneurysms had been clipped or coiled within forty eight hours of aSAH (Murai et al, 2005). After the subarachnoid hemorrhage has been managed surgically, the goal of therapy begins to focus on the treatment of cerebral vasospasm.

Typically after surgery today, patients are then treated with oral nimodipine and a combination of induced hypertension, hemodilution, and volume expansion ("Triple-H") therapy to minimize the effects of cerebral vasospasm (Komotar et al, 2008). Nimodipine, a dihydropyridine calcium channel blocker, which blocks L-type, slow conducting, voltagedependent, calcium channels, has been shown to reduce cerebral infarction, when compared to untreated patients (Weant et al, 2010) , while triple-H therapy focuses on maintaining high cerebral perfusion pressures to increase cerebral blood flow during vasospasm (Komotar et al, 2008).

These treatments, however, are not applied without controversy. With Triple-H therapy comes the risk of possible organ damage, pulmonary edema, and organ ischemia. On the other hand, the use of nimodipine in the treatment of cerebral vasospasm has raised questions about the connection between cerebral vasospasm and poor outcomes. Mechanistically, the administration of a calcium channel blocker "makes sense"; prevention of an increasing concentration of intracellular calcium should reduce smooth muscle contraction within the cerebral vasculature.

While Pickard et al. do report a significant reduction in cerebral infarction events in those treated with nimodipine after aSAH (Pickard et al, 1989), they do not find a change in Transcranial Doppler Velocities between those treated and the controls. It has been suggested that antithrombotic actions of nimodipine might be responsible for its therapeutic effects (Weant et al, 2010). Nimodpine's clinical benefits without changing Transcranial Doppler Velocities suggests that vasospasm may be correlated with adverse clinical outcomes but may not cause them. Similarly, Frontera et al. report that a Transcranial Doppler Velocity greater than 120 cm/sec, a measurement indicative of vasospasm, is not necessarily a predictor of clinical outcome (Frontera et al, 2009). A recent meta-analysis by Etminan et al., investigating the efficacy of pharmaceutical treatment on delayed cerebral ischemia (DCI), also reported a decrease in radiographic vasospasm without clinical benefit (Etminan et al, 2011). The exact relationship between vasospasm and clinical outcome must still be fully elucidated.

Although nimodipine and Triple-H therapy have been shown to improve clinical outcome, even administration of these therapies are not standardized. While Zweinenberg-Lee et al. report a protocol (Zwienenberg-Lee et al, 2008) of maintaining hematocrit levels between 30- 35%, Oskouian et al.'s protocol (Oskouian et al, 2002) calls for a target of 31-35%. Similarly, across these studies on the treatment of vasospasm, a common, unifying goal of hypertensive therapy is not present. Rosenwasser et al. report elevating mean arterial pressure to 130-140 mm Hg (Rosenwasser et al, 1999), while Oskouian et al. present a protocol calling for a perfusion pressure of 70 mm Hg (Oskouian et al, 2002) and Coyne et al. report a maintenance level of 240 mm Hg for systolic blood pressure (Coyne et al, 1994). The methods to achieve high levels of cerebral blood flow and hypertension are also not standardized. While Keuskamp et al. report using neosynephrine, ephedrine, and dopamine in their triple-H therapy (Keuskamp et al, 2008), Murai et al. use dobutamine alone (Murai et al, 2005). Therefore, the current "gold standard," a combination of Triple-H therapy and nimodipine, is not uniformly executed.

Angioplasty, Various Techniques and Challenges in 110 Treatment of Congenital and Acquired Vascular Stenoses

2011) calls for surgery within twenty four hours of the aSAH, Murai et al. include patients whose aneurysms had been clipped or coiled within forty eight hours of aSAH (Murai et al, 2005). After the subarachnoid hemorrhage has been managed surgically, the goal of therapy

Typically after surgery today, patients are then treated with oral nimodipine and a combination of induced hypertension, hemodilution, and volume expansion ("Triple-H") therapy to minimize the effects of cerebral vasospasm (Komotar et al, 2008). Nimodipine, a dihydropyridine calcium channel blocker, which blocks L-type, slow conducting, voltagedependent, calcium channels, has been shown to reduce cerebral infarction, when compared to untreated patients (Weant et al, 2010) , while triple-H therapy focuses on maintaining high cerebral perfusion pressures to increase cerebral blood flow during vasospasm

These treatments, however, are not applied without controversy. With Triple-H therapy comes the risk of possible organ damage, pulmonary edema, and organ ischemia. On the other hand, the use of nimodipine in the treatment of cerebral vasospasm has raised questions about the connection between cerebral vasospasm and poor outcomes. Mechanistically, the administration of a calcium channel blocker "makes sense"; prevention of an increasing concentration of intracellular calcium should reduce smooth muscle

While Pickard et al. do report a significant reduction in cerebral infarction events in those treated with nimodipine after aSAH (Pickard et al, 1989), they do not find a change in Transcranial Doppler Velocities between those treated and the controls. It has been suggested that antithrombotic actions of nimodipine might be responsible for its therapeutic effects (Weant et al, 2010). Nimodpine's clinical benefits without changing Transcranial Doppler Velocities suggests that vasospasm may be correlated with adverse clinical outcomes but may not cause them. Similarly, Frontera et al. report that a Transcranial Doppler Velocity greater than 120 cm/sec, a measurement indicative of vasospasm, is not necessarily a predictor of clinical outcome (Frontera et al, 2009). A recent meta-analysis by Etminan et al., investigating the efficacy of pharmaceutical treatment on delayed cerebral ischemia (DCI), also reported a decrease in radiographic vasospasm without clinical benefit (Etminan et al, 2011). The exact relationship between vasospasm and clinical outcome must

Although nimodipine and Triple-H therapy have been shown to improve clinical outcome, even administration of these therapies are not standardized. While Zweinenberg-Lee et al. report a protocol (Zwienenberg-Lee et al, 2008) of maintaining hematocrit levels between 30- 35%, Oskouian et al.'s protocol (Oskouian et al, 2002) calls for a target of 31-35%. Similarly, across these studies on the treatment of vasospasm, a common, unifying goal of hypertensive therapy is not present. Rosenwasser et al. report elevating mean arterial pressure to 130-140 mm Hg (Rosenwasser et al, 1999), while Oskouian et al. present a protocol calling for a perfusion pressure of 70 mm Hg (Oskouian et al, 2002) and Coyne et al. report a maintenance level of 240 mm Hg for systolic blood pressure (Coyne et al, 1994). The methods to achieve high levels of cerebral blood flow and hypertension are also not standardized. While Keuskamp et al. report using neosynephrine, ephedrine, and dopamine in their triple-H therapy (Keuskamp et al, 2008), Murai et al. use dobutamine alone (Murai et al, 2005). Therefore, the current "gold standard," a combination of Triple-H

begins to focus on the treatment of cerebral vasospasm.

contraction within the cerebral vasculature.

therapy and nimodipine, is not uniformly executed.

(Komotar et al, 2008).

still be fully elucidated.

#### **5. Experimental endovascular treatments for vasospasm**

Besides medical therapy with intravenous or oral nimodipine and Triple-H therapy, cerebral vasospasm after aSAH, has been experimentally treated with methods that are theoretically sound. While nitric oxide donors, phosphodiesterase inhibitors, endothelin antogonists, statins, and magnesium (Weant et al, 2010; Fathi et al, 2001; Shankar et al, 2011) have all been investigated for treating cerebral vasospasm through expected vasodilatory effects, the focus of current endovascular studies has predominantly remained on intra-arterial medical therapy with the calcium channel antagonist ,verapamil ,or the posphodiesterase inhibtor, papaverine, or transluminal balloon angioplasty of the affected vessels.

#### **a. Intra-arterial medical treatment and its efficacy**

The methods of administering intra-arterial medical therapy differ slightly from group to group and depend on the specific article from the review of the literature. A representative technique, however, is described by Feng et al . A 5F or 6F guiding catheter is used to infuse the specified drug in the internal carotid or vertebral arteries. With this technique, the physician hopes to deliver medical therapy to the spastic vessels (Feng et al, 2002). Some groups, such as Jun et al., report a slightly different protocol if severe vasospasm is present in the ACA or MCA.; they describe using a microcatheter to reach the spastic portions of the ACA and MCA to deliver medical therapy (Jun et al, 2010).

Although most studies evaluating the efficacy of intra-arterial medical therapy and angioplasty are retrospective with a relatively small sample size, they do show some promise in the treatment of cerebral vasospasm. While Kaku et al. report an improvement in neurological function in 80% of patients treated with intra-arterial papaverine (Kaku et al, 1992), Keuskamp et al. describe a median reduction of 2 units on their vasospasm scale after treatment with intra-arterial verapamil (Keuskamp et al, 2008). However, the data on intraarterial medical treatment of cerebral vasospasm are not completely straightforward; Coenen et al. report that the benefits from intra-arterial papaverine administration are neither reliable nor sustained. Another problem that arises in comparing studies, evaluating the efficacy of intra-arterial medical treatment, is the dosage of drug administered (Coenen et al, 1998). While Kassell et. al use 100-300 mg of papaverine in their protocol (Kassell et al, 1992) , Firlik et al. report using between 300 and 600 mg of the same drug (Firlik et al, 1997). It is difficult to generalize the efficacy of intra-arterial medical therapy given the variety of dosage protocols across studies in this literature review.

However, intra-arterial treatment of cerebral vasospasm does not come without risk. Investigating the risks of intra-arterial verapamil infusion and papaverine therapy respectively, Feng et al. and Keuskamp et al. find no significant changes in intracranial pressure, heart rate, or hemodynamic parameters after intra-arterial treatment (Feng et al, 2002; Keuskamp et al, 2008). These are not the only parameters, however, by which safety of intra-arterial therapies should be assessed. Intra-arterial administration of papaverine and verapamil have both been associated with case reports of seizures (Zubkov et al, 1984) while papaverine alone has been linked to aphasia, mental status changes, and even respiratory arrest. On the cellular level, papaverine might also adversely affect neuronal mitochondrial respiration (Weant et al, 2010). Although Feng et al. and Keuskamp et al. report that intraarterial therapy is safe, further research should be conducted before verapamil or papaverine use is widely accepted as treatment for vasospasm.

#### **b. Angioplasty for cerebral vasospasm and its efficacy**

Beginning in 1984, the treatment of cerebral vasospasm after aSAH came to include the physical dilation of cerebral arteries using transluminal balloon angioplasty. The original

Evidence-Based Invasive Treatments for Cerebral

arterial medical therapy in the same treatment.

Vasospasm Following Aneurysmal Subarachnoid Hemorrhage 113

results. Elliott et al. report a favorable clinical outcome in 67% of patients after angioplasty compared with a 62% favorable outcome after treatment with papaverine (Elliott et al, 1998), while Katoh et al. report a 58% clinical improvement after angioplasty compared with a 25% improvement after papaverine (Katoh et al, 1999). Elliiott et al. also report an increase in Transcranial Doppler velocities on Day 2 after treatment with papaverine, suggesting an absence of sustainable effect from the papaverine (Elliott et al, 1998). Although these studies suggest that angioplasty is a more effective endovascular treatment for cerebral vasospasm, the data are not all one-sided. Coenen et al. report that both angioplasty and papaverine are equivalently ineffective in producing reliable and sustained results (Coenen et al, 1998). Theoretically, an interesting procedure would be combining both angioplasty and intra-

**d. Combination therapy with angioplasty and intra-arterial medical treatment** 

combinations of medical endovascular treatment with angioplasty.

accessible arteries where a large risk of rupture is present.

from several groups, reviewed in the literature.

**7. Recommendations for invasive treatments** 

**6. Limitations to efficacy comparisons across studies** 

Since it is believed that angioplasty in smaller, more distal vessels, is too risky, it is logical that a combination of intra-arterial medical treatment with angioplasty might be effective in treating both proximal and distal cerebral vasospasm. In a retrospective study by Frontera et al. the group compares combined therapy with chemical vasodilation alone. Frontera et al. find that while 39% of patients undergoing combination therapy developed recurrent angiographic and symptomatic vasospasm, 82% of patients receiving chemical vasodilation, alone, developed vasospasm (Frontera et al, 2011). Future, large-scaled and multicenter trials on the efficacy of combination therapy should help elucidate the most effective

Amongst these experimental, endovascular treatments, angioplasty seems beneficial for the larger, more proximal, and more accessible cerebral vessels while treatment with intraarterial papaverine and verapamil is more appropriate for smaller, more distal, and less

However, problems with these studies, investigating the efficacy of experimental treatments for cerebral vasospasm, do exist. The small sample sizes and retrospective nature of a vast majority of these studies make it difficult to establish definitive conclusions with respect to efficacy of different endovascular treatments. Also, the criteria to begin endovascular treatment differ from group to group. For example, while Bejjani et al report treating vasospasm with angioplasty only after Triple-H therapy has failed (Bejjani et al, 1998) , Santillan et al. use a decrease in vessel diameter via angiography as one if their indications for treatment (Santillan et al, 2011). Therefore, constructing a meta-analysis, combining the results of these studies, is difficult as different groups make their own decisions about when to treat patients endovascularly. Table 2, below, lists the criteria to treat cerebral vasospasm,

Although most experimental studies investigating the efficacy of invasive treatments for cerebral vasospasm after aSAH are retrospective in nature, effective patterns can be extracted from these studies. From the studies in this literature review, it appears that Triple-H therapy combined with administration of nimodipine is the first line of treatment or prevention of cerebral vasospasm. Once the vasospasm is deemed refractory to this

technique of angioplasty, described by Zubkov et al., involved puncturing the common carotid artery and placing a balloon catheter in the internal carotid artery. In an X-ray room, the balloon catheter was then repetitively inflated and deflated in the proximal part of the affected artery. This procedure then continued distally and after this technique, cerebral blood flow was monitored with a Xe-133 administration (Zubkov et al, 1984).

Since Zubkov's original paper, the actual technique of angioplasty has progressed at a relatively slow rate; today, angioplasty very much resembles the original procedure performed by Zubkov, including the repetitive inflation-deflation cycles. Similar to the description of intra-arterial medical treatment for vasospasm, the current techniques of angioplasty differ slightly from group to group and depend on the specific article from the literature. A representative method of angioplasty for cerebral vasospasm is described by Jun et al (Jun et al, 2010). In this study, Jun et al. report intravenous heparinization prior to angioplasty. Unlike Zubkov et al., they begin treating the distal portions of the spastic artery before the proximal portions. Although angioplasty for cerebral vasospasm has shown promise with respect to clinical outcomes, the technique is not without limitations. Terada et al. and Jun et al. both exclude smaller, distal cerebral arteries as targets of treatment with angioplasty for fear of vessel rupture (Terada et al, 1997; Jun et al, 2010). While each group "sets their own limits" with respect to the smallest vessel they will treat with angioplasty, Jun et al. report treating vasospasm in the supraclinoid ICA, M1 MCA, A1 ACA, intracranial vertebral artery, basilar artery, and P1 PCA (so called "proximal vessels"), while they find treatment of M2 MCA, A2 ACA, P2 PCA (so called "distal vessels") to be too risky (Jun et al, 2010). With every procedure comes the possibility of complications. While the risks of mechanical dilation of spastic cerebral vessels by transluminal angioplasty are lessened by a skilled physician, they are still present. Vessel rupture, thrombosis, and occlusion are possible complications during the angioplasty procedure (Weant et al, 2010).

Since Zubkov's paper, studies have investigated the efficacy of his technique. Overall, the results of cerebral angioplasty have been promising; in a 50 patient pilot study, Eskridge et al. report a 61% sustained neurological improvement after angioplasty (Eskridge et al, 1998). Although most studies in this literature review look positively upon angioplasty for cerebral vasospasm, not all trials have proven to be efficacious. While Fujii et al. and Eskridge et al., respectively, describe an 83% increase in diameters of affected cerebral arteries (Fujii et al, 1995) and a 73% recovery in patients experiencing focal neurological deficits after treatment (Eskridge et al, 1990), Coenen et al. find angioplasty to be an unreliable method of treating cerebral vasospasm. Similar to other conclusions made in this literature review, the results of these retrospective angioplasty trials do not provide a straightforward judgment on its efficacy (Coenen et al, 1998).

Once again, comparing these studies, which assess the efficacy of angioplasty for cerebral vasospasm, is difficult given the absence of standardization of the procedure. One difference, amongst groups, lies in the type and size of balloon used during angioplasty. For example, while Eskridge et al. use a 3 mm. x 12 mm. silicone balloon from Target Therapeutics (Eskridge et al, 1998) , Bejjani et al. report using a 3.5 mm. Cirrus balloon (Bejjani et al, 1998). While these differences might not practically affect the procedure or its results, they should be considered when evaluating the efficacy of this technique.

#### **c. Comparison of angioplasty with intra-arterial medical therapy**

Although retrospectively, the efficacy of intra-arterial medical therapy and angioplasty for vasospasm have been compared. Similar to the studies on the efficacy of both of these modes of treatment, the groups comparing these two therapies have produced mixed Angioplasty, Various Techniques and Challenges in 112 Treatment of Congenital and Acquired Vascular Stenoses

technique of angioplasty, described by Zubkov et al., involved puncturing the common carotid artery and placing a balloon catheter in the internal carotid artery. In an X-ray room, the balloon catheter was then repetitively inflated and deflated in the proximal part of the affected artery. This procedure then continued distally and after this technique, cerebral

Since Zubkov's original paper, the actual technique of angioplasty has progressed at a relatively slow rate; today, angioplasty very much resembles the original procedure performed by Zubkov, including the repetitive inflation-deflation cycles. Similar to the description of intra-arterial medical treatment for vasospasm, the current techniques of angioplasty differ slightly from group to group and depend on the specific article from the literature. A representative method of angioplasty for cerebral vasospasm is described by Jun et al (Jun et al, 2010). In this study, Jun et al. report intravenous heparinization prior to angioplasty. Unlike Zubkov et al., they begin treating the distal portions of the spastic artery before the proximal portions. Although angioplasty for cerebral vasospasm has shown promise with respect to clinical outcomes, the technique is not without limitations. Terada et al. and Jun et al. both exclude smaller, distal cerebral arteries as targets of treatment with angioplasty for fear of vessel rupture (Terada et al, 1997; Jun et al, 2010). While each group "sets their own limits" with respect to the smallest vessel they will treat with angioplasty, Jun et al. report treating vasospasm in the supraclinoid ICA, M1 MCA, A1 ACA, intracranial vertebral artery, basilar artery, and P1 PCA (so called "proximal vessels"), while they find treatment of M2 MCA, A2 ACA, P2 PCA (so called "distal vessels") to be too risky (Jun et al, 2010). With every procedure comes the possibility of complications. While the risks of mechanical dilation of spastic cerebral vessels by transluminal angioplasty are lessened by a skilled physician, they are still present. Vessel rupture, thrombosis, and occlusion are

blood flow was monitored with a Xe-133 administration (Zubkov et al, 1984).

possible complications during the angioplasty procedure (Weant et al, 2010).

efficacy (Coenen et al, 1998).

Since Zubkov's paper, studies have investigated the efficacy of his technique. Overall, the results of cerebral angioplasty have been promising; in a 50 patient pilot study, Eskridge et al. report a 61% sustained neurological improvement after angioplasty (Eskridge et al, 1998). Although most studies in this literature review look positively upon angioplasty for cerebral vasospasm, not all trials have proven to be efficacious. While Fujii et al. and Eskridge et al., respectively, describe an 83% increase in diameters of affected cerebral arteries (Fujii et al, 1995) and a 73% recovery in patients experiencing focal neurological deficits after treatment (Eskridge et al, 1990), Coenen et al. find angioplasty to be an unreliable method of treating cerebral vasospasm. Similar to other conclusions made in this literature review, the results of these retrospective angioplasty trials do not provide a straightforward judgment on its

Once again, comparing these studies, which assess the efficacy of angioplasty for cerebral vasospasm, is difficult given the absence of standardization of the procedure. One difference, amongst groups, lies in the type and size of balloon used during angioplasty. For example, while Eskridge et al. use a 3 mm. x 12 mm. silicone balloon from Target Therapeutics (Eskridge et al, 1998) , Bejjani et al. report using a 3.5 mm. Cirrus balloon (Bejjani et al, 1998). While these differences might not practically affect the procedure or its

Although retrospectively, the efficacy of intra-arterial medical therapy and angioplasty for vasospasm have been compared. Similar to the studies on the efficacy of both of these modes of treatment, the groups comparing these two therapies have produced mixed

results, they should be considered when evaluating the efficacy of this technique.

**c. Comparison of angioplasty with intra-arterial medical therapy** 

results. Elliott et al. report a favorable clinical outcome in 67% of patients after angioplasty compared with a 62% favorable outcome after treatment with papaverine (Elliott et al, 1998), while Katoh et al. report a 58% clinical improvement after angioplasty compared with a 25% improvement after papaverine (Katoh et al, 1999). Elliiott et al. also report an increase in Transcranial Doppler velocities on Day 2 after treatment with papaverine, suggesting an absence of sustainable effect from the papaverine (Elliott et al, 1998). Although these studies suggest that angioplasty is a more effective endovascular treatment for cerebral vasospasm, the data are not all one-sided. Coenen et al. report that both angioplasty and papaverine are equivalently ineffective in producing reliable and sustained results (Coenen et al, 1998). Theoretically, an interesting procedure would be combining both angioplasty and intraarterial medical therapy in the same treatment.

#### **d. Combination therapy with angioplasty and intra-arterial medical treatment**

Since it is believed that angioplasty in smaller, more distal vessels, is too risky, it is logical that a combination of intra-arterial medical treatment with angioplasty might be effective in treating both proximal and distal cerebral vasospasm. In a retrospective study by Frontera et al. the group compares combined therapy with chemical vasodilation alone. Frontera et al. find that while 39% of patients undergoing combination therapy developed recurrent angiographic and symptomatic vasospasm, 82% of patients receiving chemical vasodilation, alone, developed vasospasm (Frontera et al, 2011). Future, large-scaled and multicenter trials on the efficacy of combination therapy should help elucidate the most effective combinations of medical endovascular treatment with angioplasty.

Amongst these experimental, endovascular treatments, angioplasty seems beneficial for the larger, more proximal, and more accessible cerebral vessels while treatment with intraarterial papaverine and verapamil is more appropriate for smaller, more distal, and less accessible arteries where a large risk of rupture is present.

#### **6. Limitations to efficacy comparisons across studies**

However, problems with these studies, investigating the efficacy of experimental treatments for cerebral vasospasm, do exist. The small sample sizes and retrospective nature of a vast majority of these studies make it difficult to establish definitive conclusions with respect to efficacy of different endovascular treatments. Also, the criteria to begin endovascular treatment differ from group to group. For example, while Bejjani et al report treating vasospasm with angioplasty only after Triple-H therapy has failed (Bejjani et al, 1998) , Santillan et al. use a decrease in vessel diameter via angiography as one if their indications for treatment (Santillan et al, 2011). Therefore, constructing a meta-analysis, combining the results of these studies, is difficult as different groups make their own decisions about when to treat patients endovascularly. Table 2, below, lists the criteria to treat cerebral vasospasm, from several groups, reviewed in the literature.

#### **7. Recommendations for invasive treatments**

Although most experimental studies investigating the efficacy of invasive treatments for cerebral vasospasm after aSAH are retrospective in nature, effective patterns can be extracted from these studies. From the studies in this literature review, it appears that Triple-H therapy combined with administration of nimodipine is the first line of treatment or prevention of cerebral vasospasm. Once the vasospasm is deemed refractory to this

Evidence-Based Invasive Treatments for Cerebral

Vasospasm Following Aneurysmal Subarachnoid Hemorrhage 115

Fujii, 1995 developed symptomatic vasospasm in spite of intensive medical supportive

Jun, 2010 Severe proximal CV (luminal narrowing >60%) treated with PTA and distal CV

Choi, 2011 CT scan in patients with clinical deterioration; vasospasm defined as increase in

Santillan, 2011 Indication for TBA neurological deficits were referable to vascular territory of

Murai, 2005 DINDs assumed vasospasm if between 3-14 days after SAH; some had

Coyne, 1994 Symptomatic vasospasm defined as onset of delayed neurological deficit (2 or

treatment, invasive treatments should be employed next. A combination of verapamil or papaverine to treat distal vasospasm with angioplasty to treat proximal vasospasm in larger, more available vessels falls in line with conclusions of many of the studies reviewed. Timing of invasive treatments may also prove to be critical. Rosenwasser's retrospective study finds improved clinical and angiographic outcomes in patients treated with angioplasty within a two hour window (Rosenwasser et al, 1999). Therefore, combined intra-arterial treatment with either papaverine or verapamil and angioplasty within a timely manner appears to be

A review of the literature on invasive treatments for cerebral vasospasm has highlighted a possible disconnect between the presence of cerebral vasospasm and clinical outcome. Frontera's group and Macdonald's group respectively find that Transcranial Doppler Velocities (Frontera et al, 2009) and angiography (Macdonald et al, 2008), consistent with cerebral vasospasm, are not necessarily predictors of a specific clinical outcome. These findings have led to the hypothesis that other mechanisms, after aSAH, may be responsible for poor clinical outcomes. Specifically, early brain injury, before the onset of vasospasm, has been explored. Classically, cerebral vasospasm is thought to occur between four and nine days after the ictus. Early brain injury, defined as injury within 72 hours of the aSAH, may provide insight into poor clinical outcomes after aSAH (Pluta et al, 2009). Within these 72 hours, early brain injury has been associated with an elevation of intracranial pressure, a

angioplasty if neurological deficit/CT showed no improvement

(luminal narrowing >30%) with verapamil

approximately 2 mm in size.

distribution of vasospasm

**8. Unclear role of vasospasm in clinical outcomes** 

Table 2.

the most effective treatment.

therapy including hypertension, volume expansion, and administration of brain protective agents, the cases whose showed either consciousness deterioration worse than 30 in Japan Coma Scale and/or distinct neurological deficit, and cases whose angiogram performed as early as possible after emergence of

TCD flow to 150 cm/second. If greater than 150 cm/second, MRI, DWI and MRA; if infraction or narrowing by MRA, angioplasty was recommended

the VSP angiographically, vessel diameter less than 50% of initial diameter angiographically, no evidence of hypodensity on non-contrast head CT scan suggestive of ischemic infarct due to VSP prior to angiogram, and baseline diameter of vessel on initial cerebral angiogram or CT was not less than

angiograms to determine vasospasm (50% or more narrowing when compared to admission CT); heparinization w/angioplasty if deficit could be related to

more decrease on Glasgow Coma Scale); treated initially with hypervolemia, hypertensive therapy; maintain a capillary wedge pressure of 14 to 18 mm Hg. Maintain a systolic BP of 240 mm HG in clipping or 160 mm HG in unclipped;

symptoms showed the responsible narrowing in intracranial arteries.



Table 2.

Angioplasty, Various Techniques and Challenges in 114 Treatment of Congenital and Acquired Vascular Stenoses

Feng, 2002 Verapamil was given "to prevent catheter-induced vasospasm," for treatment

Bejjani, 1998 Do angioplasty after failed HHH therapy; digital subtraction angiography

Kaku 1992 Angioplasty (to deliver papaverine) if onset of new neurological deficit

Terada, 1997 Endovascular therapy if new neurological signs appear after SAH, not deriving

Andaluz, 2002 Refractory vasospasm (not clearly defined) to HHH therapy; included if all

Eskridge, 1998 hypertensive therapy started if suspicion of vasospasm; angioplasty if new

Rosenwasser, 1999 If new deficit, CT scan to eliminate hydrocephalus or bleeding. HHH therapy

Beck, 2006 HHH protocol; symptoms still then get MR; if PW DW mismatch then continue

Frontera 2011 All patients digital subtraction angiography; vessels which responded to IACV

Eskridge, 1990 Inclusion criteria included new onset of a neurologic deficit after subarachnoid

apparent vasospasm in location responsible for deficit Muizelaar, 2001 All patients had SAH and Fisher Grade III on CT scan w/in first two days of

Randomized to either angioplasty or no angioplasty

w/in 12 hours of onset of symptoms

Jestaedt, 2008 Clinical symptoms or high grade vessel narrowing (>70%)

HHH; then DS angiography then TBA

residual vasospasm after IACV then TBA

aneurysm; then TBP could be performed

in a distribution that could explain the deficit

Firlik, 1997 CBF new region < 20 ml/100 g/minute were treated with angioplasty

of mild vasospasm that did not warrant angioplasty, and for the treatment of moderate to severe vasospasm that could not be safely treated with angioplasty

not attributable to other causes, no evidence of infarction on CT, unsuccessful treatment of neurological deficit by conventional medical and pharmacological therapies, mean flow velocity 100 cm/sec or increase in mean flow velocity greater than 30 cm/sec w/in 24 hours in affected vessel by TCD, and vasospasm seen angiographically in location consistent with neurological

from hematoma, brain edema, or hydrocephalus, neurological signs are related to vascular territory of vasospasm, vessel diameter is less than 50% of initial diameter angiographically, no low density area is related to vasospasm on CT, clinical signs progress despite medical treatment, and ruptured aneurysm has

aneurysm clipped or coiled before Day 3 after SAH, clinical vasospasm defined by the presence of a new neurologic deficit not explained by hydrocephalus, infection, electrolyte imbalance, or other medical complication, clinical vasospasm in patients treated with nimodipine and with symptoms not reversed by maximal HHH treatment, and endovascular therapy instituted

onset of a neurological deficit not attributable to other causes, no evidence of established cerebral infarction on CT scans, deficit persisting despite hypertensive, hypervolemic therapy, and angiographic evidence of vasospasm

maximized to elevate MAP to 130-140 mm Hg. If not reversible then go to get

and could not be treated with angioplasty only IACV; accessible vessels with

hemorrhage that was not attributable to other causes, such as hydrocephalus, hematoma, mass effect, no evidence of infarction on CT scan, neurologic deficit not reversed by hypervolemic and hypertensive therapy, and angiographically

SAH; had to have surgical or neurointerventional treatment of ruptured

Author/Date Indication for Endovascular Treatment

performed first.

deficit.

been treated

angioplasty

Zwienenberg-Lee,

2008

treatment, invasive treatments should be employed next. A combination of verapamil or papaverine to treat distal vasospasm with angioplasty to treat proximal vasospasm in larger, more available vessels falls in line with conclusions of many of the studies reviewed. Timing of invasive treatments may also prove to be critical. Rosenwasser's retrospective study finds improved clinical and angiographic outcomes in patients treated with angioplasty within a two hour window (Rosenwasser et al, 1999). Therefore, combined intra-arterial treatment with either papaverine or verapamil and angioplasty within a timely manner appears to be the most effective treatment.

#### **8. Unclear role of vasospasm in clinical outcomes**

A review of the literature on invasive treatments for cerebral vasospasm has highlighted a possible disconnect between the presence of cerebral vasospasm and clinical outcome. Frontera's group and Macdonald's group respectively find that Transcranial Doppler Velocities (Frontera et al, 2009) and angiography (Macdonald et al, 2008), consistent with cerebral vasospasm, are not necessarily predictors of a specific clinical outcome. These findings have led to the hypothesis that other mechanisms, after aSAH, may be responsible for poor clinical outcomes. Specifically, early brain injury, before the onset of vasospasm, has been explored. Classically, cerebral vasospasm is thought to occur between four and nine days after the ictus. Early brain injury, defined as injury within 72 hours of the aSAH, may provide insight into poor clinical outcomes after aSAH (Pluta et al, 2009). Within these 72 hours, early brain injury has been associated with an elevation of intracranial pressure, a

Evidence-Based Invasive Treatments for Cerebral

amongst the studies in this review of the literature.

the pathogenesis of this condition.

Neurosurg 73(6): 654-67.

**11. References** 

131-138.

Vasospasm Following Aneurysmal Subarachnoid Hemorrhage 117

therapies. Although most studies in this review provided protocols that used Triple-H therapy and nimodipine as a first line treatment for cerebral vasospasm, the variation in institutional protocols in these studies made comparisons difficult. Similarly, the absence of a unifying or "gold standard" definition of vasospasm suggests that different indications in each study might call for the same treatment. Given that studies in this analysis use either CT angiography, symptoms, or Transcranial Doppler Velocities to assess for vasospasm, it is difficult to know if each study would treat the same patient for the same degree of vasospasm. It is therefore difficult to compare the results of different studies, investigating the same treatment. Similarly, the actual endovascular therapy, either intra-arterial medical treatment or transluminal angioplasty, was not the same in each study. Both the dosage of intra-arterial drug administered and the type and size of angioplasty balloon differed

The retrospective nature and small sample size of an overwhelming majority of the studies in this review call for a newly designed, novel study in the endovascular treatment of vasospasm. Zweinenberg-Lee et al. provide data from a Phase II, Multicenter, Randomized, Clinical Trial assessing the effects of prophylactic angioplasty on infarction rates after cerebral vasospasm. The results of this trial, that prophylactic angioplasty provided an absolute risk reduction of 5.9% for developing an infarction after cerebral vasospasm (Zweienenberg-Lee et al, 2008), may serve as a model for future trials assessing the efficacy of endovascular treatments of vasospasm although not all the data were statistically significant. Future research on endovascular treatment of vasospasm should also follow the study design of trials investigating non-endovascular, pharmaceutical therapy for vasospasm. These studies, included in Etminan's meta-analysis, are prospective, randomized, adequately blinded, and placebo or vehicle controlled (Etminan et al, 2011). This literature review has highlighted the need for a highly controlled, randomized, multicenter, clinical trial, assessing the efficacy of endovascular treatment. A randomized, controlled, clinical trial placing patients into either an intra-arterial papaverine group, an intra-arterial verapamil group, an intra-arterial papaverine and angioplasty group, an intraarterial verapamil and angioplasty group, and an angioplasty group alone would provide the groundwork for a standardized protocol for effectively treating cerebral vasospasm endovascularly. Similarly, future studies should investigate vasospasm's role in affecting clinical outcomes and possible novel treatments. The future of vasospasm treatment, however, depends on further elucidation of the pathophysiology of vasospasm after aSAH. The role of the immune system and lipid peroxidation after aSAH should be investigated in

Al-Tamimi YZ, Orsi NM, Quinn AC, Homer-Vanniasinkam S, Ross SA (2010) A review of

Andaluz N, Tomsick TA, Tew JM, van Loveren HR, Yeh HS, Zuccarello M (2002) Indications

delayed ischemic neurologic deficit following aneurysmal subarachnoid hemorrhage: historical overview, current treatment, and pathophysiology. World

for endovascular therapy for refractory vasospasm after aneurysmal subarachnoid hemorrhage: Experience at the University of Cincinnati. Surgical Neurology 58:2

reduction in cerebral blood flow, blood-brain barrier disruption and neuronal cell death (Pluta et al, 2009). These changes, and not cerebral vasospasm, may be responsible for the subsequent clinical outcome.

Another recently proposed mechanism for the development of poor clinical outcomes has also been suggested. A mixture, similar to that of cerebrospinal fluid after SAH, has been shown to cause spreading cortical depolarization after application to the subarachnoid space (Pluta et al, 2009). This, in turn, has led to eventual ischemia and cortical necrosis. Similarly, 13 out of 18 patients, receiving surgical treatment after aSAH, have been shown to have similar waves of depolarization, consistent with the start of clinical deterioration (Pluta et al, 2009). Therefore, in addition to vasospasm, early brain injury and spreading cortical depolarization should be investigated for their importance in clinical outcomes.

#### **9. Future directions in the treatment of cerebral vasospasm**

Theoretically, endovascular therapy for cerebral vasospasm may include treatments other than intra-arterial pharmaceutical administration and cerebral artery angioplasty. Komotar et al. mention the possibility of using intra-aortic balloon counterpulsation to treat vasospasm. In this technique, an aortic balloon is placed distally to the origin of the left subclavian artery endovascularly. During diastole, the balloon inflates, redirecting blood to the coronary, carotid, and vertebral arteries in this part of the cardiac cycle (Komotar et al, 2008). The balloon then deflates during systole. The authors of this study report an average increase in cerebral blood flow by 69.3% (Nussbaum et al, 1998). Since the goal of Triple-H therapy is to improve cerebral blood flow, the intra-aortic balloon might be used in combination therapy with medical treatment for the reduction of cerebral vasospasm and ischemia after aSAH. As this device is implanted in the femoral artery, risks such as hemorrhage and dissection of the femoral artery are present (Komotar et al, 2008). A case report, by Appelboom et al., describes a similar procedure with a Neuroflo, intra-aortic, dual balloon catheter. In this report, two balloons, one above and one below the renal arteries, are inflated to redirect blood flow to the cerebral arteries during refractory vasospasm. An advantage of this technique is the avoidance of complications associated with direct manipulation of cerebral vasculature (Appelboom et al, 2010).

The future of cerebral vasospasm therapy depends on further elucidation of the pathophysiology of this condition. Komotar et al. report initial success with another free radical trapping agent. Just like tirilizad mesylate, disodium 2,4-disulfophenyl-N-tertbutylnitrone inhibits lipid peroxidation and has been associated with improvement in neurological function in primates (Komotar et al, 2008). Other evidence has suggested that the pathogenesis of vasospasm may depend on the immune system. Preventing the interaction between leukocytes and endothelial cells with blocking antibodies has also inhibited vasospasm after aSAH (Baybek et al, 1998). Similarly, patients undergoing therapy with steroids have a lower risk of developing delayed ischemic deficits after aSAH (Chyatte et al, 1987). The interplay between the immune system and development of cerebral vasospasm needs to be further investigated before immune modulating therapy can be directed towards the treatment of vasospasm.

#### **10. Conclusion**

A review of the literature on endovascular treatment for cerebral vasospasm has suggested the need for commonly used protocols and definitions to determine the efficacy of these Angioplasty, Various Techniques and Challenges in 116 Treatment of Congenital and Acquired Vascular Stenoses

reduction in cerebral blood flow, blood-brain barrier disruption and neuronal cell death (Pluta et al, 2009). These changes, and not cerebral vasospasm, may be responsible for the

Another recently proposed mechanism for the development of poor clinical outcomes has also been suggested. A mixture, similar to that of cerebrospinal fluid after SAH, has been shown to cause spreading cortical depolarization after application to the subarachnoid space (Pluta et al, 2009). This, in turn, has led to eventual ischemia and cortical necrosis. Similarly, 13 out of 18 patients, receiving surgical treatment after aSAH, have been shown to have similar waves of depolarization, consistent with the start of clinical deterioration (Pluta et al, 2009). Therefore, in addition to vasospasm, early brain injury and spreading cortical

Theoretically, endovascular therapy for cerebral vasospasm may include treatments other than intra-arterial pharmaceutical administration and cerebral artery angioplasty. Komotar et al. mention the possibility of using intra-aortic balloon counterpulsation to treat vasospasm. In this technique, an aortic balloon is placed distally to the origin of the left subclavian artery endovascularly. During diastole, the balloon inflates, redirecting blood to the coronary, carotid, and vertebral arteries in this part of the cardiac cycle (Komotar et al, 2008). The balloon then deflates during systole. The authors of this study report an average increase in cerebral blood flow by 69.3% (Nussbaum et al, 1998). Since the goal of Triple-H therapy is to improve cerebral blood flow, the intra-aortic balloon might be used in combination therapy with medical treatment for the reduction of cerebral vasospasm and ischemia after aSAH. As this device is implanted in the femoral artery, risks such as hemorrhage and dissection of the femoral artery are present (Komotar et al, 2008). A case report, by Appelboom et al., describes a similar procedure with a Neuroflo, intra-aortic, dual balloon catheter. In this report, two balloons, one above and one below the renal arteries, are inflated to redirect blood flow to the cerebral arteries during refractory vasospasm. An advantage of this technique is the avoidance of complications associated with direct

The future of cerebral vasospasm therapy depends on further elucidation of the pathophysiology of this condition. Komotar et al. report initial success with another free radical trapping agent. Just like tirilizad mesylate, disodium 2,4-disulfophenyl-N-tertbutylnitrone inhibits lipid peroxidation and has been associated with improvement in neurological function in primates (Komotar et al, 2008). Other evidence has suggested that the pathogenesis of vasospasm may depend on the immune system. Preventing the interaction between leukocytes and endothelial cells with blocking antibodies has also inhibited vasospasm after aSAH (Baybek et al, 1998). Similarly, patients undergoing therapy with steroids have a lower risk of developing delayed ischemic deficits after aSAH (Chyatte et al, 1987). The interplay between the immune system and development of cerebral vasospasm needs to be further investigated before immune modulating therapy can be

A review of the literature on endovascular treatment for cerebral vasospasm has suggested the need for commonly used protocols and definitions to determine the efficacy of these

depolarization should be investigated for their importance in clinical outcomes.

**9. Future directions in the treatment of cerebral vasospasm** 

manipulation of cerebral vasculature (Appelboom et al, 2010).

directed towards the treatment of vasospasm.

**10. Conclusion** 

subsequent clinical outcome.

therapies. Although most studies in this review provided protocols that used Triple-H therapy and nimodipine as a first line treatment for cerebral vasospasm, the variation in institutional protocols in these studies made comparisons difficult. Similarly, the absence of a unifying or "gold standard" definition of vasospasm suggests that different indications in each study might call for the same treatment. Given that studies in this analysis use either CT angiography, symptoms, or Transcranial Doppler Velocities to assess for vasospasm, it is difficult to know if each study would treat the same patient for the same degree of vasospasm. It is therefore difficult to compare the results of different studies, investigating the same treatment. Similarly, the actual endovascular therapy, either intra-arterial medical treatment or transluminal angioplasty, was not the same in each study. Both the dosage of intra-arterial drug administered and the type and size of angioplasty balloon differed amongst the studies in this review of the literature.

The retrospective nature and small sample size of an overwhelming majority of the studies in this review call for a newly designed, novel study in the endovascular treatment of vasospasm. Zweinenberg-Lee et al. provide data from a Phase II, Multicenter, Randomized, Clinical Trial assessing the effects of prophylactic angioplasty on infarction rates after cerebral vasospasm. The results of this trial, that prophylactic angioplasty provided an absolute risk reduction of 5.9% for developing an infarction after cerebral vasospasm (Zweienenberg-Lee et al, 2008), may serve as a model for future trials assessing the efficacy of endovascular treatments of vasospasm although not all the data were statistically significant. Future research on endovascular treatment of vasospasm should also follow the study design of trials investigating non-endovascular, pharmaceutical therapy for vasospasm. These studies, included in Etminan's meta-analysis, are prospective, randomized, adequately blinded, and placebo or vehicle controlled (Etminan et al, 2011).

This literature review has highlighted the need for a highly controlled, randomized, multicenter, clinical trial, assessing the efficacy of endovascular treatment. A randomized, controlled, clinical trial placing patients into either an intra-arterial papaverine group, an intra-arterial verapamil group, an intra-arterial papaverine and angioplasty group, an intraarterial verapamil and angioplasty group, and an angioplasty group alone would provide the groundwork for a standardized protocol for effectively treating cerebral vasospasm endovascularly. Similarly, future studies should investigate vasospasm's role in affecting clinical outcomes and possible novel treatments. The future of vasospasm treatment, however, depends on further elucidation of the pathophysiology of vasospasm after aSAH. The role of the immune system and lipid peroxidation after aSAH should be investigated in the pathogenesis of this condition.

#### **11. References**


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symptomatic cerebral vasospasm after subarachnoid hemorrhage: transluminal balloon angioplasty compared with intraarterial papaverine. Neurosurg Focus 5

angioplasty for cerebral vasospasm after subarachnoid hemorrhage. Can J Surg

hemorrhage: an overview for the practicing neurologist. Semin Neurol 30(5): 545-54. Elliott JP, Newell DW, Lam DJ, Eskridge JM, Douville CM, Le Roux PD, Lewis DH, Mayberg

MR, Grady MS, Winn, HR (1998) Comparison of balloon angioplasty and papaverine infusion for the treatment of vasospasm following aneurysmal

Winn RH (1998) Balloon Angioplasty for the Treatment of Vasospasm: Results of

treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and

Spellman J (2002) Intraarterially Administered Verapamil as Adjunct Therapy for

Cerebral Vasospasm: Safety and 2-Year Experience. AJNR AM J Neuroradiol 23: 1284-1290.


**7** 

*Japan* 

**Angiography for Peripheral** 

*Cardiology, Kishiwada Tokushuaki Hospital, Osaka* 

The use of endovascular technique for peripheral vascular disease (PVD) has evolved and new devices and techniques were being developed. Even after recent development of noninvasive diagnosis of PVD, angiography is still the gold standard for the evaluation of stenotic and occluded lesions. Without precise angiographic information, endovascular therapy can not be performed. In this chapter, the angiographic technique to visualize major

Excellent imaging is the key for the success of endovascular therapies. Flat-panel X ray image detectors for use in digital fluoroscopy and angiography are essential for peripheral artery intervention. The ability of three-dimensional (3D) visualization techniques and bolus chasing are also required. Various types of imaging sizes are available but we have to compromise considering of function on the machine. Careful planning and professional

We have two types of our peripheral angiography suite. One is single plane arm with 31cm X 31cm flat panel detector (Fig. Suite1A). And the other biplane with the 30cm X 40cm flat panel detector (Fig. Suite1B). Both machines have its merit and demerit. Single plane machine has the versatile function and more suited for intervention. Biplane system could obtain the multiple images and reduce the dosage of dye. But except for cerebral angiography, it takes time to adjust two images in centred position. For the diagnostic purpose, biplane System has the advantage, but interventional work, the single plane system has more versatile function and much safer for the patient's care during procedure.

In angiographic table, operators usually stand on the right side, but for left limb intervention or left brachial approach, operator needs to be positioned on the left side of the table. In these circumstances, the extra monitor is useful for left side operator. Without moving central image monitor, main operator can do the procedure with assistant who are seeing central monitor from right side (Fig. Suite2A). This is the convenient way to intervene

**1. Introduction** 

arteries of atherosclerotic disease is described.

**2.1 Single plane vs. biplane system** 

**2.2 Extra monitor** 

**2. Angiography suite for peripheral vascular intervention** 

expertise is a key factor for choosing every endovascular suite.

**Vascular Intervention** 

Yoshiaki Yokoi


## **Angiography for Peripheral Vascular Intervention**

 Yoshiaki Yokoi *Cardiology, Kishiwada Tokushuaki Hospital, Osaka Japan* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 120 Treatment of Congenital and Acquired Vascular Stenoses

Nussbaum ES, Sebring LA, Ganz WF, Madison MT (1998) Intra-aortic balloon counterpulsation

Oskouian RJ, Martin NA, Lee JH, Glenn TC, Guthrie D, Gonzalez NR, Afari A, Viñuela F

Pickard JD, Murray GD, Illingowrth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang

Pluta RM, Hansen-Schawrtz J, Dreier J, Vajkoczy P, Macdonald RL, Nishizawa S, Kasuya H,

Rosenwasser RH, Armonda RA, Thomas JE, Benitez RP, Gannon PM, Harrop J (1999)

Santillan A, Knopman J, Zink W, Patsalides A, Gobin YP (2011) Transluminal balloon

Shankar JJ, dos Santos MP, Deus-Silva L, Lum C (2011) Angiographic evaluation of the effect

Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, Nagata I, Kikuchi H, Takemae T,

Terada T, Kinoshita Y, Yokote H, Tsuura M, Nakai K, Itakura T, Hyotani G, Kuriyama T, Naka

Vergouwen MD, Meijers JC, Geskus RB, Coert BA, Horn J, Stroes ES, van der Poll T,

Weant KA, Ramsey CN, and Cook AM (2010) Role of Intraarterial Therapy for Cerebral

Zubkov YN, Nikirov BM, Shustin VA (1984) Balloon catheter technique for dilatation of constricted cerebral arteries after aneurysmal SAH. Acta Neurochir 70(1-2): 65-79 Zwienenberg-Lee M, Hartman J, Rudisill N, Madden LK, Smith K, Eskridge J, Newell D,

enhanced computed tomography study. Neurosurgery 42(1):206-13.

Velocities, and Cerebral Artery Diameters. Neurosurgery 51:1 30-43.

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30:4 , 405-417.

39: 1759-1765.

world of thought. Neurol Res 31(2):151-8.

trial. J Neurosurg 76(4): 571-7.

endovascular options. Neurosurgery 44: 975–979.

subarachnoid hemorrhage. Neuroradiology 53(2): 123-128.

Limitation and Pitfalls. Acta Neurochir (Wien) 139:227-234.

randomized trial. J Cereb Blood Flow Metab 29(8): 1444-53.

augments cerebral blood flow in the patient with cerebral vasospasm: a xenon-

(2002) Multimodal Quantitation of the Effects of Endovascular Therapy for Vasospasm on Cerebral Blood Flow, Transcranial Doppler Ultrasonographic

DA, Nelson R, Richards P (1989) Effect of oral nimodipine on cerebral infarction and coutcome after subarachnoid hemorrhage: British aneurysm nimodipine trial. Br Med

Wellman G, Keller E, Zauner A, Dorsch N, Clark J, Ono S, Kiris T, Leroux P, Zhang JH (2009) Cerebral vasospasm following subarachnoid hemorrhage: time for a new

Therapeutic modalities for the management of cerebral vaso- spasm: timing of

angioplasty for symptomatic distal vasospasm refractory to medical therapy in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery [Epub ahead of

of intra-arterial milrinone therapy in patients with vasospasm from aneurysmal

Hidaka H (1992) Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind

Y, Kido T (1997) The Effect of Endovascular Therapy for Cerebral Artery Spasm, its

Vermeulen M, Roos YB (2009) Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled

Vasospasm Secondary to Aneurysmal Subarachnoid Hemorrhage. Pharmacotherapy

Verweij B, Bullock MR, Baker A, Coplin W, Mericle R, Dai J, Rocke D, Muizelaar JP (2008) Effect of Prophylactic Transluminal Balloon Angioplasty on Cerebral Vasospasm and Outcome in Patients With Fisher Grade III Subarachnoid Hemorrhage: Results of a Phase II Multicenter, Randomized, Clinical Trial Stroke The use of endovascular technique for peripheral vascular disease (PVD) has evolved and new devices and techniques were being developed. Even after recent development of noninvasive diagnosis of PVD, angiography is still the gold standard for the evaluation of stenotic and occluded lesions. Without precise angiographic information, endovascular therapy can not be performed. In this chapter, the angiographic technique to visualize major arteries of atherosclerotic disease is described.

#### **2. Angiography suite for peripheral vascular intervention**

Excellent imaging is the key for the success of endovascular therapies. Flat-panel X ray image detectors for use in digital fluoroscopy and angiography are essential for peripheral artery intervention. The ability of three-dimensional (3D) visualization techniques and bolus chasing are also required. Various types of imaging sizes are available but we have to compromise considering of function on the machine. Careful planning and professional expertise is a key factor for choosing every endovascular suite.

#### **2.1 Single plane vs. biplane system**

We have two types of our peripheral angiography suite. One is single plane arm with 31cm X 31cm flat panel detector (Fig. Suite1A). And the other biplane with the 30cm X 40cm flat panel detector (Fig. Suite1B). Both machines have its merit and demerit. Single plane machine has the versatile function and more suited for intervention. Biplane system could obtain the multiple images and reduce the dosage of dye. But except for cerebral angiography, it takes time to adjust two images in centred position. For the diagnostic purpose, biplane System has the advantage, but interventional work, the single plane system has more versatile function and much safer for the patient's care during procedure.

#### **2.2 Extra monitor**

In angiographic table, operators usually stand on the right side, but for left limb intervention or left brachial approach, operator needs to be positioned on the left side of the table. In these circumstances, the extra monitor is useful for left side operator. Without moving central image monitor, main operator can do the procedure with assistant who are seeing central monitor from right side (Fig. Suite2A). This is the convenient way to intervene

Angiography for Peripheral Vascular Intervention 123

For most of small vessel and selective angiography, hand injection is adequate. However, for the optimal opacification of high-flow blood vessels like aorta, the use of power injector is mandatory. Constant and high volume of dye should be injected through electronically calibrated power injector. There are two types of injector. One is old fashioned power injector and the other is the assisted device which could give the small or large amount of dye by the injector attached to catheter table. Any contrast volume is adjusted by manually. Even a small dose of dye can be injected. However, the space of left side of table is occupied by this assisted device. We prefer conventional power injector which is mounted to the celling. This method gives us more space around

In the assisted device, the operator is supposed to stand only on the right side of the table and can not be away from the table during injection. To prevent for radiation exposure,

conventional use of power injector is more preferable (Fig. Suite4).

Fig. Angiosuite 3: Celling mounted Power injector

**2.4 Image size and contrast volume** 

Celling mounted power injector gives more space around catheter table

injection and et al. Therefore contrast dose should be individurized on each case

Contrast volume for opacification of the major arteries were listed in Table 1.was listed. These injection volumes are mainly used in our catheter laboratory. But, real contrast volume depends on the patient' condition, catheter size, amount of contrast, speed of

**2.3 Power injectors** 

catheter table.

right femoropopliteal artery or left subclavian artery. In left below the knee procedure via cross over approach, C-arm is rotated to the left side. Cranial side operator may not see the central image. In this situation, extra monitor can be placed in left cranial side (Fig. Suite2B).

Fig. Angiosuite 1: Peripheral angiography suite

A: Single plane flat panel system.

A single plane system has more versatile function compared to the biplane system. Single system is suited for interventional work

B: Biplane system: Biplane system allows the two images both on fluoro and images. Dye consumption could reduce. However, lateral tube might limit the patient's care. Mostly employed for neuroangiography.

Fig. Angiosuite 2: Extra monitor

A: Operators usually stand on the right side of the table. But for left limb intervention or left brachial approach, operator needs to be positioned on the left side of the table. In these circumstances, the extra monitor is useful for left side standing operator without moving central image monitor

B: In left below the knee procedure via cross over approach, C-arm is rotated to the left side. Cranial side operator may not see the central image. In this situation, extra monitor can be placed in left cranial side. Primary operator could see the image on the cranial side monitor and assistant could see the central monitor.

#### **2.3 Power injectors**

Angioplasty, Various Techniques and Challenges in 122 Treatment of Congenital and Acquired Vascular Stenoses

right femoropopliteal artery or left subclavian artery. In left below the knee procedure via cross over approach, C-arm is rotated to the left side. Cranial side operator may not see the central image. In this situation, extra monitor can be placed in left cranial side (Fig. Suite2B).

A single plane system has more versatile function compared to the biplane system. Single

B: Biplane system: Biplane system allows the two images both on fluoro and images. Dye consumption could reduce. However, lateral tube might limit the patient's care. Mostly

A: Operators usually stand on the right side of the table. But for left limb intervention or left brachial approach, operator needs to be positioned on the left side of the table. In these circumstances, the extra monitor is useful for left side standing operator without moving

B: In left below the knee procedure via cross over approach, C-arm is rotated to the left side. Cranial side operator may not see the central image. In this situation, extra monitor can be placed in left cranial side. Primary operator could see the image on the cranial side monitor

Fig. Angiosuite 1: Peripheral angiography suite

**A B**

**A B**

A: Single plane flat panel system.

employed for neuroangiography.

Fig. Angiosuite 2: Extra monitor

and assistant could see the central monitor.

central image monitor

system is suited for interventional work

For most of small vessel and selective angiography, hand injection is adequate. However, for the optimal opacification of high-flow blood vessels like aorta, the use of power injector is mandatory. Constant and high volume of dye should be injected through electronically calibrated power injector. There are two types of injector. One is old fashioned power injector and the other is the assisted device which could give the small or large amount of dye by the injector attached to catheter table. Any contrast volume is adjusted by manually. Even a small dose of dye can be injected. However, the space of left side of table is occupied by this assisted device. We prefer conventional power injector which is mounted to the celling. This method gives us more space around catheter table.

In the assisted device, the operator is supposed to stand only on the right side of the table and can not be away from the table during injection. To prevent for radiation exposure, conventional use of power injector is more preferable (Fig. Suite4).

Fig. Angiosuite 3: Celling mounted Power injector Celling mounted power injector gives more space around catheter table

#### **2.4 Image size and contrast volume**

Contrast volume for opacification of the major arteries were listed in Table 1.was listed. These injection volumes are mainly used in our catheter laboratory. But, real contrast volume depends on the patient' condition, catheter size, amount of contrast, speed of injection and et al. Therefore contrast dose should be individurized on each case

Angiography for Peripheral Vascular Intervention 125

important cause of ischemic stroke. In symptomatic patients, carotid revascularization is indicated in the presence of a stenosis 50~70% or more **(2)**. There are many arguments about the indication for asymptomatic patients. But asymptomatic stenoses are usually treated only if luminal narrowing exceeds 60%**(2)**. Carotid artery stenting (CAS) is a preferred treatment strategy in high-risk patients requiring Carotid endoatherectomy (CEA). Even though indication of CAS is still controversial, CAS is a less invasive and attractive way for revascularization for carotid artery disease. To indicate carotid artery revascularization, meticulous angiographic approach should be taken to evaluate of carotid artery stenosis.

Fig. Carotid 1: Progression of carotid artery disease

B: Mostly lesion starts at the bifurcation. Mild stenosis is seen

Carotid bulb is filled with plaque and the flow at the bifurcation show thc complex hemodynamics. This hemodynamics is postulated to lead carotid artery stenosis

There are classifications that categorize aortic arch anatomy **(3)** (Fig. Carotid 2).

Engagement of catheter to the brachiocephalic or left CCA is required to perform carotid artery angiography. In selecting catheter, the aortic arch anatomy plays an important role for the success of the procedure. In CAS, not only engaging the catheter, guiding sheath have to be placed into common CCA. It does mean the technique of the deep engagement of diagnostic catheter to CCA or external carotid artery (ECA) is the important procedure for

The aortic arch angiography in left anterior oblique view shows three type of aortic arch (Fig. Carotid 3). The vertical distance from the origin of the innominate artery to the top of the arch determines the arch type. In type 3, engagement of catheter, particularly to left common carotid artery is difficult and may account for the failure of carotid artery stenting.

A: The carotid bulb forms a focal dilatation

C: In progressive form of atherosclerosis.

**3.1 Aortic arch type** 

carotid artery angiography.

Fig. Angiosuite4: Radiation exposure Radiation exposure should be minimalized during injection of dye by using power injector



Table 1. Commonly used imaging size, injection rates and contrast volume AP: antero-posterior, SFA: superficial femoral artery

#### **3. Carotid artery angiography**

The atherosclerotic plaque accumulates at the carotid bifurcation. There are a number of factors, including geometry, velocity profile, and shear stress. The carotid bulb forms a focal dilatation. The flow at the bifurcation is considered to be a complex hemodynamics and postulated to lead carotid artery stenosis (Fig. Carotid 1) **(1)**. Carotid disease is one of Angioplasty, Various Techniques and Challenges in 124 Treatment of Congenital and Acquired Vascular Stenoses

Radiation exposure should be minimalized during injection of dye by using power injector

**Angiogram Image size Injection rate Contrast** 

Aortic Arch 30cm 20cc/s 20-30cc Carotid (Selective) 20cm 4-6cc/s 7-9cc Cerebral: AP 20cm 4-6cc/s 7-9cc Cerebral: Lateral 30cm 4-6cc/s 7-9cc Abdominal aorta 20-40cm 16-20cc/s 16-25cc Renal (Selective) 20cm 4-6cc/s (by hand) 4-6cc Iliac (Selective) 20cm 6-10cc/s 8-10cc

SFA 30cm 4-6cc/s 10cc SFA (Selective) 20—30cm 4-6cc/s 10cc Below the knee (Bolus) 30cm 3cc/s 7-9cc Tibial 20cm 3cc/s 5cc Tibial (Selective) 20cm 1-2cc/s (by hand) 2-3cc

The atherosclerotic plaque accumulates at the carotid bifurcation. There are a number of factors, including geometry, velocity profile, and shear stress. The carotid bulb forms a focal dilatation. The flow at the bifurcation is considered to be a complex hemodynamics and postulated to lead carotid artery stenosis (Fig. Carotid 1) **(1)**. Carotid disease is one of

Femoropopliteal-Tibial (Bolus) 30cm 4cc/s 16-20

Table 1. Commonly used imaging size, injection rates and contrast volume

AP: antero-posterior, SFA: superficial femoral artery

**3. Carotid artery angiography** 

**volume** 

**2.5 Table 1 Commonly used imaging size, injection rates and contrast volume for** 

Fig. Angiosuite4: Radiation exposure

**major arteries** 

important cause of ischemic stroke. In symptomatic patients, carotid revascularization is indicated in the presence of a stenosis 50~70% or more **(2)**. There are many arguments about the indication for asymptomatic patients. But asymptomatic stenoses are usually treated only if luminal narrowing exceeds 60%**(2)**. Carotid artery stenting (CAS) is a preferred treatment strategy in high-risk patients requiring Carotid endoatherectomy (CEA). Even though indication of CAS is still controversial, CAS is a less invasive and attractive way for revascularization for carotid artery disease. To indicate carotid artery revascularization, meticulous angiographic approach should be taken to evaluate of carotid artery stenosis.

Fig. Carotid 1: Progression of carotid artery disease

A: The carotid bulb forms a focal dilatation

B: Mostly lesion starts at the bifurcation. Mild stenosis is seen

C: In progressive form of atherosclerosis.

Carotid bulb is filled with plaque and the flow at the bifurcation show thc complex hemodynamics. This hemodynamics is postulated to lead carotid artery stenosis

#### **3.1 Aortic arch type**

Engagement of catheter to the brachiocephalic or left CCA is required to perform carotid artery angiography. In selecting catheter, the aortic arch anatomy plays an important role for the success of the procedure. In CAS, not only engaging the catheter, guiding sheath have to be placed into common CCA. It does mean the technique of the deep engagement of diagnostic catheter to CCA or external carotid artery (ECA) is the important procedure for carotid artery angiography.

There are classifications that categorize aortic arch anatomy **(3)** (Fig. Carotid 2).

The aortic arch angiography in left anterior oblique view shows three type of aortic arch (Fig. Carotid 3). The vertical distance from the origin of the innominate artery to the top of the arch determines the arch type. In type 3, engagement of catheter, particularly to left common carotid artery is difficult and may account for the failure of carotid artery stenting.

Angiography for Peripheral Vascular Intervention 127

Since an aortic arch angiogram or CT angiography can accurately reveal aortic arch type, complex anatomic variations and angulated takeoff. The assessment of aortic arch type is

**A B**

A and B are the typical bovine arch. Access to left common carotid artery is easy in A, but In B, selection to left common may be a difficult due to the sharp bend from top of aortic arch

**A B**

A and B are typical type 3 arch. Cannulation of catheter to common carotid artery is difficult. Manipulation in these shaggy aortic arch carries the risks of embolization and a

important for the success of CAS.

Fig. Carotid 4: Bovine arch

Fig. Carotid 5: Type 3 arch

predictor of periprocedural complications.

Fig. Carotid 2: Schematic classification of aortic arch (3).

Above figures are quoted from reference 3

A: Type 1 arch: The origins of the great vessels to be catheterized are at the level of the superior arch line

B: Type 2 arch: The origins of the great vessels to be catheterized are between the superior and the inferior arch line

C: Type 3 arch: The origins of the great vessels to be catheterized below the level of the inferior arch line.

Fig. Carotid 3: Angiographic classification of aortic arch In Type 1(A) and Type 2(B), catheter can be easily selected. In Type 3(C), steep curve between the top of aortic arch and the origin of arch vessel is shown. This type 3 arch is difficult to negotiate to access to common carotid artery

The anomalies of bovine arch can frequently occur and may lead to prolonged fluoroscopy time to select left common carotid artery (Fig. Carotid 4). Fig. Carotid 4 A and B are the typical bovine arch. Access to left common carotid artery is easy in Fig. Carotid 4A, but In Fig. Carotid 4B, selection to left common may be difficult due to the sharp bend from top of aortic arch Most of the type 3 aortic arch is shaggy and cannulation of selective catheter carries the risks of embolization (Fig. Carotid 5). Even in type 1 aortic arch, horizontally angulated left common carotid artery makes it difficult to engage the catheter from transfemoral approach (Fig. Carotid 6). In recent multi-detector CT angiography, the similar information of aortic arch can be obtained (Fig. Carotid 7).

Angioplasty, Various Techniques and Challenges in 126 Treatment of Congenital and Acquired Vascular Stenoses

A: Type 1 arch: The origins of the great vessels to be catheterized are at the level of the

C: Type 3 arch: The origins of the great vessels to be catheterized below the level of the

Type Type 2 Type 3

**A B C**

In Type 1(A) and Type 2(B), catheter can be easily selected. In Type 3(C), steep curve between the top of aortic arch and the origin of arch vessel is shown. This type 3 arch is

The anomalies of bovine arch can frequently occur and may lead to prolonged fluoroscopy time to select left common carotid artery (Fig. Carotid 4). Fig. Carotid 4 A and B are the typical bovine arch. Access to left common carotid artery is easy in Fig. Carotid 4A, but In Fig. Carotid 4B, selection to left common may be difficult due to the sharp bend from top of aortic arch Most of the type 3 aortic arch is shaggy and cannulation of selective catheter carries the risks of embolization (Fig. Carotid 5). Even in type 1 aortic arch, horizontally angulated left common carotid artery makes it difficult to engage the catheter from transfemoral approach (Fig. Carotid 6). In recent multi-detector CT angiography, the similar information of aortic

B: Type 2 arch: The origins of the great vessels to be catheterized are between the superior

Fig. Carotid 2: Schematic classification of aortic arch (3).

Fig. Carotid 3: Angiographic classification of aortic arch

difficult to negotiate to access to common carotid artery

arch can be obtained (Fig. Carotid 7).

Above figures are quoted from reference 3

superior arch line

inferior arch line.

and the inferior arch line

Since an aortic arch angiogram or CT angiography can accurately reveal aortic arch type, complex anatomic variations and angulated takeoff. The assessment of aortic arch type is important for the success of CAS.

Fig. Carotid 4: Bovine arch

A and B are the typical bovine arch. Access to left common carotid artery is easy in A, but In B, selection to left common may be a difficult due to the sharp bend from top of aortic arch

Fig. Carotid 5: Type 3 arch

A and B are typical type 3 arch. Cannulation of catheter to common carotid artery is difficult. Manipulation in these shaggy aortic arch carries the risks of embolization and a predictor of periprocedural complications.

Angiography for Peripheral Vascular Intervention 129

In both images, tight stenosis were seen but CTA overestimates the stenosis. In calcified lesion, CTA does not reveal the real lumen. In Fig.8C,D, CTA image does not clarify the

**<sup>A</sup> <sup>C</sup> <sup>B</sup> <sup>D</sup>**

Fig. Carotid 8: Comparison of carotid artery stenosis between CT angiography and

subtraction angiography (B). CT angiography overestimates the stenosis.

Left internal carotid artery (ICA) stenosis by CT angiography (A) was confirmed by digital

In calcified lesion, CT angiography failed to show the ICA stenosis (C) and DSA revealed

The percentage of stenosis is expressed using the NASCET criteria **(5)**. The NASCET criteria of 70% stenosis is the indication for CEA in symptomatic carotid stenosis. In NASCET, the stenosis calculated as the ratio of the diameter at the narrowest point to the diameter point at which beyond the area of post stentic dilatation. Before intervening carotid artery stenosis, quantitative angiographic assessment is required to measure the stenosis. So called NASCET measurement causes some confusion about the reference point of distal internal carotid artery. To avoid this confusion, minimal lumen Diameter (MLD) should be measured in mm (Carotid 9). In this case, % stenosis based on NASCET was calculated at

Basic angiographic view for carotid bifurcation can be obtained by anterior-posterior and lateral view. In most of the cases, lateral view shows the stenosis (Fig. Carotid 10). To indicate CAS or CEA, angiographic significant stenosis has to be found in multiple views. In these circumstances, 3D angiography is employed. In Fig Carotid 11, moderate stenosis was seen on either anterior or lateral view. In 3D angiography, right anterior oblique view at

stenosis due to calcification.

angiography

the ulcerated ICA stenosis (D).

87% with MLD 0.7mm.

60°could reveal the tight stenosis.

**3.2.2 Quantitative stenosis measurement** 

**3.2.3 Angiographic view for carotid artery stenosis** 

Fig. Carotid 6: Difficult aorta of type 1 Even in type 1 aortic arch, horizontaly angulated left common carotid artery makes it difficult to engage the catheter from transfemoral approach

Fig. Carotid 7: Aortic arch assessment by 3D CT angiography and aortic arch angiography Aortic arch angiogram on the same patient. Similar aortic arch assessment can be obtained on either CT angiography (A) or angiogram(B)

#### **3.2 Selective carotid angiography 3.2.1 CTA vs. DSA**

To evaluate carotid stenosis, selective carotid angiography remains the golden standard. But multidetector CT angiography is rapidly becoming the preferred examination for the initial evaluation of carotid artery stenosis **(4)**. CT angiography correlates to DSA. CTA (Fig. Carotid 8A) and DSA (Fig. Carotid 8B) images of left carotid stenosis were compared. Angioplasty, Various Techniques and Challenges in 128 Treatment of Congenital and Acquired Vascular Stenoses

Even in type 1 aortic arch, horizontaly angulated left common carotid artery makes it

**A B**

Fig. Carotid 7: Aortic arch assessment by 3D CT angiography and aortic arch angiography Aortic arch angiogram on the same patient. Similar aortic arch assessment can be obtained

To evaluate carotid stenosis, selective carotid angiography remains the golden standard. But multidetector CT angiography is rapidly becoming the preferred examination for the initial evaluation of carotid artery stenosis **(4)**. CT angiography correlates to DSA. CTA (Fig. Carotid 8A) and DSA (Fig. Carotid 8B) images of left carotid stenosis were compared.

Fig. Carotid 6: Difficult aorta of type 1

on either CT angiography (A) or angiogram(B)

**3.2 Selective carotid angiography** 

**3.2.1 CTA vs. DSA** 

difficult to engage the catheter from transfemoral approach

In both images, tight stenosis were seen but CTA overestimates the stenosis. In calcified lesion, CTA does not reveal the real lumen. In Fig.8C,D, CTA image does not clarify the stenosis due to calcification.

Fig. Carotid 8: Comparison of carotid artery stenosis between CT angiography and angiography

Left internal carotid artery (ICA) stenosis by CT angiography (A) was confirmed by digital subtraction angiography (B). CT angiography overestimates the stenosis.

In calcified lesion, CT angiography failed to show the ICA stenosis (C) and DSA revealed the ulcerated ICA stenosis (D).

#### **3.2.2 Quantitative stenosis measurement**

The percentage of stenosis is expressed using the NASCET criteria **(5)**. The NASCET criteria of 70% stenosis is the indication for CEA in symptomatic carotid stenosis. In NASCET, the stenosis calculated as the ratio of the diameter at the narrowest point to the diameter point at which beyond the area of post stentic dilatation. Before intervening carotid artery stenosis, quantitative angiographic assessment is required to measure the stenosis. So called NASCET measurement causes some confusion about the reference point of distal internal carotid artery. To avoid this confusion, minimal lumen Diameter (MLD) should be measured in mm (Carotid 9). In this case, % stenosis based on NASCET was calculated at 87% with MLD 0.7mm.

#### **3.2.3 Angiographic view for carotid artery stenosis**

Basic angiographic view for carotid bifurcation can be obtained by anterior-posterior and lateral view. In most of the cases, lateral view shows the stenosis (Fig. Carotid 10). To indicate CAS or CEA, angiographic significant stenosis has to be found in multiple views. In these circumstances, 3D angiography is employed. In Fig Carotid 11, moderate stenosis was seen on either anterior or lateral view. In 3D angiography, right anterior oblique view at 60°could reveal the tight stenosis.

Angiography for Peripheral Vascular Intervention 131

A B C

Fig. Carotid 11: 3D angiography for carotid artery stenosis assessment

anterior oblique view at 60° could see the tight stenosis.

**3.2.4 Level of carotid artery bifurcation and lesion** 

Moderate stenosis were seen on either anterior or lateral view. In 3D angiography, right

Carotid artery bifurcates at the level of around C4. To indicate CAS, either anatomical or clinical high risks for CEA have to be clarified. One of the common indications is high position of bifurcation. The level of bifurcation or lesion level must be clearly demonstrated by lateral view. In Fig. Carotid 12A, bifurcation level is normal at the level of C4 In Fig. Carotid 12B, bifurcation is at the C3, but lesion extends to C2. In Fig. Carotid 12C shows the

Carotid artery plaque is evaluated by ultrasound or MRI, but angiogram also could show the large plaque burden (Fig. Carotid 13). Ulcer is commonly seen and the main source of cerebral emboli (Fig. Carotid 13A). Severe long stenosis is seen in Fig. Carotid 13B. This suggests the large plaque burden and CEA is recommended. Severe tight stenosis shows the string sings (Fig. Carotid 13C). This is the near occlusion and shows the sluggish antegrade flow. Real vessel size of distal ICA cannot be determined. In these cases, CEA is better indicated than CAS for thinking of complex plaque

Protection device is placed at distal ICA or petrous portion. Atherosclerotic ICA sometimes shows the tortuosity. To place the protection device by the filter, the landing zone that was relative straight and 3~4 cm away from lesion site must be found. If there is no lamding

A: Anterior view B: Lateral view

C: Right anterior oblique 60° view

unusually low bifurcation.

**3.2.5 Plaque morphology** 

morphology.

**3.2.6 Tortuosity of ICA** 

Fig. Carotid 9: Quantitative stenosis measurement

A: Distal internal carotid artery (ICA)

B: minimal lesion diameter (MLD)

C: Common carotid artery (CCA)

D: Reference catheter outer diameter

MLD should be express in mm. Distal ICA, MLD and CCA with reference catheter outerdiametr are needed to caluculate stenosis.

Fig. Carotid 10: Antero-posterior amd lateral view of left carotid artery bifurcation A: Antero-posterior view

B: Lateral view

Basic angiographic view for carotid bifurcation can be obtained by anterior-posterior (A) and lateral view(B). In most of the cases, lateral view shows the bifurcation stenosis

Fig. Carotid 11: 3D angiography for carotid artery stenosis assessment

A: Anterior view

B: Lateral view

Angioplasty, Various Techniques and Challenges in 130 Treatment of Congenital and Acquired Vascular Stenoses

**A**

**B**

5.2mm

0.7mm

8.3mm

2.3mm

Fig. Carotid 9: Quantitative stenosis measurement

outerdiametr are needed to caluculate stenosis.

MLD should be express in mm. Distal ICA, MLD and CCA with reference catheter

**C**

**D**

**A B**

Fig. Carotid 10: Antero-posterior amd lateral view of left carotid artery bifurcation

Basic angiographic view for carotid bifurcation can be obtained by anterior-posterior (A) and lateral view(B). In most of the cases, lateral view shows the bifurcation stenosis

A: Distal internal carotid artery (ICA) B: minimal lesion diameter (MLD) C: Common carotid artery (CCA) D: Reference catheter outer diameter

A: Antero-posterior view

B: Lateral view

C: Right anterior oblique 60° view

Moderate stenosis were seen on either anterior or lateral view. In 3D angiography, right anterior oblique view at 60° could see the tight stenosis.

#### **3.2.4 Level of carotid artery bifurcation and lesion**

Carotid artery bifurcates at the level of around C4. To indicate CAS, either anatomical or clinical high risks for CEA have to be clarified. One of the common indications is high position of bifurcation. The level of bifurcation or lesion level must be clearly demonstrated by lateral view. In Fig. Carotid 12A, bifurcation level is normal at the level of C4 In Fig. Carotid 12B, bifurcation is at the C3, but lesion extends to C2. In Fig. Carotid 12C shows the unusually low bifurcation.

#### **3.2.5 Plaque morphology**

Carotid artery plaque is evaluated by ultrasound or MRI, but angiogram also could show the large plaque burden (Fig. Carotid 13). Ulcer is commonly seen and the main source of cerebral emboli (Fig. Carotid 13A). Severe long stenosis is seen in Fig. Carotid 13B. This suggests the large plaque burden and CEA is recommended. Severe tight stenosis shows the string sings (Fig. Carotid 13C). This is the near occlusion and shows the sluggish antegrade flow. Real vessel size of distal ICA cannot be determined. In these cases, CEA is better indicated than CAS for thinking of complex plaque morphology.

#### **3.2.6 Tortuosity of ICA**

Protection device is placed at distal ICA or petrous portion. Atherosclerotic ICA sometimes shows the tortuosity. To place the protection device by the filter, the landing zone that was relative straight and 3~4 cm away from lesion site must be found. If there is no lamding

Angiography for Peripheral Vascular Intervention 133

**A B C**

These cases suggest carotid artery stenting are not a good indication for anatomical reasons.

Internal carotid artery stenosis is an important cause of ipsilateral stroke. CAS is becoming a valid alternative to CEA. Therefore angiography should be taken for thinking of CAS can be possible or not. Precise angiographic stenosis assessment, lesion location and lesion morphology are suitable for CAS. And also, place for filter landing zone have to be taken

Occlusive disease of the supra-aortic trunks still remains an angiographic challenge. Among the proximal supra-aortic trunk disease, atherosclerosis is the most common cause of large

In this chapter, angiographic approach for left subclavian artery disease will be discussed.

Branch disease is defined of innominate, left common carotid, left subclavian artery (SCA) disease. In angiographic assessment of aortic branch disease, left anterior oblique (LAO) projection of aortography is the basic view. However, bony structure of thorathic cage and calcification of aorta made it difficult to obtain the clear image of arch. Severe proximal stenosis of three aortic arch vessels caused by atherosclerosis was shown in In Fig. SCA 1B, proximal left common carotid artery is stenosed. Stenosis or occlusion of innominate and ostium of left common carotid artery are not suited for revascularization by endovascular technique (6). In three aortic arch branch, left SCA stenosis most commonly seen and can be intervened by endovascular approach (Fig. SCA 1C). Atherosclerotic right SCA stenosis is mostly located at the ostium at the bifurcation of right common carotid artery. Aortography by LAO view showed right subclavian artery stenosis at the ostium (Fig. SCA 2A). Selective innominate artery angiography by right anterior oblique (RAO) view reveals that stenosis is located at the bifurcation of right common carotid artery (Fig. SCA 2B). Angioplasty to the right SCA ostium might affect right common carotid artery ostium. Extra caution is needed

Fig. 14: Tortuosity of internal carotid artery (ICA)

B: 90 degree rightward shift of proximal ICA.

**4. Subclavian artery angiography** 

artery occlusive disorder in the upper extremity.

**4.1 Aortic arch angiography for branch disease** 

A: S curve of ICA.

**3.3 Summary** 

account.

C: Marked tortuosity of ICA

Fig. Carotid 12: Level of bifurcation and lesion A: Bifurcation level is normal at the level of C4 B: Bifurcation is at the level of C3, but lesion extends to C2. C: Low bifurcation.

Fig. Carotid 13: Plaque morphology

A: Typical ulcer.

B: Severe long stenosis is seen and this suggests the large plaque burden

C: String sing is the preocclusion and shows the sluggish antegrade flow.

zone for filter, we have to consider proximal protection or balloon occlusion. In Fig. Carotid 14A, there is a landing zone but thinking of stent distal and filter position could be a very close and have the risks of filter trouble. In Fig. Carotid 14B, lesion show the directed to horizontally and upward bending of distal ICA. In this case, conformable stent is desirable and there is a risk of filter retrieval. In Fig. Carotid 14C, ICA shows the extreme tortuosity and CAS shoul be abandoned.

Fig. 14: Tortuosity of internal carotid artery (ICA) A: S curve of ICA. B: 90 degree rightward shift of proximal ICA. C: Marked tortuosity of ICA These cases suggest carotid artery stenting are not a good indication for anatomical reasons.

#### **3.3 Summary**

Angioplasty, Various Techniques and Challenges in 132 Treatment of Congenital and Acquired Vascular Stenoses

A B C

**C2**

Fig. Carotid 12: Level of bifurcation and lesion A: Bifurcation level is normal at the level of C4

**C2**

Fig. Carotid 13: Plaque morphology

and CAS shoul be abandoned.

A: Typical ulcer.

C: Low bifurcation.

B: Bifurcation is at the level of C3, but lesion extends to C2.

B: Severe long stenosis is seen and this suggests the large plaque burden C: String sing is the preocclusion and shows the sluggish antegrade flow.

**A B C**

**C2**

zone for filter, we have to consider proximal protection or balloon occlusion. In Fig. Carotid 14A, there is a landing zone but thinking of stent distal and filter position could be a very close and have the risks of filter trouble. In Fig. Carotid 14B, lesion show the directed to horizontally and upward bending of distal ICA. In this case, conformable stent is desirable and there is a risk of filter retrieval. In Fig. Carotid 14C, ICA shows the extreme tortuosity Internal carotid artery stenosis is an important cause of ipsilateral stroke. CAS is becoming a valid alternative to CEA. Therefore angiography should be taken for thinking of CAS can be possible or not. Precise angiographic stenosis assessment, lesion location and lesion morphology are suitable for CAS. And also, place for filter landing zone have to be taken account.

#### **4. Subclavian artery angiography**

Occlusive disease of the supra-aortic trunks still remains an angiographic challenge. Among the proximal supra-aortic trunk disease, atherosclerosis is the most common cause of large artery occlusive disorder in the upper extremity.

In this chapter, angiographic approach for left subclavian artery disease will be discussed.

#### **4.1 Aortic arch angiography for branch disease**

Branch disease is defined of innominate, left common carotid, left subclavian artery (SCA) disease. In angiographic assessment of aortic branch disease, left anterior oblique (LAO) projection of aortography is the basic view. However, bony structure of thorathic cage and calcification of aorta made it difficult to obtain the clear image of arch. Severe proximal stenosis of three aortic arch vessels caused by atherosclerosis was shown in In Fig. SCA 1B, proximal left common carotid artery is stenosed. Stenosis or occlusion of innominate and ostium of left common carotid artery are not suited for revascularization by endovascular technique (6). In three aortic arch branch, left SCA stenosis most commonly seen and can be intervened by endovascular approach (Fig. SCA 1C). Atherosclerotic right SCA stenosis is mostly located at the ostium at the bifurcation of right common carotid artery. Aortography by LAO view showed right subclavian artery stenosis at the ostium (Fig. SCA 2A). Selective innominate artery angiography by right anterior oblique (RAO) view reveals that stenosis is located at the bifurcation of right common carotid artery (Fig. SCA 2B). Angioplasty to the right SCA ostium might affect right common carotid artery ostium. Extra caution is needed

Angiography for Peripheral Vascular Intervention 135

Fig. SCA 3: Non-substracted and subtracted angiogram of left subclavian stenosis

B: Digital subtraction angiography (DSA) clearly delineates subclaviar artery stenosis

As the initial angiographic approach for left SCA stenosis or occlusion, aortic arch angiography should be taken in left anterior oblique (LAO) 30~45°view by DSA (Fig. SCA 4A). Contrast volume and speed are at least 18cc/s, total 20~30cc by using 5Fr Pigtail catheter. In Fig. SCA 4A the image was taken by 30cm in size and delayed image reveals the distal SCA via collateral from right vertebral artery (Fig. SCA 4B). Selective right vertebral angiogram proves the reversed flow of left vertebral artery through basal artery (Fig. SCA4C). Image size of aortic arch angiography is usually taken by 30-40cm image (Fig. SCA 5A). Thinking of interventional approach, 20cm image is more practical to cannulate catheter to left SCA (Fig. SCA 5B). But to confirm the exact location of stenosis, selective left subclavian artery angiogram is required (Fig. SCA 5C). In Fig. SCA 6A, aortogram showed the total occlusion of proximal left SCA, but

**A B C**

A: Non subtracted angiography gives the anatomical information

**A B**

Fig. SCA 4: Angiogram of left subclavian artery occlusion

B: Delayed image reveals the distal SCA via a collateral from right vertebral artery C: Selective right vertebral angiogram proves the reversed flow of left vertebral artery

A: Aortography by LAO 45°by 30cm image size

through basal artery

for right SCA ostium intervention, such as distal protection for right carotid artery territory. Among the three aortic arch branch vessels, atherosclerotic left SCA is commonly found in proximal to vertebral artery and left SCA is most favourable fort endovascular therapy. In this chapter, left SCA angiogram for interventional approach is discribed.

Fig. SCA 1: Aortic arch angiogram of aortic branch disease A: Innominate, left common, left subclavian artery are diseased. B: A tight ostial stenosis of left common carotid artery in type 3 arch C: Typical left subclavian artery stenosis. Bovine arch is noted.

Fig. SCA 2: Ostial location of right subclavian artery stenosis

A: Aortography by left anterior oblique view showed right subclavian artery stenosis at the ostium

B: Selective innominate artery angiography by right anterior oblique view reveals that stenosis is located at the bifurcation of right common carotid artery.

#### **4.2 Aortic arch angiogram for left subclavian artery stenosis**

In subclavian artery angiography, nonsubtracted image gives the anatomical information but does not show the detail of subclavian artery stenosis (Fig. SCA 3A). Digital subtraction angiography (DSA) clearly delineates subclavian artery from the background (Fig.SCA3B).

Angioplasty, Various Techniques and Challenges in 134 Treatment of Congenital and Acquired Vascular Stenoses

for right SCA ostium intervention, such as distal protection for right carotid artery territory. Among the three aortic arch branch vessels, atherosclerotic left SCA is commonly found in proximal to vertebral artery and left SCA is most favourable fort endovascular therapy. In

**A B C**

this chapter, left SCA angiogram for interventional approach is discribed.

Fig. SCA 1: Aortic arch angiogram of aortic branch disease A: Innominate, left common, left subclavian artery are diseased. B: A tight ostial stenosis of left common carotid artery in type 3 arch C: Typical left subclavian artery stenosis. Bovine arch is noted.

Fig. SCA 2: Ostial location of right subclavian artery stenosis

stenosis is located at the bifurcation of right common carotid artery.

**4.2 Aortic arch angiogram for left subclavian artery stenosis** 

ostium

(Fig.SCA3B).

A: Aortography by left anterior oblique view showed right subclavian artery stenosis at the

**A B**

In subclavian artery angiography, nonsubtracted image gives the anatomical information but does not show the detail of subclavian artery stenosis (Fig. SCA 3A). Digital subtraction angiography (DSA) clearly delineates subclavian artery from the background

B: Selective innominate artery angiography by right anterior oblique view reveals that

Fig. SCA 3: Non-substracted and subtracted angiogram of left subclavian stenosis A: Non subtracted angiography gives the anatomical information B: Digital subtraction angiography (DSA) clearly delineates subclaviar artery stenosis

As the initial angiographic approach for left SCA stenosis or occlusion, aortic arch angiography should be taken in left anterior oblique (LAO) 30~45°view by DSA (Fig. SCA 4A). Contrast volume and speed are at least 18cc/s, total 20~30cc by using 5Fr Pigtail catheter. In Fig. SCA 4A the image was taken by 30cm in size and delayed image reveals the distal SCA via collateral from right vertebral artery (Fig. SCA 4B). Selective right vertebral angiogram proves the reversed flow of left vertebral artery through basal artery (Fig. SCA4C). Image size of aortic arch angiography is usually taken by 30-40cm image (Fig. SCA 5A). Thinking of interventional approach, 20cm image is more practical to cannulate catheter to left SCA (Fig. SCA 5B). But to confirm the exact location of stenosis, selective left subclavian artery angiogram is required (Fig. SCA 5C). In Fig. SCA 6A, aortogram showed the total occlusion of proximal left SCA, but

Fig. SCA 4: Angiogram of left subclavian artery occlusion A: Aortography by LAO 45°by 30cm image size B: Delayed image reveals the distal SCA via a collateral from right vertebral artery C: Selective right vertebral angiogram proves the reversed flow of left vertebral artery through basal artery

Angiography for Peripheral Vascular Intervention 137

Although there is a paucity of long-term data of endovascular therapy, subclavian artery stenting is now the standard approach and offer many advantage over surgery in terms of morbidity and mortality. To succeed in left SCA stenting, a precise location of stenosis or

Fig. SCA 7 shows the typical left SCA stenosis. Initial aortogam by LAO view reveals left SCA stenosis (Fig. SCA 7A). To intervene left SCA stenosis, stenosis should be exactly located. Selective angiography combined with brachial artery catheter injection of dye clearly demonstrates the tight stenosis of left SCA (Fig. SCA 7B). Based on this angiogram, further stenting became the straightforward procedure (Fig. SCA 7C). The simultaneous injection of dye from distal and proximal SCA is very useful technique for subclavian artery intervention. To confirm SCA occlusion, the similar technique is applied during aortography. Selective SCA angiogram by injecting dye through catheter from brachial artery at the time of aortography showed the exact occlusion site (Fig. SCA 8A). This kind of angiogram leads to the successful intervention. Same angiographic technique was taken

**B C**

Figure. SCA7: Angiographic technique to assess left subclavian stenosis

detected and successful stent placement was confirmed (Fig. SCA 9B).

**4.4 Angiographic assessment for coronary- internal mammary steal** 

B: Selective angiography combined with brachial artery catheter injection of dye clearly

Not all angiogram could show the clear image of subclavian stenosis. In these cases, hemodynamic assessment is the useful to confirm a significant stenosis. In Fig. SCA 9A, simultaneous pressure recording was performed and showed 40mmHg peak systolic gradient and left SCA stenosis was located at the ostium. After stenting, no gradient was

The increased employment of internal mammary artery (IMA) grafts for coronary revascularization, proximal SCA stenosis is becoming well known cause of coronary-

C: Selective angiogram of post stenting. Distal and proximal injection of dye clearly

A: Initial aortagram by LAO view reveals left SCA stenosis

**A**

**4.3 Angiography for subclavian artery intervention.** 

occlusion must be visualized.

after stenting (Fig. SCA 8B).

demonstrates the tight stenosis

demonstrate successful stent implantation

selective injection revealed the 95% stenosis (Fig. SCA 6). To determine subtotal or occlusion, selective angiography is needed.

Fig. SCA 5: Angiographic image size of for left subclavian artery disease A: Aortic arch angiography is usually taken by 30cm image

B: To cannulate catheter selectively to left subclavian artery, 20cm image of angiogram is appropriate

C: Selective left subclavian artery angiogram is needed to confirm the stenosis.

Fig. SCA 6: Aortography and selective angiography A: Aortagram showed the total occlusion of proximal left subclavian artery B: Selective left subclabian artery angiogram showed subtotal stenosis. Selective angiography is necessary to intervene the lesion.

Angioplasty, Various Techniques and Challenges in 136 Treatment of Congenital and Acquired Vascular Stenoses

selective injection revealed the 95% stenosis (Fig. SCA 6). To determine subtotal or

30 cm 20 cm selective

**A B C**

Fig. SCA 5: Angiographic image size of for left subclavian artery disease

C: Selective left subclavian artery angiogram is needed to confirm the stenosis.

B: To cannulate catheter selectively to left subclavian artery, 20cm image of angiogram is

**A B**

A: Aortic arch angiography is usually taken by 30cm image

Fig. SCA 6: Aortography and selective angiography

Selective angiography is necessary to intervene the lesion.

A: Aortagram showed the total occlusion of proximal left subclavian artery B: Selective left subclabian artery angiogram showed subtotal stenosis.

appropriate

occlusion, selective angiography is needed.

#### **4.3 Angiography for subclavian artery intervention.**

Although there is a paucity of long-term data of endovascular therapy, subclavian artery stenting is now the standard approach and offer many advantage over surgery in terms of morbidity and mortality. To succeed in left SCA stenting, a precise location of stenosis or occlusion must be visualized.

Fig. SCA 7 shows the typical left SCA stenosis. Initial aortogam by LAO view reveals left SCA stenosis (Fig. SCA 7A). To intervene left SCA stenosis, stenosis should be exactly located. Selective angiography combined with brachial artery catheter injection of dye clearly demonstrates the tight stenosis of left SCA (Fig. SCA 7B). Based on this angiogram, further stenting became the straightforward procedure (Fig. SCA 7C). The simultaneous injection of dye from distal and proximal SCA is very useful technique for subclavian artery intervention. To confirm SCA occlusion, the similar technique is applied during aortography. Selective SCA angiogram by injecting dye through catheter from brachial artery at the time of aortography showed the exact occlusion site (Fig. SCA 8A). This kind of angiogram leads to the successful intervention. Same angiographic technique was taken after stenting (Fig. SCA 8B).

Figure. SCA7: Angiographic technique to assess left subclavian stenosis

A: Initial aortagram by LAO view reveals left SCA stenosis

B: Selective angiography combined with brachial artery catheter injection of dye clearly demonstrates the tight stenosis

C: Selective angiogram of post stenting. Distal and proximal injection of dye clearly demonstrate successful stent implantation

Not all angiogram could show the clear image of subclavian stenosis. In these cases, hemodynamic assessment is the useful to confirm a significant stenosis. In Fig. SCA 9A, simultaneous pressure recording was performed and showed 40mmHg peak systolic gradient and left SCA stenosis was located at the ostium. After stenting, no gradient was detected and successful stent placement was confirmed (Fig. SCA 9B).

#### **4.4 Angiographic assessment for coronary- internal mammary steal**

The increased employment of internal mammary artery (IMA) grafts for coronary revascularization, proximal SCA stenosis is becoming well known cause of coronary-

Angiography for Peripheral Vascular Intervention 139

reversed flow and draining into left SCA is seen. This image was taken by coronary mode, but point is to prove coronary to left SCA steal phenomenon and DSA image can be used

Fig. SCA10: Left coronary angiography for coronary-subclavian steal

**A B**

**A B**

flow of left IMA. This angiogram was taken by coronary mode.

B. Left subclavian artery angiogram by antero-posterior view. Relation between left IMA and proximal SCA stenosis is well seen.

A: Suspected coronary steal patient. Left coronary angiogram showed revealed reversed

B: Similar left coronary angiogram was taken by digital subtraction angiography. IMA is more well visulalized. Either method can be used to prove IMA to left SCA. 30cm of image

Fig. SCA 11: Relation between proximal left subclavian artery stenosis and origin of left

A: Left subclavian artery angiogram by left anterior oblique (LAO) view. Origin of left IMA

with 30cm image (Fig. SCA10B).

is preferable.

internal mammary artery (IMA)

is not identified by LAO view.

Fig. SCA 8: Angiographic technique for left subclavian occlusion A: Aortography with simultaneous injection of dye through the catheter from brachial artery. This angiogram gives the precise morphologic information of occlusion. B: Aortography of post stenting.

Same angiographic technique was taken and shows the successful stent placement.

Fig. SCA 9: Simultaneous pressure tracing for subclavian artery stenosis A: Aortography with selective distal SCA angiogram. Angiogram does not clearly reveal SCA stenosis. Simultaneous pressure tracing confirmed the siginificant stenosis. B: Aortography of post stenting. Distal and proximal pressure were equalized and successful stenting was proven by hemodynamic study.

subclavial steal. Left SCA stenting is the good indication for coronary to left IMA steal **(7)**. In coronary steal to left IMA, selective left coronary angiogram is needed to prove reversed flow of IMA. The 70-year-old patient with suspected coronary steal was shown in Fig. SCA 10A. The left coronary angiogram showed the typical coronary steal which left IMA shows Angioplasty, Various Techniques and Challenges in 138 Treatment of Congenital and Acquired Vascular Stenoses

Fig. SCA 8: Angiographic technique for left subclavian occlusion

**A B**

B: Aortography of post stenting.

A: Aortography with simultaneous injection of dye through the catheter from brachial artery. This angiogram gives the precise morphologic information of occlusion.

Same angiographic technique was taken and shows the successful stent placement.

Fig. SCA 9: Simultaneous pressure tracing for subclavian artery stenosis

successful stenting was proven by hemodynamic study.

A: Aortography with selective distal SCA angiogram. Angiogram does not clearly reveal

subclavial steal. Left SCA stenting is the good indication for coronary to left IMA steal **(7)**. In coronary steal to left IMA, selective left coronary angiogram is needed to prove reversed flow of IMA. The 70-year-old patient with suspected coronary steal was shown in Fig. SCA 10A. The left coronary angiogram showed the typical coronary steal which left IMA shows

SCA stenosis. Simultaneous pressure tracing confirmed the siginificant stenosis. B: Aortography of post stenting. Distal and proximal pressure were equalized and reversed flow and draining into left SCA is seen. This image was taken by coronary mode, but point is to prove coronary to left SCA steal phenomenon and DSA image can be used with 30cm image (Fig. SCA10B).

Fig. SCA10: Left coronary angiography for coronary-subclavian steal A: Suspected coronary steal patient. Left coronary angiogram showed revealed reversed flow of left IMA. This angiogram was taken by coronary mode.

B: Similar left coronary angiogram was taken by digital subtraction angiography. IMA is more well visulalized. Either method can be used to prove IMA to left SCA. 30cm of image is preferable.

Fig. SCA 11: Relation between proximal left subclavian artery stenosis and origin of left internal mammary artery (IMA)

A: Left subclavian artery angiogram by left anterior oblique (LAO) view. Origin of left IMA is not identified by LAO view.

B. Left subclavian artery angiogram by antero-posterior view.

Relation between left IMA and proximal SCA stenosis is well seen.

Angiography for Peripheral Vascular Intervention 141

have an increased risk of adverse cardiovascular events **(9)**. However, the efficacy of renal artery stenting for ARAS is a bit of controversial since ASTRAL trial was published **(10)**. Discordance exists between the procedural success rate and the equivocal clinical response rate after renal stent placement, which is likely to be a result of poor patients selection and inadequate angiographic assessment of lesion severity. Angiographic technique for ARAS

Aortography and selective renal artery angiography considered to be the gold standard for assessing renal artery anatomy and renal artery stenosis. 3D CT angiography consists of a continuously overlapping transaxial images and is now replacing aortography for the diagnostic purpose. The drawback of aortography, only one shot image can be obtained and the image may not be in a single plane to see the both renal artery ostium. We usually take left anterior oblique view 15~30° for initial aortography (Fig. Renal 1). In Fig. Renal 1,

will be discussed in this chapter.

**5.1 Aortography for renal artery stenosis** 

bilateral renal artery stenosis is well visualized in one flame.

Fig. Renal 1: Aortography for the assessment of renal artery stenosis

renal artery stenosis is shown in one flame.

all renal arteries were confirmed.

Aortography was taken by left anterior oblique view 30°. Typical bilateral atherosclerotic

• **Multiple renal arteries:** Computed tomography angiography (CTA) with multiple detector-row CT (MDCT) has evolved into an established technique for imaging of renal and mesenteric vessels. Particularly, in multiple renal arteries, MDCT is superior to DSA to detect all renal arteries. To make a correct diagnosis of multiple renal arteries, MDCT and DSA could be used complimentary. In Fig. Renal 2, a case of multiple renal arteries are shown in both MDCT and DSA. In DSA, many other arteries were shown and we might miss to identify all 4 renal arteries. With the information of MDCT image,

Most of the initial left SCA angiogram is taken by LAO view. However, in this view, in some cases, left IMA origin is not well seen (Fig. SCA 11A). Relation between left SCA stenosis and IMA is very important for stent placement. The left SCA selective angiogram was taken by anterior-posterior (AP) view (Fig. SCA 11B). In AP view, origin of left IMA is visualized and relation between left SCA stenosis and IMA is well understood. This could lead to successful stent placement.

Fig. SCA12: Pre and post left subclavian artery stenting in coronary-subclavian steal A: Aortic arch angiogram.

A 65 year-old female post coronary bypass patient, lesion was located at left SCA ostium. B: Aortic arch angiogram post stenting. This angiogram showed the successful stenting.

In left SCA ostium disease, precise lesion location is mandatory. In Fig. SCA 12, a 65 yearold female post coronary bypass patient, lesion was located at left SCA ostium. This was confirmed aortography combined with brachial side simultaneous injection of dye (Fig. SCA 12A). Based on the angiogram, stent was precisely implanted and same angiographic technique was repeated to confirm successful procedure.

#### **4.5 Summary**

Primary stenting for a symptomatic SCA stenosis can be performed with relatively safe procedure risks. However, to succeed SCA stenting, the stenosis or occlusion must be clearly visualized by angiography. Aortic arch angiography with selective angiography by using distal injection of dye gives the precise lesion location and could lead to successful intervention. When patient presents after coronary bypass with coronary-subclavian steal, SCA stenting is the good option. But, origination of IMA must be precisely identified. Thereis no clinical randomized study about SCA stenting. To intervene to subclvian artery, a meticulous angiographic assessment is required.

#### **5. Renal artery angiography**

Atherosclerotic renal artery stenosis (ARAS) is an increasingly recognized cause of severe hypertension and declining kidney function **(8)**. Typically involving the renal artery ostium or proximal segment of the renal artery. Patients with ARAS have been demonstrated to Angioplasty, Various Techniques and Challenges in 140 Treatment of Congenital and Acquired Vascular Stenoses

Most of the initial left SCA angiogram is taken by LAO view. However, in this view, in some cases, left IMA origin is not well seen (Fig. SCA 11A). Relation between left SCA stenosis and IMA is very important for stent placement. The left SCA selective angiogram was taken by anterior-posterior (AP) view (Fig. SCA 11B). In AP view, origin of left IMA is visualized and relation between left SCA stenosis and IMA is well understood. This could lead to

Fig. SCA12: Pre and post left subclavian artery stenting in coronary-subclavian steal

**A B**

technique was repeated to confirm successful procedure.

meticulous angiographic assessment is required.

**5. Renal artery angiography** 

A 65 year-old female post coronary bypass patient, lesion was located at left SCA ostium. B: Aortic arch angiogram post stenting. This angiogram showed the successful stenting.

In left SCA ostium disease, precise lesion location is mandatory. In Fig. SCA 12, a 65 yearold female post coronary bypass patient, lesion was located at left SCA ostium. This was confirmed aortography combined with brachial side simultaneous injection of dye (Fig. SCA 12A). Based on the angiogram, stent was precisely implanted and same angiographic

Primary stenting for a symptomatic SCA stenosis can be performed with relatively safe procedure risks. However, to succeed SCA stenting, the stenosis or occlusion must be clearly visualized by angiography. Aortic arch angiography with selective angiography by using distal injection of dye gives the precise lesion location and could lead to successful intervention. When patient presents after coronary bypass with coronary-subclavian steal, SCA stenting is the good option. But, origination of IMA must be precisely identified. Thereis no clinical randomized study about SCA stenting. To intervene to subclvian artery, a

Atherosclerotic renal artery stenosis (ARAS) is an increasingly recognized cause of severe hypertension and declining kidney function **(8)**. Typically involving the renal artery ostium or proximal segment of the renal artery. Patients with ARAS have been demonstrated to

successful stent placement.

A: Aortic arch angiogram.

**4.5 Summary** 

have an increased risk of adverse cardiovascular events **(9)**. However, the efficacy of renal artery stenting for ARAS is a bit of controversial since ASTRAL trial was published **(10)**. Discordance exists between the procedural success rate and the equivocal clinical response rate after renal stent placement, which is likely to be a result of poor patients selection and inadequate angiographic assessment of lesion severity. Angiographic technique for ARAS will be discussed in this chapter.

#### **5.1 Aortography for renal artery stenosis**

Aortography and selective renal artery angiography considered to be the gold standard for assessing renal artery anatomy and renal artery stenosis. 3D CT angiography consists of a continuously overlapping transaxial images and is now replacing aortography for the diagnostic purpose. The drawback of aortography, only one shot image can be obtained and the image may not be in a single plane to see the both renal artery ostium. We usually take left anterior oblique view 15~30° for initial aortography (Fig. Renal 1). In Fig. Renal 1, bilateral renal artery stenosis is well visualized in one flame.

Fig. Renal 1: Aortography for the assessment of renal artery stenosis Aortography was taken by left anterior oblique view 30°. Typical bilateral atherosclerotic renal artery stenosis is shown in one flame.

• **Multiple renal arteries:** Computed tomography angiography (CTA) with multiple detector-row CT (MDCT) has evolved into an established technique for imaging of renal and mesenteric vessels. Particularly, in multiple renal arteries, MDCT is superior to DSA to detect all renal arteries. To make a correct diagnosis of multiple renal arteries, MDCT and DSA could be used complimentary. In Fig. Renal 2, a case of multiple renal arteries are shown in both MDCT and DSA. In DSA, many other arteries were shown and we might miss to identify all 4 renal arteries. With the information of MDCT image, all renal arteries were confirmed.

Angiography for Peripheral Vascular Intervention 143

A: The straight aorta with minimal atherosclerotic change is seen. This suggests easy access

**A B**

Selective renal artery angiography is the definitive gold standard for the diagnosis of the significant renal artery stenosis. In aortography, clear relation between aorta and renal artery ostium is shown (Fig. Renal 5A). However, in aortography, information of intrarenal arteries is not obtained. Only selective renal artery angiography could show the picture of

B: There is a marked tortuosity of aorta. Selective angiography by tranfemoral approach might be difficult procedure to reach both renal artery. In this case, transbrachial or

Fig. Renal 4: Access for selective renal artery catheter placement

intrarenal artery as well as proximal stenosis (Fig. Renal 5B).

Fig. Renal 5: Aortography and selective renal artery angiography

of intrarenal arteries.

A: Aortography shows the clear relation between aorta and renal artery ostium stenosis. B: Selective renal artery angiography could show precise renal artery stenosis and anatomy

for left renal catheter engagement.

transradial approach is recommended.

**5.2 Selective renal artery angiography** 

Fig. Renal 2: CT angiography and angiography for multiple renal arteries A: CT angiography showed two renal arteries on both kidney. B: The same view was taken by angiography. 4 renal arteries were seen but many other arteries are included and might miss multiple renal arteries.

• **Right renal artery ostium and super mesenteric artery:** Often times, right renal artery overraps to superior mesenteric artery (SMA) by antero-posterior view and proximal right renal is not visualized (Fig. Renal 3A). Selective right renal artery angiography confirmed the tight stenosis in right renal artery ostium (Fig. Renal 3B). There are reports about the detection of renal artery stenosis by aortography at the time of coronary angiography. But in reality, the simple aortogram might not identify the stenosis of right renal artery proximal stenosis.

Fig. Renal 3: Relation between right renal artery ostium and super mesenteric artery A: In aortography of left anterior oblique view, right renal artery overraps to superior mesenteric artery and proximal right renal artery is not shown

B: Selective right renal artery angiography confirmed tight stenosis in proximal right renal artery ostium

• **Access for selective renal artery catheter placement:** Aortography gives the important information about the access to selective renal artery angiography. The straight aorta with minimal atherosclerotic change is seen in Fig. Renal 4A. This suggests easy access for left renal catheter engagement. In Fig. Renal 4B, there is a marked tortuosity of aorta and tranfemoral approach may face difficulty to reach both renal artery ostium. In this case, transbrachial or transradial approach should be considered.

Angioplasty, Various Techniques and Challenges in 142 Treatment of Congenital and Acquired Vascular Stenoses

Fig. Renal 2: CT angiography and angiography for multiple renal arteries

**A B**

B: The same view was taken by angiography. 4 renal arteries were seen but many other

Fig. Renal 3: Relation between right renal artery ostium and super mesenteric artery A: In aortography of left anterior oblique view, right renal artery overraps to superior

B: Selective right renal artery angiography confirmed tight stenosis in proximal right renal

• **Access for selective renal artery catheter placement:** Aortography gives the important information about the access to selective renal artery angiography. The straight aorta with minimal atherosclerotic change is seen in Fig. Renal 4A. This suggests easy access for left renal catheter engagement. In Fig. Renal 4B, there is a marked tortuosity of aorta and tranfemoral approach may face difficulty to reach both renal artery ostium. In this case, transbrachial or transradial approach should be

mesenteric artery and proximal right renal artery is not shown

**A B**

artery ostium

considered.

• **Right renal artery ostium and super mesenteric artery:** Often times, right renal artery overraps to superior mesenteric artery (SMA) by antero-posterior view and proximal right renal is not visualized (Fig. Renal 3A). Selective right renal artery angiography confirmed the tight stenosis in right renal artery ostium (Fig. Renal 3B). There are reports about the detection of renal artery stenosis by aortography at the time of coronary angiography. But in reality, the simple aortogram might not identify the

A: CT angiography showed two renal arteries on both kidney.

arteries are included and might miss multiple renal arteries.

stenosis of right renal artery proximal stenosis.

Fig. Renal 4: Access for selective renal artery catheter placement A: The straight aorta with minimal atherosclerotic change is seen. This suggests easy access for left renal catheter engagement.

B: There is a marked tortuosity of aorta. Selective angiography by tranfemoral approach might be difficult procedure to reach both renal artery. In this case, transbrachial or transradial approach is recommended.

#### **5.2 Selective renal artery angiography**

Selective renal artery angiography is the definitive gold standard for the diagnosis of the significant renal artery stenosis. In aortography, clear relation between aorta and renal artery ostium is shown (Fig. Renal 5A). However, in aortography, information of intrarenal arteries is not obtained. Only selective renal artery angiography could show the picture of intrarenal artery as well as proximal stenosis (Fig. Renal 5B).

Fig. Renal 5: Aortography and selective renal artery angiography A: Aortography shows the clear relation between aorta and renal artery ostium stenosis. B: Selective renal artery angiography could show precise renal artery stenosis and anatomy of intrarenal arteries.

Angiography for Peripheral Vascular Intervention 145

Fig. Renal 7: Catheter tip position of selective renal artery angiography

**A B**

In selective angiography, catheter tip goes into further stenosis. Relation between ostium

**A B**

A: Catheter tip attached to stenosis and injection of dye at this place might damage the

B: The ideal renal artery angiography. Catheter tip is located in aorta and could see the

Fig. Renal 9: Lesion location of atherosclerotic renal artery stenosis. Atherosclerotic renal artery stenosis is basically localized in proximal renal artery. There are 3 types of lesion locations. One is typical ostial stenosis (A). Lesion located in middle of the proximal renal artery is

called renal type(B). In most of the cases, mixed type of stenosis is seen (C).

**A B C**

A: Aortography of typical bilateral ARAS B: Selective right renal artery angiography.

stenosis and aortic wall is not elucidated.

Fig. Renal 8: Ideal selective renal artery angiography

proximal stenosis with distal renal vasculature.

vessel.

#### **5.2.1 Digital subtracted image**

By using digital subtraction angiography (DSA), the excellent renal artery angiography is Taken (Fig. Renal 6A). But in reality, it is very difficult to take excellent DSA image. Recent advances of digital image, distinction between subtracted and non subtracted image are relatively small (Fig. Renal 6B). Non DSA image is more important for renal artery intervention. In the near future, good quality digital image might replace DSA at least in renal artery.

Fig. Renal 6: Digital subtracted and non subtracted selective renal artery angiography A: Digital subtracted renal artery angiography.

B: Non subtracted image

Digital subtraction angiography (DSA) gives excellent image of renal artery vasculature(A). Recent advances of digital angiography shows that image quality between subtracted and non subtracted image are relatively small(B).

#### **5.2.2 Ideal renal artery angiography**

In selective renal artery angiography, catheter tip is in the renal artery ostium, but most of catheter goes into distal to stenosis and relationship between ostium and stenosis is not clarified. Aortagraphy of typical bilateral ARAS is shown in Fig. Renal 7A). In selective right renal artery angiography, catheter tip goes further to stenosis (Fig. Renal 7B) and relationship between ostium and stenosis is not clear. The ideal selective renal artery angiography is shown in Fig. Renal 8. In Fig. 8A, catheter tip attached to stenosis and is not recommended to inject dye. The ideal renal artery angiography is catheter tip located in aorta and could see the proximal stenosis (Fig. Renal 8B). To take the good quality renal artery angiogram, lesion is crossed by soft coil 0.014inc. wire. After confirming normal aortic pressure pattern, dye should be injected. If the catheter is too close to stenosis, slight drawback of catheter is needed to take the good quality angiogram. By doing this procedure, correct stenosis assessment can be made.

#### **5.2.3 Lesion location**

In ARAS, stenosis is basically localized in proximal renal artery. There are 3 types of lesion locations **(11)**. One is typical ostial stenosis (Fig. Renal 9A). Lesion located in middle of the proximal renal artery is called renal type (Fig. Renal 9B). In most of the cases, mixed type of stenosis is seen (Fig. Renal 9C).

Angioplasty, Various Techniques and Challenges in 144 Treatment of Congenital and Acquired Vascular Stenoses

By using digital subtraction angiography (DSA), the excellent renal artery angiography is Taken (Fig. Renal 6A). But in reality, it is very difficult to take excellent DSA image. Recent advances of digital image, distinction between subtracted and non subtracted image are relatively small (Fig. Renal 6B). Non DSA image is more important for renal artery intervention. In the near future, good quality digital image might replace DSA at least in

Fig. Renal 6: Digital subtracted and non subtracted selective renal artery angiography

Digital subtraction angiography (DSA) gives excellent image of renal artery vasculature(A). Recent advances of digital angiography shows that image quality between subtracted and

In selective renal artery angiography, catheter tip is in the renal artery ostium, but most of catheter goes into distal to stenosis and relationship between ostium and stenosis is not clarified. Aortagraphy of typical bilateral ARAS is shown in Fig. Renal 7A). In selective right renal artery angiography, catheter tip goes further to stenosis (Fig. Renal 7B) and relationship between ostium and stenosis is not clear. The ideal selective renal artery angiography is shown in Fig. Renal 8. In Fig. 8A, catheter tip attached to stenosis and is not recommended to inject dye. The ideal renal artery angiography is catheter tip located in aorta and could see the proximal stenosis (Fig. Renal 8B). To take the good quality renal artery angiogram, lesion is crossed by soft coil 0.014inc. wire. After confirming normal aortic pressure pattern, dye should be injected. If the catheter is too close to stenosis, slight drawback of catheter is needed to take the good quality angiogram. By doing this

In ARAS, stenosis is basically localized in proximal renal artery. There are 3 types of lesion locations **(11)**. One is typical ostial stenosis (Fig. Renal 9A). Lesion located in middle of the proximal renal artery is called renal type (Fig. Renal 9B). In most of the cases, mixed type of

**5.2.1 Digital subtracted image** 

A: Digital subtracted renal artery angiography.

**A B**

non subtracted image are relatively small(B).

procedure, correct stenosis assessment can be made.

**5.2.2 Ideal renal artery angiography** 

B: Non subtracted image

**5.2.3 Lesion location** 

stenosis is seen (Fig. Renal 9C).

renal artery.

Fig. Renal 7: Catheter tip position of selective renal artery angiography

A: Aortography of typical bilateral ARAS

B: Selective right renal artery angiography.

In selective angiography, catheter tip goes into further stenosis. Relation between ostium stenosis and aortic wall is not elucidated.

Fig. Renal 8: Ideal selective renal artery angiography

A: Catheter tip attached to stenosis and injection of dye at this place might damage the vessel.

B: The ideal renal artery angiography. Catheter tip is located in aorta and could see the proximal stenosis with distal renal vasculature.

Fig. Renal 9: Lesion location of atherosclerotic renal artery stenosis. Atherosclerotic renal artery stenosis is basically localized in proximal renal artery. There are 3 types of lesion locations. One is typical ostial stenosis (A). Lesion located in middle of the proximal renal artery is called renal type(B). In most of the cases, mixed type of stenosis is seen (C).

Angiography for Peripheral Vascular Intervention 147

artery. The image field at least 30cm is needed. In Fig. Iliac 1, 31X31 cm and 30X40 cm image field are shown (Fig. Iliac 1). In both angiogram show from terminal aorta to common femoral artery. However, in 31cm image field, we are lifting a table to maximize image field ( Fig. Iliac 2). Typical long left iliac artery total occlusion is shown in Fig Iliac 2A. This image was taken by lifting table to obtained collateral vessels to common femoral artery (Fig. Iliac 2B). DSA image is considered to be the standard angiography for iliac artery disease, but pelvic vessels often times interfered by bowel movement and gas. In recent advanced digital angiography, similar image to subtracted angiogram can be obtained. In Fig. Iliac 3, subtracted (In Fig. Iliac 3A) and nonsubtracted (In Fig. Iliac 3B) are shown. Even nonsubtracted image is acceptable with bony

31X31cm 30X40cm

**B**

**6.1 Aortography for iliac artery disease** 

Fig. Iliac 1: Aortography for iliac artery

Both angiogram could show from terminal aorta to common femoral artery.

To visualize aorto iliac disease, more than 30 cm image field is required. But in reality, image of 30 cm often times misses the complicated stenostic lesion. In Fig. Iliac 4A, there is a tight stenosis in left external iliac artery. In 20cm image, ulcerated tight stenosis in left common iliac artery clearly visualized (Fig. Iliac 4B). To intervene the iliac artery disease, the information of vessels size and lesion length is needed. 30cm image could confirm the disease of common femoral artery, but to obtain the precise lesion morphology, 20cm image

The anteriorposterior (AP) pelvic angiogram is the basic angiogram. The oblique images should be obtained. If contrast load permits, basically we are taking three view of aortogram

A: 31X31cm image, B: 30X40cm image

**6.2 Image size** 

is better than 30cm image.

**6.3 Basic 3 views for iliac artery** 

landmark.

**A**

#### **5.2.4 Reference vessel**

To select the correct stent size, accurate vessel diameter must be measured **(12).** To make a correct assessment of stenosis and vessel size, reference point is chosen. In Fig. Renal 10A, reference vessel is considered to be about 2cm distal to stenosis. However, in Fig. Renal 10B, post-stenostic dilatation is seen and bifurcation follows (Fig. Renal 10B). In this case, reference vessels cannot be determined. The bifurcation located at the ostium, real vessel size is not known (Fig. Renal 10C). This fact is not well understood and this is the main cause of recent confusion of stenosis evaluation.

Fig. Renal 10: Reference vessel

To calculate % diameter stenosis or minimal lesion diameter, reference vessel must be determined.

A: Reference vessel can be determined about 2cm distal to stenosis.

B: Typical post-stenostic dilatation is seen and bifurcation follows. In this case, reference vessels can not be determined.

C: The bifurcation located at the ostium and real vessel size is not known.

• **Summary:** Renal artery angiography is the gold standard diagnostic test.

However, to make a correct diagnosis of ARAS, excellent visualization of renal vasculature should be performed. Aortography is now replacing to CT angiography. But in placing catheter to renal artery ostium, we still need aortography for the safe catheter manipulation. Selective angiography identifies the severity of stenosis with intra renal vasculature information. Confusion for the indication of renal artery stenting is mostly coming from poor angiographic image of renal artery stenosis.

#### **6. Iliac artery angiography**

Peripheral arterial disease at the level of iliac artery is well known for good indication of angioplasty. Currently, stenting for the treatment of iliac occlusive disease is the most effective modality and endovascular treatment of iliac artery disease should be considered as a first-line therapy for symptomatic PAD. The most commonly quoted classification of iliac lesions has been set forth by the TransAtlantic inter-Society Consensus (TASC II) group with recommended treatment options **(13)**. The type A and B lesions are treated preferentially by endovascular techniques and typed C and D lesions are more suited for surgical treatment. However, recent development of endovascular technique, even type D lesions sometimes is treated by endovascular procedure. To maximize the success of iliac artery stenting, good quality angiogram is needed.

Angioplasty, Various Techniques and Challenges in 146 Treatment of Congenital and Acquired Vascular Stenoses

To select the correct stent size, accurate vessel diameter must be measured **(12).** To make a correct assessment of stenosis and vessel size, reference point is chosen. In Fig. Renal 10A, reference vessel is considered to be about 2cm distal to stenosis. However, in Fig. Renal 10B, post-stenostic dilatation is seen and bifurcation follows (Fig. Renal 10B). In this case, reference vessels cannot be determined. The bifurcation located at the ostium, real vessel size is not known (Fig. Renal 10C). This fact is not well understood and this is the main

To calculate % diameter stenosis or minimal lesion diameter, reference vessel must be

B: Typical post-stenostic dilatation is seen and bifurcation follows. In this case, reference

However, to make a correct diagnosis of ARAS, excellent visualization of renal vasculature should be performed. Aortography is now replacing to CT angiography. But in placing catheter to renal artery ostium, we still need aortography for the safe catheter manipulation. Selective angiography identifies the severity of stenosis with intra renal vasculature information. Confusion for the indication of renal artery stenting is mostly coming from

Peripheral arterial disease at the level of iliac artery is well known for good indication of angioplasty. Currently, stenting for the treatment of iliac occlusive disease is the most effective modality and endovascular treatment of iliac artery disease should be considered as a first-line therapy for symptomatic PAD. The most commonly quoted classification of iliac lesions has been set forth by the TransAtlantic inter-Society Consensus (TASC II) group with recommended treatment options **(13)**. The type A and B lesions are treated preferentially by endovascular techniques and typed C and D lesions are more suited for surgical treatment. However, recent development of endovascular technique, even type D lesions sometimes is treated by endovascular procedure. To maximize the success of iliac artery stenting, good quality angiogram is

A: Reference vessel can be determined about 2cm distal to stenosis.

C: The bifurcation located at the ostium and real vessel size is not known.

**A B C**

• **Summary:** Renal artery angiography is the gold standard diagnostic test.

**5.2.4 Reference vessel** 

Fig. Renal 10: Reference vessel

vessels can not be determined.

**6. Iliac artery angiography** 

poor angiographic image of renal artery stenosis.

determined.

needed.

cause of recent confusion of stenosis evaluation.

#### **6.1 Aortography for iliac artery disease**

artery. The image field at least 30cm is needed. In Fig. Iliac 1, 31X31 cm and 30X40 cm image field are shown (Fig. Iliac 1). In both angiogram show from terminal aorta to common femoral artery. However, in 31cm image field, we are lifting a table to maximize image field ( Fig. Iliac 2). Typical long left iliac artery total occlusion is shown in Fig Iliac 2A. This image was taken by lifting table to obtained collateral vessels to common femoral artery (Fig. Iliac 2B). DSA image is considered to be the standard angiography for iliac artery disease, but pelvic vessels often times interfered by bowel movement and gas. In recent advanced digital angiography, similar image to subtracted angiogram can be obtained. In Fig. Iliac 3, subtracted (In Fig. Iliac 3A) and nonsubtracted (In Fig. Iliac 3B) are shown. Even nonsubtracted image is acceptable with bony landmark.

Fig. Iliac 1: Aortography for iliac artery A: 31X31cm image, B: 30X40cm image Both angiogram could show from terminal aorta to common femoral artery.

#### **6.2 Image size**

To visualize aorto iliac disease, more than 30 cm image field is required. But in reality, image of 30 cm often times misses the complicated stenostic lesion. In Fig. Iliac 4A, there is a tight stenosis in left external iliac artery. In 20cm image, ulcerated tight stenosis in left common iliac artery clearly visualized (Fig. Iliac 4B). To intervene the iliac artery disease, the information of vessels size and lesion length is needed. 30cm image could confirm the disease of common femoral artery, but to obtain the precise lesion morphology, 20cm image is better than 30cm image.

#### **6.3 Basic 3 views for iliac artery**

The anteriorposterior (AP) pelvic angiogram is the basic angiogram. The oblique images should be obtained. If contrast load permits, basically we are taking three view of aortogram

Angiography for Peripheral Vascular Intervention 149

A B

To visualize iliac artery disease, more than 30 cm image field is required. But for the purpose of interventional work, image of 30 cm often times misses the complicated stenotic lesion. There is a tight stenosis in left external iliac artery(A). In 20cm image, ulcerated tight

(Fig. Iliac 5). In a right anterior oblique view, the left iliac artery is best visualized and could separate bifurcation of internal iliac artery (Fig. Iliac 5A). Similarly, right iliac artery is taken by left anterior oblique (Fig. Iliac 5C) with the projection 30°. In complex disease anatomy, this approach is very important before intervention. In Fig. Iliac 6, severely diseased bilateral external iliac artery are shown in three views. In AP view, right external iliac artery over rap and left external iliac artery is not well visualized (Fig. Iliac 6B). The right internal anterior oblique view shows occlusion of left external iliac artery iliac artery (Fig. Iliac 6A). Left anterior view clearly delineate right external and internal iliac artery (Fig.

In iliac artery disease, primary iliac stenting is performed in most of the cases. To stent, exact lesion location must be visualized. In Fig. Iliac 7, left external iliac artery focal stenosis is shown (Fig. Iliac 7A). In DSA image, bony landmark is not seen and DSA image converted to non-subtracted image (Fig. Iliac 7B). By seeing femoral head, precise stenting was

Iliac artery stenting is becoming the routine procedure and angiography can be simplified. In ipsilateral retrograde femoral approach, sheath is placed and this sheath can be used

Fig. Iliac 4: Image size of Iliac artery disease

**6.4 Working image for intervention** 

**6.5 Contrast injection from sheath** 

performed (Fig. Iliac 7C).

stenosis in left common iliac artery clearly visualized (B).

A: 31cm of image B: 20cm of image

Iliac 6C).

Fig. Iliac 2: Aortography by 31X31cm image field

A: Aortography of 31X31cm image. Left common femoral artery is visulaized through collateral.

B: Catheter table is lifted to maximize image field

Fig. Iliac 3: Subtracted and non subtracted Aortography

A: Image of digital subtraction angiography

Image of digital subtraction angiography is considered to be the standard for the

visualization of iliac artery disease

B: Non subtracted image

Pelvic vessels are interfered by bowel movement and bowel gas. Recent digital angiography could give the similar image to subtracted angiogram.

Angioplasty, Various Techniques and Challenges in 148 Treatment of Congenital and Acquired Vascular Stenoses

**A B**

A: Aortography of 31X31cm image. Left common femoral artery is visulaized through

Fig. Iliac 2: Aortography by 31X31cm image field

B: Catheter table is lifted to maximize image field

**A B**

Fig. Iliac 3: Subtracted and non subtracted Aortography

could give the similar image to subtracted angiogram.

Image of digital subtraction angiography is considered to be the standard for the

Pelvic vessels are interfered by bowel movement and bowel gas. Recent digital angiography

A: Image of digital subtraction angiography

visualization of iliac artery disease

B: Non subtracted image

collateral.

Fig. Iliac 4: Image size of Iliac artery disease A: 31cm of image B: 20cm of image

To visualize iliac artery disease, more than 30 cm image field is required. But for the purpose of interventional work, image of 30 cm often times misses the complicated stenotic lesion. There is a tight stenosis in left external iliac artery(A). In 20cm image, ulcerated tight stenosis in left common iliac artery clearly visualized (B).

(Fig. Iliac 5). In a right anterior oblique view, the left iliac artery is best visualized and could separate bifurcation of internal iliac artery (Fig. Iliac 5A). Similarly, right iliac artery is taken by left anterior oblique (Fig. Iliac 5C) with the projection 30°. In complex disease anatomy, this approach is very important before intervention. In Fig. Iliac 6, severely diseased bilateral external iliac artery are shown in three views. In AP view, right external iliac artery over rap and left external iliac artery is not well visualized (Fig. Iliac 6B). The right internal anterior oblique view shows occlusion of left external iliac artery iliac artery (Fig. Iliac 6A). Left anterior view clearly delineate right external and internal iliac artery (Fig. Iliac 6C).

#### **6.4 Working image for intervention**

In iliac artery disease, primary iliac stenting is performed in most of the cases. To stent, exact lesion location must be visualized. In Fig. Iliac 7, left external iliac artery focal stenosis is shown (Fig. Iliac 7A). In DSA image, bony landmark is not seen and DSA image converted to non-subtracted image (Fig. Iliac 7B). By seeing femoral head, precise stenting was performed (Fig. Iliac 7C).

#### **6.5 Contrast injection from sheath**

Iliac artery stenting is becoming the routine procedure and angiography can be simplified. In ipsilateral retrograde femoral approach, sheath is placed and this sheath can be used

Angiography for Peripheral Vascular Intervention 151

**A B C** 

To stent, exact lesion location has to be visualized. Foca stenosis in left external iliac artery is shown by DSA image (A). Bony landmark is not seen and DSA image converted to nonsubtracted image (B). By seeing femoral head, precise stenting was performed (C).

**A B** 

In ipsilateral retrograde femoral approach, sheath can be used to injection of dye. There is a focal stenosis in left external iliac artery (A). Angiogram was performed through this sheath

to injection of dye. There is a focal stenosis in left external iliac artery (Fig. Iliac 8A). Angiogram was performed through this sheath and ballooning and stenting was performed. (Fig. Iliac 8B). However, in retrograde approach, hand injection cannot visualize proximal iliac artery. Power injector should be employed and test injection is needed to check the tip

Fig. Iliac 7: Working image for intervention

Fig. Iliac 8: Ipsilateral contrast injection from sheath

and ballooning and stenting was performed. (B).

of sheath position is in vessel lumen.

B: Post stenting angiogram

A: Angiogram by injecting dye through left femoral artery sheath

A: Subtracted image B: Non subtravted image

C: Post stenting

Fig. Iliac 5: Basic 3 views for iliac artery

A: 30° right anterior oblique view

B: Anteriorposterior (AP) view C: 30° left anterior oblique view

In a right anterior oblique view, the left iliac artery is best visualized and separate bifurcation of internal iliac artery (A). In AP view, both external iliac artery are shortened(B) Similary the right iliac artery is taken by a left anterior oblique with the projection 30°angle(C).

Fig. Iliac 6: Basic 3 views for iliac artery diease

A: 30° right anterior oblique view

B: Anteriorposterior (AP) view

C: 30° left anterior oblique view

The right internal anterior oblique view shows occlusion of left external iliac artery iliac artery (A). In AP view, right external iliac artery over rap with right internal iliac artery and left external iliac artery is not well visualized (B). The left anterior view clearly delineate right external and internal iliac artery and shows diffusely diseased right external iliac artery (C).

Angioplasty, Various Techniques and Challenges in 150 Treatment of Congenital and Acquired Vascular Stenoses

RAO AP LAO

**A B C** 

In a right anterior oblique view, the left iliac artery is best visualized and separate

Similary the right iliac artery is taken by a left anterior oblique with the projection

The right internal anterior oblique view shows occlusion of left external iliac artery iliac artery (A). In AP view, right external iliac artery over rap with right internal iliac artery and left external iliac artery is not well visualized (B). The left anterior view clearly delineate right external and internal iliac artery and shows diffusely diseased right external iliac

bifurcation of internal iliac artery (A). In AP view, both external iliac artery are shortened(B)

RAO AP LAO

**A B C** 

Fig. Iliac 5: Basic 3 views for iliac artery A: 30° right anterior oblique view B: Anteriorposterior (AP) view C: 30° left anterior oblique view

Fig. Iliac 6: Basic 3 views for iliac artery diease

A: 30° right anterior oblique view B: Anteriorposterior (AP) view C: 30° left anterior oblique view

30°angle(C).

artery (C).

Fig. Iliac 7: Working image for intervention A: Subtracted image B: Non subtravted image C: Post stenting

To stent, exact lesion location has to be visualized. Foca stenosis in left external iliac artery is shown by DSA image (A). Bony landmark is not seen and DSA image converted to nonsubtracted image (B). By seeing femoral head, precise stenting was performed (C).

Fig. Iliac 8: Ipsilateral contrast injection from sheath

A: Angiogram by injecting dye through left femoral artery sheath

B: Post stenting angiogram

In ipsilateral retrograde femoral approach, sheath can be used to injection of dye. There is a focal stenosis in left external iliac artery (A). Angiogram was performed through this sheath and ballooning and stenting was performed. (B).

to injection of dye. There is a focal stenosis in left external iliac artery (Fig. Iliac 8A). Angiogram was performed through this sheath and ballooning and stenting was performed. (Fig. Iliac 8B). However, in retrograde approach, hand injection cannot visualize proximal iliac artery. Power injector should be employed and test injection is needed to check the tip of sheath position is in vessel lumen.

Angiography for Peripheral Vascular Intervention 153

**A B**

B: In left anterior oblique view, separation between SFA proximal and prfund femoal are

**A B**

Fig. SFA 1: Anteroposterior view and left anterior oblique view for proximal left femoral artery

Fig. SFA 2: Anteroposterior view and left anterior oblique view for proximal left femoral diseased artery

profunda artery is longer than AP view

A: The SFA proximal stenosis is not delineated by anterior posterior (AP) view B: Left anterior oblique view shows SFA ostial stenosis and lesion length of proximal

well seen

A: AP view shows that profunda femoral override to SFA

#### **6.6 Summary**

Iliac artery stenting is recognized as an effective treatment and became the standard therapy for iliac artery disease. CTA and vascular echo can be utilized for diagnostic purpose and diagnostic angiography is less performed. But pelvic vessels are difficult to diagnose by echo. CTA can be misread by calcification. The angiogram is still the golden standard for final decision making of iliac artery stenting.

#### **7. Femoropopliteal artery angiography**

Patients with disease limited to superficial femoral artery (SFA) usually present with claudication. However, most of severe claudication shows multi level involvement. In SFA, popliteal and infrapopliteal artery disease could be a cause of critical limb. Interventional approach to SFA is much easier than infrapopliteal artery and precise assessment of femoropopliteal artery disease in very important to deal with severe claudication and critical limb.

#### **7.1 Proximal femoral artery**

proximal femoral artery disease. In AP view, profunda femoral override to SFA (Fig. SFA 1A). In ipsilateral oblique view, separation between SFA proximal and profund femoral are well seen (Fig. SFA 1B). This view is particular important for diseased proximal femoral artery. The SFA proximal stenosis is not delineated by anterior posterior (AP) view (Fig. SFA 2A). Left anterior oblique view shows SFA ostial stenosis and found that lesion length of proximal profunda artery is longer than AP view (Fig. SFA2B). This angled view is particular useful to guide the wire into SFA ostial occlusion. In Fig SFA 3 shows the typical SFA long occlusion originating from SFA ostium (Fig. SFA 3A). In AP view, SFA ostium is not identified (Fig. SFA 3B). In left anterior oblique view, SFA ostium occlusion is well visualized (Fig. SFA 3C).

#### **7.2 Bolus chase for limb artery angiography**

To see the entire limb artery, a bolus chasing angiography is very useful method. In some angiographic system, this angiography can be done by digital subtraction with small amount contrast. We usually give 4cc/second, total 16~18cc of contrast to visualize from femoral to tibial artery. In Fig SFA 4A is the bolus chase of right limb. Infrapopliteal arteries are not well seen, but this angiogram give the right limb is not severely diseased. In Fig. SFA 4B shows the two focal stenosis with three tibial vessels run-off. The typical SFA occlusion with well developed collateral via profunda femoral artery is well seen (Fig. SFA4C).

#### **7.3 Lesion length**

marking is placed in SFA. Tape measurement is fairly consistent with marker wire and this tape can be used to measure lesion length (Fig. SFA 5). By using this tape, lesion length can be measured. Short focal lesion was measured at 1cm (Fig. SFA 6A). The lesion length of short CTO is measured at 6.5cm. In Fig. SFA 6C, 20cm long CTO is shown. In long diffuse lesion, another way to measure lesion length is to employ balloon marker. In Fig. SFA 7A, long SFA lesion is shown. By using 10cm balloon marker (Fig. SFA 7B), lesion was calculated about 20cm and two 6mmX100mm stent were implanted (Fig. SFA 7C).

Angioplasty, Various Techniques and Challenges in 152 Treatment of Congenital and Acquired Vascular Stenoses

Iliac artery stenting is recognized as an effective treatment and became the standard therapy for iliac artery disease. CTA and vascular echo can be utilized for diagnostic purpose and diagnostic angiography is less performed. But pelvic vessels are difficult to diagnose by echo. CTA can be misread by calcification. The angiogram is still the golden standard for

Patients with disease limited to superficial femoral artery (SFA) usually present with claudication. However, most of severe claudication shows multi level involvement. In SFA, popliteal and infrapopliteal artery disease could be a cause of critical limb. Interventional approach to SFA is much easier than infrapopliteal artery and precise assessment of femoropopliteal artery disease in very important to deal with severe claudication and

proximal femoral artery disease. In AP view, profunda femoral override to SFA (Fig. SFA 1A). In ipsilateral oblique view, separation between SFA proximal and profund femoral are well seen (Fig. SFA 1B). This view is particular important for diseased proximal femoral artery. The SFA proximal stenosis is not delineated by anterior posterior (AP) view (Fig. SFA 2A). Left anterior oblique view shows SFA ostial stenosis and found that lesion length of proximal profunda artery is longer than AP view (Fig. SFA2B). This angled view is particular useful to guide the wire into SFA ostial occlusion. In Fig SFA 3 shows the typical SFA long occlusion originating from SFA ostium (Fig. SFA 3A). In AP view, SFA ostium is not identified (Fig. SFA 3B). In left anterior oblique view, SFA ostium occlusion is well

To see the entire limb artery, a bolus chasing angiography is very useful method. In some angiographic system, this angiography can be done by digital subtraction with small amount contrast. We usually give 4cc/second, total 16~18cc of contrast to visualize from femoral to tibial artery. In Fig SFA 4A is the bolus chase of right limb. Infrapopliteal arteries are not well seen, but this angiogram give the right limb is not severely diseased. In Fig. SFA 4B shows the two focal stenosis with three tibial vessels run-off. The typical SFA occlusion with well developed collateral via profunda femoral artery is well seen (Fig.

marking is placed in SFA. Tape measurement is fairly consistent with marker wire and this tape can be used to measure lesion length (Fig. SFA 5). By using this tape, lesion length can be measured. Short focal lesion was measured at 1cm (Fig. SFA 6A). The lesion length of short CTO is measured at 6.5cm. In Fig. SFA 6C, 20cm long CTO is shown. In long diffuse lesion, another way to measure lesion length is to employ balloon marker. In Fig. SFA 7A, long SFA lesion is shown. By using 10cm balloon marker (Fig. SFA 7B), lesion was calculated about 20cm and two 6mmX100mm stent were implanted

**6.6 Summary** 

critical limb.

**7.1 Proximal femoral artery** 

visualized (Fig. SFA 3C).

SFA4C).

**7.3 Lesion length** 

(Fig. SFA 7C).

**7.2 Bolus chase for limb artery angiography** 

final decision making of iliac artery stenting.

**7. Femoropopliteal artery angiography** 

Fig. SFA 1: Anteroposterior view and left anterior oblique view for proximal left femoral artery A: AP view shows that profunda femoral override to SFA B: In left anterior oblique view, separation between SFA proximal and prfund femoal are well seen

Fig. SFA 2: Anteroposterior view and left anterior oblique view for proximal left femoral diseased artery A: The SFA proximal stenosis is not delineated by anterior posterior (AP) view B: Left anterior oblique view shows SFA ostial stenosis and lesion length of proximal profunda artery is longer than AP view

Angiography for Peripheral Vascular Intervention 155

To measure lesion length, maker tape is attached to frontal leg muscle. This tape is validated

**A B C**

with marker wire placed in SFA. This tape can be used to measure lesion length.

Fig. SFA 5: Marker wire and measure tape

Fig. SFA 6: Lesion length of SFA disease A: Focal lesion was measured at 1cm B: Short CTO was measured at 6.5cm. C: SFA long CTO was measured at 20cm

Fig. SFA 3: Anteroposterior view and left anterior oblique view for proximal left femoral artery occlusion A: Typical SFA long occlusion originating from ostium B: In AP view, SFA ostium is not clearly seen C: In left anterior oblique view, the stump of SFA ostium occlusion is well visualized

Fig. SFA 4: Bolus chase for limb vessel angiography

To see the entire limb artery, bolus chasing is very useful method. This angiogram can be obtained by digital subtraction with small amount dye.

A: Bolus chase of right limb. Infrapopliteal arteries are not well seen, but this angiogram shows the right lower limb is not severely diseased.

B: Two focal stenosis with three vessels run-off is shown

C: Typical SFA occlusion with well developed collateral via profunda femoral artery is well seen

Angioplasty, Various Techniques and Challenges in 154 Treatment of Congenital and Acquired Vascular Stenoses

**A B C**

C: In left anterior oblique view, the stump of SFA ostium occlusion is well visualized

**A B C**

To see the entire limb artery, bolus chasing is very useful method. This angiogram can be

A: Bolus chase of right limb. Infrapopliteal arteries are not well seen, but this angiogram shows

C: Typical SFA occlusion with well developed collateral via profunda femoral artery is well seen

Fig. SFA 3: Anteroposterior view and left anterior oblique view for proximal left femoral artery occlusion A: Typical SFA long occlusion originating from ostium

Fig. SFA 4: Bolus chase for limb vessel angiography

the right lower limb is not severely diseased.

obtained by digital subtraction with small amount dye.

B: Two focal stenosis with three vessels run-off is shown

B: In AP view, SFA ostium is not clearly seen

Fig. SFA 5: Marker wire and measure tape

To measure lesion length, maker tape is attached to frontal leg muscle. This tape is validated with marker wire placed in SFA. This tape can be used to measure lesion length.

Fig. SFA 6: Lesion length of SFA disease A: Focal lesion was measured at 1cm B: Short CTO was measured at 6.5cm. C: SFA long CTO was measured at 20cm

Angiography for Peripheral Vascular Intervention 157

**A B C D**

Fig. SFA 8: Lesion classification based on TASC ll guideline (13)

A: TASC A is a single focal lesion less than 10 cm in length

C: TASC C is multiple stenosis more than 15cm lesion length D: TASC D is a long CTO and lesion length is more than 20cm

**A B C**

B: TASC B is a single CTO lesion less than 15cm

Fig. SFA 9: Balloon angioplasty

A: A sort focal lesion in distal SFA

In short lesion, initial approach is the balloon angioplasty

B: Balloon angioplasty was performed 5X40mm balloon at 8 ATM

C: Post balloon angioplasty showed a residual less than 50% stenosis at ballooning site

surgery.

TASC II guideline gives the standard indication of interventional treatment or bypass

Fig. SFA 7: Lesion length measured by balloon marker


C: Lesion was calculated about 20cm and two 6mmX100mm stent were implanted

#### **7.4 TASC II Classification(13)**

Before intervening the lesion, lesion length and morphology can be classified according to TASC II guideline (13). It will give the standard indication of interventional treatment or bypass surgery. Fig. SFA 8A shows a single focal lesion less than 10 cm in length and did not involve the origins of SFA. This lesion is classified into type A (Fig. SFA8A). Fig. SFA 8B is a single CTO lesion less than 15cm and considered to be type B (Fig. SFA 8B). Fig. SFA 8C shows multiple stenosis more than 15cm lesion length and a typical example of type C (Fig. SFA 8C). Fig. SFA 8D shows the long CTO and lesion length is more than 20cm (Fig.SFA 8D). This is the typical type D and stenting for this kind of lesion could be a high chance of restenosis.

#### **7.5 Ballooning or stenting**

In iliac artery disease, primary stenting is firmly established. In femoropopliteal artery disease, it is still controversial about primary stenting. In short lesion, the initial approach is still balloon angioplasty (Fig. SFA 9A, B). Angiogram of post balloon angioplasty shows suboptimal result (Fig. SFA 9C). But in reality, most of the lesion needs to be stented. Fig. SFA 10A shows the typical 5cm stenostic lesion and balloon angioplasty was performed (Fig. SFA10B). Balloon dilatation resulted in dissection and bail out stenting was performed. Nitionol stenting could seal dissection with no residual stenosis (Fig. SFA 10C).

Angioplasty, Various Techniques and Challenges in 156 Treatment of Congenital and Acquired Vascular Stenoses

SMART 6 X100

SMART 6 X100

5mmX100mm

Fig. SFA 7: Lesion length measured by balloon marker

A B C

B: Measring lesion length by using 10cm balloon marker

C: Lesion was calculated about 20cm and two 6mmX100mm stent were implanted

typical type D and stenting for this kind of lesion could be a high chance of restenosis.

Nitionol stenting could seal dissection with no residual stenosis (Fig. SFA 10C).

Before intervening the lesion, lesion length and morphology can be classified according to TASC II guideline (13). It will give the standard indication of interventional treatment or bypass surgery. Fig. SFA 8A shows a single focal lesion less than 10 cm in length and did not involve the origins of SFA. This lesion is classified into type A (Fig. SFA8A). Fig. SFA 8B is a single CTO lesion less than 15cm and considered to be type B (Fig. SFA 8B). Fig. SFA 8C shows multiple stenosis more than 15cm lesion length and a typical example of type C (Fig. SFA 8C). Fig. SFA 8D shows the long CTO and lesion length is more than 20cm (Fig.SFA 8D). This is the

In iliac artery disease, primary stenting is firmly established. In femoropopliteal artery disease, it is still controversial about primary stenting. In short lesion, the initial approach is still balloon angioplasty (Fig. SFA 9A, B). Angiogram of post balloon angioplasty shows suboptimal result (Fig. SFA 9C). But in reality, most of the lesion needs to be stented. Fig. SFA 10A shows the typical 5cm stenostic lesion and balloon angioplasty was performed (Fig. SFA10B). Balloon dilatation resulted in dissection and bail out stenting was performed.

A: SFA long diffuse lesion

**7.4 TASC II Classification(13)** 

**7.5 Ballooning or stenting** 

Fig. SFA 8: Lesion classification based on TASC ll guideline (13) TASC II guideline gives the standard indication of interventional treatment or bypass surgery.

A: TASC A is a single focal lesion less than 10 cm in length

B: TASC B is a single CTO lesion less than 15cm

C: TASC C is multiple stenosis more than 15cm lesion length

D: TASC D is a long CTO and lesion length is more than 20cm

Fig. SFA 9: Balloon angioplasty

In short lesion, initial approach is the balloon angioplasty

A: A sort focal lesion in distal SFA

B: Balloon angioplasty was performed 5X40mm balloon at 8 ATM

C: Post balloon angioplasty showed a residual less than 50% stenosis at ballooning site

Angiography for Peripheral Vascular Intervention 159

**A B**

A: Wall stent was implanted at 8 years ago. The stent showed complete traverse liner

**A B C**

separation without stent displacement. This is called type 3 stent dissection.

Fig. SFA 11: Stent fracture

B: There is no restenosis at fractured site

Fig. SFA 12: Stent fracture with restenosis

**8. Below the knee angiography** 

A: There is a focal restenosis at SMART stent implanted site. B: In plain view, multiple separation of strut are seen

C: More magnified view shows, multiple stent strut were separated

Infrapopliteal atherosclerotic lesions are common in critical limb ischemia and to assess these lesions, a meticulous angiographic technique should be taken. In Below the knee (BTK) angiogram, 4 BTK arterial segments (tibioperoneal trunk, anterior tibial, posterior tibial arteries and peroneal artery) must be separated and identified. And also, continuation

Fig. SFA 10: Bail out stenting post balloon angioplasty

A: 5cm stenostic lesion

B: Balloon angioplasty was performed and resulted in dissection

C: Nitinol stenting for bail out purpose succeeded to seal the dissection

#### **7.6 Stent fracture**

Stent fracture in SFA is a growing concern **(14)**. In most of the cases, stent fracture are not related to restenosis. Wall stent was implanted at 8 years ago (Fig. 10A). The stent showed complete traverse liner separation without stent displacement. This is called type 3 stent fracture. But there is a stent fracture related to restenosis. In Fig. SFA 11A, there is a focal restenosis at SMART stent implanted site. In plain view, multiple separation of strut is seen (Fig. SFFA 11B). Magnified view shows, multiple stent strut were separated (Fig. SFA 11C). This stent fracture could be a cause of restenosis.

#### **7.7 Stent restenosis**

In recent years, studies have demonstrated the superiority of stents over balloon angioplasty as far as primary patency is concerned **(15)**. In some center, SFA Nitinol stent is empoloyed as primary use. However, stent restenosis is still the big issue for primary stenting. SFA long CTO originating from SFA ostium was shown in Fig. SFA 12A. Successful recanalization was obtained with stenting (Fig. SFA 12B). Angiogram at 6 months showed stent restenosis with new stenosis in profund femoral artery (Fig. SFA 12C). This restenosis is clearly seen in non subtracted angiogram (Fig. SFA12D). This suggest stent affecting to other vessel as the chronic cell proliferation.

#### **7.8 Summary**

SFA is the longest vessel and is difficult to visualize entire vessel. In proximal part of SFA should be taken by ipsilateral view. To evaluate lesion severity, lesion length is the important factor for endovascular approach. The precise lesion length measurement must be made. Stent restenosis after endovascular treatment of SFA obstructions is still the big concern.

Angioplasty, Various Techniques and Challenges in 158 Treatment of Congenital and Acquired Vascular Stenoses

Pre Post ballooning Post stenting

**A B C**

Stent fracture in SFA is a growing concern **(14)**. In most of the cases, stent fracture are not related to restenosis. Wall stent was implanted at 8 years ago (Fig. 10A). The stent showed complete traverse liner separation without stent displacement. This is called type 3 stent fracture. But there is a stent fracture related to restenosis. In Fig. SFA 11A, there is a focal restenosis at SMART stent implanted site. In plain view, multiple separation of strut is seen (Fig. SFFA 11B). Magnified view shows, multiple stent strut were separated (Fig. SFA 11C).

In recent years, studies have demonstrated the superiority of stents over balloon angioplasty as far as primary patency is concerned **(15)**. In some center, SFA Nitinol stent is empoloyed as primary use. However, stent restenosis is still the big issue for primary stenting. SFA long CTO originating from SFA ostium was shown in Fig. SFA 12A. Successful recanalization was obtained with stenting (Fig. SFA 12B). Angiogram at 6 months showed stent restenosis with new stenosis in profund femoral artery (Fig. SFA 12C). This restenosis is clearly seen in non subtracted angiogram (Fig. SFA12D). This suggest stent affecting to other vessel as the

SFA is the longest vessel and is difficult to visualize entire vessel. In proximal part of SFA should be taken by ipsilateral view. To evaluate lesion severity, lesion length is the important factor for endovascular approach. The precise lesion length measurement must be made. Stent restenosis after endovascular treatment of SFA obstructions is still the big

Fig. SFA 10: Bail out stenting post balloon angioplasty

This stent fracture could be a cause of restenosis.

B: Balloon angioplasty was performed and resulted in dissection C: Nitinol stenting for bail out purpose succeeded to seal the dissection

A: 5cm stenostic lesion

**7.6 Stent fracture** 

**7.7 Stent restenosis** 

chronic cell proliferation.

**7.8 Summary** 

concern.

Fig. SFA 11: Stent fracture

A: Wall stent was implanted at 8 years ago. The stent showed complete traverse liner separation without stent displacement. This is called type 3 stent dissection. B: There is no restenosis at fractured site

Fig. SFA 12: Stent fracture with restenosis

A: There is a focal restenosis at SMART stent implanted site.

B: In plain view, multiple separation of strut are seen

C: More magnified view shows, multiple stent strut were separated

#### **8. Below the knee angiography**

Infrapopliteal atherosclerotic lesions are common in critical limb ischemia and to assess these lesions, a meticulous angiographic technique should be taken. In Below the knee (BTK) angiogram, 4 BTK arterial segments (tibioperoneal trunk, anterior tibial, posterior tibial arteries and peroneal artery) must be separated and identified. And also, continuation

Angiography for Peripheral Vascular Intervention 161

**E**

**F**

**D**

**A B C**

A: Ipsilateral left femoropopliteal to infrapoplital artery angiogram. This angiogram could

Proximal left anterotibial artery is well seen. But posterotibial and peroneal artery are over

artery is not seen and considered two vessels run off. In Fig. BTK 3C, peroneal and posterotibial artery are patent and means two vessel runoff., In Fig. BTK 3D, only personal

In Fig. BTK 4, both cases are single vessel disease with peroneal artery patent. These 2 cases, one peroneal artery is patent, but have active ulcer. It means that peroneal artery is not good enough for supplying foot arteries.(Fig. BTK 4). Peroneal artery terminates at the ankle and gives collateral to planter artery (Fig. BTK 4A). In Fig. BTK 4B, peroneal artery gives the collateral to dorsal pedis. This means to revascularize either anterotibial or posteriotibial artery

Before intervening BTK vessels, target vessel have to be clearly identified. In Fig. BTK 5, patient is a 65 year old man with diabetes and presented with right 4th and 5th toe ulcer. Pre

D: Lower right anterio oblique view. In this view, distal 3 tibial arteies are separated.

Figure BTK 1: Basic below the knee angiography

Proximal three tibial arteries are well separated.

artery is patent and shows the one vessel run off.

must be recanalaized for the successful angioplasty.

**8.5 BTK angiogram of pre and post balloon angioplasty** 

**8.4 Single vessel run off of peroneal artery** 

B: BTK angiography shows the entire three tibial arteries.

rule out the inflow disease.

rapped.

C: Upper right anterio oblique view.

E: Upper left anterior oblique view.

F: Lower left anterior oblique view. Distal Posterotibial artery is well seen.

Figure SFA 13: Stent restenosis

A: SFA occlusion originating from ostium

B: Succeful recanalization was obtained with Nitinol stenting

C: At 6 months, angiography showed SFA stent restenosis with a new stenosis in profund femoral artery.

D: This restenosis is clearly seen in non subtracted angiogram

from anterotibial artery to dorsal pedis and posetotibial to planter artery have to be delineated. BTK arteries are most complicated vessels and difficult to identify each three vessels. Meticulous angiographic approach should be taken to visualize three tibila arteries.

#### **8.1 Basic angiography for BTK**

Femoropopliteal artery angiogram must be taken to rule out inflow disease (Fig. BTK 1A). After confirming no inflow disease is present, BTK angiography is performed through the catheter located at distal popliteal artery (Fig. BTK 1B). This BTK angiogram is to show three tibial arteries and antero tibial artery is occluded. To locate exact lesion location, we take 4 views. These are two right anterior oblique view (RAO) (Fig. BTK 1C, 1D)and two left anterior oblique view (LAO) taken (Fig. BTK 1E, 1F). In upper RAO, proximal left anterotibial artery is well seen (Fig. BTK 1C). In lower RAO view, distal three tibial arteries are well seen (Fig. BTK 1D). In this case, distal anterotibial artery is occluded. In upper LAO, three tibial arteries are separated (Fig. BTK 1E). In lower LAO view, anterotibial and peroneal artery overrap and could not separate these two vessels (Fig. BTK 1F).

#### **8.2 Anatomical variation of infrapopliteal arteries**

Branching variations of the popliteal artery are not uncommon. A practical triad classification of the anatomical variation in the branching pattern is reported **(17)**. Type 1 indicates a normal level of popliteal arterial branching, including the usual pattern (Fig. BTK 2A) and trifurcation (Fig. BTK 2B). Type 2 indicates a high division of popliteal artery branching. In Fig. BTK 2C, anterotibial artery arises at the knee joint. Type 3 indicates hypoplastic or branching with an altered distal supply, including a hypoplastic posterotibial (Fig. BTK 2D) and a hypoplastic antrotibial (Fig. BTK 2E) .There are more other variation, but we have to keep in mind variant tibial arteries are not uncommon.

#### **8.3 Numbers of patent tibial arteries**

After completing initial angiogram, we have to evaluate how many tibial arteries are patent. In normal BTK arteries, three vessels are patent (Fig. BTK 3A.) In Fig. BTK 3B, peroneal Angioplasty, Various Techniques and Challenges in 160 Treatment of Congenital and Acquired Vascular Stenoses

**A B C D**

C: At 6 months, angiography showed SFA stent restenosis with a new stenosis in profund

from anterotibial artery to dorsal pedis and posetotibial to planter artery have to be delineated. BTK arteries are most complicated vessels and difficult to identify each three vessels. Meticulous angiographic approach should be taken to visualize three tibila arteries.

Femoropopliteal artery angiogram must be taken to rule out inflow disease (Fig. BTK 1A). After confirming no inflow disease is present, BTK angiography is performed through the catheter located at distal popliteal artery (Fig. BTK 1B). This BTK angiogram is to show three tibial arteries and antero tibial artery is occluded. To locate exact lesion location, we take 4 views. These are two right anterior oblique view (RAO) (Fig. BTK 1C, 1D)and two left anterior oblique view (LAO) taken (Fig. BTK 1E, 1F). In upper RAO, proximal left anterotibial artery is well seen (Fig. BTK 1C). In lower RAO view, distal three tibial arteries are well seen (Fig. BTK 1D). In this case, distal anterotibial artery is occluded. In upper LAO, three tibial arteries are separated (Fig. BTK 1E). In lower LAO view, anterotibial and

Branching variations of the popliteal artery are not uncommon. A practical triad classification of the anatomical variation in the branching pattern is reported **(17)**. Type 1 indicates a normal level of popliteal arterial branching, including the usual pattern (Fig. BTK 2A) and trifurcation (Fig. BTK 2B). Type 2 indicates a high division of popliteal artery branching. In Fig. BTK 2C, anterotibial artery arises at the knee joint. Type 3 indicates hypoplastic or branching with an altered distal supply, including a hypoplastic posterotibial (Fig. BTK 2D) and a hypoplastic antrotibial (Fig. BTK 2E) .There are more other variation, but

After completing initial angiogram, we have to evaluate how many tibial arteries are patent. In normal BTK arteries, three vessels are patent (Fig. BTK 3A.) In Fig. BTK 3B, peroneal

peroneal artery overrap and could not separate these two vessels (Fig. BTK 1F).

**8.2 Anatomical variation of infrapopliteal arteries** 

**8.3 Numbers of patent tibial arteries** 

we have to keep in mind variant tibial arteries are not uncommon.

Figure SFA 13: Stent restenosis

**8.1 Basic angiography for BTK** 

femoral artery.

A: SFA occlusion originating from ostium

B: Succeful recanalization was obtained with Nitinol stenting

D: This restenosis is clearly seen in non subtracted angiogram

Figure BTK 1: Basic below the knee angiography

A: Ipsilateral left femoropopliteal to infrapoplital artery angiogram. This angiogram could rule out the inflow disease.

B: BTK angiography shows the entire three tibial arteries.

C: Upper right anterio oblique view.

Proximal left anterotibial artery is well seen. But posterotibial and peroneal artery are over rapped.

D: Lower right anterio oblique view. In this view, distal 3 tibial arteies are separated.

E: Upper left anterior oblique view.

Proximal three tibial arteries are well separated.

F: Lower left anterior oblique view.

Distal Posterotibial artery is well seen.

artery is not seen and considered two vessels run off. In Fig. BTK 3C, peroneal and posterotibial artery are patent and means two vessel runoff., In Fig. BTK 3D, only personal artery is patent and shows the one vessel run off.

#### **8.4 Single vessel run off of peroneal artery**

In Fig. BTK 4, both cases are single vessel disease with peroneal artery patent. These 2 cases, one peroneal artery is patent, but have active ulcer. It means that peroneal artery is not good enough for supplying foot arteries.(Fig. BTK 4). Peroneal artery terminates at the ankle and gives collateral to planter artery (Fig. BTK 4A). In Fig. BTK 4B, peroneal artery gives the collateral to dorsal pedis. This means to revascularize either anterotibial or posteriotibial artery must be recanalaized for the successful angioplasty.

#### **8.5 BTK angiogram of pre and post balloon angioplasty**

Before intervening BTK vessels, target vessel have to be clearly identified. In Fig. BTK 5, patient is a 65 year old man with diabetes and presented with right 4th and 5th toe ulcer. Pre

Angiography for Peripheral Vascular Intervention 163

**A B**

Fig. BTK 4: Single vesses runoff of peroneal artery in patients with critical limb A: Peroneal artery terminates at the ankle and gives collateral to planter artery B: Peroneal artery terminates at the ankle and gives collateral to dorsal pedis.

**A B**

Fig. BTK 5: Pre interventional BTK angiography for critical limb ischemia A 65 year old man with diabetes and presented with right 4th and 5th toe ulcer.

Right anterotibial and posterotibial arteries were occluded and peroneal artery is patent

**C**

**D**

**E**

Right dorsal pedis was patent; D: The upper LAO view - Only peroneal artery is patent E: The lower LAO view - Right antrotibial artery was occluded at the ankle and dorsal pedis artery is getting collateral through peroneal artery. Right planter artery is not well seen

Three tibial arteries and right antrotibial artery was occluded at proximal portion

giving sufficient flow distal to ankle.

A: Bolus chase

B: The upper RAO view

C: The lower RAO view

In these two cases, single vessel are patent but ulcer does not heal. Peroneal artery is not

Fig. BTK 2: Anatomical variation of tibial arteries

A: Type 1-A

A normal level of arterial branching and most common pattern. The first brach is antrotibial artery and peroneal trunk separate to peroneal and posterotibial artery.

B: Type 1-B

A normal level of arterial branching. The three tibial arteries show trifurcation.

C: Type 2-A

A high division of popliteal artery branching and antrotibial artery arises at the knee joint. D: Type3-A

Hypoplastic posterotibial artery and peroneal artery is giving a distal supply. E: Type 3-B

Hypoplastic anterotibial artery and peroneal artery is giving a distal supply.

D: One vessel, peroneal arterry is patent

Fig. BTK 3: Number of patent tibial arteries

A: Three vessels are patent

B: Two vessels are with occluded peroneal artery

C: Two vessels are with occluded anterotibial artery

Angioplasty, Various Techniques and Challenges in 162 Treatment of Congenital and Acquired Vascular Stenoses

Type1-A Type1-B Type2-A Type3-A Type3-B

**A B C D E**

A normal level of arterial branching and most common pattern. The first brach is antrotibial

A high division of popliteal artery branching and antrotibial artery arises at the knee joint.

**A B C D**

artery and peroneal trunk separate to peroneal and posterotibial artery.

A normal level of arterial branching. The three tibial arteries show trifurcation.

Hypoplastic posterotibial artery and peroneal artery is giving a distal supply.

Hypoplastic anterotibial artery and peroneal artery is giving a distal supply.

Fig. BTK 2: Anatomical variation of tibial arteries

D: One vessel, peroneal arterry is patent

Fig. BTK 3: Number of patent tibial arteries

B: Two vessels are with occluded peroneal artery C: Two vessels are with occluded anterotibial artery

A: Three vessels are patent

A: Type 1-A

B: Type 1-B

C: Type 2-A

D: Type3-A

E: Type 3-B

Fig. BTK 4: Single vesses runoff of peroneal artery in patients with critical limb A: Peroneal artery terminates at the ankle and gives collateral to planter artery B: Peroneal artery terminates at the ankle and gives collateral to dorsal pedis. In these two cases, single vessel are patent but ulcer does not heal. Peroneal artery is not giving sufficient flow distal to ankle.

Fig. BTK 5: Pre interventional BTK angiography for critical limb ischemia A 65 year old man with diabetes and presented with right 4th and 5th toe ulcer. A: Bolus chase

Right anterotibial and posterotibial arteries were occluded and peroneal artery is patent B: The upper RAO view

Three tibial arteries and right antrotibial artery was occluded at proximal portion C: The lower RAO view

Right dorsal pedis was patent; D: The upper LAO view - Only peroneal artery is patent E: The lower LAO view - Right antrotibial artery was occluded at the ankle and dorsal pedis artery is getting collateral through peroneal artery. Right planter artery is not well seen

Angiography for Peripheral Vascular Intervention 165

**D**

**E**

Fig. BTK 7: Post interventional BTK angiography for critical limb ischemia

The continutity between anterotibial and dorsal pedis artery is confirmed.

Right anterotibial artery was recanalized and straight line to dorsal pedis artery was

**C**

Right anterotibial artery was patent but midportion of anterotibial artery overrides with

In dealing with critical limb ischemia, precise knowledge of foot artery anatomy is needed. However, severe ischemic limb, foot artery angiogram is hard to obtain by the patient's leg movement. To minimize this problem, injection of small amount of contrast with inflow revascularization is mandatory. In Fig. BTK 8, typical ischemic foot artery is shown. Basically two views are good enough. One is antero-posterior view and the other is lateral view. In lateral view, complete occlusion of poterotibial artery is well seen and dorsal pedis show the short occlusion (Fig. BTK 8A). In anterior view, plantaris medial and lateralis are well separated (Fig. BTK 8B). And in anterior view, dorsalis pedis is well seen and suited for

The effectiveness of BTK angioplasty for revascularization is well known **(18).** However, BTK angiography is one of the most difficult vessel for angiogram. Tibial arteries are small

A: Bolus chase

peroneal artery.

**8.7 Summary** 

B: The upper RAO view

C: The lower RAO view

D: The upper LAO view

E: The lower LAO view

**8.6 Foot artery angiogram** 

Recanalized right anterotibial artey is well seen

**A B**

Right anterotibial to dorsal pedis artey is shown.

Retrograde dorsal pedis puncture (Fig. BTK 8B).

established.

intervention angiography showed right anterotibial and posterotibial arteries were occluded (Fig. BTK 5A). Two right anterior oblique view (RAO) (Fig. BTK 5B, C) and two left anterior oblique (LAO) (Fig. BTK 5D, E) views were taken. The upper RAO showed three tibial arteries and right antrotibial artery was occluded at proximal portion (Fig. BTK 5B). The lower RAO view showed right dorsal pedis was patent (Fig. BTK 5C). The upper LAO view showed only peroneal is patent t (Fig. BTK 5D). The lower LAO view revealed right antrotibial artery was occluded at the ankle and right planter artery is not well seen (Fig. BTK 5E). Based on these angiograms, right antrotibial artery occlusion was targeted. By using 2.5mmX10cm over the wire balloon system, occluded anteoritibial artery was recanalaized (Fig. BTK 6). Post angioplasty angiogram was shown in Fig. BTK 7. Post intervention angiography showed right anterotibial was successfully recanalaized.and (Fig. BTK 7A). Two right anterior oblique view(RAO) (Fig. BTK 7B,C) and two left anterior oblique(LAO) (Fig. BTK 7D,E) views were taken to confirm the recanalized right antrotibial artery. The upper RAO showed three tibial arteries and right antrotibial artery was recanalized(Fig. BTK 5B). The lower RAO view showed peroneal override with anterotibial artery and could not separate two vessels(Fig. BTK 7C). The upper LAO view showed opened antrotibial artery(Fig. BTK 7D). The lower LAO view showed continuity between antrotibial to dorsal pedis was established (Fig. BTK 7E).

Fig. BTK 6: Balloon angioplasty to occluded anterotibial artery

Based on these angiograms, right antrotibial artery occlusion was targeted.

A: By using 2.5mmX10cm over the wire balloon system, the occluded proximal anteoritibila artery was recanalaized

B: The wire advanced to dorsal pedis and succeeded to recanalization

Angioplasty, Various Techniques and Challenges in 164 Treatment of Congenital and Acquired Vascular Stenoses

intervention angiography showed right anterotibial and posterotibial arteries were occluded (Fig. BTK 5A). Two right anterior oblique view (RAO) (Fig. BTK 5B, C) and two left anterior oblique (LAO) (Fig. BTK 5D, E) views were taken. The upper RAO showed three tibial arteries and right antrotibial artery was occluded at proximal portion (Fig. BTK 5B). The lower RAO view showed right dorsal pedis was patent (Fig. BTK 5C). The upper LAO view showed only peroneal is patent t (Fig. BTK 5D). The lower LAO view revealed right antrotibial artery was occluded at the ankle and right planter artery is not well seen (Fig. BTK 5E). Based on these angiograms, right antrotibial artery occlusion was targeted. By using 2.5mmX10cm over the wire balloon system, occluded anteoritibial artery was recanalaized (Fig. BTK 6). Post angioplasty angiogram was shown in Fig. BTK 7. Post intervention angiography showed right anterotibial was successfully recanalaized.and (Fig. BTK 7A). Two right anterior oblique view(RAO) (Fig. BTK 7B,C) and two left anterior oblique(LAO) (Fig. BTK 7D,E) views were taken to confirm the recanalized right antrotibial artery. The upper RAO showed three tibial arteries and right antrotibial artery was recanalized(Fig. BTK 5B). The lower RAO view showed peroneal override with anterotibial artery and could not separate two vessels(Fig. BTK 7C). The upper LAO view showed opened antrotibial artery(Fig. BTK 7D). The lower LAO view showed continuity between

antrotibial to dorsal pedis was established (Fig. BTK 7E).

Fig. BTK 6: Balloon angioplasty to occluded anterotibial artery

artery was recanalaized

Based on these angiograms, right antrotibial artery occlusion was targeted.

B: The wire advanced to dorsal pedis and succeeded to recanalization

A: By using 2.5mmX10cm over the wire balloon system, the occluded proximal anteoritibila

Fig. BTK 7: Post interventional BTK angiography for critical limb ischemia

A: Bolus chase Right anterotibial artery was recanalized and straight line to dorsal pedis artery was established.

B: The upper RAO view

Right anterotibial artery was patent but midportion of anterotibial artery overrides with peroneal artery.

C: The lower RAO view

The continutity between anterotibial and dorsal pedis artery is confirmed.

D: The upper LAO view

Recanalized right anterotibial artey is well seen

E: The lower LAO view

Right anterotibial to dorsal pedis artey is shown.

#### **8.6 Foot artery angiogram**

In dealing with critical limb ischemia, precise knowledge of foot artery anatomy is needed. However, severe ischemic limb, foot artery angiogram is hard to obtain by the patient's leg movement. To minimize this problem, injection of small amount of contrast with inflow revascularization is mandatory. In Fig. BTK 8, typical ischemic foot artery is shown. Basically two views are good enough. One is antero-posterior view and the other is lateral view. In lateral view, complete occlusion of poterotibial artery is well seen and dorsal pedis show the short occlusion (Fig. BTK 8A). In anterior view, plantaris medial and lateralis are well separated (Fig. BTK 8B). And in anterior view, dorsalis pedis is well seen and suited for Retrograde dorsal pedis puncture (Fig. BTK 8B).

#### **8.7 Summary**

The effectiveness of BTK angioplasty for revascularization is well known **(18).** However, BTK angiography is one of the most difficult vessel for angiogram. Tibial arteries are small

Angiography for Peripheral Vascular Intervention 167

[3] Nedeltchev K, Pattynama PM, Biaminoo G, Diehm N, Jaff MR, Hopkins LN, Ramee S,

[4] Saba L, Mallarini G. MDCTA of carotid plaque degree of stenosis: evaluation of interobserver agreement. AJR Am J Roentgenol. 2008 Jan;190(1):W41-6. [5] North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial

[6] Peeters P, Verbist J, Deloose K, Bosiers M. Endovascular treatment strategies for supra-

[7] Donmez H, Mavili E, Kaya MG, Soylu SO, Toker B. Endovascular treatment of coronary steal. Cardiovasc Revasc Med. 2011 Jan-Feb;12(1):67.e1-3. Epub 2010 Oct 20. [8] Textor SC, Lerman L, McKusick M. The uncertain value of renal artery interventions:

[9] Kalra PA, Guo H, Kausz AT, Gilbertson DT, Liu J, Chen SC, Ishani A, Collins AJ, Foley

[10] ASTRAL Investigators, Wheatley K, Ives N, Gray R, Kalra PA, Moss JG, Baigent C, Carr

[11] Cicuto KP, McLean GK, Oleaga JA, Freiman DB, Grossman RA, Ring EJ. Renal artery

[12] Lederman RJ, Mendelsohn FO, Santos R, Phillips HR, Stack RS, Crowley JJ.Primary

[13] Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II

[14] Jaff M, Dake M, Pompa J, Ansel G, Yoder T. Standardized evaluation and reporting of

[15] Mewissen MW. Primary nitinol stenting for femoropopliteal disease. J Endovasc Ther.

[16] Laird JR. Limitations of percutaneous transluminal angioplasty and stenting for the

[17] Day CP, Orme R. Popliteal artery branching patterns -- an angiographic study. Clin

Arterial Disease (TASCII). J Vasc Surg. 2007 Jan;45 Suppl S:S5-67.

Where are we now? JACC Cardiovasc Interv 2009;2:175–182

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effect of carotid endarterectomy in symptomatic patients with high-grade stenosis.

aortic arterial occlusive disease. J Cardiovasc Surg (Torino). 2005 Jun;46(3):193-

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Fig. BTK 8: Foot artery angiogram:

A: Lateral view of left foot

Complete occlusion of poterotibial artery is well seen and dorsal pedis show the short occlusion

B: Anteroposterior view

Plantaris medial and lateralis artery are well separated. In anterior view, occluded dorsalis pedis artery is well seen

sized vessels with complicated anatomy. The amount of dye for injection is limited by patient's leg movement. However, angiogram is the only way to get the correct information BTK. The meticulous approach for BTK angiography should be taken.

#### **9. Reference**


Angioplasty, Various Techniques and Challenges in 166 Treatment of Congenital and Acquired Vascular Stenoses

Complete occlusion of poterotibial artery is well seen and dorsal pedis show the short

BTK. The meticulous approach for BTK angiography should be taken.

value of this guideline. Circulation. 2006; 113:e409–e449.

Radiol. 2004 ;15(1 Pt 2):S111-21.

Plantaris medial and lateralis artery are well separated. In anterior view, occluded dorsalis

sized vessels with complicated anatomy. The amount of dye for injection is limited by patient's leg movement. However, angiogram is the only way to get the correct information

[1] Wakhloo AK, Lieber BB, Seong J, Sadasivan C, Gounis MJ, Miskolczi L, Sandhu

[2] Sacco RL , Adams R, Albers G, et al; American Heart Association/American Stroke

JS.Hemodynamics of carotid artery atherosclerotic occlusive disease. J Vasc Interv

Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guideline for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council onStroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the

Fig. BTK 8: Foot artery angiogram:

A: Lateral view of left foot

B: Anteroposterior view

pedis artery is well seen

**9. Reference** 

occlusion


**Arterial Angioplasty in Congential Heart Disease** 

This chapter will describe the historical background, technical issues, outcomes, and future considerations of angioplasty to treat various congenital heart lesions in both the systemic and pulmonary arteries. Intravascular stent placement will be mentioned briefly, but the primary focus will be balloon angioplasty of arterial stenosis. Peripheral stenoses secondary

Coarctation of the aorta is a condition where the aorta is narrowed in the area where the ductus arteriosus inserts (Figure 1). Coarctation represents 5-10% of all congenital heart disease. Coarctation is more common in Caucasian than Asian individuals and is less common among Native Americans. Males are affected 1.6-1.8 times as often as females. The overall incidence of coarctation in the United States is 64 per 100,000. The presentation can range from shock in infancy after closure of the ductus arteriosus to systemic hypertension

The three treatment modalities for coarctation of the aorta are surgery, stent placement, and balloon angioplasty (BA). Candidates for BA will be discussed in detail below. In native coarctation of the aorta, the anatomy most suitable for BA is discrete, rather than diffuse, stenosis (Figures 2a and 2b). This is not necessarily the case in recurrent coarctation, where

Balloon angioplasty of coarctation of the aorta in neonates/infants can typically be performed with low-profile balloon angioplasty catheters due to the smaller final inflation diameter required in this age group. The most common diameter used in this age group is 6- 8 mm, although as the patient approaches 12 months of age, the diameter shifts to the 8-10 mm range. The most commonly used balloons are the TyShak II balloons (NuMed Corp, Hopkington, New York). Up to 8 mm diameter balloons take an 0.021" wire, can be introduced through 4-Fr sheaths, and have a rated burst pressure (RBP) of at least 4 atmospheres (ATMs). The 9-12 mm diameter balloons take an 0.025" (9-10 mm) or 0.035" (12 mm) wire, can be introduced through 5-Fr sheaths, and have a RBP of 3.5 ATMs. TyShak Mini balloons (NuMed), with diameters from 4-10 mm, are even lower profile, using 3-Fr

discrete or diffuse lesions secondary to surgical scarring are each amenable to BA. 1-3

**1. Introduction** 

to acquired arterial lesions will not be discussed.

**2. Coarctation of the aorta 2.1 Historical background** 

in early childhood to adulthood.

**2.2 Neonates/infants** 

Thomas J. Forbes, Srinath Gowda and Daniel R. Turner *Wayne State University/Children's Hospital of Michigan, Detroit, MI* 

*USA* 

[18] Bosiers M, Deloose K, Verbist J, Peeters P. Update management below knee intervention. Minerva Cardioangiol. 2009 Feb;57(1):117-29. **8** 

## intervention. Minerva Cardioangiol. 2009 Feb;57(1):117-29. **8**

### **Arterial Angioplasty in Congential Heart Disease**

Thomas J. Forbes, Srinath Gowda and Daniel R. Turner *Wayne State University/Children's Hospital of Michigan, Detroit, MI USA* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 168 Treatment of Congenital and Acquired Vascular Stenoses

[18] Bosiers M, Deloose K, Verbist J, Peeters P. Update management below knee

This chapter will describe the historical background, technical issues, outcomes, and future considerations of angioplasty to treat various congenital heart lesions in both the systemic and pulmonary arteries. Intravascular stent placement will be mentioned briefly, but the primary focus will be balloon angioplasty of arterial stenosis. Peripheral stenoses secondary to acquired arterial lesions will not be discussed.

#### **2. Coarctation of the aorta**

#### **2.1 Historical background**

Coarctation of the aorta is a condition where the aorta is narrowed in the area where the ductus arteriosus inserts (Figure 1). Coarctation represents 5-10% of all congenital heart disease. Coarctation is more common in Caucasian than Asian individuals and is less common among Native Americans. Males are affected 1.6-1.8 times as often as females. The overall incidence of coarctation in the United States is 64 per 100,000. The presentation can range from shock in infancy after closure of the ductus arteriosus to systemic hypertension in early childhood to adulthood.

The three treatment modalities for coarctation of the aorta are surgery, stent placement, and balloon angioplasty (BA). Candidates for BA will be discussed in detail below. In native coarctation of the aorta, the anatomy most suitable for BA is discrete, rather than diffuse, stenosis (Figures 2a and 2b). This is not necessarily the case in recurrent coarctation, where discrete or diffuse lesions secondary to surgical scarring are each amenable to BA. 1-3

#### **2.2 Neonates/infants**

Balloon angioplasty of coarctation of the aorta in neonates/infants can typically be performed with low-profile balloon angioplasty catheters due to the smaller final inflation diameter required in this age group. The most common diameter used in this age group is 6- 8 mm, although as the patient approaches 12 months of age, the diameter shifts to the 8-10 mm range. The most commonly used balloons are the TyShak II balloons (NuMed Corp, Hopkington, New York). Up to 8 mm diameter balloons take an 0.021" wire, can be introduced through 4-Fr sheaths, and have a rated burst pressure (RBP) of at least 4 atmospheres (ATMs). The 9-12 mm diameter balloons take an 0.025" (9-10 mm) or 0.035" (12 mm) wire, can be introduced through 5-Fr sheaths, and have a RBP of 3.5 ATMs. TyShak Mini balloons (NuMed), with diameters from 4-10 mm, are even lower profile, using 3-Fr

Arterial Angioplasty in Congential Heart Disease 171

Corp, Bloomington, IN). Each are similar, although certain sizes of PowerFlex and ATB balloons can be advanced through sheaths that are 1-Fr size smaller than Z-Med II. Rarely, cutting balloons (CB) may be required for coarctation angioplasty.4 More specific

The standard approach for native or recurrent coarctation of the aorta is retrograde via femoral- or umbilical-arterial access. This approach offers the most direct route to treat the coarctation site. In very small infants (< 1.5 kg), alternative approaches have been reported (Figures 3a, 3b, and 3c).5 Angiograms of the coarctation and transverse aortic arch are performed prior to balloon angioplasty. In over 20% of patients, most commonly in cases of symptomatic neonatal/infant coarctation of the aorta, transverse aortic arch hypoplasia may be present. The definition of transverse aortic arch hypoplasia is a transverse arch-todescending aortic ratio of < 0.60.6-8 Measurements at the transverse aortic arch and descending aorta at the level of the diaphragm are made. The smaller of these diameters determines the size of the balloon catheter used to perform coarctation angioplasty. It is particularly important that the balloon be de-aired prior to inflation, as balloon rupture may cause air emboli into the brachiocephalic vessels. On initial inflation, one tries not to exceed a balloon-to-coarctation ratio of > 4:1.7 Pre- and immediately post-pressure measurements are obtained. After the angioplasty, it is extremely important to obtain standard and orthogonal angiographic views of the coarctation area to exclude a small dissection or aneurysm. If high pressure or cutting balloon catheters are required for adequate dilation of the coarctation segment, a covered stent should be available in the catheterization lab in case

information on CB will be given in the pulmonary angioplasty section.

one encounters aneurysm formation, an acute dissection, or vessel tear.

*Courtesy of Prada F, et al.* Rev Esp Cardiol. *2010 Jun;63(6):741-3.* 

with no evidence of recoarctation.

Fig. 3. a-c. Balloon angioplasty of a critical coarcation in a 1200 gram premature infant per the left carotid artery via a 3 Fr sheath using the Seldinger technique. A 4 mm TyShak Mini balloon was used with the coarctation segment increasing from 1.5 to 3.2 mm and a decrease in the systolic gradient from 35 to 7 mmHg. The infant developed recoarctation 2 months later and at 2200 grams underwent repeat balloon angioplasty from the femoral arterial system. At 6 months out from the procedure (5600 grams) the infant continues to do well

#### Fig. 1. Coarctation

#### Fig. 2. a-b.

sheaths up to 8 mm diameter and 4-Fr sheaths for the 9-10 mm sizes. They take an 0.014" wire and can reach RBP of at least 3.5 ATMs. Most coarctations require 3 ATMs to obtain adequate dilation of the narrowed segment.

On occasion, high-profile, non-compliant balloon angioplasty catheters may be required to adequately dilate the coarctation segment. There are numerous balloon angioplasty catheters available: PowerFlex series (4-12 mm diameter, Cordis Corp, Warren, New Jersey), Z-Med II balloons (4-30 mm diameter, NuMed), and Cook ATB (4-10 mm diameter, Cook Angioplasty, Various Techniques and Challenges in 170 Treatment of Congenital and Acquired Vascular Stenoses

sheaths up to 8 mm diameter and 4-Fr sheaths for the 9-10 mm sizes. They take an 0.014" wire and can reach RBP of at least 3.5 ATMs. Most coarctations require 3 ATMs to obtain

On occasion, high-profile, non-compliant balloon angioplasty catheters may be required to adequately dilate the coarctation segment. There are numerous balloon angioplasty catheters available: PowerFlex series (4-12 mm diameter, Cordis Corp, Warren, New Jersey), Z-Med II balloons (4-30 mm diameter, NuMed), and Cook ATB (4-10 mm diameter, Cook

Fig. 1. Coarctation

Fig. 2. a-b.

adequate dilation of the narrowed segment.

Corp, Bloomington, IN). Each are similar, although certain sizes of PowerFlex and ATB balloons can be advanced through sheaths that are 1-Fr size smaller than Z-Med II. Rarely, cutting balloons (CB) may be required for coarctation angioplasty.4 More specific information on CB will be given in the pulmonary angioplasty section.

The standard approach for native or recurrent coarctation of the aorta is retrograde via femoral- or umbilical-arterial access. This approach offers the most direct route to treat the coarctation site. In very small infants (< 1.5 kg), alternative approaches have been reported (Figures 3a, 3b, and 3c).5 Angiograms of the coarctation and transverse aortic arch are performed prior to balloon angioplasty. In over 20% of patients, most commonly in cases of symptomatic neonatal/infant coarctation of the aorta, transverse aortic arch hypoplasia may be present. The definition of transverse aortic arch hypoplasia is a transverse arch-todescending aortic ratio of < 0.60.6-8 Measurements at the transverse aortic arch and descending aorta at the level of the diaphragm are made. The smaller of these diameters determines the size of the balloon catheter used to perform coarctation angioplasty. It is particularly important that the balloon be de-aired prior to inflation, as balloon rupture may cause air emboli into the brachiocephalic vessels. On initial inflation, one tries not to exceed a balloon-to-coarctation ratio of > 4:1.7 Pre- and immediately post-pressure measurements are obtained. After the angioplasty, it is extremely important to obtain standard and orthogonal angiographic views of the coarctation area to exclude a small dissection or aneurysm. If high pressure or cutting balloon catheters are required for adequate dilation of the coarctation segment, a covered stent should be available in the catheterization lab in case one encounters aneurysm formation, an acute dissection, or vessel tear.

*Courtesy of Prada F, et al.* Rev Esp Cardiol. *2010 Jun;63(6):741-3.* 

Fig. 3. a-c. Balloon angioplasty of a critical coarcation in a 1200 gram premature infant per the left carotid artery via a 3 Fr sheath using the Seldinger technique. A 4 mm TyShak Mini balloon was used with the coarctation segment increasing from 1.5 to 3.2 mm and a decrease in the systolic gradient from 35 to 7 mmHg. The infant developed recoarctation 2 months later and at 2200 grams underwent repeat balloon angioplasty from the femoral arterial system. At 6 months out from the procedure (5600 grams) the infant continues to do well with no evidence of recoarctation.

Arterial Angioplasty in Congential Heart Disease 173

coarctation of the aorta in this age group. Although BA is considered the treatment of choice for this lesion in children and adults,12 controversy surrounds the use of BA for native

BA is performed from the retrograde femoral arterial route in the majority of children and adults undergoing BA for either recurrent or native coarctation. Recently, there have been reports of using radial access for recognition and treatment of potential complications, some advocating for BA though we, and others, feel radial access is more appropriate for stent treatment of coarctation of the aorta. 13 After a complete right and left heart catheterization is performed, the coarctation segment is approached retrograde from the descending to ascending aorta. It is important to rule out any potential left-sided lesions, including mitral valve stenosis, subaortic valve stenosis, or aortic valve stenosis, as these lesions can be also associated with coarctation of the aorta. Furthermore, significant diastolic dysfunction and increased diastolic pressures can be encountered in this patient group. For severe or nearly atretic coarctation of the aorta, crossing the narrowed segment retrograde may be quite difficult. Under those circumstances, transseptal technique is used to enter the left heart antegrade and the coarctation can then be crossed more easily from the ascending to descending aorta. Typically, either an angled 0.035" glide wire (Cook Corp, Bloomington, Indiana) or Wholey wire (Covidian Inc. Mansfield, MA) are used. The wire is then snared retrograde from the distal descending aorta and an arterial-venous loop is created, then

 Fig. 4. a-b. Comparison between the Atlas and Z Med II balloon catheters. The tapered shoulder on the Atlas balloon significantly increases the actual balloon length as well as

inflation/deflation time in comparison to the shorter Z Med II balloon.

coarctation of the aorta in these patients presenting with hypertension.

allowing retrograde delivery of the balloon to the coarctation segment.

**3.2 Technique** 

#### **2.3 Outcomes**

Infantile coarctation of the aorta typically occurs in conjunction with severe heart failure or shock. In this setting, coarctation is frequently associated with other congenital heart lesions (bicuspid aortic valve in 60-70%, ventricular septal defect in 40%, and other left-sided lesions, i.e. mitral valve stenosis, subaortic valve stenosis, and hypoplastic left ventricle 3% of the time). Performance of coarctation angioplasty is not recommended in patients with associated congenital lesions requiring surgery. The predominant treatment for isolated native coarctation of the aorta presenting in infancy is surgical repair with extended end-toend anastomoses**.** Although many believe that surgical repair is the standard of care, some have advocated that BA in high-risk patients is a reasonable initial procedure to improve their surgical candidacy.9 The overall outcome of BA is poor in infants presenting in heart failure or shock. Liang et al. performed a recent study where they evaluated 18 infants with native coarctation of the aorta and congestive heart failure who underwent balloon angioplasty. The mean age was just less than three months and the mean body weight was 4 kg. Congestive heart failure symptoms improved markedly in all patients immediately after BA. The incidence of re-coarctation was high in infants, requiring surgery if the systolic pressure gradient > 10 mmHg from ascending to descending aorta or if the coarctation diameter measured < 3 mm. The recurrent coarctation rate was 44% (8/18 patients) and the conclusion was that balloon angioplasty, in this setting, was ineffective and not recommended as a primary treatment alternative.9

In another recent study by Rau, et al., 51 infants less than 3 months of age who presented with heart failure underwent balloon coarctation angioplasty from the umbilical artery (16/51), femoral artery (26/51) and femoral venous antegrade across the inter-atrial communication (9/51). Findings included acute reduction in the peak gradient across the coarctation segment, increase in the diameter of the coarctation segment, and improved symptomatology following BA. Effective palliation was achieved in 47/51 infants (92%). At intermediate follow-up, 22/51 (43%) developed re-coarctation withn three months after balloon angioplasty, requiring either repeat BA (14/22) or surgical (8/22) intervention. Using avoidance of surgery for four weeks as the definition of success, the authors concluded that BA is an excellent alternative to surgical intervention for the management of native coarctation in the neonatal period. With > 50% of patients requiring reintervention within 10 months of initial BA, we believe that surgical treatment of this condition remains the standard of care in this subgroup of patients. 10

#### **2.4 Challenges for the future**

The development of bioabsorable stents could potentially change this treatment paradigm. There are two current challenges with bioabsorable stent technology: (1) to reliably make a stent that can reach 6-7 mm diameter with adequate radial strength to overcome the coarctation; and (2) to be able to deliver the stent though a low profile sheath (4-5-Fr if performed retrograde and up to 7-Fr if performed antegrade from the venous route). There are currently two bioabsorbable stents being evaluated with the potential to enter clinical use in Europe within the next several years.

#### **3. Aortic coarctation in children and adults**

#### **3.1 Historical overview**

Balloon angioplasty for the treatment of native or recurrent coarctation of the aorta has been performed since the mid 1980s.11 There is excellent data to support BA to treat recurrent coarctation of the aorta in this age group. Although BA is considered the treatment of choice for this lesion in children and adults,12 controversy surrounds the use of BA for native coarctation of the aorta in these patients presenting with hypertension.

#### **3.2 Technique**

Angioplasty, Various Techniques and Challenges in 172 Treatment of Congenital and Acquired Vascular Stenoses

Infantile coarctation of the aorta typically occurs in conjunction with severe heart failure or shock. In this setting, coarctation is frequently associated with other congenital heart lesions (bicuspid aortic valve in 60-70%, ventricular septal defect in 40%, and other left-sided lesions, i.e. mitral valve stenosis, subaortic valve stenosis, and hypoplastic left ventricle 3% of the time). Performance of coarctation angioplasty is not recommended in patients with associated congenital lesions requiring surgery. The predominant treatment for isolated native coarctation of the aorta presenting in infancy is surgical repair with extended end-toend anastomoses**.** Although many believe that surgical repair is the standard of care, some have advocated that BA in high-risk patients is a reasonable initial procedure to improve their surgical candidacy.9 The overall outcome of BA is poor in infants presenting in heart failure or shock. Liang et al. performed a recent study where they evaluated 18 infants with native coarctation of the aorta and congestive heart failure who underwent balloon angioplasty. The mean age was just less than three months and the mean body weight was 4 kg. Congestive heart failure symptoms improved markedly in all patients immediately after BA. The incidence of re-coarctation was high in infants, requiring surgery if the systolic pressure gradient > 10 mmHg from ascending to descending aorta or if the coarctation diameter measured < 3 mm. The recurrent coarctation rate was 44% (8/18 patients) and the conclusion was that balloon angioplasty, in this setting, was ineffective and not

In another recent study by Rau, et al., 51 infants less than 3 months of age who presented with heart failure underwent balloon coarctation angioplasty from the umbilical artery (16/51), femoral artery (26/51) and femoral venous antegrade across the inter-atrial communication (9/51). Findings included acute reduction in the peak gradient across the coarctation segment, increase in the diameter of the coarctation segment, and improved symptomatology following BA. Effective palliation was achieved in 47/51 infants (92%). At intermediate follow-up, 22/51 (43%) developed re-coarctation withn three months after balloon angioplasty, requiring either repeat BA (14/22) or surgical (8/22) intervention. Using avoidance of surgery for four weeks as the definition of success, the authors concluded that BA is an excellent alternative to surgical intervention for the management of native coarctation in the neonatal period. With > 50% of patients requiring reintervention within 10 months of initial BA, we believe that surgical treatment of this condition remains

The development of bioabsorable stents could potentially change this treatment paradigm. There are two current challenges with bioabsorable stent technology: (1) to reliably make a stent that can reach 6-7 mm diameter with adequate radial strength to overcome the coarctation; and (2) to be able to deliver the stent though a low profile sheath (4-5-Fr if performed retrograde and up to 7-Fr if performed antegrade from the venous route). There are currently two bioabsorbable stents being evaluated with the potential to enter clinical

Balloon angioplasty for the treatment of native or recurrent coarctation of the aorta has been performed since the mid 1980s.11 There is excellent data to support BA to treat recurrent

**2.3 Outcomes** 

recommended as a primary treatment alternative.9

the standard of care in this subgroup of patients. 10

use in Europe within the next several years.

**3. Aortic coarctation in children and adults** 

**2.4 Challenges for the future** 

**3.1 Historical overview** 

BA is performed from the retrograde femoral arterial route in the majority of children and adults undergoing BA for either recurrent or native coarctation. Recently, there have been reports of using radial access for recognition and treatment of potential complications, some advocating for BA though we, and others, feel radial access is more appropriate for stent treatment of coarctation of the aorta. 13 After a complete right and left heart catheterization is performed, the coarctation segment is approached retrograde from the descending to ascending aorta. It is important to rule out any potential left-sided lesions, including mitral valve stenosis, subaortic valve stenosis, or aortic valve stenosis, as these lesions can be also associated with coarctation of the aorta. Furthermore, significant diastolic dysfunction and increased diastolic pressures can be encountered in this patient group. For severe or nearly atretic coarctation of the aorta, crossing the narrowed segment retrograde may be quite difficult. Under those circumstances, transseptal technique is used to enter the left heart antegrade and the coarctation can then be crossed more easily from the ascending to descending aorta. Typically, either an angled 0.035" glide wire (Cook Corp, Bloomington, Indiana) or Wholey wire (Covidian Inc. Mansfield, MA) are used. The wire is then snared retrograde from the distal descending aorta and an arterial-venous loop is created, then allowing retrograde delivery of the balloon to the coarctation segment.

Fig. 4. a-b. Comparison between the Atlas and Z Med II balloon catheters. The tapered shoulder on the Atlas balloon significantly increases the actual balloon length as well as inflation/deflation time in comparison to the shorter Z Med II balloon.

Arterial Angioplasty in Congential Heart Disease 175

noted complete resolution of the peri-aortic hematoma with no evidence of dissection or

**(n = 26)** 

Any Complications1 23.1% 32.1% 8.3% 0.003\* Aortic Wall Injury (%) 11.5% 21.4% 3.1% 0.004\* Dissection / Intimal Tear (%) 0.0% 7.1% 0.0% 0.062 Aneurysm (%) 11.5% 14.3% 3.1% 0.040\* Coarct / Dao ratio (mean) 0.91 0.73 0.82 0.003\* Coarct / Dao 0.6 87% 79% 90% 0.247 Any Re-obstruction 19.2% 32.1% 15.4% 0.057

1Defined as any moderate to severe reobstruction, aortic wall injury (aneurysm, dissection, intimal tear)

**(n = 16)** 

Any Complications1 25.0% 43.8% 12.5% 0.020\* Aortic Wall Injury (%) 12.5% 43.8% 7.1% 0.003\* Dissection / Intimal Tear (%) 0.0% 6.3% 1.8% 0.598 Aneurysm (%) 12.5% 43.8% 5.4% <0.001 Coarct / Dao ratio (mean) 0.98 0.79 0.80 0.011\* Coarct / Dao 0.6 88% 93% 89% 1.000 Any Re-obstruction 18.8% 18.8% 14.3% 0.923

1Defined as any moderate to severe reobstruction, aortic wall injury (aneurysm, dissection, intimal tear)

 Mild2 6.3% 18.8% 12.5% Moderate 6.3% 0% 1.8% Severe 6.3% 0% 0%

2Mild reobstruction was not considered as a complication in our analysis.

Table 2. Intermediate Follow-up Outcomes by Integrated Imaging

**Balloon (n = 16)** 

**Stent (n = 56)** 

**p-value (2-sided)** 

**Balloon (n = 28)** 

**Stent (n = 97)** 

**p-value (2-sided)** 

**Outcomes Surgery** 

 Mild2 7.7% 17.9% 11.3% Moderate 7.7% 3.6% 4.1% Severe 3.9% 10.7% 0%

2Mild reobstruction was not considered as a complication in our analysis.

Table 1. Short-Term Follow-up Outcomes by Integrated Imaging

**Outcomes Surgery** 

aneurysm formation (Figures 6a-d).

or stent fracture.

or stent fracture.

\* P- value < 0.05

\* P- value < 0.05

Higher RBP for coarctation BA is more important as patients age. Although lower profile (TyShak II) balloons may be used, less compliant, higher profile balloon angioplasty catheters are usually required. PowerFlex, Maxi-Plus (Cordis corp, Warren, NJ), Z-Med II, Mullins (NuMed corp., Hopkington, NY), and Atlas (Bard Medical, Tempe, AZ) balloon angioplasty catheters have all been used. The Atlas balloon catheter has enhanced low profile (2-3 Fr sizes less than the others) and high RBP. The tapered shoulders of the Atlas balloon makes the balloon quite long and longer inflation/deflation times are required, making it more difficult to adequately position this balloon catheter across the coarctation segment (Figures 4a-b).

As one exceeds 5-6 atmospheres of pressure to achieve successful dilation of the coarctation segment, there is an increased likelihood of creating an acute dissection, aneurysm, or in rare cases, rupture of the aorta.7 It has been recommended that one not exceed four times the narrowest coarctation segment during dilation in the initial setting. Patients with extremely tight coarctation segments therefore require a staged approach.

#### **3.3 Outcomes**

Balloon angioplasty of native coarctation of the aorta is part of the treatment paradigm in children and adults. In the Congenital Cardiovascular Interventional Study Consortium (CCISC) registry comparing surgical vs. stent vs. balloon angioplasty treatment of native coarctation of the aorta in children and adults, BA appeared to have an increased risk of aneurysm formation and dissection at short-term and intermediate follow-up (Tables 1 and 2) (Journal American College of Cardiology, *in press*). The overall hemodynamic outcome related to blood pressure management and upper to lower extremity blood pressure gradient appear to be equal between the three groups at short-term and intermediate follow-up. In the subgroup of patients undergoing balloon angioplasty, the incidence of aneurysm formation was as high as 43% at intermediate follow-up, some patients requiring placement of a covered stent (Figures 5a-b). Cowley et al., in comparing surgery with balloon angioplasty for native coarctation of the aorta, showed that aneurysm formation and the need for re-intervention was significantly higher in the balloon angioplasty group compared to the surgical group.14 Hassan, et.al., looked at balloon angioplasty in the older adolescent and young adult populations only, age range from 14-54 years. In this age group, the aneurysm rate was much lower (7%) at intermediate followup.15, 16 The difference between these studies may be related to the age group of patients treated with balloon angioplasty. In the Forbes study, the mean age was 6.8 years vs. 22 years in Hassan's study. Perhaps older patients are more likely to have successful outcomes and less likely to have aneurysm formation following BA.

The most severe complication, aortic rupture or large dissection, is rare, but occurs with increased incidence in older patients. As expected, it is the non compliant, adult aorta where this is more likely to occur. Aortic rupture or large aneurysm formation does not appear to be related to exceeding the balloon:coarctation ratios of 4:1, but may be related to exceeding 6 ATMs during initial balloon inflation. In one case, a 43 yo lady with moderate hypertension and coarctation of the aorta presented for transcatheter treatment of the coarctation segment. BA was unsuccessful in relieving the gradient. Stent placement was performed using a high pressure balloon angioplasty catheter. At the end of the procedure, a small amount of contrast was observed outside of the stent posteriorly. CT scan revealed near complete transection of the aorta. One month and one year follow-up CT imaging


noted complete resolution of the peri-aortic hematoma with no evidence of dissection or aneurysm formation (Figures 6a-d).

1Defined as any moderate to severe reobstruction, aortic wall injury (aneurysm, dissection, intimal tear) or stent fracture.

2Mild reobstruction was not considered as a complication in our analysis.

\* P- value < 0.05

Angioplasty, Various Techniques and Challenges in 174 Treatment of Congenital and Acquired Vascular Stenoses

Higher RBP for coarctation BA is more important as patients age. Although lower profile (TyShak II) balloons may be used, less compliant, higher profile balloon angioplasty catheters are usually required. PowerFlex, Maxi-Plus (Cordis corp, Warren, NJ), Z-Med II, Mullins (NuMed corp., Hopkington, NY), and Atlas (Bard Medical, Tempe, AZ) balloon angioplasty catheters have all been used. The Atlas balloon catheter has enhanced low profile (2-3 Fr sizes less than the others) and high RBP. The tapered shoulders of the Atlas balloon makes the balloon quite long and longer inflation/deflation times are required, making it more difficult to adequately position this balloon catheter across the coarctation

As one exceeds 5-6 atmospheres of pressure to achieve successful dilation of the coarctation segment, there is an increased likelihood of creating an acute dissection, aneurysm, or in rare cases, rupture of the aorta.7 It has been recommended that one not exceed four times the narrowest coarctation segment during dilation in the initial setting. Patients with extremely

Balloon angioplasty of native coarctation of the aorta is part of the treatment paradigm in children and adults. In the Congenital Cardiovascular Interventional Study Consortium (CCISC) registry comparing surgical vs. stent vs. balloon angioplasty treatment of native coarctation of the aorta in children and adults, BA appeared to have an increased risk of aneurysm formation and dissection at short-term and intermediate follow-up (Tables 1 and 2) (Journal American College of Cardiology, *in press*). The overall hemodynamic outcome related to blood pressure management and upper to lower extremity blood pressure gradient appear to be equal between the three groups at short-term and intermediate follow-up. In the subgroup of patients undergoing balloon angioplasty, the incidence of aneurysm formation was as high as 43% at intermediate follow-up, some patients requiring placement of a covered stent (Figures 5a-b). Cowley et al., in comparing surgery with balloon angioplasty for native coarctation of the aorta, showed that aneurysm formation and the need for re-intervention was significantly higher in the balloon angioplasty group compared to the surgical group.14 Hassan, et.al., looked at balloon angioplasty in the older adolescent and young adult populations only, age range from 14-54 years. In this age group, the aneurysm rate was much lower (7%) at intermediate followup.15, 16 The difference between these studies may be related to the age group of patients treated with balloon angioplasty. In the Forbes study, the mean age was 6.8 years vs. 22 years in Hassan's study. Perhaps older patients are more likely to have successful outcomes

The most severe complication, aortic rupture or large dissection, is rare, but occurs with increased incidence in older patients. As expected, it is the non compliant, adult aorta where this is more likely to occur. Aortic rupture or large aneurysm formation does not appear to be related to exceeding the balloon:coarctation ratios of 4:1, but may be related to exceeding 6 ATMs during initial balloon inflation. In one case, a 43 yo lady with moderate hypertension and coarctation of the aorta presented for transcatheter treatment of the coarctation segment. BA was unsuccessful in relieving the gradient. Stent placement was performed using a high pressure balloon angioplasty catheter. At the end of the procedure, a small amount of contrast was observed outside of the stent posteriorly. CT scan revealed near complete transection of the aorta. One month and one year follow-up CT imaging

tight coarctation segments therefore require a staged approach.

and less likely to have aneurysm formation following BA.

segment (Figures 4a-b).

**3.3 Outcomes** 

Table 1. Short-Term Follow-up Outcomes by Integrated Imaging


1Defined as any moderate to severe reobstruction, aortic wall injury (aneurysm, dissection, intimal tear) or stent fracture.

2Mild reobstruction was not considered as a complication in our analysis.

\* P- value < 0.05

Table 2. Intermediate Follow-up Outcomes by Integrated Imaging

Arterial Angioplasty in Congential Heart Disease 177

**9**

**19**

**15** 

**21** 

**9.8 11.2** 

Fig. 6. a.

Fig. 6. b-c.

Fig. 5. a-b.

Fig. 6. a.

Angioplasty, Various Techniques and Challenges in 176 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 5. a-b.

Fig. 6. b-c.

Arterial Angioplasty in Congential Heart Disease 179

extremity/bowel ischemia. The current medications that may have a role in this are similar to the current medications being placed on drug eluting stents. These can be broken down into cytotoxic/cytostatic drugs, which have recently been undergoing head-to-head trials in applications to coronary stenting 18, 19 20 or "pro-healing" drugs such as endogenous growth factors or endothelial progenotor cells.21 What role, if any, in this approach to coarctation of

Balloon angioplasty, first described for use in pulmonary valve stenosis in 1983,22 has become the treatment of choice for balloon angioplasty of branch pulmonary artery stenosis in most pediatric cardiology centers. 23, 24 Surgical repair of branch pulmonary artery stenosis has been sub-optimal, associated with increased morbidity, especially in young

As with any interventional procedure, the first step in evaluating a pulmonary artery for BA is to understand the anatomy and pathophysiology of the stenotic lesion to be addressed. Generally, as in coarctation of the aorta, discrete lesions tend to be more amenable to BA compared to long segmental lesions. In Figures 7a-c, a patient with Tetralogy of Fallot with pulmonary valve atresia has multiple discrete and long segment stenosis of the right upper lobe segment. BA is performed both in the distal discrete stenosis and the more proximal long segment stenosis. Follow up imaging noted resolution of the distal discrete stenosis with persistence of the proximal stenosis, which required stent placement. In another patient with RPA stenosis following the arterial switch procedure (Figure 8), MRI imaging shows the RPA stenosis to be secondary to posterior compression from the aorta. Therefore stent

Performance of branch pulmonary artery BA is relatively straightforward and can be through a short sheath. The most difficult part of the procedure is usually crossing the stenotic segment. Accurate angiographic imaging is essential. For proximal stenosis (prior to the takeoff of the upper lobe branch), the lesion is crossed with either a 0.025 or 0.035" wire where, depending on patient size, a 4-5 Fr pigtail or multipurpose catheter is advanced over the wire into the stenosed pulmonary artery. Hand or power angiography is performed. For distal branch stenosis, the stenotic lesion is usually crossed with a glide wire and then a 4-Fr JB-1 or similar glide catheter (Cook Corp, Bloomington, IN) is advanced over the wire distal to the lesion. Hand injections can be performed through the catheter with the wire remaining in place. BA is usually carried out over that same wire. If multiple lobar segments are involved, the BA catheter is pulled back into the proximal pulmonary arterial segment and the soft tipped 0.018" wire is used to cross other stenoses. Stent treatment of multiple branch PA stenosis is usually not recommended, as many of the affected branch vessels

The balloons typically required for branch pulmonary artery BA are the higher-pressure, non-compliant balloon catheters. Typically, the more distal or peripheral the stenosis, the greater the need for higher atmosphere balloons or cutting balloons (or both) to achieve

placement, not BA, was necessary to treat this mechanical RPA stenosis.

would be "jailed off" by the stent (Figure 9a-b).

adequate BA of the stenotic segment.

the aorta, remains to be seen.

**4.1 Historical background** 

infants and children.

**4.2 Technique** 

**4. Pulmonary artery stenosis** 

Re-obstruction, as defined as an upper to lower blood pressure gradient > 20 mmHg or narrowed segment > 50% of the native vessel diameter, appears to be less common as the age at the time of initial treatment increases. Re-obstruction frequency ranges from 3-20% in older children/adults undergoing primary BA of native coarctation compared to the nearly 50% re-obstruction rate seen in infant balloon angioplasty of their native coarctation. 9, 10, 15

#### **3.4 Challenges for the future**

Stent treatment, particularly in older children and adults, appears to be the treatment of choice in treatment of native and recurrent coarctation of the aorta.7, 8, 13, 17 Permeating balloons, where a drug is injected into the vessel wall during angioplasty to prevent the development of re-stenosis, have not been successful for adequate drug delivery in animal studies. The primary challenge involves unintentional delivery of the drug directly into the blood stream, and not into the vessel wall. Placement of markers 5 mm apart, marking the permeating holes within the balloon catheter may assist us in delivering the treatment drug directly into the vessel wall, though this remains to be seen. The length of time for inflation required to deliver the medication (1-3 minutes) would require adequate collateralization around the coactation lesion to decrease the likelihood of encountering lower extremity/bowel ischemia. The current medications that may have a role in this are similar to the current medications being placed on drug eluting stents. These can be broken down into cytotoxic/cytostatic drugs, which have recently been undergoing head-to-head trials in applications to coronary stenting 18, 19 20 or "pro-healing" drugs such as endogenous growth factors or endothelial progenotor cells.21 What role, if any, in this approach to coarctation of the aorta, remains to be seen.

#### **4. Pulmonary artery stenosis**

#### **4.1 Historical background**

Balloon angioplasty, first described for use in pulmonary valve stenosis in 1983,22 has become the treatment of choice for balloon angioplasty of branch pulmonary artery stenosis in most pediatric cardiology centers. 23, 24 Surgical repair of branch pulmonary artery stenosis has been sub-optimal, associated with increased morbidity, especially in young infants and children.

#### **4.2 Technique**

Angioplasty, Various Techniques and Challenges in 178 Treatment of Congenital and Acquired Vascular Stenoses

Peri-aortic

Re-obstruction, as defined as an upper to lower blood pressure gradient > 20 mmHg or narrowed segment > 50% of the native vessel diameter, appears to be less common as the age at the time of initial treatment increases. Re-obstruction frequency ranges from 3-20% in older children/adults undergoing primary BA of native coarctation compared to the nearly 50% re-obstruction rate seen in infant balloon angioplasty of their native coarctation. 9, 10, 15

Stent treatment, particularly in older children and adults, appears to be the treatment of choice in treatment of native and recurrent coarctation of the aorta.7, 8, 13, 17 Permeating balloons, where a drug is injected into the vessel wall during angioplasty to prevent the development of re-stenosis, have not been successful for adequate drug delivery in animal studies. The primary challenge involves unintentional delivery of the drug directly into the blood stream, and not into the vessel wall. Placement of markers 5 mm apart, marking the permeating holes within the balloon catheter may assist us in delivering the treatment drug directly into the vessel wall, though this remains to be seen. The length of time for inflation required to deliver the medication (1-3 minutes) would require adequate collateralization around the coactation lesion to decrease the likelihood of encountering lower

Fig. 6. d.

**3.4 Challenges for the future** 

As with any interventional procedure, the first step in evaluating a pulmonary artery for BA is to understand the anatomy and pathophysiology of the stenotic lesion to be addressed. Generally, as in coarctation of the aorta, discrete lesions tend to be more amenable to BA compared to long segmental lesions. In Figures 7a-c, a patient with Tetralogy of Fallot with pulmonary valve atresia has multiple discrete and long segment stenosis of the right upper lobe segment. BA is performed both in the distal discrete stenosis and the more proximal long segment stenosis. Follow up imaging noted resolution of the distal discrete stenosis with persistence of the proximal stenosis, which required stent placement. In another patient with RPA stenosis following the arterial switch procedure (Figure 8), MRI imaging shows the RPA stenosis to be secondary to posterior compression from the aorta. Therefore stent placement, not BA, was necessary to treat this mechanical RPA stenosis.

Performance of branch pulmonary artery BA is relatively straightforward and can be through a short sheath. The most difficult part of the procedure is usually crossing the stenotic segment. Accurate angiographic imaging is essential. For proximal stenosis (prior to the takeoff of the upper lobe branch), the lesion is crossed with either a 0.025 or 0.035" wire where, depending on patient size, a 4-5 Fr pigtail or multipurpose catheter is advanced over the wire into the stenosed pulmonary artery. Hand or power angiography is performed. For distal branch stenosis, the stenotic lesion is usually crossed with a glide wire and then a 4-Fr JB-1 or similar glide catheter (Cook Corp, Bloomington, IN) is advanced over the wire distal to the lesion. Hand injections can be performed through the catheter with the wire remaining in place. BA is usually carried out over that same wire. If multiple lobar segments are involved, the BA catheter is pulled back into the proximal pulmonary arterial segment and the soft tipped 0.018" wire is used to cross other stenoses. Stent treatment of multiple branch PA stenosis is usually not recommended, as many of the affected branch vessels would be "jailed off" by the stent (Figure 9a-b).

The balloons typically required for branch pulmonary artery BA are the higher-pressure, non-compliant balloon catheters. Typically, the more distal or peripheral the stenosis, the greater the need for higher atmosphere balloons or cutting balloons (or both) to achieve adequate BA of the stenotic segment.

Arterial Angioplasty in Congential Heart Disease 181

working height of 0.11-0.18 mm. Prior to dilation, the folds of the balloon cover the microsurgical blades and following dilation, the blades wrap into the folds of the balloon with deflation. Use of the CB requires a long sheath, 4-Fr for a 4 mm CB, 6-Fr for a 5 mm CB, and 7- Fr for a 6-8 mm CB. Wires are 0.014" up to 4 mm diameter and 0.018" from 5-8 mm diameter. These balloons reach full inflation at 6 ATMs with burst pressure at 10 ATMs. Aggressive balloon angioplasty of the vessel (up to 22 ATM pressure) with a standard balloon angioplasty catheter is usually performed prior to performing CB. (Figure 11a-d). The CB is usually dilated 1-2 mm larger than the narrowest segment of the stenosis. Following this, standard BA is performed up to the native vessel size. The balloons may undergo repeat dilation, but it is recommended that no more than 10 inflation/deflation cycles be used for one balloon catheter. Rapid inflation and deflation of CB should not be performed; rather slowly inflating and deflating these balloons over a one minute period of time is recommended. Finally, exceeding the burst pressure of these balloons should never be undertaken. Balloon rupture, which typically is longitudinal, prevents the proper folding of the balloon and subsequent coverage of the microblades, thereby making it more likely to strip a blade off the balloon catheter during removal of the CB. CB angioplasty is performed via either long flexor sheaths (Cook

Patients with multiple bilateral peripheral pulmonary artery stenoses can suffer from reperfusion injury following dilation of multiple affected lung segments. This situation can be life threatening in patients who are already compromised with severe elevation of the right ventricular pressure. Multiple techniques have been addressed in an attempt to avoid this circumstance. One is to dilate one segment or pulmonary arterial side with no treatment of the contralateral side at the same cath procedure. Another is selectively ventilating the contralateral lung segment during the BA procedure, thereby decreasing blood flow to the treated lung and theoretically decreasing the likelihood of encountering re-perfusion injury

Flexor, Cook corp, Bloominton, IN) or various guiding sheaths.

Fig. 8.

of those involved segments. 25

Fig. 7. a-c. Patient with Pulmonary Atresia and Ventricular Septal Defect with multiple distal stenosis of the RPA segment. BA is performed up to 19 ATMs with a 4 mm balloon angioplasty catheter. Left lower panel notes resolution of the distal discrete stenosis, though persistence of the proximal stenosis.

The cutting balloon (CB) is a dilation balloon made of noncompliant modified polyethylene terephthalate with available balloon diameters from 2-8 mm and lengths 10, 15, and 20 mm (Boston Scientific Corp., Natick, Massachusetts, Figure 10 a-b). The incremental increase in balloon size is 0.25 mm from 2-4 mm and 1 mm from 5-8 mm. Depending on the balloon diameter, 3 or 4 microsurgical blades are attached every 90 or 120 degrees, each blade with a Angioplasty, Various Techniques and Challenges in 180 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 7. a-c. Patient with Pulmonary Atresia and Ventricular Septal Defect with multiple distal stenosis of the RPA segment. BA is performed up to 19 ATMs with a 4 mm balloon angioplasty catheter. Left lower panel notes resolution of the distal discrete stenosis, though

The cutting balloon (CB) is a dilation balloon made of noncompliant modified polyethylene terephthalate with available balloon diameters from 2-8 mm and lengths 10, 15, and 20 mm (Boston Scientific Corp., Natick, Massachusetts, Figure 10 a-b). The incremental increase in balloon size is 0.25 mm from 2-4 mm and 1 mm from 5-8 mm. Depending on the balloon diameter, 3 or 4 microsurgical blades are attached every 90 or 120 degrees, each blade with a

persistence of the proximal stenosis.

working height of 0.11-0.18 mm. Prior to dilation, the folds of the balloon cover the microsurgical blades and following dilation, the blades wrap into the folds of the balloon with deflation. Use of the CB requires a long sheath, 4-Fr for a 4 mm CB, 6-Fr for a 5 mm CB, and 7- Fr for a 6-8 mm CB. Wires are 0.014" up to 4 mm diameter and 0.018" from 5-8 mm diameter. These balloons reach full inflation at 6 ATMs with burst pressure at 10 ATMs. Aggressive balloon angioplasty of the vessel (up to 22 ATM pressure) with a standard balloon angioplasty catheter is usually performed prior to performing CB. (Figure 11a-d). The CB is usually dilated 1-2 mm larger than the narrowest segment of the stenosis. Following this, standard BA is performed up to the native vessel size. The balloons may undergo repeat dilation, but it is recommended that no more than 10 inflation/deflation cycles be used for one balloon catheter. Rapid inflation and deflation of CB should not be performed; rather slowly inflating and deflating these balloons over a one minute period of time is recommended. Finally, exceeding the burst pressure of these balloons should never be undertaken. Balloon rupture, which typically is longitudinal, prevents the proper folding of the balloon and subsequent coverage of the microblades, thereby making it more likely to strip a blade off the balloon catheter during removal of the CB. CB angioplasty is performed via either long flexor sheaths (Cook Flexor, Cook corp, Bloominton, IN) or various guiding sheaths.

#### Fig. 8.

Patients with multiple bilateral peripheral pulmonary artery stenoses can suffer from reperfusion injury following dilation of multiple affected lung segments. This situation can be life threatening in patients who are already compromised with severe elevation of the right ventricular pressure. Multiple techniques have been addressed in an attempt to avoid this circumstance. One is to dilate one segment or pulmonary arterial side with no treatment of the contralateral side at the same cath procedure. Another is selectively ventilating the contralateral lung segment during the BA procedure, thereby decreasing blood flow to the treated lung and theoretically decreasing the likelihood of encountering re-perfusion injury of those involved segments. 25

Arterial Angioplasty in Congential Heart Disease 183

The performance of pulmonary balloon valvuloplasty to treat pulmonary valve stenosis has been an extremely effective procedure. Unfortunately, balloon dilation of stenoses of the pulmonary arteries distal to the pulmonary valve has not been as satisfactory.23, 26 Although the stenotic vessels often can be dilated with angioplasty balloons, even to three or four times the original size, the stenoses frequently recur immediately after balloon deflation. The recurrence of obstruction following dilation is thought to be due to the natural elastic recoil of the tissue in native pulmonary arterial stenosis or to resilience and resistance of scar tissue in postoperative cases. Rothman, et al. reported the only large series of balloon pulmonary artery dilations in 135 patients. 27 They noted that previous reports of surgery for the direct relief of pulmonary artery lesions was difficult and often ineffective.28 The mean diameter of the lesion increased from 3.8 +/- 1.7 to 5.5 +/- 2.1 mm with dilation (p = 0.001). The overall success rate was 58% (127/218 dilations), assessed by the following criteria: an increase greater than or equal to 50% of predilation diameter, an increase greater than 20% in flow to the affected lung, or a decrease greater than 20% in systolic right ventricular to aortic pressure ratio. A pulmonary artery aneurysm occurred in 5% of the pulmonary arteries dilated. Two patients died at angioplasty. Restenosis occurred in 16% of the restudied patients with initial successful dilation. They concluded that balloon angioplasty was an established, highly useful procedure in the management of branch pulmonary artery

The use of cutting balloons (CB) has increased the success rate of pulmonary artery BA from 50-60% to 80%, irrespective of whether CB were used de novo or following failure of standard balloon angioplasty.26 One area where CB have been particularly effective is in severe, multiple discrete stenosis of the distal pulmonary arterial branches (Figure 9a-b). 29, 30

Fig. 10. a-b.

stenosis. 27

**4.3 Outcomes** 

*Courtesy Allison Cabalka, Mayo Clinic, Rochester, MN* 

Fig. 9. a-b. Multiple right and left pulmonary artery stenosis of the distal branches. Patient has systemic right sided pressures and is planning on undergoing multiple balloon angioplasty dilations. One can see discrete as well as diffuse stenosis of the distal branch vessels.

Angioplasty, Various Techniques and Challenges in 182 Treatment of Congenital and Acquired Vascular Stenoses

*Courtesy Allison Cabalka, Mayo Clinic, Rochester, MN* 

vessels.

Fig. 9. a-b. Multiple right and left pulmonary artery stenosis of the distal branches. Patient has systemic right sided pressures and is planning on undergoing multiple balloon angioplasty dilations. One can see discrete as well as diffuse stenosis of the distal branch

#### **4.3 Outcomes**

The performance of pulmonary balloon valvuloplasty to treat pulmonary valve stenosis has been an extremely effective procedure. Unfortunately, balloon dilation of stenoses of the pulmonary arteries distal to the pulmonary valve has not been as satisfactory.23, 26 Although the stenotic vessels often can be dilated with angioplasty balloons, even to three or four times the original size, the stenoses frequently recur immediately after balloon deflation. The recurrence of obstruction following dilation is thought to be due to the natural elastic recoil of the tissue in native pulmonary arterial stenosis or to resilience and resistance of scar tissue in postoperative cases. Rothman, et al. reported the only large series of balloon pulmonary artery dilations in 135 patients. 27 They noted that previous reports of surgery for the direct relief of pulmonary artery lesions was difficult and often ineffective.28 The mean diameter of the lesion increased from 3.8 +/- 1.7 to 5.5 +/- 2.1 mm with dilation (p = 0.001). The overall success rate was 58% (127/218 dilations), assessed by the following criteria: an increase greater than or equal to 50% of predilation diameter, an increase greater than 20% in flow to the affected lung, or a decrease greater than 20% in systolic right ventricular to aortic pressure ratio. A pulmonary artery aneurysm occurred in 5% of the pulmonary arteries dilated. Two patients died at angioplasty. Restenosis occurred in 16% of the restudied patients with initial successful dilation. They concluded that balloon angioplasty was an established, highly useful procedure in the management of branch pulmonary artery stenosis. 27

The use of cutting balloons (CB) has increased the success rate of pulmonary artery BA from 50-60% to 80%, irrespective of whether CB were used de novo or following failure of standard balloon angioplasty.26 One area where CB have been particularly effective is in severe, multiple discrete stenosis of the distal pulmonary arterial branches (Figure 9a-b). 29, 30

Arterial Angioplasty in Congential Heart Disease 185

This is a rare condition that can be idiopathic or associated with William's/Alagille syndrome. 29, 31 Primary stenting is generally not recommended for these lesions due to the likelihood of jailing off adjacent pulmonary arterial branches. Balloon angioplasty of these lesions almost always requires high-pressure balloons and in many cases is resistant to standard BA. 23 Aneurysm, dissection, and vessel perforation have been associated with BA of pulmonary artery stenosis, with one patient having a late rupture of an aneurysm with subsequent death. 32 These procedures can be tedious but the outcomes, over time, can be

Surgical repair of pulmonary arterial stenosis has also been ineffective and carries considerably greater morbidity and probably greater mortality. 28 Surgical problems with these lesions relate to the location of the narrowings, often in the distal branch pulmonary arteries, an area difficult to reach from a standard midline sternotomy or lateral thoracotomy. Recurrent stenosis has been reported in up to 31% of patients who had

Although BA has its limitations, it remains a very important treatment modality for pulmonary and systemic arterial stenosis. CBs have improved the treatment of resistant lesions. The improvement of balloon technology has significantly decreased the number of vascular complications over the past 15 years. Drug delivery through permeable balloons (see section under Challenges for the Future in Coarctation) has significant potential application for the treatment of stenosis in the pulmonary arterial system. The tolerance of longer inflation times and smaller vessel size observed in the pulmonary arterial system makes this a technically easier undertaking in comparison to attempting drug delivery in

Balloon angioplasty has proven to be successful in the treatment of pulmonary artery stenosis and coactation of the aorta. Significant challenges remain, primarily in the prevention of recurrent stenosis. The development of biodegradable stents and permeable balloon catheters will undoubtedly improve outcomes for both pulmonary artery and aortic

Yetman AT, Nykanen D, McCrindle BW, Sunnegardh J, Adatia I, Freedom RM, Benson L.

Li F, Zhou A, Gao W, Wang R, Yu Z, Huang M, Yang J. Percutaneous balloon angioplasty of

McCrindle BW, Jones TK, Morrow WR, Hagler DJ, Lloyd TR, Nouri S, Latson LA. Acute

Balloon angioplasty of recurrent coarctation: a 12-year review. *J Am Coll Cardiol.* 

coarctation of the aorta in children: 12-year follow-up results. *Chin Med J (Engl).* 

results of balloon angioplasty of native coarctation versus recurrent aortic obstruction are equivalent. Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry Investigators. *J Am Coll Cardiol.* 1996;28(7):1810-1817.

coarctation angioplasty, most importantly in the area of restenoses.

surgical repair of the right pulmonary artery after Waterston shunt placement.28

dramatic.

**4.4 Challenges for the future** 

the systemic arterial system.

1997;30(3):811-816.

2001;114(5):459-461.

**5. Conclusion** 

**6. References** 

*Courtesy Jaqueline Kreutzer, Children's Hospital of Pittsburgh, Pittsburgh, PA* 

Fig. 11. a-d. Cutting balloon angioplasty of distal branch left lower lobe pulmonary artery stenosis. Upper left panel notes the stenotic segments of the left lower lobe branches. Right upper panel notes failed aggressive balloon angioplasty at 18 ATMs. Left lower panel, successful cutting balloon dilation of the stenotic segment. Right lower panel, resolution of the left lower lobe stenosis following cutting balloon angioplasty.

Angioplasty, Various Techniques and Challenges in 184 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 11. a-d. Cutting balloon angioplasty of distal branch left lower lobe pulmonary artery stenosis. Upper left panel notes the stenotic segments of the left lower lobe branches. Right upper panel notes failed aggressive balloon angioplasty at 18 ATMs. Left lower panel, successful cutting balloon dilation of the stenotic segment. Right lower panel, resolution of

*Courtesy Jaqueline Kreutzer, Children's Hospital of Pittsburgh, Pittsburgh, PA* 

the left lower lobe stenosis following cutting balloon angioplasty.

This is a rare condition that can be idiopathic or associated with William's/Alagille syndrome. 29, 31 Primary stenting is generally not recommended for these lesions due to the likelihood of jailing off adjacent pulmonary arterial branches. Balloon angioplasty of these lesions almost always requires high-pressure balloons and in many cases is resistant to standard BA. 23 Aneurysm, dissection, and vessel perforation have been associated with BA of pulmonary artery stenosis, with one patient having a late rupture of an aneurysm with subsequent death. 32 These procedures can be tedious but the outcomes, over time, can be dramatic.

Surgical repair of pulmonary arterial stenosis has also been ineffective and carries considerably greater morbidity and probably greater mortality. 28 Surgical problems with these lesions relate to the location of the narrowings, often in the distal branch pulmonary arteries, an area difficult to reach from a standard midline sternotomy or lateral thoracotomy. Recurrent stenosis has been reported in up to 31% of patients who had surgical repair of the right pulmonary artery after Waterston shunt placement.28

#### **4.4 Challenges for the future**

Although BA has its limitations, it remains a very important treatment modality for pulmonary and systemic arterial stenosis. CBs have improved the treatment of resistant lesions. The improvement of balloon technology has significantly decreased the number of vascular complications over the past 15 years. Drug delivery through permeable balloons (see section under Challenges for the Future in Coarctation) has significant potential application for the treatment of stenosis in the pulmonary arterial system. The tolerance of longer inflation times and smaller vessel size observed in the pulmonary arterial system makes this a technically easier undertaking in comparison to attempting drug delivery in the systemic arterial system.

#### **5. Conclusion**

Balloon angioplasty has proven to be successful in the treatment of pulmonary artery stenosis and coactation of the aorta. Significant challenges remain, primarily in the prevention of recurrent stenosis. The development of biodegradable stents and permeable balloon catheters will undoubtedly improve outcomes for both pulmonary artery and aortic coarctation angioplasty, most importantly in the area of restenoses.

#### **6. References**


Arterial Angioplasty in Congential Heart Disease 187

Kim JS, Shin DH, Kim BK, Ko YG, Choi D, Jang Y, Hong MK. Optical coherence

Klauss V, Serruys PW, Pilgrim T, Buszman P, Linke A, Ischinger T, Eberli F, Corti R, Wijns

Simsek C, Magro M, Boersma E, Onuma Y, Nauta S, Daemen J, Gaspersz M, van Geuns RJ,

Klomp M, Beijk MA, Varma C, Koolen JJ, Teiger E, Richardt G, Bea F, van Geloven N,

Kan JS, Marvin WJ, Jr., Bass JL, Muster AJ, Murphy J. Balloon angioplasty--branch

De Giovanni JV. Balloon angioplasty for branch pulmonary artery stenosis--cutting balloons.

Gentles TL, Lock JE, Perry SB. High pressure balloon angioplasty for branch pulmonary artery stenosis: early experience. *J Am Coll Cardiol.* 1993;22(3):867-872. Rothman A, Levy DJ, Sklansky MS, Grossfeld PD, Auger WR, Ajami GH, Behling CA.

Wilson JM, Mack JW, Turley K, Ebert PA. Persistent stenosis and deformity of the right

Gandy KL, Tweddell JS, Pelech AN. How we approach peripheral pulmonary stenosis in

Sugiyama H, Veldtman GR, Norgard G, Lee KJ, Chaturvedi R, Benson LN. Bladed balloon

Congenital Anomalies Registry. *Am J Cardiol.* 1990;65(11):798-801.

in adult patients. *Catheter Cardiovasc Interv.* 2003;58(2):252-260.

Hospital) Registries. *J Invasive Cardiol.*23(8):336-341.

*Cardiol.* 1992;69(17):1467-1470.

*Surg.* 1981;82(2):169-175.

2009:118-121.

2004;62(1):71-77.

*Catheter Cardiovasc Interv.* 2007;69(3):459-467.

*Imaging.* 

895.

tomographic comparison of neointimal coverage between sirolimus- and resolute zotarolimus-eluting stents at 9 months after stent implantation. *Int J Cardiovasc* 

W, Morice MC, di Mario C, van Geuns RJ, van Es GA, Kalesan B, Wenaweser P, Juni P, Windecker S. 2-year clinical follow-up from the randomized comparison of biolimus-eluting stents with biodegradable polymer and sirolimus-eluting stents with durable polymer in routine clinical practice. *JACC Cardiovasc Interv.*4(8):887-

van der Giessen W, van Domburg R, Serruys P. Comparison of Six-Year Clinical Outcome of Sirolimus- and Paclitaxel-Eluting Stents to Bare-Metal Stents in Patients with ST-Segment Elevation Myocardial Infarction: An Analysis of the RESEARCH (Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital) and T-SEARCH (Taxus Stent Evaluated at Rotterdam Cardiology

Verouden NJ, Chan YK, Woudstra P, Damman P, Tijssen JG, de Winter RJ. 1-Year Outcome of TRIAS HR (TRI-Stent Adjudication Study-High Risk of Restenosis) A Multicenter, Randomized Trial Comparing Genous Endothelial Progenitor Cell Capturing Stents With Drug-Eluting Stents. *JACC Cardiovasc Interv.*4(8):896-904. Lock JE, Castaneda-Zuniga WR, Fuhrman BP, Bass JL. Balloon dilation angioplasty of

hypoplastic and stenotic pulmonary arteries. *Circulation.* 1983;67(5):962-967. Hosking MC, Thomaidis C, Hamilton R, Burrows PE, Freedom RM, Benson LN. Clinical impact of balloon angioplasty for branch pulmonary arterial stenosis. *Am J* 

pulmonary artery stenosis: results from the Valvuloplasty and Angioplasty of

Balloon angioplasty and stenting of multiple intralobar pulmonary arterial stenoses

pulmonary artery after correction of the Waterston anastomosis. *J Thorac Cardiovasc* 

Williams-Beuren syndrome. *Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu.* 

angioplasty for peripheral pulmonary artery stenosis. *Catheter Cardiovasc Interv.* 


Angioplasty, Various Techniques and Challenges in 186 Treatment of Congenital and Acquired Vascular Stenoses

Ozawa A, Predescu D, Chaturvedi R, Lee KJ, Benson LN. Cutting balloon angioplasty for

Prada F, Carretero J, Mortera C, Velasco D. Balloon angioplasty in a 1200-gram premature

Hamdan MA, Maheshwari S, Fahey JT, Hellenbrand WE. Endovascular stents for

Forbes TJ, Garekar S, Amin Z, Zahn EM, Nykanen D, Moore P, Qureshi SA, Cheatham JP,

Forbes TJ, Moore P, Pedra CA, Zahn EM, Nykanen D, Amin Z, Garekar S, Teitel D, Qureshi

Liang CD, Su WJ, Chung HT, Hwang MS, Huang CF, Lin YJ, Chien SJ, Lin IC, Ko SF.

Rao PS, Jureidini SB, Balfour IC, Singh GK, Chen SC. Severe aortic coarctation in infants less

Lock JE, Bass JL, Amplatz K, Fuhrman BP, Castaneda-Zuniga W. Balloon dilation

Reich O, Tax P, Bartakova H, Tomek V, Gilik J, Lisy J, Radvansky J, Matejka T, Tlaskal T,

Dehghani P, Collins N, Benson L, Horlick E. Role of routine radial artery access during aortic coarctation interventions. *Catheter Cardiovasc Interv.* 2007;70(4):622-623. Cowley CG, Orsmond GS, Feola P, McQuillan L, Shaddy RE. Long-term, randomized

Hassan W, Awad M, Fawzy ME, Omrani AA, Malik S, Akhras N, Shoukri M. Long-term

Hassan W, Malik S, Akhras N, Amri MA, Shoukri M, Fawzy ME. Long-term results (up to

Golden AB, Hellenbrand WE. Coarctation of the aorta: stenting in children and adults.

patients with coarctation of the aorta. *Clin Cardiol.* 2007;30(2):75-80.

coarctation of the aorta: initial results and intermediate-term follow-up. *J Am Coll* 

Ebeid MR, Hijazi ZM, Sandhu S, Hagler DJ, Sievert H, Fagan TE, Ringewald J, Du W, Tang L, Wax DF, Rhodes J, Johnston TA, Jones TK, Turner DR, Pedra CA, Hellenbrand WE. Procedural results and acute complications in stenting native and recurrent coarctation of the aorta in patients over 4 years of age: a multi-

SA, Cheatham JP, Ebeid MR, Hijazi ZM, Sandhu S, Hagler DJ, Sievert H, Fagan TE, Ringwald J, Du W, Tang L, Wax DF, Rhodes J, Johnston TA, Jones TK, Turner DR, Pass R, Torres A, Hellenbrand WE. Intermediate follow-up following intravascular stenting for treatment of coarctation of the aorta. *Catheter Cardiovasc Interv.* 

Balloon angioplasty for native coarctation of the aorta in neonates and infants with

than 3 months: successful palliation by balloon angioplasty. *J Invasive Cardiol.* 

angioplasty of aortic coarctations in infants and children. *Circulation.* 

Svobodova I, Chaloupecky V, Skovranek J. Long-term (up to 20 years) results of percutaneous balloon angioplasty of recurrent aortic coarctation without use of

comparison of balloon angioplasty and surgery for native coarctation of the aorta in

effects of balloon angioplasty on left ventricular hypertrophy in adolescent and adult patients with native coarctation of the aorta. Up to 18 years follow-up results.

18 years) of balloon angioplasty on systemic hypertension in adolescent and adult

infant with critical aortic coarctation. *Rev Esp Cardiol.*63(6):741-743.

institutional study. *Catheter Cardiovasc Interv.* 2007;70(2):276-285.

congestive heart failure. *Pediatr Neonatol.* 2009;50(4):152-157.

aortic coarctation. *J Invasive Cardiol.* 2009;21(6):295-299.

*Cardiol.* 2001;38(5):1518-1523.

2007;70(4):569-577.

2003;15(4):202-208.

1983;68(1):109-116.

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childhood. *Circulation.* 2005;111(25):3453-3456.

*Catheter Cardiovasc Interv.* 2007;70(6):881-886.

*Catheter Cardiovasc Interv.* 2007;69(2):289-299.


**9** 

*USA* 

**Carotid Angioplasty** 

Parth Shah and Michael Dahn

*Department of Surgery, Section of Vascular Surgery University of Connecticut Health Center, Farmington, CT* 

Carotid intervention for the amelioration of symptoms due to carotid stenosis has been a controversial therapeutic concept for much of its history. Operative carotid surgery (carotid endarterectomy) underwent considerable turmoil and challenge during the late 20th century, eventually becoming a generally accepted approach in the management of symptomatic critical carotid artery stenosis. A similar circumstance currently confronts carotid angioplasty. Carotid endarterectomy (CEA) now represents the clinical standard against which any carotid intervention is compared and carotid angioplasty must "measure up" to this reference procedure. However, it must be recognized that the time line for acceptance of CEA measured approximately 40 years suggesting that the clinical community must exercise patience in the evaluation of carotid angioplasty which enjoys a relatively short history. Conversely, there is considerable vested interest by several specialties for carotid angioplasty to be accepted (cardiology, radiology) or rejected (vascular surgery) indicating the need for critical analysis of this procedure's efficacy. This process of procedure assessment remains a difficult task in view of the constantly changing technological advances that surround this field. This chapter focuses on the key elements of technique and clinical experience which represent the status of carotid

The association of carotid artery blood flow to the brain as a vital element to sustain neurologic function dates back to Hippocrates (Figure). As a corollary, it has become accepted that atherosclerotic disease of the carotid artery is associated with stroke. This concept was first described by Ramsay Hunt in 1914 and subsequently popularized as one of the most significant risk factors for developing stroke. It wasn't until the 1950's, when durable reconstructive carotid surgery was described and further refined and popularized by Debakey, Eastcott, Rob, Thompson, Moore, Baker and Wylie, that the field of carotid intervention was popularized. Some of the landmark large randomized controlled trials like North American Symptomatic Carotid Endarterectomy (NASCET)1, Asymptomatic Carotid Atherosclerosis Study (ACAS)2 and European Carotid Surgery Trial (ECST)3 showed statistically significant reductions in stroke in the patients undergoing carotid endarterectomy versus medical treatment alone.

**1. Introduction** 

angioplasty today.

**2. History** 


### **Carotid Angioplasty**

#### Parth Shah and Michael Dahn

*Department of Surgery, Section of Vascular Surgery University of Connecticut Health Center, Farmington, CT USA* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 188 Treatment of Congenital and Acquired Vascular Stenoses

Zalzstein E, Moes CA, Musewe NN, Freedom RM. Spectrum of cardiovascular anomalies in

Zeevi B, Berant M, Blieden LC. Late death from aneurysm rupture following balloon

angioplasty for branch pulmonary artery stenosis. *Cathet Cardiovasc Diagn.* 

Williams-Beuren syndrome. *Pediatr Cardiol.* 1991;12(4):219-223.

1996;39(3):284-286.

Carotid intervention for the amelioration of symptoms due to carotid stenosis has been a controversial therapeutic concept for much of its history. Operative carotid surgery (carotid endarterectomy) underwent considerable turmoil and challenge during the late 20th century, eventually becoming a generally accepted approach in the management of symptomatic critical carotid artery stenosis. A similar circumstance currently confronts carotid angioplasty. Carotid endarterectomy (CEA) now represents the clinical standard against which any carotid intervention is compared and carotid angioplasty must "measure up" to this reference procedure. However, it must be recognized that the time line for acceptance of CEA measured approximately 40 years suggesting that the clinical community must exercise patience in the evaluation of carotid angioplasty which enjoys a relatively short history. Conversely, there is considerable vested interest by several specialties for carotid angioplasty to be accepted (cardiology, radiology) or rejected (vascular surgery) indicating the need for critical analysis of this procedure's efficacy. This process of procedure assessment remains a difficult task in view of the constantly changing technological advances that surround this field. This chapter focuses on the key elements of technique and clinical experience which represent the status of carotid angioplasty today.

#### **2. History**

The association of carotid artery blood flow to the brain as a vital element to sustain neurologic function dates back to Hippocrates (Figure). As a corollary, it has become accepted that atherosclerotic disease of the carotid artery is associated with stroke. This concept was first described by Ramsay Hunt in 1914 and subsequently popularized as one of the most significant risk factors for developing stroke. It wasn't until the 1950's, when durable reconstructive carotid surgery was described and further refined and popularized by Debakey, Eastcott, Rob, Thompson, Moore, Baker and Wylie, that the field of carotid intervention was popularized. Some of the landmark large randomized controlled trials like North American Symptomatic Carotid Endarterectomy (NASCET)1, Asymptomatic Carotid Atherosclerosis Study (ACAS)2 and European Carotid Surgery Trial (ECST)3 showed statistically significant reductions in stroke in the patients undergoing carotid endarterectomy versus medical treatment alone.

Carotid Angioplasty 191

Key for successful endoluminal intervention is patient evaluation and proper patient selection, choice of optimum vascular access site, a thorough evaluation of the access route, any anatomic or morphologic anomalies, appropriate selection of devices and accurate

Pre-procedural assessment of carotid artery disease is obtained by duplex ultrasound (DU). DU allows an assessment of the degrees of stenosis and extent of calcification. Highly calcified lesions may be more embologenic or unyielding to balloon angioplasty resulting in a suboptimal dilatation. Further information on the target lesion may be obtained by magnetic resonance (MR) or computed tomographic (CT) arteriography. These two imaging modalities are useful confirmatory studies following duplex imaging and offer an assessment of unsuspected occlusive disease outside the DU imaging window. Furthermore, these non-invasive means evaluate access site, aortic arch morphology and any incidental

Initially, a 4 or 5 Fr sheath access is obtained in the common femoral artery. A flush pigtail catheter may be positioned in the ascending aorta for the initial arch aortogram which is performed in left anterior oblique (LAO) position. Depending on the degree of tortuosity and configuration of the aortic arch, we like to have between 30 degrees to as much as 60 degrees of LAO projection. The performance of the arch angiogram is useful to identify the target vessel origin. In difficult anatomic arrangements, the aortogram is very helpful but it may also increase procedure morbidity. Utilizing diffusion weighted MRI imaging, silent microembolic lesions are detectable in up to two-thirds of patients undergoing CAS8. At least half of these lesions can be identified in the cerebral hemisphere contralateral to the target lesion. This suggests that manipulation of devices, including diagnostic catheters used for arch angiography, are a substantial source of

The aortic arch configuration varies due to multiple patient factors. Probably the dominant factor is age since the aorta tends to elongate with increasing age contributing to a worsening of the arch type. There are mainly three arch types depending on the

Safe selective cannulation of the great vessels is the rate-limiting step. Usually the appropriate diagnostic catheters are available in 100 cm to 125 cm lengths. The longer

For the Type I aortic arch, the standard angled catheters like the angle taper Glidecath® (Terumo Medical Corporation, Somerset, NJ, USA) or a Berenstein catheter (Boston Scientific, Natick, MA, USA) or Headhunter or JB 1 (Cook Medical, Bloomington, IN, USA)

For more challenging aortic arch morphology, with types II and III configuration, reversecurve catheters like Simmons type catheters (I or II), JB 2 or the VTK catheter (Cook Medical,

lengths are required should one use the telescoping technique (*vida infra*).

pathology in the access route which are invaluable in the planning of a procedure.

**3. Technical aspects of carotid angioplasty and stenting** 

sizing of the target lesion and vessels.

**4. Aortic arch configuration** 

embolic events during CAS.

**5. Diagnostic catheters** 

are usually successful.

radiographic morphology (Figure).

Bloomington, IN, USA) may be used.

Currently, there are approximately 165,000 carotid endarterectomy (CEA) procedures performed across United States annually and this procedure is considered the "gold standard" for revascularization of the internal carotid artery due to atherosclerotic stenosis.

Adapted From Hippocrates to Palmaz-Schatz, the history of carotid surgery. 4 Robicsek F, Roush TS, Cook JW, Reames MK. Eur J Vasc Endovasc Surg. 2004 Apr;27(4): 389-97.

Moniz described carotid and cerebral angiography in 1927 and thereafter, further improvements in the extracranial carotid imaging facilitated more patients being diagnosed with occlusive carotid diseases and hence treatment advancement. Debakey and his coworkers described intraluminal angioplasty of the internal carotid artery in 1968 for fibromuscular dysplasia.5 Percutaneous transluminal angioplasty of carotid artery was described in 1977 by Mathias and subsequently Diethrich reported the first large series of carotid angioplasty and stenting in 1995, although the risk of neurological complication was as high as 10.7% in his report. Subsequently, multiple technical advances have taken place in percutaneous carotid artery interventions including stent augmentation of carotid angioplasty, routine use of cerebral embolic protection and improved patient selection.

Carotid angioplasty and stenting (CAS) provides a few advantages over traditional CEA including avoidance of a neck incision, general anesthesia and freedom from cranial nerve injuries. These benefits have sustained the evolution of CAS over the last 20-30 years.

Angioplasty, Various Techniques and Challenges in 190 Treatment of Congenital and Acquired Vascular Stenoses

Currently, there are approximately 165,000 carotid endarterectomy (CEA) procedures performed across United States annually and this procedure is considered the "gold standard" for revascularization of the internal carotid artery due to atherosclerotic

Adapted From Hippocrates to Palmaz-Schatz, the history of carotid surgery. 4

Robicsek F, Roush TS, Cook JW, Reames MK. Eur J Vasc Endovasc Surg. 2004 Apr;27(4):

Moniz described carotid and cerebral angiography in 1927 and thereafter, further improvements in the extracranial carotid imaging facilitated more patients being diagnosed with occlusive carotid diseases and hence treatment advancement. Debakey and his coworkers described intraluminal angioplasty of the internal carotid artery in 1968 for fibromuscular dysplasia.5 Percutaneous transluminal angioplasty of carotid

large series of carotid angioplasty and stenting in 1995, although the risk of neurological complication was as high as 10.7% in his report. Subsequently, multiple technical advances have taken place in percutaneous carotid artery interventions including stent augmentation of carotid angioplasty, routine use of cerebral embolic protection and

Carotid angioplasty and stenting (CAS) provides a few advantages over traditional CEA including avoidance of a neck incision, general anesthesia and freedom from cranial nerve injuries. These benefits have sustained the evolution of CAS over the last 20-30

and subsequently Diethrich reported the first

stenosis.

389-97.

years.

artery was described in 1977 by Mathias-

improved patient selection.

#### **3. Technical aspects of carotid angioplasty and stenting**

Key for successful endoluminal intervention is patient evaluation and proper patient selection, choice of optimum vascular access site, a thorough evaluation of the access route, any anatomic or morphologic anomalies, appropriate selection of devices and accurate sizing of the target lesion and vessels.

Pre-procedural assessment of carotid artery disease is obtained by duplex ultrasound (DU). DU allows an assessment of the degrees of stenosis and extent of calcification. Highly calcified lesions may be more embologenic or unyielding to balloon angioplasty resulting in a suboptimal dilatation. Further information on the target lesion may be obtained by magnetic resonance (MR) or computed tomographic (CT) arteriography. These two imaging modalities are useful confirmatory studies following duplex imaging and offer an assessment of unsuspected occlusive disease outside the DU imaging window. Furthermore, these non-invasive means evaluate access site, aortic arch morphology and any incidental pathology in the access route which are invaluable in the planning of a procedure.

#### **4. Aortic arch configuration**

Initially, a 4 or 5 Fr sheath access is obtained in the common femoral artery. A flush pigtail catheter may be positioned in the ascending aorta for the initial arch aortogram which is performed in left anterior oblique (LAO) position. Depending on the degree of tortuosity and configuration of the aortic arch, we like to have between 30 degrees to as much as 60 degrees of LAO projection. The performance of the arch angiogram is useful to identify the target vessel origin. In difficult anatomic arrangements, the aortogram is very helpful but it may also increase procedure morbidity. Utilizing diffusion weighted MRI imaging, silent microembolic lesions are detectable in up to two-thirds of patients undergoing CAS8. At least half of these lesions can be identified in the cerebral hemisphere contralateral to the target lesion. This suggests that manipulation of devices, including diagnostic catheters used for arch angiography, are a substantial source of embolic events during CAS.

The aortic arch configuration varies due to multiple patient factors. Probably the dominant factor is age since the aorta tends to elongate with increasing age contributing to a worsening of the arch type. There are mainly three arch types depending on the radiographic morphology (Figure).

#### **5. Diagnostic catheters**

Safe selective cannulation of the great vessels is the rate-limiting step. Usually the appropriate diagnostic catheters are available in 100 cm to 125 cm lengths. The longer lengths are required should one use the telescoping technique (*vida infra*).

For the Type I aortic arch, the standard angled catheters like the angle taper Glidecath® (Terumo Medical Corporation, Somerset, NJ, USA) or a Berenstein catheter (Boston Scientific, Natick, MA, USA) or Headhunter or JB 1 (Cook Medical, Bloomington, IN, USA) are usually successful.

For more challenging aortic arch morphology, with types II and III configuration, reversecurve catheters like Simmons type catheters (I or II), JB 2 or the VTK catheter (Cook Medical, Bloomington, IN, USA) may be used.

Carotid Angioplasty 193

These are the configurations of some of the catheters commonly used in the carotid

Glidecath®

angioplasty procedure.

A Type IV arch is a term that may be applied to an exaggerated Type III arch with severe angulation of the great vessels.

Angioplasty, Various Techniques and Challenges in 192 Treatment of Congenital and Acquired Vascular Stenoses

Type I – The great vessels originate from the same horizontal plane of the outer curvature of the arch

Type II – Innominate artery originates between the horizontal planes of outer and inner curvature

Type III – Innominate artery originates below the horizontal plane of inner curvature of the arch

of the arch

A Type IV arch is a term that may be applied to an exaggerated Type III arch with severe

angulation of the great vessels.

Glidecath®

These are the configurations of some of the catheters commonly used in the carotid angioplasty procedure.

Carotid Angioplasty 195

greatest utility on the left since the right CCA can be cannulated using the double wire technique noted above. The transtemporal approach involves ultrasound guided access or direct dissection of the superficial temporal artery followed by retrograde placement of a coronary wire into the aorta where it is snared from the femoral artery. This provides through and through access permitting advancement of a Shuttle sheath into proper position for the CAS procedure. The remainder of the procedure is then performed in the

Sometimes the standard 0.014" wire is not successful in traversing an ultra-critical stenosis, in which case a 0.012" Headliner® Glidewire® (45 degrees, 200 cm) (Terumo Medical Corporation, Somerset, NJ, USA), supported by 1.9 Fr (0.026") Prowler® microcatheter (Cordis, Miami Lakes, FL, USA) may be successful. Following traversal of the lesion with the microcatheter, the 0.012" wire is replaced with a more supportive 0.014" wire which can be parked in the treatment area. The new wire may now be used to deliver a balloon, EPD or a flow arrest/reversal system (*vida infra*) for completion of

This figure shows a pre-occlusive lesion of the right internal carotid artery which would not

usual fashion.

the CAS. 9

accept a 0.014" wire.

**11. Ultra-critical stenosis** 

#### **6. Sheath access**

Positioning of a sheath in the CCA is a prerequisite to CAS. Typically, this requires placement of a diagnostic catheter into the CCA followed by advancement of a glide-wire into the ECA. This allows introduction of the catheter into the ECA followed by a wire exchange for a stiff wire forming the guide for a 6 Fr Shuttle sheath. Occasionally, the ECA is occluded or severely diseased requiring the use of a stable stiff wire access into common carotid artery (CCA) alone and a 6 Fr sheath is advanced and parked into proximal CCA.

### **7. Cannulation of internal carotid artery**

After obtaining stable sheath access into proximal CCA, the embolic protection device (EPD) is deployed into the appropriate position. The pros and cons of different cerebral EPDs are discussed in next section.

The different approches of obtaining ICA access depend upon the degree of stenosis, amount of tortuosity and type of EPD used. Usual access to the ICA is obtained with a standard 0.014" wire or EPD dedicated wire followed by delivery of the balloon and stent system.

#### **8. Telescoping catheter technique**

Positioning of the Shuttle sheath system into the CCA is a prerequisite for the CAS procedure. Typically, this is performed over a stiff wire anchored in the ECA. However, advancement of the stiff wire into the CCA through a diagnostic catheter may be a challenge. If tortuous anatomy prevents this maneuver, a softer, 125 cm 6 or 6.5 Fr catheter is used to replace the obturator of the Shuttle sheath. The additional 35 cm lead portion of this catheter which is telescoped into the 90 cm Shuttle serves as a sufficient support over which to slide the sheath once the catheter tip is introduced into the CCA. Thus, the inner catheter effectively serves as a "stiff guide".

#### **9. Right brachial/axillary artery access technique (double wire technique)**

Access to the right carotid system can be achieved under essentially all anatomically difficult circumstances with this technique. This approach has been successful even with an exaggerated Type III aortic arch configuration (effectively a Type IV arch). The technique requires gaining access to the brachial or axillary artery on the right with passage of an exchange length glide wire retrograde into the thoracic aorta. The wire is snared from a femoral access point for through and through wire control. A 7 or 8 Fr sheath is now advanced into the innominate artery. The wire may be changed out for a smaller wire to reduce occupied space within the sheath while stabilizing it. This is then followed by the transfemoral advancement of a second steerable 0.014" wire into the CCA. The second wire now permits the delivery of a cerebral protection system and completion of the CAS procedure.

#### **10. Transtemporal technique**

Access to the CCA can be quite difficult if the carotid anatomy is tortuous or the aortic arch type is unfavorable. The transtemporal approach may be used on either side but it has its Angioplasty, Various Techniques and Challenges in 194 Treatment of Congenital and Acquired Vascular Stenoses

Positioning of a sheath in the CCA is a prerequisite to CAS. Typically, this requires placement of a diagnostic catheter into the CCA followed by advancement of a glide-wire into the ECA. This allows introduction of the catheter into the ECA followed by a wire exchange for a stiff wire forming the guide for a 6 Fr Shuttle sheath. Occasionally, the ECA is occluded or severely diseased requiring the use of a stable stiff wire access into common carotid artery (CCA) alone and a 6 Fr sheath is advanced and parked into proximal CCA.

After obtaining stable sheath access into proximal CCA, the embolic protection device (EPD) is deployed into the appropriate position. The pros and cons of different cerebral EPDs are

The different approches of obtaining ICA access depend upon the degree of stenosis, amount of tortuosity and type of EPD used. Usual access to the ICA is obtained with a standard 0.014" wire or EPD dedicated wire followed by delivery of the balloon and stent

Positioning of the Shuttle sheath system into the CCA is a prerequisite for the CAS procedure. Typically, this is performed over a stiff wire anchored in the ECA. However, advancement of the stiff wire into the CCA through a diagnostic catheter may be a challenge. If tortuous anatomy prevents this maneuver, a softer, 125 cm 6 or 6.5 Fr catheter is used to replace the obturator of the Shuttle sheath. The additional 35 cm lead portion of this catheter which is telescoped into the 90 cm Shuttle serves as a sufficient support over which to slide the sheath once the catheter tip is introduced into the CCA. Thus, the inner

**9. Right brachial/axillary artery access technique (double wire technique)** 

Access to the right carotid system can be achieved under essentially all anatomically difficult circumstances with this technique. This approach has been successful even with an exaggerated Type III aortic arch configuration (effectively a Type IV arch). The technique requires gaining access to the brachial or axillary artery on the right with passage of an exchange length glide wire retrograde into the thoracic aorta. The wire is snared from a femoral access point for through and through wire control. A 7 or 8 Fr sheath is now advanced into the innominate artery. The wire may be changed out for a smaller wire to reduce occupied space within the sheath while stabilizing it. This is then followed by the transfemoral advancement of a second steerable 0.014" wire into the CCA. The second wire now permits the delivery of a cerebral protection system and completion of the CAS

Access to the CCA can be quite difficult if the carotid anatomy is tortuous or the aortic arch type is unfavorable. The transtemporal approach may be used on either side but it has its

**6. Sheath access** 

discussed in next section.

system.

procedure.

**10. Transtemporal technique** 

**7. Cannulation of internal carotid artery** 

**8. Telescoping catheter technique** 

catheter effectively serves as a "stiff guide".

greatest utility on the left since the right CCA can be cannulated using the double wire technique noted above. The transtemporal approach involves ultrasound guided access or direct dissection of the superficial temporal artery followed by retrograde placement of a coronary wire into the aorta where it is snared from the femoral artery. This provides through and through access permitting advancement of a Shuttle sheath into proper position for the CAS procedure. The remainder of the procedure is then performed in the usual fashion.

#### **11. Ultra-critical stenosis**

Sometimes the standard 0.014" wire is not successful in traversing an ultra-critical stenosis, in which case a 0.012" Headliner® Glidewire® (45 degrees, 200 cm) (Terumo Medical Corporation, Somerset, NJ, USA), supported by 1.9 Fr (0.026") Prowler® microcatheter (Cordis, Miami Lakes, FL, USA) may be successful. Following traversal of the lesion with the microcatheter, the 0.012" wire is replaced with a more supportive 0.014" wire which can be parked in the treatment area. The new wire may now be used to deliver a balloon, EPD or a flow arrest/reversal system (*vida infra*) for completion of the CAS. 9

This figure shows a pre-occlusive lesion of the right internal carotid artery which would not accept a 0.014" wire.

Carotid Angioplasty 197

This technique uses a partially open operative approach. The procedure is performed under local anesthesia utilizing a small incision just above the clavicle. A large (9 Fr) and medium (6 Fr) sheath are introduced into the CCA directed in a cephalad orientation through the incision. Additionally, a 6 Fr sheath is introduced into the jugular vein directed caudally. An over-the-wire fogerty catheter is used to occlude the external carotid artery and the proximal CCA is clamped following anticoagulation. Flow reversal in the carotid system is established by connecting the sideports of the 9 Fr arterial and 6 Fr venous sheaths and flow direction is verified using a small injection of contrast. Now, the angioplasty is performed through the 9 Fr sheath and any loose debris that results is carried into the venous system or trapped by any interposed filter. The arterial puncture sites are sutured at the time of final sheath removal. This approach appears fairly labor intensive within a small field and the use of a partially open portion of the angioplasty procedure seems to defeat the minimally invasive nature of CAS. Nonetheless, it has been suggested as a reliable means of controlling

Mathias first described the percutaneous carotid artery angioplasty (CA) technique in 1977.10 Subsequently he reported a case series of 3 high surgical risk patients undergoing percutaneous carotid angioplasty.11 During this time, percutaneous carotid intervention was limited to fibromuscular dysplasia and was not applied to atherosclerotic diseases due to risk of embolic events and secondly, CEA was considered a very safe procedure and its utilization was widespread. There were occasional case reports of CA, but it wasn't until 1990's when this technique was more systematically studied for its feasibility, safety and outcomes. The summary of early clinical studies is shown in Table 1. The most feared complication of CA is embolic phenomenon and evidence of early and delayed embolization

> Technical success

Diethrich EB13 (1996) 110 (7.6 months) 99% 12 (10.9%) 12 (10.9%) Roubin GS14 (1996) 146 (6 months) 99% 9 (6%) 11(7.5%) Gil-Peralta A15 (1996) 85 (18.7 months) 91.8% 7 (8.6%) 7 (8.6%) Yadav JS16 (1997) 107 (6 months) 100% 9 (8.4%) 10(9.3%) Jordan WD, Jr17 (1997) 107 (6 months) NA 9 (8.4%) 10 (9.3%) Vozzi CR18 (1997) 22 (10 months) NA 2 (9%) 2 (9%) Teitelbaum GP19 (1998) 25 (6 months) 96.2% 2 (7.7%) 6 (27%)

In 1992, Brown20 reviewed approximately 100 cases reported in the literature with stroke rate of 4%. In May 1998, Wholey21 published a review of 2,048 cases of carotid stents across 24 centers world-wide and reported a 98.6% technical success rate. Also the complication rates were 3.08% for minor strokes, 1.32% major strokes and 1.37% peri-procedural mortality. The 6-month re-stenosis rate was 4.8% by duplex-ultrasound or angiographic method. The stents being utilized for carotid stenting at the time were Palmaz (Cordis) or

Stroke Overall complications

(MI/Stroke/Death)

**12. Transcervical occlusion and protective shunting technique** 

embolization.

Table 1.

**13. Review of literature** 

after percutaneous CA was reported by Markus et al. 12

Study number (Follow-up)

The lesion has been passed using an 0.012" wire followed by replacement with an 0.014" wire and placement of a MOMA flow arrest device within the external carotid artery balloon inflated (long arrow).

The ICA angioplasty is complete. The MOMA flow arrest device is still in place with the ECA and CCA balloons deflated and flow re-established to the brain.

Angioplasty, Various Techniques and Challenges in 196 Treatment of Congenital and Acquired Vascular Stenoses

The lesion has been passed using an 0.012" wire followed by replacement with an 0.014" wire and placement of a MOMA flow arrest device within the external carotid artery

The ICA angioplasty is complete. The MOMA flow arrest device is still in place with the

ECA and CCA balloons deflated and flow re-established to the brain.

balloon inflated (long arrow).

#### **12. Transcervical occlusion and protective shunting technique**

This technique uses a partially open operative approach. The procedure is performed under local anesthesia utilizing a small incision just above the clavicle. A large (9 Fr) and medium (6 Fr) sheath are introduced into the CCA directed in a cephalad orientation through the incision. Additionally, a 6 Fr sheath is introduced into the jugular vein directed caudally. An over-the-wire fogerty catheter is used to occlude the external carotid artery and the proximal CCA is clamped following anticoagulation. Flow reversal in the carotid system is established by connecting the sideports of the 9 Fr arterial and 6 Fr venous sheaths and flow direction is verified using a small injection of contrast. Now, the angioplasty is performed through the 9 Fr sheath and any loose debris that results is carried into the venous system or trapped by any interposed filter. The arterial puncture sites are sutured at the time of final sheath removal. This approach appears fairly labor intensive within a small field and the use of a partially open portion of the angioplasty procedure seems to defeat the minimally invasive nature of CAS. Nonetheless, it has been suggested as a reliable means of controlling embolization.

#### **13. Review of literature**

Mathias first described the percutaneous carotid artery angioplasty (CA) technique in 1977.10 Subsequently he reported a case series of 3 high surgical risk patients undergoing percutaneous carotid angioplasty.11 During this time, percutaneous carotid intervention was limited to fibromuscular dysplasia and was not applied to atherosclerotic diseases due to risk of embolic events and secondly, CEA was considered a very safe procedure and its utilization was widespread. There were occasional case reports of CA, but it wasn't until 1990's when this technique was more systematically studied for its feasibility, safety and outcomes. The summary of early clinical studies is shown in Table 1. The most feared complication of CA is embolic phenomenon and evidence of early and delayed embolization after percutaneous CA was reported by Markus et al. 12


Table 1.

In 1992, Brown20 reviewed approximately 100 cases reported in the literature with stroke rate of 4%. In May 1998, Wholey21 published a review of 2,048 cases of carotid stents across 24 centers world-wide and reported a 98.6% technical success rate. Also the complication rates were 3.08% for minor strokes, 1.32% major strokes and 1.37% peri-procedural mortality. The 6-month re-stenosis rate was 4.8% by duplex-ultrasound or angiographic method. The stents being utilized for carotid stenting at the time were Palmaz (Cordis) or

Carotid Angioplasty 199

**16. Stenting and Angioplasty with Protection of the Patients at High Risk for** 

This multicenter, industry-supported randomized trial enrolled 747 patients from 29 centers between 2000 and 2002. The major "high-risk"criteria were significant cardiac or pulmonary disease, contralateral carotid occlusion, prior neck radiation or radical neck surgery, recurrent stenosis, contralateral recurrent laryngeal nerve palsy or age greater than 80 years. The study showed that CAS was non-inferior to CEA when evaluating the cumulative

**17. Stent-supported Percutaneous Angioplasty of the Carotid artery versus** 

The SPACE trial was designed as non-inferiority trial for CAS versus CEA. 1214 patients with symptomatic high grade stenosis of carotid artery (>70%) were randomized into CAS or CEA between March 2001 and February 2006. The primary end-point of ipsilateral stroke or death rate was 6.45% in CEA group versus 6.92% in CAS group which did not reach the statistical significance level (p=0.09) for non-inferiority for CAS. At 2-year follow-up, the overall mortality was 6.3% in CAS versus 5% in CEA (p=0.68), and the ipsilateral ischemic stroke rate was 2.2% vs 1.9%. However, recurrent stenosis (>70% by ultrasound criteria) was 10.7% in CAS versus 4.6% in CEA group (p=0.0009). The subgroup analysis showed patients greater than 68 years of age had higher event rates with CAS compared to CEA, whereas the

**18. Endarterectomy Versus Angioplasty in patients with Symptomatic Severe** 

This trial was a French multicenter, prospective randomized non-inferiority trial. The patient enrollment started in November 2000 and ended in September 2005. A total of 527 patients were enrolled and randomized into two arms. All the CAS cases after January 2003 were done with approved EPDs at the time, which left initial 73 cases being done without any cerebral protection. The 30-day risk of stroke or death was 3.9% in CEA group versus 9.6% in CAS group, and risk of any peri-procedural disabling stroke or death was 1.5% in CEA group versus 3.4% in CAS group. The 4-year hazard ratio (HR) of any disabling or fatal stroke or death was 2.0 (p=0.17) slightly favoring endarterectomy. Although the periprocedural risk was unusually higher in the stenting group, overall long-term secondary prevention of stroke was similar in both arms. The major criticism of this study was that despite a requirement of a minimum procedure volume performed prior to enrollment in the study as an operator, overall operator experience was too limited and may have

The ICSS study, also known as CAVATAS-2, was designed. A meta-analysis of 3 trials, EVA-3S (2008), SPACE (2008) and the ICSS (2010) showed significantly lower event rate in the CEA group (OR 1.73, 95% CI: 1.29 – 2.32)20. Age, greater than 70 years, was a risk factor for poorer outcomes with CAS (12%) compared to CEA (5.9%), RR = 2.04. However, the

incidence of major stroke, MI or death in 30-day period and at 1-year.

younger patients did better with CAS compared to CEA.

**19. The International Carotid Stenting Study (ICSS)30**

patients younger than 70 years had no difference in outcomes.31

**Carotid Stenosis (EVA-3S) trial<sup>29</sup>**

influenced the outcomes.

**Endarterectomy (SAPPHIRE)<sup>27</sup>**

**Endarterectomy (SPACE)28**

Palmaz-Schatz (Johnson and Johnson) balloon expandable stents (53%), followed by Wallstent (Schneider, Minneapolis, MN) (39%), Strecker (8%) and Inegra (1%) (Medi-Tech) stents. Subsequently, he reported updated data for 5,210 cases across 36 centers in June 2000. This showed a rapid rise in global popularity of this procedure. The incidence of major and minor stroke remained 1.49% and 2.72%. This review observed lower stroke rates in the centers with more than 50 procedures performed indicating the importance of a learning curve. Overall procedure-related complication rates declined from 5.72% in 1998 to 4.75% in 2000. Since the cerebral protection technology had not yet evolved, these results derived from "unprotected" procedures.

Theron et al22 first reported the use of cerebral embolic protection in carotid artery angioplasty and stenting procedures. There were no procedure related complications in 136 cases of carotid artery stenting with use of the cerebral embolic protection for atherosclerotic stenosis.

The Carotid Revascularization using Endarterectomy or Stenting Systems (CaRESS)23 was a non-randomized prospective trial designed for high-risk patients with or without symptoms. Total of 397 patients were studied and the outcomes at 4-years showed a stroke incidence of 9.6% in CAS group versus 8.6% in CEA group (p=0.444) and an overall complication (death/stroke) rate of 26.5% in CEA versus 21.8% (p=0.361) in CAS. However, at the long-term follow-up, there were significantly higher re-stenosis and re-intervention rates in the CAS arm.

#### **14. Randomized controlled trials**

#### **14.1 CAVATAS**

In 1996, the European Carotid Angioplasty trial group reported the rationale, design and protocol of the first multicenter randomized trial, the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS).24 Preceding this trial, a single center trial in the UK was stopped after enrolling 20 patients due to unacceptable rate of stroke in the carotid angioplasty arm (7/10 patients).25 The CAVATAS trial involved 22 centers across Europe, Canada and Australia and the patient enrollment was between March 1992 and July 1997. Five hundred and four patients were randomized to either CEA or CAS. The majority of patients (90%) in both arms had symptoms within 6 months of randomization and exhibited >70% carotid stenosis. Because the stents suitable for CAS were developed during the course of this study, all the patients before 1994 had primary balloon angioplasty alone versus the cases thereafter, which utilized stenting with Wallstent (Schneider, Minneapolis, MN), Streker (Medi-Tech, USA) and Palmaz (Johnson and Johnson, USA) stents. High-risk patients were excluded from the study. The major stroke and death rates were not statistically significantly different between two groups (30-day: 10% for CAS versus 10% for CEA; 3-years: 14.3% in CAS versus 14.2% in CEA). The primary limitation of this study is that very low number of patients (26%) who underwent carotid artery stenting and that the stroke and death rates were unusually high. However, subgroup analysis showed the incidence of stroke was only 2% in the stented patients, which lead to more widespread use of stent application after balloon angioplasty of a carotid artery stenosis.

#### **15. WALLSTENT26**

The Carotid WALLSTENT trial enrolled 223 patients with symptomatic carotid artery stenosis > 60%. No cerebral embolic protection was used. The trial was stopped due to unacceptably high risk of stroke in CAS group (12.1 %) versus CEA (4.5%, P=0.022).

Angioplasty, Various Techniques and Challenges in 198 Treatment of Congenital and Acquired Vascular Stenoses

Palmaz-Schatz (Johnson and Johnson) balloon expandable stents (53%), followed by Wallstent (Schneider, Minneapolis, MN) (39%), Strecker (8%) and Inegra (1%) (Medi-Tech) stents. Subsequently, he reported updated data for 5,210 cases across 36 centers in June 2000. This showed a rapid rise in global popularity of this procedure. The incidence of major and minor stroke remained 1.49% and 2.72%. This review observed lower stroke rates in the centers with more than 50 procedures performed indicating the importance of a learning curve. Overall procedure-related complication rates declined from 5.72% in 1998 to 4.75% in 2000. Since the cerebral protection technology had not yet evolved, these results derived

Theron et al22 first reported the use of cerebral embolic protection in carotid artery angioplasty and stenting procedures. There were no procedure related complications in 136 cases of carotid artery stenting with use of the cerebral embolic protection for atherosclerotic stenosis. The Carotid Revascularization using Endarterectomy or Stenting Systems (CaRESS)23 was a non-randomized prospective trial designed for high-risk patients with or without symptoms. Total of 397 patients were studied and the outcomes at 4-years showed a stroke incidence of 9.6% in CAS group versus 8.6% in CEA group (p=0.444) and an overall complication (death/stroke) rate of 26.5% in CEA versus 21.8% (p=0.361) in CAS. However, at the long-term follow-up, there were significantly higher re-stenosis and re-intervention

In 1996, the European Carotid Angioplasty trial group reported the rationale, design and protocol of the first multicenter randomized trial, the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS).24 Preceding this trial, a single center trial in the UK was stopped after enrolling 20 patients due to unacceptable rate of stroke in the carotid angioplasty arm (7/10 patients).25 The CAVATAS trial involved 22 centers across Europe, Canada and Australia and the patient enrollment was between March 1992 and July 1997. Five hundred and four patients were randomized to either CEA or CAS. The majority of patients (90%) in both arms had symptoms within 6 months of randomization and exhibited >70% carotid stenosis. Because the stents suitable for CAS were developed during the course of this study, all the patients before 1994 had primary balloon angioplasty alone versus the cases thereafter, which utilized stenting with Wallstent (Schneider, Minneapolis, MN), Streker (Medi-Tech, USA) and Palmaz (Johnson and Johnson, USA) stents. High-risk patients were excluded from the study. The major stroke and death rates were not statistically significantly different between two groups (30-day: 10% for CAS versus 10% for CEA; 3-years: 14.3% in CAS versus 14.2% in CEA). The primary limitation of this study is that very low number of patients (26%) who underwent carotid artery stenting and that the stroke and death rates were unusually high. However, subgroup analysis showed the incidence of stroke was only 2% in the stented patients, which lead to more widespread use

The Carotid WALLSTENT trial enrolled 223 patients with symptomatic carotid artery stenosis > 60%. No cerebral embolic protection was used. The trial was stopped due to

unacceptably high risk of stroke in CAS group (12.1 %) versus CEA (4.5%, P=0.022).

of stent application after balloon angioplasty of a carotid artery stenosis.

from "unprotected" procedures.

rates in the CAS arm.

**15. WALLSTENT26**

**14.1 CAVATAS** 

**14. Randomized controlled trials** 

#### **16. Stenting and Angioplasty with Protection of the Patients at High Risk for Endarterectomy (SAPPHIRE)<sup>27</sup>**

This multicenter, industry-supported randomized trial enrolled 747 patients from 29 centers between 2000 and 2002. The major "high-risk"criteria were significant cardiac or pulmonary disease, contralateral carotid occlusion, prior neck radiation or radical neck surgery, recurrent stenosis, contralateral recurrent laryngeal nerve palsy or age greater than 80 years. The study showed that CAS was non-inferior to CEA when evaluating the cumulative incidence of major stroke, MI or death in 30-day period and at 1-year.

#### **17. Stent-supported Percutaneous Angioplasty of the Carotid artery versus Endarterectomy (SPACE)28**

The SPACE trial was designed as non-inferiority trial for CAS versus CEA. 1214 patients with symptomatic high grade stenosis of carotid artery (>70%) were randomized into CAS or CEA between March 2001 and February 2006. The primary end-point of ipsilateral stroke or death rate was 6.45% in CEA group versus 6.92% in CAS group which did not reach the statistical significance level (p=0.09) for non-inferiority for CAS. At 2-year follow-up, the overall mortality was 6.3% in CAS versus 5% in CEA (p=0.68), and the ipsilateral ischemic stroke rate was 2.2% vs 1.9%. However, recurrent stenosis (>70% by ultrasound criteria) was 10.7% in CAS versus 4.6% in CEA group (p=0.0009). The subgroup analysis showed patients greater than 68 years of age had higher event rates with CAS compared to CEA, whereas the younger patients did better with CAS compared to CEA.

#### **18. Endarterectomy Versus Angioplasty in patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial<sup>29</sup>**

This trial was a French multicenter, prospective randomized non-inferiority trial. The patient enrollment started in November 2000 and ended in September 2005. A total of 527 patients were enrolled and randomized into two arms. All the CAS cases after January 2003 were done with approved EPDs at the time, which left initial 73 cases being done without any cerebral protection. The 30-day risk of stroke or death was 3.9% in CEA group versus 9.6% in CAS group, and risk of any peri-procedural disabling stroke or death was 1.5% in CEA group versus 3.4% in CAS group. The 4-year hazard ratio (HR) of any disabling or fatal stroke or death was 2.0 (p=0.17) slightly favoring endarterectomy. Although the periprocedural risk was unusually higher in the stenting group, overall long-term secondary prevention of stroke was similar in both arms. The major criticism of this study was that despite a requirement of a minimum procedure volume performed prior to enrollment in the study as an operator, overall operator experience was too limited and may have influenced the outcomes.

### **19. The International Carotid Stenting Study (ICSS)30**

The ICSS study, also known as CAVATAS-2, was designed. A meta-analysis of 3 trials, EVA-3S (2008), SPACE (2008) and the ICSS (2010) showed significantly lower event rate in the CEA group (OR 1.73, 95% CI: 1.29 – 2.32)20. Age, greater than 70 years, was a risk factor for poorer outcomes with CAS (12%) compared to CEA (5.9%), RR = 2.04. However, the patients younger than 70 years had no difference in outcomes.31

Carotid Angioplasty 201

Rx Accunet

Spider

Overall, there are three major functional principles upon which all EPDs are based. (1) Distal ICA balloon occlusion with flow arrest (2) filtration with continuous flow through (as noted in the above figures), and (3) proximal balloon occlusion with flow stagnation or flow

reversal. The pros and cons of these devices are enumerated in Table 2.

#### **20. Carotid Revascularization Endarterectomy versus Stenting Trial (CREST)32**

This North American prospective randomized controlled trial enrolled 2502 patients from 117 centers (symptomatic and asymptomatic). The primary end-points of any stroke, MI or death were similar in both groups of CEA (6.8%) and CAS (7.2%). Although there was a lower incidence of MI in the CAS group versus lower stroke rate in the CEA group, these rates did not reach statistical significance. Also the younger patients had slightly better outcomes with CAS whereas the older patients did slightly better after CEA. At one year, subgroup analysis revealed that stroke had a lasting effect on quality of life as opposed to the effects of MI. Nonetheless, overall, both procedures were safe when done by a skilled operator.

#### **21. Cerebral embolic protection devices**

The first safety and feasibility study of the ICA filter devices for cerebral embolic protection was done by Reimers et al.33 The 3-types of the filter devices used in that study are shown below.

Subsequently, the EPD field has expanded with the addition of other filtration systems such as those shown below. All of these devices are based upon a similar principal of flowthrough filtration.

Angioplasty, Various Techniques and Challenges in 200 Treatment of Congenital and Acquired Vascular Stenoses

This North American prospective randomized controlled trial enrolled 2502 patients from 117 centers (symptomatic and asymptomatic). The primary end-points of any stroke, MI or death were similar in both groups of CEA (6.8%) and CAS (7.2%). Although there was a lower incidence of MI in the CAS group versus lower stroke rate in the CEA group, these rates did not reach statistical significance. Also the younger patients had slightly better outcomes with CAS whereas the older patients did slightly better after CEA. At one year, subgroup analysis revealed that stroke had a lasting effect on quality of life as opposed to the effects of MI.

The first safety and feasibility study of the ICA filter devices for cerebral embolic protection was done by Reimers et al.33 The 3-types of the filter devices used in that study are shown below.

Angioguard

Neuroshield / Emboshield

FilterWire EX

Subsequently, the EPD field has expanded with the addition of other filtration systems such as those shown below. All of these devices are based upon a similar principal of flow-

**20. Carotid Revascularization Endarterectomy versus Stenting Trial** 

Nonetheless, overall, both procedures were safe when done by a skilled operator.

**21. Cerebral embolic protection devices** 

**(CREST)32**

through filtration.

Overall, there are three major functional principles upon which all EPDs are based. (1) Distal ICA balloon occlusion with flow arrest (2) filtration with continuous flow through (as noted in the above figures), and (3) proximal balloon occlusion with flow stagnation or flow reversal. The pros and cons of these devices are enumerated in Table 2.

Carotid Angioplasty 203

diameter of the distal ICA. At the conclusion of the procedure, the filter is retrieved and then the entire system is removed. The currently available filter-devices have a crossing profile between 3Fr and 4Fr and accommodate the vessels from 3mm to 7mm diameter.

Embolic protection during CAS can be accomplished with carotid flow arrest or reversal. The MOMA device is a 9 Fr sheath incorporating a small compliant balloon introduced into the ECA and a larger balloon located on the distal main body of the device used for CCA occlusion. Intubation of the ECA is performed using a 0.035" wire placed during a standard initial approach. The ECA wire serves as a guide for initial device placement. Following anticoagulation, the ECA and CCA balloons are inflated providing for carotid flow arrest. Any standard 0.014" wire may now be used to deliver angioplasty balloons and stents to the target lesion. An advantage to this system is that the working wire does not need to be advanced deep into the ICA territory thereby making this a favorable method when there is severe tortuosity to the ICA which will not accept distally placed filtration EPDs. Debris in the carotid

bulb and ICA is aspirated at the conclusion of the procedure prior to balloon deflation.

patients undergoing CAS with MO.MA cerebral protection device.34

Initial data in a multicenter, intention-to-treat trial, ARMOUR Trial(Proximal Protection with the MO.MA Device During Carotid Stenting), showed that the major 30-day event rate (major cardiac and cerebrovascular) was 2.7% and 30-day major stroke rate was 0.9% in the

Flow reversal uses a similar principal of ECA and CCA occlusion during the angioplasty procedure but with dynamic flow reversal of blood from the carotid bulb into the femoral vein via a system side port. The flow reversal is encouraged by the higher arterial back pressure from the ICA compared to the venous system once the balloon system is inflated. This device is called the Parodi antiembolism system (PAES). Both devices serve the role of

**23. Flow arrest or flow reversal technique** 

**MO.MA device.** (Source: Invatec Inc., Italy)

EPD as well as access sheath.


Table 2.

#### **22. Filter protection**

All filter devices have similar design. The filter is mounted on a 0.014" wire with floppy tip. The filter is made up from nitinol (nickel-titanium alloy) covered with polyurethane membrane. The porous size of the filter ranges from 30 to 140 microns. Each filter comes in with its own deployment and retrieval sheaths. The filter basket and the sheath are flushed carefully with heparinized saline with particular attention to avoid any air-bubbles. Once the filter is deployed in the distal straight portion of the ICA, the more proximal diseased area is treated over the 0.014" wire. The size of the filter is chosen considering the luminal Angioplasty, Various Techniques and Challenges in 202 Treatment of Congenital and Acquired Vascular Stenoses

Type Pros Cons Currently available

lesion

Risk of

lesion

Risk of embolism while traversing the

Technically difficult in tortuous vessels

microembolism (smaller than pore size of the filter)

Risk of filter thrombosis

Risk of embolism while traversing the

Potential for arterial injury by balloon

Inability of some patients to tolerate ICA occlusion

Inability to perform angiogram during the procedure

Potential for arterial injury by balloon

Cerebral Intolerance

All filter devices have similar design. The filter is mounted on a 0.014" wire with floppy tip. The filter is made up from nitinol (nickel-titanium alloy) covered with polyurethane membrane. The porous size of the filter ranges from 30 to 140 microns. Each filter comes in with its own deployment and retrieval sheaths. The filter basket and the sheath are flushed carefully with heparinized saline with particular attention to avoid any air-bubbles. Once the filter is deployed in the distal straight portion of the ICA, the more proximal diseased area is treated over the 0.014" wire. The size of the filter is chosen considering the luminal

Complete flow arrest or reversal during the procedure

Filter Maintains flow throughout the procedure

Distal ICA occlusion

Proximal occlusion

Table 2.

**22. Filter protection** 

Can perform angiogram during the procedure

Offers complete distal embolic protection

Does not require traversing the lesion unprotected

Offers complete distal embolic protection

in Market in the US

• Rx Accunet • Filter-wire • Angioguard • Emboshield • Spider

• GuardWire

• MO.MA • PAES (Parodi antiembolism system)

diameter of the distal ICA. At the conclusion of the procedure, the filter is retrieved and then the entire system is removed. The currently available filter-devices have a crossing profile between 3Fr and 4Fr and accommodate the vessels from 3mm to 7mm diameter.

#### **23. Flow arrest or flow reversal technique**

Embolic protection during CAS can be accomplished with carotid flow arrest or reversal. The MOMA device is a 9 Fr sheath incorporating a small compliant balloon introduced into the ECA and a larger balloon located on the distal main body of the device used for CCA occlusion. Intubation of the ECA is performed using a 0.035" wire placed during a standard initial approach. The ECA wire serves as a guide for initial device placement. Following anticoagulation, the ECA and CCA balloons are inflated providing for carotid flow arrest. Any standard 0.014" wire may now be used to deliver angioplasty balloons and stents to the target lesion. An advantage to this system is that the working wire does not need to be advanced deep into the ICA territory thereby making this a favorable method when there is severe tortuosity to the ICA which will not accept distally placed filtration EPDs. Debris in the carotid bulb and ICA is aspirated at the conclusion of the procedure prior to balloon deflation. Initial data in a multicenter, intention-to-treat trial, ARMOUR Trial(Proximal Protection with the MO.MA Device During Carotid Stenting), showed that the major 30-day event rate (major cardiac and cerebrovascular) was 2.7% and 30-day major stroke rate was 0.9% in the

patients undergoing CAS with MO.MA cerebral protection device.34

**MO.MA device.** (Source: Invatec Inc., Italy)

Flow reversal uses a similar principal of ECA and CCA occlusion during the angioplasty procedure but with dynamic flow reversal of blood from the carotid bulb into the femoral vein via a system side port. The flow reversal is encouraged by the higher arterial back pressure from the ICA compared to the venous system once the balloon system is inflated. This device is called the Parodi antiembolism system (PAES). Both devices serve the role of EPD as well as access sheath.

Carotid Angioplasty 205

Post-procedure sonography is performed in order to (1) identify undetected procedural faults associated with residual stenosis, (2) evaluate the occurrence of neointimal hyperplasia at the stented site, and (3) monitor the progression of contralateral disease. The incidence of significant contralateral disease ranges 25-50% making this the most compelling reason for ongoing duplex surveillance. Assessment of restenosis at the angioplasty site

Risk factors for restenosis after CAS largely remain undefined. When various factors are analyzed, a history of head and neck cancer and prior carotid endarterectomy (CEA) were found to be marginally significant for the development of early in-stent restenosis (ISR).36,37 The time line for the occurrence of ISR is somewhat variable but the majority (>70%) of these cases are identified within 12 months following the index procedure3. However, this disease process may be ongoing as evidenced by an increasing incidence over a five year follow-up. Lal et al38, reported ISR rates of 2.7% and 6.4% at 1 and 5 years, respectively. These data utilize 80% stenosis as a measure of disease with this frequency rising if lower degrees of restenosis criteria are selected. Interestingly, ISR may regress over time but the temporal profile of this

The baseline post-procedural duplex velocities for stented vessels tend to exhibit higher values than unstented vessels of normal luminal caliber. This may result from either under dilatation of the ICA during CAS or a change in the mechanical properties of the ICA. A common notion is that the purpose of balloon dilatation is to ensure an adequate ICA lumen and not an anatomically cosmetic perfect result. This conservative approach may predispose to a minor residual stenosis exemplified by a peak systolic velocity (PSV) higher than normal. Alternatively, some authorities have reported that the introduction of a stent into the carotid bulb and ICA alters the biomechanical properties of the vessel resulting in a stent-arterial complex with decreased compliance. This translates into an elevated PSV because energy normally applied to dilate the artery is now expended as increased flow velocity39. Consequently, recommendations have been advocated for the increase of velocity criteria corresponding to higher degrees of stenosis following CAS.

The variability of the recommended criteria values depends upon the balance between sensitivity and specificity desired by the laboratory performing the studies. Surveillance is usually performed every six months following CAS for at least two years. If the patient

Stenosis PSV (cm/sec) EDV (cm/sec) ICA/CCA ratio

represents the second most frequent need for longitudinal surveillance.35

process as well as factors predictive of regression remain undefined.

Table 3 shows current recommendations by several clinical laboratories.

exhibits contralateral disease, this surveillance may be continued indefinitely.

 >50% >225 - >2.540 >240 - >2.4542

 >70% >170 >12041 - >350 - >4.7540 >450 - >4.342

 >80% >340 - >4.1538 >325 >119 >4.5339

Table 3. Recommended Velocity Criteria for Restenosis of the ICA following CAS

PSV=peak systolic velocity; EDV=end diastolic velocity

**25.2 Duplex ultrasound criteria** 

#### **24. Neurorescue during carotid artery stenting**

#### **24.1 Procedural embolization**

Embolization can occur during the carotid artery stenting procedure and that can be in the form of micro- or macro-embolization. However, the risk of embolization is particularly high during the diagnostic phase, deployment of EPD period and during retrieval of the EPD. Most cases with micro-embolization are asymptomatic at the time of the procedure and in the immediate post-procedural phase, but their impact on long-term functional outcome (eg., cognitive function) is largely unknown.

The risk of embolization can be minimized by peri-procedural antiplatelet therapy (oral or intravenous GPIIB-IIIA inhibitors) and anticoagulation. These agents reduce platelet aggregation when subintimal tissue or stent material is exposed to the blood system during CAS. However, should macro-embolization occur, mainly due to technical error or failure of EPD, one should be prepared with mechanical retrieval/aspiration systems or catheterdirected thrombolysis.

#### **24.2 Thrombosis**

Thrombosis during the CAS procedure is associated with the use of EPDs. This is usually treated with direct aspiration of thrombus and/or direct administration of a thrombolytic (ie. Alteplase) or GPIIb-IIIa inhibitor intra-arterially, if possible. Also, distal embolization can be prevented by adopting an incomplete filter-retrieval technique in which case the filter retrieval system is not closed completely upon removal in order to prevent thrombus from being squeezed out of the system.

Acute stent thrombosis is rare (< 2%) and can be further minimized by appropriate periprocedural antiplatelet and anticoagulation strategy. The treatment consists of direct infusion of thrombolytic agent and/or GPIIb-IIIa inhibitor. This latter maneuver must be weighed against the risk of precipitating embolization during the lysis of an established ICA clot. In rare circumstances, when endoluminal techniques fail, the patient should immediately be taken to operating room and thrombectomy should be performed after appropriate anticoagulation and obtaining distal control to prevent progression of thrombosis and distal embolization.

#### **24.3 Dissection**

Dissection is fortunately a rare phenomenon and is usually related to stent insertion and/or balloon dilation. If the dissection does not limit the flow-lumen significantly, "wait-andobserve" strategy can be employed with or without use of continued anticoagulation. In case of significant flow-limiting dissection, the deployment of second stent may be advocated versus open surgical repair.

#### **25. CAS surveillance**

#### **25.1 Carotid restenosis**

The need for post-procedure surveillance is typically recommended by physicians who perform CAS. Surveillance options include duplex ultrasound (DU), MRA and CTA. MRA suffers from signal degradation due to the presence of a metallic stent and CTA involves significant ionizing radiation and the use of iodinated contrast, which may cause nephrotoxicity and allergic reactions35. Consequently, because of the absence of risk, DU surveillance after CAS has become the standard.

Angioplasty, Various Techniques and Challenges in 204 Treatment of Congenital and Acquired Vascular Stenoses

Embolization can occur during the carotid artery stenting procedure and that can be in the form of micro- or macro-embolization. However, the risk of embolization is particularly high during the diagnostic phase, deployment of EPD period and during retrieval of the EPD. Most cases with micro-embolization are asymptomatic at the time of the procedure and in the immediate post-procedural phase, but their impact on long-term functional

The risk of embolization can be minimized by peri-procedural antiplatelet therapy (oral or intravenous GPIIB-IIIA inhibitors) and anticoagulation. These agents reduce platelet aggregation when subintimal tissue or stent material is exposed to the blood system during CAS. However, should macro-embolization occur, mainly due to technical error or failure of EPD, one should be prepared with mechanical retrieval/aspiration systems or catheter-

Thrombosis during the CAS procedure is associated with the use of EPDs. This is usually treated with direct aspiration of thrombus and/or direct administration of a thrombolytic (ie. Alteplase) or GPIIb-IIIa inhibitor intra-arterially, if possible. Also, distal embolization can be prevented by adopting an incomplete filter-retrieval technique in which case the filter retrieval system is not closed completely upon removal in order to prevent thrombus from

Acute stent thrombosis is rare (< 2%) and can be further minimized by appropriate periprocedural antiplatelet and anticoagulation strategy. The treatment consists of direct infusion of thrombolytic agent and/or GPIIb-IIIa inhibitor. This latter maneuver must be weighed against the risk of precipitating embolization during the lysis of an established ICA clot. In rare circumstances, when endoluminal techniques fail, the patient should immediately be taken to operating room and thrombectomy should be performed after appropriate anticoagulation and obtaining distal control to prevent progression of

Dissection is fortunately a rare phenomenon and is usually related to stent insertion and/or balloon dilation. If the dissection does not limit the flow-lumen significantly, "wait-andobserve" strategy can be employed with or without use of continued anticoagulation. In case of significant flow-limiting dissection, the deployment of second stent may be

The need for post-procedure surveillance is typically recommended by physicians who perform CAS. Surveillance options include duplex ultrasound (DU), MRA and CTA. MRA suffers from signal degradation due to the presence of a metallic stent and CTA involves significant ionizing radiation and the use of iodinated contrast, which may cause nephrotoxicity and allergic reactions35. Consequently, because of the absence of risk, DU

**24. Neurorescue during carotid artery stenting** 

outcome (eg., cognitive function) is largely unknown.

**24.1 Procedural embolization** 

directed thrombolysis.

being squeezed out of the system.

thrombosis and distal embolization.

advocated versus open surgical repair.

surveillance after CAS has become the standard.

**25. CAS surveillance 25.1 Carotid restenosis** 

**24.2 Thrombosis** 

**24.3 Dissection** 

Post-procedure sonography is performed in order to (1) identify undetected procedural faults associated with residual stenosis, (2) evaluate the occurrence of neointimal hyperplasia at the stented site, and (3) monitor the progression of contralateral disease. The incidence of significant contralateral disease ranges 25-50% making this the most compelling reason for ongoing duplex surveillance. Assessment of restenosis at the angioplasty site represents the second most frequent need for longitudinal surveillance.35

Risk factors for restenosis after CAS largely remain undefined. When various factors are analyzed, a history of head and neck cancer and prior carotid endarterectomy (CEA) were found to be marginally significant for the development of early in-stent restenosis (ISR).36,37 The time line for the occurrence of ISR is somewhat variable but the majority (>70%) of these cases are identified within 12 months following the index procedure3. However, this disease process may be ongoing as evidenced by an increasing incidence over a five year follow-up. Lal et al38, reported ISR rates of 2.7% and 6.4% at 1 and 5 years, respectively. These data utilize 80% stenosis as a measure of disease with this frequency rising if lower degrees of restenosis criteria are selected. Interestingly, ISR may regress over time but the temporal profile of this process as well as factors predictive of regression remain undefined.

#### **25.2 Duplex ultrasound criteria**

The baseline post-procedural duplex velocities for stented vessels tend to exhibit higher values than unstented vessels of normal luminal caliber. This may result from either under dilatation of the ICA during CAS or a change in the mechanical properties of the ICA. A common notion is that the purpose of balloon dilatation is to ensure an adequate ICA lumen and not an anatomically cosmetic perfect result. This conservative approach may predispose to a minor residual stenosis exemplified by a peak systolic velocity (PSV) higher than normal. Alternatively, some authorities have reported that the introduction of a stent into the carotid bulb and ICA alters the biomechanical properties of the vessel resulting in a stent-arterial complex with decreased compliance. This translates into an elevated PSV because energy normally applied to dilate the artery is now expended as increased flow velocity39. Consequently, recommendations have been advocated for the increase of velocity criteria corresponding to higher degrees of stenosis following CAS. Table 3 shows current recommendations by several clinical laboratories.

The variability of the recommended criteria values depends upon the balance between sensitivity and specificity desired by the laboratory performing the studies. Surveillance is usually performed every six months following CAS for at least two years. If the patient exhibits contralateral disease, this surveillance may be continued indefinitely.


PSV=peak systolic velocity; EDV=end diastolic velocity

Table 3. Recommended Velocity Criteria for Restenosis of the ICA following CAS

Carotid Angioplasty 207

[14] Roubin GS, Yadav S, Iyer SS, Vitek J. Carotid stent-supported angioplasty: a

[15] Gil-Peralta A, Mayol A, Marcos JR, Gonzalez A, Ruano J, Boza F, Duran F.

[18] Vozzi CR, Rodriguez AO, Paolantonio D, Smith JA, Wholey MH. Extracranial carotid

[19] Teitelbaum GP, Lefkowitz MA, Giannotta SL Carotid angioplasty and stenting in high-

[20] Brown MM. Balloon angioplasty for cerebrovascular disease. Neurol Res 1992;

[21] Wholey MH, Wholey M, Bergeron P, Diethrich EB, Henry M, Laborde JC, Mathias K,

[22] Theron JG, Payelle GG, Coskun O, Huet HF, Guimaraens L. Carotid artery stenosis:

[23] Zarins CK, White RA, Diethrich EB, Shackelton RJ, Siami FS; CaRESS Steering Committee

systems (CaRESS): 4-year outcomes. J Endovasc Ther. 2009 Aug;16(4):397-409. [24] Sivaguru A, Venables GS, Beard JD, Gaines PA. European Carotid Angioplasty Trial. J

[25] Naylor AR, Bolia A, Abbott RJ, Pye IF, Smith J, Lennard N, Lloyd AJ, London NJ, Bell

[27] Yadav JS, Wholey MH, Kuntz RE, Fayad P, Katzen BT, Mishkel GJ, Bajwa TK, Whitlow

endarterectomy: a stopped trial. J Vasc Surg. 1998 Aug;28(2):326-34. [26] Alberts MJ. Results of a multicenter prospective randomized trial of carotid artery

risk patients. Surg Neurol. 1998 Oct;50(4):300-11; discussion 311-2.

stent placement. Cathet Cardiovasc Diagn. 1998 May;44(1):1-6.

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1997;24(3):167-72.

14(suppl): 159-173

Dec;201(3):627-36.

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stenting vs. carotid endarterectomy. Stroke 2001.

neurovascular intervention to prevent stroke. Am J Cardiol. 1996 Aug 14;78(3A):8-12.

Percutaneous transluminal angioplasty of the symptomatic atherosclerotic carotid arteries. Results, complications, and follow-up. Stroke. 1996 Dec;27(12):2271-3. [16] Yadav JS, Roubin GS, King P, Iyer S, Vitek J. Angioplasty and stenting for restenosis after carotid endarterectomy. Initial experience. Stroke. 1996 Nov;27(11):2075-9. [17] Jordan WD Jr, Schroeder PT, Fisher WS, McDowell HA. A comparison of angioplasty

with stenting versus endarterectomy for treatment of carotid artery stenosis. Ann

angioplasty and stenting. Initial results and short term follow-up. Tex Heart Inst J.

Myla S, Roubin GS, Shawl F, Theron JG, Yadav JS, Dorros G, Guimaraens J, Higashida R, Kumar V, Leon M, Lim M, Londero H, Mesa J, Ramee S, Rodriguez A, Rosenfield K, Teitelbaum G, Vozzi C. Current global status of carotid artery

treatment with protected balloon angioplasty and stent placement. Radiology. 1996

and CaRESS Investigators. Carotid revascularization using endarterectomy or stenting

PR. Randomized study of carotid angioplasty and stenting versus carotid

P, Strickman NE, Jaff MR, Popma JJ, Snead DB, Cutlip DE, Firth BG, Ouriel K; Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med. 2004 Oct 7;351(15):1493-501. [28] Eckstein HH, Ringleb P, Allenberg JR, Berger J, Fraedrich G, Hacke W, Hennerici M,

Stingele R, Fiehler J, Zeumer H, Jansen O. Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol. 2008 Oct;7(10):893-902. Epub 2008 Sep 5. Erratum in: Lancet Neurol. 2009 Feb;8(2):135. [29] Mas JL, Trinquart L, Leys D, Albucher JF, Rousseau H, Viguier A, Bossavy JP, Denis B,

Piquet P, Garnier P, Viader F, Touzé E, Julia P, Giroud M, Krause D, Hosseini H, Becquemin JP, Hinzelin G, Houdart E, Hénon H, Neau JP, Bracard S, Onnient Y,

### **26. Conclusion**

Carotid angioplasty and stenting is very slowly increasing in popularity. Currently, approximately 12% of carotid interventions in the United States involve CAS. The major limitation in its adaption is the reimbursement climate. Presently, the Center for Medicare Services restricts reimbursement for CAS to high risk, symptomatic patients (stenosis > 50%) and high risk asymptomatic patients (stenosis >80%) who are on a clinical trial or registry. At least one private insurance carrier has elected to support payment for high risk asymptomatic patients (>80%) indicating that reimbursement restrictions are gradually relaxing. Furthermore, the FDA has approved the use of the Acculink/Accunet carotid stent system in asymptomatic patients. These changes in regulatory requirements for CAS suggest that eventually, in the not too distant future, this procedure will be approved for all patients exhibiting carotid stenosis. Whether CAS should be performed in asymptomatic patients remains a controversial issue and will remain a topic in evolution as pharmaceutical therapy and life-style changes become increasingly aggressive.

#### **27. References**


Angioplasty, Various Techniques and Challenges in 206 Treatment of Congenital and Acquired Vascular Stenoses

Carotid angioplasty and stenting is very slowly increasing in popularity. Currently, approximately 12% of carotid interventions in the United States involve CAS. The major limitation in its adaption is the reimbursement climate. Presently, the Center for Medicare Services restricts reimbursement for CAS to high risk, symptomatic patients (stenosis > 50%) and high risk asymptomatic patients (stenosis >80%) who are on a clinical trial or registry. At least one private insurance carrier has elected to support payment for high risk asymptomatic patients (>80%) indicating that reimbursement restrictions are gradually relaxing. Furthermore, the FDA has approved the use of the Acculink/Accunet carotid stent system in asymptomatic patients. These changes in regulatory requirements for CAS suggest that eventually, in the not too distant future, this procedure will be approved for all patients exhibiting carotid stenosis. Whether CAS should be performed in asymptomatic patients remains a controversial issue and will remain a topic in evolution as pharmaceutical

[1] North American Symptomatic Carotid Endarterectomy Trial Collaborators, Beneficial

[2] Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA. 1995 May 10;273(18):1421-8. [3] European Carotid Surgery Trialists' Collaborative Group, Ran-domised trial of

[6] Mathias K. [A new catheter system for percutaneous transluminal angioplasty (PTA) of carotid artery stenoses]. Fortschr Med. 1977 Apr 21;95(15):1007-11. German. [7] Diethrich EB, Ndiaye M, Reid DB. Stenting in the Carotid artery. Initial experience in

[8] Hammer FD, Lacroix V, Duprez T, et al: Cerebral microembolization after protected

[9] Dahn M, Cheema M, Bozeman P, Divinagracia T. Crossing an ultracritical carotid

[10] Mathias K. [A new catheter system for percutaneous transluminal angioplasty (PTA) of carotid artery stenoses]. Fortschr Med. 1977 Apr 21;95(15):1007-11. German. [11] Bockenheimer SA, Mathias K. Percutaneous transluminal angioplasty in arteriosclerotic internal carotid artery stenosis. AJNR Am J Neuroradiol. 1983 May-Jun;4(3):791-2. [12] Markus HS, Clifton A, Buckenham T, Brown MM. Carotid angioplasty. Detection of embolic signals during and after the procedure. Stroke. 1994 Dec;25(12):2403-6. [13] Diethrich EB, Ndiaye M, Reid DB. Stenting in the Carotid artery. Initial experience in

carotid artery stenting in surgical high-risk patients: Results of a 2-year prospective

stenosis for carotid angioplasty. Vasc Endovascular Surg. 2009 Dec;43(6):589-91.

effect of carotid endarterectomy in symptomatic patients with high grade carotid

endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998 May 9;351(9113):1379-87. [4] Robicsek F, Roush TS, Cook JW, Reames MK. From Hippocrates to Palmaz-Schatz, the history of carotid surgery. Eur J Vasc Endovasc Surg. 2004 Apr;27(4):389-97. [5] Morris GC Jr, Lechter A, DeBakey ME. Surgical treatment of fibromuscular disease of

therapy and life-style changes become increasingly aggressive.

stenosis. N Engl J Med. 1991 Aug 15;325(7):445-53

the carotid arteries. Arch Surg. 1968 Apr;96(4):636-43.

110 patients. J Endovasc Surg. 1996 Feb;3(1):42-62.

110 patients. J Endovasc Surg. 1996 Feb;3(1):42-62.

study. J Vasc Surg 2005;42:847-53.

Epub 2009 Oct 14.

**26. Conclusion** 

**27. References**


**10** 

*Italy* 

**Revascularization of Tibial and Foot Arteries:** 

**Below the Knee Angioplasty for Limb Salvage** 

Advanced atherosclerosis with extended tibial arteries lesions is a common concern, especially in diabetic patients having critical-limb ischemia (CLI) and skin wounds. Chronic critical limb ischemia is a major worldwide cause of morbidity and, especially when threatening the limb, mortality (Faglia E. et al. 2006). Certainly, major and minor amputations are associated with significant increases in mortality risk, and every efforts should be pursued to minimize

Infragenicular atherosclerotic is the most common cause of CLI, usually due to multilevel and diffuse arterial disease with compromised foot arteries run-off. Vascular disease is very often associated with arterial wall calcifications, that are usually severe and diffuse. The combination of severe peripheral arterial occlusion with the increased blood flow requirement necessary to achieve the healing of the skin wounds or surgical incisions, makes this population very challenging. Additionally, diabetics and CLI population have a

Clinical manifestations range from Intermittent claudication to limb-threatening ischemia,

Despite the benefits of pharmacologic therapy (e.g. Angiotensin-converting enzyme inhibitors, antidiabetic drugs, antiplatelet agents and statins), arterial revascularization remains a mainstay in the management of CLI, with restoration of arterial blood flow to the

In the last decade surgical revascularization has been adopted as the elective treatment option in patients with suitable anatomical conditions, however surgical by-pass is not always feasible due to the involvement of the foot arteries by the atherosclerotic disease, or recommended because of high surgical risk or contraindications in several cases, lack of venous conduits or poor vessels run-off, that compromise surgical by-pass patency

In recent years, related to good technical and clinical results, endovascular treatment options growing acceptance as the primary therapeutic strategy, especially in subjects with significant risk factors for surgical by-pass. In fact, since its initial applications, endovascular recanalization of tibial vessels and foot arteries has proven to be feasible and safe. Actually it is an established treatment option for limb salvage, avoiding amputations in lot of cases and improving wound healing(Adam DJ, et al. 2005; Balmer H, et al. 2002; Dorros G, et al. 2001; Faglia E, et al. 2005, 2006; Ferraresi R, et al. 2009; Romiti M, et al. 2008; Soder HR, et al 2000;

amputations and ensure limb salvage (Norgen L. et al. 2007).

foot, achieving a relief of rest pain and improving wound healing.

(HerstenNR, et al. 2007; Norgen L, et al. 2007; Walsh Db, et al. 1991).

high rate of comorbidities (Bargelini I, et al. 2008).

with rest pain, non healing ulcers and gangrene.

**1. Introduction** 

Wack C, et al. 1994).

Marco Manzi, Luis Mariano Palena and Giacomo Cester *Interventional Radiology Unit -Policlinico Abano Terme, Padua* 

Padovani R, Chatellier G; EVA-3S investigators. Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial. Lancet Neurol. 2008 Oct;7(10):885-92. Epub 2008 Sep 5.


### **Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage**

Marco Manzi, Luis Mariano Palena and Giacomo Cester *Interventional Radiology Unit -Policlinico Abano Terme, Padua Italy* 

#### **1. Introduction**

Angioplasty, Various Techniques and Challenges in 208 Treatment of Congenital and Acquired Vascular Stenoses

[30] International Carotid Stenting Study investigators, Ederle J, Dobson J, Featherstone RL,

controlled trial. Lancet. 2010 Mar 20;375(9719):985-97. Epub 2010 Feb 25. [31] Bonati LH, Fraedrich G; Carotid Stenting Trialists' Collaboration. Age modifies the

[32] Brott TG, Hobson RW, Howard G, Roubin GS, Clark WM, Brooks W, et al: Stenting

[33] Reimers B, Corvaja N, Moshiri S, Saccà S, Albiero R, Di Mario C, Pascotto P, Colombo

[34] Ansel GM, Hopkins LN, Jaff MR, Rubino P, Bacharach JM, Scheinert D, Myla S, Das T,

[35] Rizzo JA, Dodge A, White P, Martin ED. Magnetic resonance angiography in the

[36] Skelly CL, et al. Risk factors for restenosis after carotid artery angioplasty and stenting.

[37] Zhou W, et al. Management of in-stent restenosis after carotid artery stenting in high

[38] Lal BK, et al. In-stent recurrent stenosis after carotid artery stenting: Life table analysis

[39] Abu Rahma AF, et al. Optimal carotid duplex velocity criteria for defining the severity

[40] Stanziale SF, et al. Determining in-stent restenosis of carotid arteries by duplex

[41] Peterson BG, et al. Duplex ultrasound remains a reliable test even after carotid

[42] Chi YN, White CJ, Woods TC, Goldman CK. Ultrasound velocity criteria for carotid in-

Oct;7(10):885-92. Epub 2008 Sep 5.

Feb;41(2):153-8. Epub 2011 Jan 26.

Circulation. 2001 Jul 3;104(1):12-5.

J Vasc Surg 2006;44:1010-5.

risk patients. J Vasc Surg 2006;43:305-12.

stenting. Ann Vasc Surg 2005;19:793-7.

and clinical relevance. J Vasc Surg 2003;38:1162-9.

ultrasound criteria. J Endovasc Ther 2005;12:346-53.

of carotid in-stent restenosis. J Vasc Surg 2008;48:589-94.

stent restenosis. Catheter Cardiovasc Interv 2006;69:349-54.

2010;363:11-23.

Jul 1;76(1):1-8.

Padovani R, Chatellier G; EVA-3S investigators. Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial. Lancet Neurol. 2008

Bonati LH, van der Worp HB, de Borst GJ, Lo TH, Gaines P, Dorman PJ, Macdonald S, Lyrer PA, Hendriks JM, McCollum C, Nederkoorn PJ, Brown MM. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised

relative risk of stenting versus endarterectomy for symptomatic carotid stenosis--a pooled analysis of EVA-3S, SPACE and ICSS. Eur J Vasc Endovasc Surg. 2011

versus endarterectomy for treatment of carotid artery stenosis. N Engl J Med

A. Cerebral protection with filter devices during carotid artery stenting.

Cremonesi A; Investigators for the ARMOUR Pivotal Trial. Safety and effectiveness of the INVATEC MO.MA proximal cerebral protection device during carotid artery stenting: results from the ARMOUR pivotal trial. Catheter Cardiovasc Interv. 2010

evaluation of carotid stent patency. Perspect Vasc Surg Endovasc Ther 2010;22:261-3.

Advanced atherosclerosis with extended tibial arteries lesions is a common concern, especially in diabetic patients having critical-limb ischemia (CLI) and skin wounds. Chronic critical limb ischemia is a major worldwide cause of morbidity and, especially when threatening the limb, mortality (Faglia E. et al. 2006). Certainly, major and minor amputations are associated with significant increases in mortality risk, and every efforts should be pursued to minimize amputations and ensure limb salvage (Norgen L. et al. 2007).

Infragenicular atherosclerotic is the most common cause of CLI, usually due to multilevel and diffuse arterial disease with compromised foot arteries run-off. Vascular disease is very often associated with arterial wall calcifications, that are usually severe and diffuse. The combination of severe peripheral arterial occlusion with the increased blood flow requirement necessary to achieve the healing of the skin wounds or surgical incisions, makes this population very challenging. Additionally, diabetics and CLI population have a high rate of comorbidities (Bargelini I, et al. 2008).

Clinical manifestations range from Intermittent claudication to limb-threatening ischemia, with rest pain, non healing ulcers and gangrene.

Despite the benefits of pharmacologic therapy (e.g. Angiotensin-converting enzyme inhibitors, antidiabetic drugs, antiplatelet agents and statins), arterial revascularization remains a mainstay in the management of CLI, with restoration of arterial blood flow to the foot, achieving a relief of rest pain and improving wound healing.

In the last decade surgical revascularization has been adopted as the elective treatment option in patients with suitable anatomical conditions, however surgical by-pass is not always feasible due to the involvement of the foot arteries by the atherosclerotic disease, or recommended because of high surgical risk or contraindications in several cases, lack of venous conduits or poor vessels run-off, that compromise surgical by-pass patency (HerstenNR, et al. 2007; Norgen L, et al. 2007; Walsh Db, et al. 1991).

In recent years, related to good technical and clinical results, endovascular treatment options growing acceptance as the primary therapeutic strategy, especially in subjects with significant risk factors for surgical by-pass. In fact, since its initial applications, endovascular recanalization of tibial vessels and foot arteries has proven to be feasible and safe. Actually it is an established treatment option for limb salvage, avoiding amputations in lot of cases and improving wound healing(Adam DJ, et al. 2005; Balmer H, et al. 2002; Dorros G, et al. 2001; Faglia E, et al. 2005, 2006; Ferraresi R, et al. 2009; Romiti M, et al. 2008; Soder HR, et al 2000; Wack C, et al. 1994).

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 211

severe stages of the disease, such as chronic CLI. Other studies have, however, shown a more equal distribution of PAD between genders and even a predominance of women

The striking increase in both the incidence and prevalence of PAD with increasing age is

The relationship between smoking and PAD has been recognized since 1911, when Erb reported that IC was three-times more common among smokers than among non-smokers. It has been suggested that the association between smoking and PAD may be even stronger than that between smoking and coronary artery disease (CAD). Furthermore, a diagnosis of PAD is made approximately a decade earlier in smokers than in non-smokers. The severity of PAD tends to increase with the number of cigarettes smoked. Heavy smokers have a fourfold higher risk of developing IC compared with non-smokers. Smoking cessation is

Results from the Edinburgh Artery Study found that the relative risk of IC was 3.7 in 7 smokers compared with 3.0 in ex-smokers (who had discontinued smoking for less than 5

Many studies have shown an association between diabetes mellitus and the development of PAD. Overall, IC is about twice as common among diabetic patients than among nondiabetic patients. In patients with diabetes, for every 1% increase in hemoglobin A1c there is

Over the last decade, mounting evidence has suggested that insulin resistance plays a key role in a clustering of cardiometabolic risk factors which include hyperglycemia, dyslipidemia, hypertension and obesity. Insulin resistance is a risk factor for PAD even in subjects without diabetes, raising the risk approximately 40% to 50%. PAD in patients with diabetes is more aggressive compared to non-diabetics, with early large vessel involvement coupled with distal symmetrical neuropathy. The need for a major amputation is five- to ten-times higher in diabetics than non-diabetics. This is contributed to by sensory neuropathy and decreased resistance to infection. Based on these observations, a consensus statement from the American Diabetes Association recommends PAD screening with an ABI

Hypertension is associated with all forms of cardiovascular disease, including PAD. However, the relative risk for developing PAD is less for hypertension than diabetes or

In the Framingham study, a fasting cholesterol level greater than 7 mmol/L (270 mg/dL) was associated with a doubling of the incidence of IC but the ratio of total to high-density lipoprotein (HDL) cholesterol was the best predictor of occurrence of PAD. In another study, patients with PAD had significantly higher levels of serum triglycerides, very lowdensity lipoprotein (VLDL) cholesterol, VLDL triglycerides, VLDL proteins, intermediate

apparent from the earlier discussion of epidemiology (Norgen L, et al. 2007).

associated with a decline in the incidence of IC (Norgen L, et al. 2007).

a corresponding 26% increased risk of PAD (Selvin E, et al. 2004).

every 5 years in patients with diabetes (Norgen L, et al. 2007).

with CLI.

**3.2 Smoking** 

years).

**3.3 Diabetes mellitus** 

**3.4 Hypertension** 

**3.5 Dyslipidemia** 

smoking (Norgen L, et al. 2007).

The development of new technologies, such as dedicated guide-wire or low profile catheter balloons helps the interventionists to achieve technical and clinical results. Nevertheless, the knowledge of the most important techniques should be indispensable to obtain the procedural success and clinical outcome. In fact, the advances in distal lower extremity revascularization have revolutionized salvage of the ischemic limb.

#### **2. Epidemiology of peripheral arterial disease**

The management of the patient with peripheral arterial disease (PAD) has to be planned in the context of the epidemiology of the disease, its natural history and, in particular, the modifiable risk factors for the systemic disease as well as those that predict deterioration of the circulation to the limb (Norgen L, et al. 2007).

#### **2.1 Incidence of peripheral arterial disease**

Total disease prevalence based on objective testing has been evaluated in several epidemiologic studies and is in the range of 3-10%, increasing to 15% to 20% in persons over 70 years (Criqui MH et al. 1985; Hiatt WR, et al. 1995; Norgen et al. 2007; Selvin E, et al. 2004).

Intermittent claudication (IC) s usually diagnosed by a history of muscular leg pain on exercise that is relieved by a short rest. This symptom does not always predict the presence or absence of PAD. A patient with quite severe PAD may not have the symptom of IC because some other condition limits exercise or they are sedentary. In contrast, some patients with what seems to be IC may not have PAD. Likewise, patients with very mild PAD may develop symptoms of IC only when they become very physically active.

Black ethnicity increases the risk of PAD by over two-fold, and this risk is not explained by higher levels of other risk factors such as diabetes, hypertension or obesity (Criqui MH, et al. 2005). A high prevalence of arteritis affecting the distal arteries of young black South Africans has also been described.

#### **3. Risk factors of peripheral arterial disease**

Although the various factors described in this section are usually referred to as risk factors, in most cases the evidence is only for an association. The criteria used to support a risk factor require a prospective, controlled study showing that altering the factor alters the development or course of the PAD, such as has been shown for smoking cessation or treatment of dyslipidemia. Risk may be conferred by other metabolic or circulatory abnormalities associated with diabetes (Norgen L, et al. 2007).

#### **3.1 Race, gender and age**

The National Health and Nutrition Examination Survey in the United States found that an ABI 0.90 was more common in non-Hispanic Blacks (7.8%) than in Whites (4.4%). Such a difference in the prevalence of PAD was confirmed by the recent GENOA (Genetic Epidemiology Network of Arteriopathy) study (Kullo IJ, et al. 2003), which also showed that the difference was not explained by a difference in classical risk factors for atherosclerosis.

The prevalence of PAD, symptomatic or asymptomatic, is slightly greater in men than women, particularly in the younger age groups. In patients with IC, the ratio of men to women is between 1:1 and 2:1. This ratio increases in some studies to at least 3:1 in more

severe stages of the disease, such as chronic CLI. Other studies have, however, shown a more equal distribution of PAD between genders and even a predominance of women with CLI.

The striking increase in both the incidence and prevalence of PAD with increasing age is apparent from the earlier discussion of epidemiology (Norgen L, et al. 2007).

#### **3.2 Smoking**

Angioplasty, Various Techniques and Challenges in 210 Treatment of Congenital and Acquired Vascular Stenoses

The development of new technologies, such as dedicated guide-wire or low profile catheter balloons helps the interventionists to achieve technical and clinical results. Nevertheless, the knowledge of the most important techniques should be indispensable to obtain the procedural success and clinical outcome. In fact, the advances in distal lower extremity

The management of the patient with peripheral arterial disease (PAD) has to be planned in the context of the epidemiology of the disease, its natural history and, in particular, the modifiable risk factors for the systemic disease as well as those that predict deterioration of

Total disease prevalence based on objective testing has been evaluated in several epidemiologic studies and is in the range of 3-10%, increasing to 15% to 20% in persons over 70 years (Criqui MH et al. 1985; Hiatt WR, et al. 1995; Norgen et al. 2007; Selvin E, et

Intermittent claudication (IC) s usually diagnosed by a history of muscular leg pain on exercise that is relieved by a short rest. This symptom does not always predict the presence or absence of PAD. A patient with quite severe PAD may not have the symptom of IC because some other condition limits exercise or they are sedentary. In contrast, some patients with what seems to be IC may not have PAD. Likewise, patients with very mild

Black ethnicity increases the risk of PAD by over two-fold, and this risk is not explained by higher levels of other risk factors such as diabetes, hypertension or obesity (Criqui MH, et al. 2005). A high prevalence of arteritis affecting the distal arteries of young black South

Although the various factors described in this section are usually referred to as risk factors, in most cases the evidence is only for an association. The criteria used to support a risk factor require a prospective, controlled study showing that altering the factor alters the development or course of the PAD, such as has been shown for smoking cessation or treatment of dyslipidemia. Risk may be conferred by other metabolic or circulatory

The National Health and Nutrition Examination Survey in the United States found that an ABI 0.90 was more common in non-Hispanic Blacks (7.8%) than in Whites (4.4%). Such a difference in the prevalence of PAD was confirmed by the recent GENOA (Genetic Epidemiology Network of Arteriopathy) study (Kullo IJ, et al. 2003), which also showed that the difference was not explained by a difference in classical risk factors for atherosclerosis. The prevalence of PAD, symptomatic or asymptomatic, is slightly greater in men than women, particularly in the younger age groups. In patients with IC, the ratio of men to women is between 1:1 and 2:1. This ratio increases in some studies to at least 3:1 in more

PAD may develop symptoms of IC only when they become very physically active.

revascularization have revolutionized salvage of the ischemic limb.

**2. Epidemiology of peripheral arterial disease** 

the circulation to the limb (Norgen L, et al. 2007).

**2.1 Incidence of peripheral arterial disease** 

Africans has also been described.

**3.1 Race, gender and age** 

**3. Risk factors of peripheral arterial disease** 

abnormalities associated with diabetes (Norgen L, et al. 2007).

al. 2004).

The relationship between smoking and PAD has been recognized since 1911, when Erb reported that IC was three-times more common among smokers than among non-smokers. It has been suggested that the association between smoking and PAD may be even stronger than that between smoking and coronary artery disease (CAD). Furthermore, a diagnosis of PAD is made approximately a decade earlier in smokers than in non-smokers. The severity of PAD tends to increase with the number of cigarettes smoked. Heavy smokers have a fourfold higher risk of developing IC compared with non-smokers. Smoking cessation is associated with a decline in the incidence of IC (Norgen L, et al. 2007).

Results from the Edinburgh Artery Study found that the relative risk of IC was 3.7 in 7 smokers compared with 3.0 in ex-smokers (who had discontinued smoking for less than 5 years).

#### **3.3 Diabetes mellitus**

Many studies have shown an association between diabetes mellitus and the development of PAD. Overall, IC is about twice as common among diabetic patients than among nondiabetic patients. In patients with diabetes, for every 1% increase in hemoglobin A1c there is a corresponding 26% increased risk of PAD (Selvin E, et al. 2004).

Over the last decade, mounting evidence has suggested that insulin resistance plays a key role in a clustering of cardiometabolic risk factors which include hyperglycemia, dyslipidemia, hypertension and obesity. Insulin resistance is a risk factor for PAD even in subjects without diabetes, raising the risk approximately 40% to 50%. PAD in patients with diabetes is more aggressive compared to non-diabetics, with early large vessel involvement coupled with distal symmetrical neuropathy. The need for a major amputation is five- to ten-times higher in diabetics than non-diabetics. This is contributed to by sensory neuropathy and decreased resistance to infection. Based on these observations, a consensus statement from the American Diabetes Association recommends PAD screening with an ABI every 5 years in patients with diabetes (Norgen L, et al. 2007).

#### **3.4 Hypertension**

Hypertension is associated with all forms of cardiovascular disease, including PAD. However, the relative risk for developing PAD is less for hypertension than diabetes or smoking (Norgen L, et al. 2007).

#### **3.5 Dyslipidemia**

In the Framingham study, a fasting cholesterol level greater than 7 mmol/L (270 mg/dL) was associated with a doubling of the incidence of IC but the ratio of total to high-density lipoprotein (HDL) cholesterol was the best predictor of occurrence of PAD. In another study, patients with PAD had significantly higher levels of serum triglycerides, very lowdensity lipoprotein (VLDL) cholesterol, VLDL triglycerides, VLDL proteins, intermediate

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 213

wounds at foot and ankle level. In particular, the angiosome concept can help to select the target vessel for revascularization, that is, the artery which will yield the best local results.

By definition the popliteal artery ends at the origin of the first tibial artery, which typically is the Anterior Tibial Artery. In about 4% of cases we find a so-called high origin of the Anterior tibial Artery at the level of the knee joint or even some centimetres more proximal. Similarly, in a small proportion of the population (1-2%) a high origin of the posterior tibial artery has been described. Normally, the direct continuation of the popliteal artery, after the branch of the anterior tibial artery, is the tibioperoneal trunk. This vascular segment splits

As a variation, a triforcation of the popliteal artery into all three lower leg arteries at the same point has been observed in 0.4% of patients. The posterior tibial artery may be missing

The vascular anatomy of the foot is composed of the anterior and posterior circulation, connected through the pedal arches. The anterior tibial artery continues into the dorsal pedal artery. The posterior tibial artery continues into the common plantar artery and then in the lateral and medial plantar arteries. The peroneal artery splits above the ankle joint into and anterior and posterior branch, the ramus perforans that anastomoses with the dorsal pedal artery, and the ramus communicans that anastomoses with the plantar arteries. The dorsalis pedis artery and the lateral plantar artery communicate via the plantar arch

The digital branches origin from the plantar arch and there are a dorsal and plantar branches for each toe. The plantar digital branch for first toe ususally origin from medial

Both tibial arteries, together with the peroneal artery, supply different portions of the foot and ankle. The plantar foot and the medial ankle are fed by the posterior tibial artery, the anterior ankle and the dorsum of the foot by the anterior tibial artery, and the antero-lateral

As a anatomic variations of the foot dorsalis pedis artery may be absent in 6-12% of cases; in this patient the lateral tarsal artery often became predominant and develop anastomosis

In some cases the lateral plantar artery, through plantar arch, is the predominant artery for the I toe. In a few cases has been described the absence of plantar arch, in this situation the dorsalis pedis is the predominant artery for the I and II toe and the lateral plantar artery, is

The angiosome principle was defined by Ian Taylor's landmark anatomic study and divides the body into individual angiosomes: three-dimensional blocks of tissue fed by "source" arteries. He defined an angiosome as a three-dimensional anatomic unit of tissue fed by a source artery and defined at least 40 angiosomes in the body, including six in the foot and ankle region. Adjacent angiosomes are bordered by choke vessels, which link neighboring angiosomes to one another and demarcate the border of each angiosome. In addition, these choke vessels are important safety conduits that allow a given angiosome to provide blood flow to an adjacent angiosome if the latter's source artery is damaged (Calligari PR, et al.

**4.1 Normal vascular anatomy and main variations** 

completely in 1-5% of a normal adult population.

ankle and rear foot by the peroneal artery.

1992; Taylor GI, et al. 1992a, 1992b).

through the plantar arch to the plantar circulation.

the predominant artery supplying the III, IV and V toe.

**4.2 Angiosome and wound related artery concept** 

(Fig. 2 and Fig. 3).

plantar artery.

into the posterior tibial artery and the peroneal artery (Fig. 1).

density lipoprotein (IDL) cholesterol, and IDL triglycerides and lower levels of HDL than controls (Attinder CE, et al. 2001; Criqui MH, et al. 1985; Fowkes FG, et al. 2004; Norgen L, et al. 2007; Selvin E, et al. 2004; Senti M, et al. 1992).

Although some studies have also shown that total cholesterol is a powerful independent risk factor for PAD, others have failed to confirm this association. It has been suggested that cigarette smoking may enhance the effect of hypercholesterolemia. There is evidence that treatment of hyperlipidemia reduces both the progression of PAD and the incidence of IC. An association between PAD and hypertriglyceridemia has also been reported and has been shown to be associated with the progression and systemic complications of PAD. Lipoprotein(a) is a significant independent risk factor for PAD.

#### **3.6 Hyperviscosity and hypercoagulable states**

Raised hematocrit levels and hyperviscosity have been reported in patients with PAD, possibly as a consequence of smoking. Increased plasma levels of fibrinogen, which is also a risk factor for thrombosis, have been associated with PAD in several studies. Both hyperviscosity and hypercoagulability have also been shown to be markers or risk factors for a poor prognosis (Norgen L, et al. 2007).

#### **3.7 Hyperhomocysteinemia**

The prevalence of hyperhomocysteinemia is as high in the vascular disease population, compared with 1% in the general population. It is reported that hyperhomocysteinemia is detected in about 30% of young patients with PAD. The suggestion that hyperhomocysteinemia may be an independent risk factor for atherosclerosis has now been substantiated by several studies. It may be a stronger risk factor for PAD than for CAD (Norgen L, et al. 2007).

#### **3.8 Chronic renal insufficiency**

There is an association of renal insufficiency with PAD, with some recent evidence suggesting it may be causal. In the HERS study (Heart and Estrogen/Progestin Replacement Study), renal insufficiency was independently associated with future PAD events in postmenopausal women (O'Hare AM, et al. 2004; Norgen L, et al. 2007).

#### **4. Vascular anatomy and angiosome concept - The first step toward pedal recanalization**

Knowledge of vascular anatomy of the leg, ankle and foot, and an understanding of the dynamic nature of that vasculature are essential for limb salvage (Taylor G, et al. 1992).

The concept that divides the body into three-dimensional vascular territories supplied by specific source arteries, known as the angiosome principle, was introduced by Taylor and expanded for the clinical treatment of ischemic lesions at the foot and ankle level by Attinger (Attinger CE, et al. 2001). The foot and the ankle can be divided into six distinct angiosomes; each fed by a specific arterial branch. Recent data suggest a different clinical outcome of successful revascularization procedures based on the possibility of providing inline vascular supply to the specific angiosome of the ischemic wound.

By combining the anatomic and functional aspects of foot circulation, the angiosome theory can be useful in planning the endovascular revascularization strategy in cases of ischemic wounds at foot and ankle level. In particular, the angiosome concept can help to select the target vessel for revascularization, that is, the artery which will yield the best local results.

#### **4.1 Normal vascular anatomy and main variations**

Angioplasty, Various Techniques and Challenges in 212 Treatment of Congenital and Acquired Vascular Stenoses

density lipoprotein (IDL) cholesterol, and IDL triglycerides and lower levels of HDL than controls (Attinder CE, et al. 2001; Criqui MH, et al. 1985; Fowkes FG, et al. 2004; Norgen L, et

Although some studies have also shown that total cholesterol is a powerful independent risk factor for PAD, others have failed to confirm this association. It has been suggested that cigarette smoking may enhance the effect of hypercholesterolemia. There is evidence that treatment of hyperlipidemia reduces both the progression of PAD and the incidence of IC. An association between PAD and hypertriglyceridemia has also been reported and has been shown to be associated with the progression and systemic complications of PAD.

Raised hematocrit levels and hyperviscosity have been reported in patients with PAD, possibly as a consequence of smoking. Increased plasma levels of fibrinogen, which is also a risk factor for thrombosis, have been associated with PAD in several studies. Both hyperviscosity and hypercoagulability have also been shown to be markers or risk factors

The prevalence of hyperhomocysteinemia is as high in the vascular disease population, compared with 1% in the general population. It is reported that hyperhomocysteinemia is detected in about 30% of young patients with PAD. The suggestion that hyperhomocysteinemia may be an independent risk factor for atherosclerosis has now been substantiated by several studies. It may be a stronger risk factor for PAD than for CAD

There is an association of renal insufficiency with PAD, with some recent evidence suggesting it may be causal. In the HERS study (Heart and Estrogen/Progestin Replacement Study), renal insufficiency was independently associated with future PAD events in

**4. Vascular anatomy and angiosome concept - The first step toward pedal** 

Knowledge of vascular anatomy of the leg, ankle and foot, and an understanding of the dynamic nature of that vasculature are essential for limb salvage (Taylor G, et al. 1992). The concept that divides the body into three-dimensional vascular territories supplied by specific source arteries, known as the angiosome principle, was introduced by Taylor and expanded for the clinical treatment of ischemic lesions at the foot and ankle level by Attinger (Attinger CE, et al. 2001). The foot and the ankle can be divided into six distinct angiosomes; each fed by a specific arterial branch. Recent data suggest a different clinical outcome of successful revascularization procedures based on the possibility of providing

By combining the anatomic and functional aspects of foot circulation, the angiosome theory can be useful in planning the endovascular revascularization strategy in cases of ischemic

postmenopausal women (O'Hare AM, et al. 2004; Norgen L, et al. 2007).

inline vascular supply to the specific angiosome of the ischemic wound.

al. 2007; Selvin E, et al. 2004; Senti M, et al. 1992).

**3.6 Hyperviscosity and hypercoagulable states** 

for a poor prognosis (Norgen L, et al. 2007).

**3.7 Hyperhomocysteinemia** 

(Norgen L, et al. 2007).

**recanalization** 

**3.8 Chronic renal insufficiency** 

Lipoprotein(a) is a significant independent risk factor for PAD.

By definition the popliteal artery ends at the origin of the first tibial artery, which typically is the Anterior Tibial Artery. In about 4% of cases we find a so-called high origin of the Anterior tibial Artery at the level of the knee joint or even some centimetres more proximal. Similarly, in a small proportion of the population (1-2%) a high origin of the posterior tibial artery has been described. Normally, the direct continuation of the popliteal artery, after the branch of the anterior tibial artery, is the tibioperoneal trunk. This vascular segment splits into the posterior tibial artery and the peroneal artery (Fig. 1).

As a variation, a triforcation of the popliteal artery into all three lower leg arteries at the same point has been observed in 0.4% of patients. The posterior tibial artery may be missing completely in 1-5% of a normal adult population.

The vascular anatomy of the foot is composed of the anterior and posterior circulation, connected through the pedal arches. The anterior tibial artery continues into the dorsal pedal artery. The posterior tibial artery continues into the common plantar artery and then in the lateral and medial plantar arteries. The peroneal artery splits above the ankle joint into and anterior and posterior branch, the ramus perforans that anastomoses with the dorsal pedal artery, and the ramus communicans that anastomoses with the plantar arteries. The dorsalis pedis artery and the lateral plantar artery communicate via the plantar arch (Fig. 2 and Fig. 3).

The digital branches origin from the plantar arch and there are a dorsal and plantar branches for each toe. The plantar digital branch for first toe ususally origin from medial plantar artery.

Both tibial arteries, together with the peroneal artery, supply different portions of the foot and ankle. The plantar foot and the medial ankle are fed by the posterior tibial artery, the anterior ankle and the dorsum of the foot by the anterior tibial artery, and the antero-lateral ankle and rear foot by the peroneal artery.

As a anatomic variations of the foot dorsalis pedis artery may be absent in 6-12% of cases; in this patient the lateral tarsal artery often became predominant and develop anastomosis through the plantar arch to the plantar circulation.

In some cases the lateral plantar artery, through plantar arch, is the predominant artery for the I toe. In a few cases has been described the absence of plantar arch, in this situation the dorsalis pedis is the predominant artery for the I and II toe and the lateral plantar artery, is the predominant artery supplying the III, IV and V toe.

#### **4.2 Angiosome and wound related artery concept**

The angiosome principle was defined by Ian Taylor's landmark anatomic study and divides the body into individual angiosomes: three-dimensional blocks of tissue fed by "source" arteries. He defined an angiosome as a three-dimensional anatomic unit of tissue fed by a source artery and defined at least 40 angiosomes in the body, including six in the foot and ankle region. Adjacent angiosomes are bordered by choke vessels, which link neighboring angiosomes to one another and demarcate the border of each angiosome. In addition, these choke vessels are important safety conduits that allow a given angiosome to provide blood flow to an adjacent angiosome if the latter's source artery is damaged (Calligari PR, et al. 1992; Taylor GI, et al. 1992a, 1992b).

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 215

Fig. 2. Anterior and dorsal circulation. The major arteries are visualized in the lateraloblique view (left side) and in the antero-posterior view (right side) angiographic

Fig. 3. Posterior and plantar circulation. The major arteries are visualized in antero-posterior

The choke vessel system links the angiosomes to one another. A unified network is created so that one source artery can provide blood flow to multiple angiosomes beyond its

While the choke vessels provide an indirect connection among angiosomes, there are also direct arterial-arterial connections that allow blood flow to immediately bypass local

view (left side) and in the lateral-oblique view (right side) angiographic projections.

projections.

immediate border.

obstructions in the vascular tree.

Fig. 1. A. Anteroposterior view of the tibial trifurcation show anterior tibial artery ( ), tibioperoneal trunk ( ), peroneal artery ( ) and posterior tibial artery ( ). B. Lateral view at the distal leg and ankle level show the anterior ( ) and posterior ( )tibial arteries and the peroneal artery ( ) with the collateral branches.

Angioplasty, Various Techniques and Challenges in 214 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 1. A. Anteroposterior view of the tibial trifurcation show anterior tibial artery ( ), tibioperoneal trunk ( ), peroneal artery ( ) and posterior tibial artery ( ). B. Lateral view at the distal leg and ankle level show the anterior ( ) and posterior ( )tibial arteries and the

peroneal artery ( ) with the collateral branches.

Fig. 2. Anterior and dorsal circulation. The major arteries are visualized in the lateraloblique view (left side) and in the antero-posterior view (right side) angiographic projections.

Fig. 3. Posterior and plantar circulation. The major arteries are visualized in antero-posterior view (left side) and in the lateral-oblique view (right side) angiographic projections.

The choke vessel system links the angiosomes to one another. A unified network is created so that one source artery can provide blood flow to multiple angiosomes beyond its immediate border.

While the choke vessels provide an indirect connection among angiosomes, there are also direct arterial-arterial connections that allow blood flow to immediately bypass local obstructions in the vascular tree.

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 217

Antegrade access in the common femoral artery is, in our experience, the best approach to perform tibial and foot arteries revascularization, with excellent guide-ability of the guidewire and good push-ability of the catheter balloons due to this access is closer to the lesions. Contra-lateral approach is indicated in cases in which iliac treatment is required or is possible to treat contro-lateral common femoral artery or Superficial femoral artery. In cases of BTK interventions makes the procedure more difficult, require long shafts catheter balloons, limits some technical strategies and makes complications management

In some selected cases antegrade access in the popliteal artery could be useful, because it is closer to the lesions and ensure more push-ability of the devices, but the prone position of

Previously to begging the procedure are injected, systematically, a intra-arterial bolus of 5.000 I.U of heparin. The patients are undergo to double anti-platelets therapy with ticlopidine, 250 mg daily and acetylsalicylic acid 100 mg daily, 3 days before the procedure. The double antiaggregation is continued for 6 weeks after the procedure and acetylsalicylic

Transluminal recanalization is the preferred techniques to treat stenotic lesions, very short occlusions (<1 cm) (Hauser H, et al. 1996) or lesions that involve the bifurcations. In our experience, is the best technical strategy to recanalize calcified vessels and it could be the

The classic approach to intraluminal recanalization use a guide-wire in conjunction with a

In our experience we prefer to use a 0.014"-in. guide-wire (Pilot®200 - Abbott) with an angulated tip (45° angle), that allows to guide the guide-wire, avoiding subintimal progression or vessel spills. A straight CTO dedicated guide-wire can also be used, with

The first step is to penetrate the proximal occlusion followed by negotiation the full extent of the occlusion, until the distal patent lumen. A drilling motion of the guide-wire is performed to properly penetrate and cross the lesion. Often times, a short and low profile coaxial catheter balloon can be used as a support catheter (Patel PJ, et al. 2010). Coaxial catheter balloon system is preferred to monorail system, because monorail system work well when the sheath tip can be placed close to the lesion. Coaxial system allows to remove the guide-wire, inject contrast media and check the position of the catheter and, if necessary, change the guide-wire . When the recanalization is completed, we perform a pre-dilatation with the support catheter balloon. A definitive dilatation is performed with a long catheter balloon, and based in the authors experience, in a heavy calcified vessels we prefer to avoid dissections during PTA dilating the crural vessels to 2.5 mm and the foot arteries to 2 mm in diameter (Fig 4 and 5). Diagnostic angiography. (A-B) Obstruction of the anterior and posterior arteries, patency of the tibio-peroneal trunk and peroneal artery. (C-D) patency of common plantar artery,

(E-H) Intraluminale recanalization of the posterior tibial artery, lateral plantar artery, plantar arch and the digital branch for the first toe and angioplasty of the digital branch (1.5 x 20 mm catheter balloon). (I-J) Intraluminal PTA of the posterior and anterior tibial arteries

**5.2 Technical strategies** 

considerably more complex.

acid is prescribed quoad vitam.

(2.5 x 220 mm catheter balloon).

**5.2.1 Transluminal recanalization** 

first choice in CTO lesions with very heavy calcified arteries.

dorsalis pedis artery and plantar arch, in a heavy calcified vessels.

support catheter to cross the lesion (Patel PJ, et al. 2010).

good results, in calcified and insuperable lesions.

the patient is required.

The six angiosomes of the foot and ankle originate from the three main arteries to the foot and ankle. The posterior tibial artery supplies the medial ankle and the plantar foot, the anterior tibial artery supplies the dorsum of the foot, and the peroneal artery supplies the anterolateral ankle and the lateral rear foot. The large angiosomes of the foot can be further broken into angiosomes of the major branches of the above arteries. The three main branches of the posterior tibial artery each supply distinct portions of the plantar foot: the calcaneal branch (heel), the medial plantar artery (instep), and the lateral plantar artery (lateral midfoot and forefoot). The two branches of the peroneal artery supply the anterolateral portion of the ankle and rear foot, the anterior perforating branch (lateral anterior upper ankle) and the calcaneal branch (plantar heel). The anterior tibial artery supplies the anterior ankle and then becomes the dorsalis pedis artery that supplies the dorsum of the foot (Attinger CE, et al. 1997; Attinger CE, et al. 2001; Sarrafain SK. 1993; Taylor GI, et al. 1998).

The dorsalis pedis artery follows a curved pathway on the forefoot to join the first plantar space, where meets the posterior circulation through the perforating deep artery.

In according with angiosome concept, the foot lesion location is related to an specific angiosome and the revascularization of this specific angiosome is our target vessel or wound related artery.

#### **5. Endovascular intervention**

Endovascular recanalization of tibial vessels and foot arteries should be the first line treatment in patients with CLI, because of its good technical and clinical outcomes.

Endovascular treatment is possible in most cases, with the known low complication rate of PTA. In cases in which endovascular revascularization failed, all surgical options remain open.

The primary indications for tibial and foot arteries intervention is limb salvage, to avoid amputations. Patients with chronic leg ischemia face a gloomy future, in fact, long-term survival rate with CLI is significantly lower than that of a matched population.

Limb salvage is of more importance to these patients. The most plausible explanation for this is that healing the wounds and/or infection will reduce the oxygenation demand.

#### **5.1 Vessel features**

Calcified vessels are the most difficult situation in endovascular treatment, especially when calcifications are very dark and thick, in a visual evaluation. We propose intraluminal approach in very heavy calcified vessels, using dedicated 0.014' guide wire and short, lowprofile OTW dedicated catheter balloons, like coronary balloons. OTW catheter balloon are necessary in order to be able to inject contrast material and check the position and to change the wire, when necessary.

Non calcified vessel allows different recanalization alternative, as endoluminal or subintimal approach. It the occluded tract is short, may be endoluminal approache could be the first alternative. In long occlusions, especially when there is a good distal re-entry, subintimal approach could be a good alternative.

In calcified vessel, when is imposible to cross the lesion trough the true lumen and vascular situation are dramatic and the indications to revascularization, related to wounds on the foot are present, a more aggressive strategy could be adopted. A subintimal attempt is justified in these cases and could bring to good result.

#### **5.2 Technical strategies**

Angioplasty, Various Techniques and Challenges in 216 Treatment of Congenital and Acquired Vascular Stenoses

The six angiosomes of the foot and ankle originate from the three main arteries to the foot and ankle. The posterior tibial artery supplies the medial ankle and the plantar foot, the anterior tibial artery supplies the dorsum of the foot, and the peroneal artery supplies the anterolateral ankle and the lateral rear foot. The large angiosomes of the foot can be further broken into angiosomes of the major branches of the above arteries. The three main branches of the posterior tibial artery each supply distinct portions of the plantar foot: the calcaneal branch (heel), the medial plantar artery (instep), and the lateral plantar artery (lateral midfoot and forefoot). The two branches of the peroneal artery supply the anterolateral portion of the ankle and rear foot, the anterior perforating branch (lateral anterior upper ankle) and the calcaneal branch (plantar heel). The anterior tibial artery supplies the anterior ankle and then becomes the dorsalis pedis artery that supplies the dorsum of the foot (Attinger CE, et al. 1997; Attinger CE, et al. 2001; Sarrafain SK. 1993;

The dorsalis pedis artery follows a curved pathway on the forefoot to join the first plantar

In according with angiosome concept, the foot lesion location is related to an specific angiosome and the revascularization of this specific angiosome is our target vessel or

Endovascular recanalization of tibial vessels and foot arteries should be the first line

Endovascular treatment is possible in most cases, with the known low complication rate of PTA. In cases in which endovascular revascularization failed, all surgical options remain

The primary indications for tibial and foot arteries intervention is limb salvage, to avoid amputations. Patients with chronic leg ischemia face a gloomy future, in fact, long-term

Limb salvage is of more importance to these patients. The most plausible explanation for this is that healing the wounds and/or infection will reduce the oxygenation demand.

Calcified vessels are the most difficult situation in endovascular treatment, especially when calcifications are very dark and thick, in a visual evaluation. We propose intraluminal approach in very heavy calcified vessels, using dedicated 0.014' guide wire and short, lowprofile OTW dedicated catheter balloons, like coronary balloons. OTW catheter balloon are necessary in order to be able to inject contrast material and check the position and to change

Non calcified vessel allows different recanalization alternative, as endoluminal or subintimal approach. It the occluded tract is short, may be endoluminal approache could be the first alternative. In long occlusions, especially when there is a good distal re-entry,

In calcified vessel, when is imposible to cross the lesion trough the true lumen and vascular situation are dramatic and the indications to revascularization, related to wounds on the foot are present, a more aggressive strategy could be adopted. A subintimal attempt is

space, where meets the posterior circulation through the perforating deep artery.

treatment in patients with CLI, because of its good technical and clinical outcomes.

survival rate with CLI is significantly lower than that of a matched population.

Taylor GI, et al. 1998).

wound related artery.

**5.1 Vessel features** 

the wire, when necessary.

subintimal approach could be a good alternative.

justified in these cases and could bring to good result.

open.

**5. Endovascular intervention** 

Antegrade access in the common femoral artery is, in our experience, the best approach to perform tibial and foot arteries revascularization, with excellent guide-ability of the guidewire and good push-ability of the catheter balloons due to this access is closer to the lesions. Contra-lateral approach is indicated in cases in which iliac treatment is required or is possible to treat contro-lateral common femoral artery or Superficial femoral artery. In cases of BTK interventions makes the procedure more difficult, require long shafts catheter balloons, limits some technical strategies and makes complications management considerably more complex.

In some selected cases antegrade access in the popliteal artery could be useful, because it is closer to the lesions and ensure more push-ability of the devices, but the prone position of the patient is required.

Previously to begging the procedure are injected, systematically, a intra-arterial bolus of 5.000 I.U of heparin. The patients are undergo to double anti-platelets therapy with ticlopidine, 250 mg daily and acetylsalicylic acid 100 mg daily, 3 days before the procedure. The double antiaggregation is continued for 6 weeks after the procedure and acetylsalicylic acid is prescribed quoad vitam.

#### **5.2.1 Transluminal recanalization**

Transluminal recanalization is the preferred techniques to treat stenotic lesions, very short occlusions (<1 cm) (Hauser H, et al. 1996) or lesions that involve the bifurcations. In our experience, is the best technical strategy to recanalize calcified vessels and it could be the first choice in CTO lesions with very heavy calcified arteries.

The classic approach to intraluminal recanalization use a guide-wire in conjunction with a support catheter to cross the lesion (Patel PJ, et al. 2010).

In our experience we prefer to use a 0.014"-in. guide-wire (Pilot®200 - Abbott) with an angulated tip (45° angle), that allows to guide the guide-wire, avoiding subintimal progression or vessel spills. A straight CTO dedicated guide-wire can also be used, with good results, in calcified and insuperable lesions.

The first step is to penetrate the proximal occlusion followed by negotiation the full extent of the occlusion, until the distal patent lumen. A drilling motion of the guide-wire is performed to properly penetrate and cross the lesion. Often times, a short and low profile coaxial catheter balloon can be used as a support catheter (Patel PJ, et al. 2010). Coaxial catheter balloon system is preferred to monorail system, because monorail system work well when the sheath tip can be placed close to the lesion. Coaxial system allows to remove the guide-wire, inject contrast media and check the position of the catheter and, if necessary, change the guide-wire . When the recanalization is completed, we perform a pre-dilatation with the support catheter balloon. A definitive dilatation is performed with a long catheter balloon, and based in the authors experience, in a heavy calcified vessels we prefer to avoid dissections during PTA dilating the crural vessels to 2.5 mm and the foot arteries to 2 mm in diameter (Fig 4 and 5).

Diagnostic angiography. (A-B) Obstruction of the anterior and posterior arteries, patency of the tibio-peroneal trunk and peroneal artery. (C-D) patency of common plantar artery, dorsalis pedis artery and plantar arch, in a heavy calcified vessels.

(E-H) Intraluminale recanalization of the posterior tibial artery, lateral plantar artery, plantar arch and the digital branch for the first toe and angioplasty of the digital branch (1.5 x 20 mm catheter balloon). (I-J) Intraluminal PTA of the posterior and anterior tibial arteries (2.5 x 220 mm catheter balloon).

Fig. 4. Case 1. Diabetic patient with apical ulcer on the first toe, TcPO2: 13 mmHg.

dorsalis pedis artery and plantar arch, in a heavy calcified vessels.

posterior and anterior tibial arteries (2.5 x 220 mm catheter balloon / Bantam

Diagnostic angiography. (A-B) Obstruction of the anterior and posterior arteries, patency of the tibio-peroneal trunk and peroneal artery. (C-D) patency of common plantar artery,

(E-H) Intraluminale recanalization of the posterior tibial artery, lateral plantar artery, plantar arch and the digital branch for the first toe and angioplasty of the digital branch (1.5 x 20 mm catheter balloon / FlexeCTO – Clearstream). (I-J) Intraluminal PTA of the


– Clearstream).

Fig. 4. Case 1. Diabetic patient with apical ulcer on the first toe, TcPO2: 13 mmHg.

Diagnostic angiography. (A-B) Obstruction of the anterior and posterior arteries, patency of the tibio-peroneal trunk and peroneal artery. (C-D) patency of common plantar artery, dorsalis pedis artery and plantar arch, in a heavy calcified vessels.

(E-H) Intraluminale recanalization of the posterior tibial artery, lateral plantar artery, plantar arch and the digital branch for the first toe and angioplasty of the digital branch (1.5 x 20 mm catheter balloon / FlexeCTO – Clearstream). (I-J) Intraluminal PTA of the posterior and anterior tibial arteries (2.5 x 220 mm catheter balloon / Bantam-– Clearstream).

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 221

during the subintimal progression of the guide-wire, rupture of the arterial wall and failure

We perform a subintimal recanalization in crural arteries with a 0.018"-in guide-wire (V18®

The 0.014"-in guide-wire should be preferred to perform a subintimal recanalization in the

Is also possible to perform a subintimal dissection using a 0.035"-in hydrophilic guide-wire, but in our opinion this more aggressive approach in reserved for cases with heavy calcified vessel and is not indicated for Pedal arteries recanalization. A diagnostic catheter (Berenstain II® - Cordis) or a balloon catheter, is used to support the guide-wire during

We prefer to avoid a pre-dilatations of the subintimal dissection before to reach the distal patent lumen and check the re-entry. This is just a modification of Bolia technique, in order to avoid the risk of potential bleeding secondary to vessel perforation or to prevent the dilatation of the subintimal dissection that could not re-entry and could need to change the subintimal way to obtain technical success. When the re-entry is achieve, we change a guide-wire with a

After pedal distal patent lumen recanalization, we deploy a low profile catheter balloon and perform a pre-dilatations of the crural vessel. After short balloon pre-dilatation, a longer one can be placed and a final dilatation performed. We usually dilate crural vessels with a 3 mm diameter balloon and Pedal arteries, including Pedal arch with 2.5 mm diameter balloon.

In a recent published study (Met R, et al. 2005) a systematic review showed that subintimal recanalization can be a useful option in the treatment of patients with CLI, with primary success rate of 80-90% and 1 year limb salvage rate as high as 90% and conclude that despite the moderate long-term patency rates of the revascularized segments, subintimal angioplasty

In our experience antegrade approach should be the first choice to treat tibial vessels and foot arteries and a retrograde recanalization should be seen as a support or problem solving strategy, in cases of antegrade failure, such as the inability to re-enter in the true patent

In this context, the retrograde recanalization can be performed and there are different technical options, such as trans-collateral navigation and retrograde recanalization, Pedal-

In our opinion, perform a distal retrograde access is the last technical strategy in order to

In many cases of extreme vascular intervention, it is not possible to perform regular antegrade recanalization of occluded tibial arteries, which makes even the most expert interventionist resort to unusual techniques (Bolia A, 2005; Fusaro M, et al. 2008; Graziani L, et al. 2008, 2011) to restore direct blood flow to the foot. Combined retrograde-antegrade arterial recanalization through collateral vessels, essentially combined retrograde and

This technical strategy, largely tested by the authors, has been described in published papers (Fusaro M, et al 2008, Graziani L, et al. 2011) and is intended as option to recanalize tibial arteries.


new one, usually 0.014"-in to avoid spasm in the foot arteries and Pedal arch.

may serve as a "temporary by-pass", providing wound healing and limb salvage.

Plantar Loop technique or, retrograde distal access and recanalization.

antegrade arterial recanalization using a single entry site.

When the result is still not satisfactory, dilatation can be repeated.

**5.3 Antegrade and retrograde recanalization** 

distal lumen after subintimal recanalization.

create a re-entry or resolve problems.

**5.3.1 Trans-collateral recanalization**

of the recanalization.

subintimal progression.

Pedal arteries.

Fig. 5. Case 1. Technical and clinical results.

(A-D) Angiographic results of the intraluminal recanalization of the anterior and posterior tibial arteries; lateral plantar and dorsali pedis arteries, plantar arch and the first digital branch, with excellent blood flow in the target vessel.

Clinical follow up at 4 months show increased of the TcPO2 to 42 mmHg and ulcer healing, avoiding amputation.

#### **5.2.2 Subintimal recanalization**

On the other hand, when the arteries are not calcified or low and incomplete calcifications are observed, a subintimal recanalization is proposed as the first technical strategy. Subintimal angioplasty was first described by Bolia (Bolia A et al. 1990) and since them there have been a lot of publications confirming the value and assess the clinical results of this technique to treat tibial vessels (Alexandrescu V, et al. 2009; Bolia A, et al. 1994, Bown MJ, et al. 2009; Chun JY, et al. 2010; Ingle H, et al. 2002; Met R, et al. 2008; Reekers J, et al. 1994, Spinosa DJ, et al. 2004).

A subintimal recanalization in a heavy calcified crural vessels can also be considered, after failure of intraluminal attempts, with the impossibility to cross the lesion (Bolia A. 1998.)

This technical strategy could also be used in Pedal arteries and a published paper described this technical option to recanalize the Pedal arch (Fusaro M, et al. 2007).

The principal advantages of this technique are the ability to cross long chronic occlusions and the option of recanalization of more than one crural vessel. In our experience, the failure of this technical strategy is related to heavy calcified vessels, with fissuring the arterial wall Angioplasty, Various Techniques and Challenges in 220 Treatment of Congenital and Acquired Vascular Stenoses

(A-D) Angiographic results of the intraluminal recanalization of the anterior and posterior tibial arteries; lateral plantar and dorsali pedis arteries, plantar arch and the first digital

Clinical follow up at 4 months show increased of the TcPO2 to 42 mmHg and ulcer healing,

On the other hand, when the arteries are not calcified or low and incomplete calcifications are observed, a subintimal recanalization is proposed as the first technical strategy. Subintimal angioplasty was first described by Bolia (Bolia A et al. 1990) and since them there have been a lot of publications confirming the value and assess the clinical results of this technique to treat tibial vessels (Alexandrescu V, et al. 2009; Bolia A, et al. 1994, Bown MJ, et al. 2009; Chun JY, et al. 2010; Ingle H, et al. 2002; Met R, et al. 2008; Reekers J, et al. 1994, Spinosa DJ, et al. 2004). A subintimal recanalization in a heavy calcified crural vessels can also be considered, after failure of intraluminal attempts, with the impossibility to cross the lesion (Bolia A. 1998.) This technical strategy could also be used in Pedal arteries and a published paper described

The principal advantages of this technique are the ability to cross long chronic occlusions and the option of recanalization of more than one crural vessel. In our experience, the failure of this technical strategy is related to heavy calcified vessels, with fissuring the arterial wall

this technical option to recanalize the Pedal arch (Fusaro M, et al. 2007).

Fig. 5. Case 1. Technical and clinical results.

avoiding amputation.

**5.2.2 Subintimal recanalization** 

branch, with excellent blood flow in the target vessel.

during the subintimal progression of the guide-wire, rupture of the arterial wall and failure of the recanalization.

We perform a subintimal recanalization in crural arteries with a 0.018"-in guide-wire (V18® - Boston Scientific) or, less frequent, with 0.014"-in guide-wire (Pilot®200 - Abbott).

The 0.014"-in guide-wire should be preferred to perform a subintimal recanalization in the Pedal arteries.

Is also possible to perform a subintimal dissection using a 0.035"-in hydrophilic guide-wire, but in our opinion this more aggressive approach in reserved for cases with heavy calcified vessel and is not indicated for Pedal arteries recanalization. A diagnostic catheter (Berenstain II® - Cordis) or a balloon catheter, is used to support the guide-wire during subintimal progression.

We prefer to avoid a pre-dilatations of the subintimal dissection before to reach the distal patent lumen and check the re-entry. This is just a modification of Bolia technique, in order to avoid the risk of potential bleeding secondary to vessel perforation or to prevent the dilatation of the subintimal dissection that could not re-entry and could need to change the subintimal way to obtain technical success. When the re-entry is achieve, we change a guide-wire with a new one, usually 0.014"-in to avoid spasm in the foot arteries and Pedal arch.

After pedal distal patent lumen recanalization, we deploy a low profile catheter balloon and perform a pre-dilatations of the crural vessel. After short balloon pre-dilatation, a longer one can be placed and a final dilatation performed. We usually dilate crural vessels with a 3 mm diameter balloon and Pedal arteries, including Pedal arch with 2.5 mm diameter balloon. When the result is still not satisfactory, dilatation can be repeated.

In a recent published study (Met R, et al. 2005) a systematic review showed that subintimal recanalization can be a useful option in the treatment of patients with CLI, with primary success rate of 80-90% and 1 year limb salvage rate as high as 90% and conclude that despite the moderate long-term patency rates of the revascularized segments, subintimal angioplasty may serve as a "temporary by-pass", providing wound healing and limb salvage.

#### **5.3 Antegrade and retrograde recanalization**

In our experience antegrade approach should be the first choice to treat tibial vessels and foot arteries and a retrograde recanalization should be seen as a support or problem solving strategy, in cases of antegrade failure, such as the inability to re-enter in the true patent distal lumen after subintimal recanalization.

In this context, the retrograde recanalization can be performed and there are different technical options, such as trans-collateral navigation and retrograde recanalization, Pedal-Plantar Loop technique or, retrograde distal access and recanalization.

In our opinion, perform a distal retrograde access is the last technical strategy in order to create a re-entry or resolve problems.

#### **5.3.1 Trans-collateral recanalization**

In many cases of extreme vascular intervention, it is not possible to perform regular antegrade recanalization of occluded tibial arteries, which makes even the most expert interventionist resort to unusual techniques (Bolia A, 2005; Fusaro M, et al. 2008; Graziani L, et al. 2008, 2011) to restore direct blood flow to the foot. Combined retrograde-antegrade arterial recanalization through collateral vessels, essentially combined retrograde and antegrade arterial recanalization using a single entry site.

This technical strategy, largely tested by the authors, has been described in published papers (Fusaro M, et al 2008, Graziani L, et al. 2011) and is intended as option to recanalize tibial arteries.

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 223

(A-D) Diagnostic angiography shown patency of the posterior tibial artery and obstruction of the peroneal and anterior tibial arteries. On the foot patency of the first tract of the medial plantar artery and tarsal branch, obstruction of the lateral plantar and dorsalis pedis arteries.

Fig. 6. (cont). (F-H) recanalization of the peroneal artery and, through the "deep arch", retrogradely recanalization of the anterior tibial artery. After antegrade catheterization of the anterior tibial artery, (I) injection of the contrast material shown patency of the lateral tarsal branch. (J-K) PTA of the lateral tarsal branch (2 x 40 mm / FlexeCTO – Clearstream) and PTA

– Clearstream).

of the anterior tibial artery (2.5 x 220 mm catheter balloon / Bantam-

In our experience it could also be used to recanalize foot arteries, using a natural anastomoses in the foot, such as the so-called "Deep arch" of the foot, that communicate medial plantar artery with lateral tarsal branch and can be tracking in each other sense, to recanalize anterior or posterior tibial artery or in order to arrive to the Pedal arch, through the tarsal branch.

In the same way, there is a natural anastomoses between peroneal artery and the "Deep arch" of the foot (Palena LM, et al. 2011), through a perforating deep branch and tracking this way is possible to retrogradely racanalize the other tibial arteries, via peroneal artery, using a "Deep arch" of the foot.

The vessels are finally recanalized by antegrade PTA (Fig. 6 and 7).

There are another collateral ways or natural anastomoses between tibial and foot arteries that allows to perform retrograde-antegrade recanalization of the tibial and the foot arteries, and its represent an alternative option to recanalize the target vessel.

However, the use of this technique may be considered selectively, even in last-attempt efforts, when other options are not possible or are contraindicated. This technique may be of value specifically when a proximal occlusion stump is not evident, when a dissection flap or a perforation in the proximal tract of the target vessel impairs guide-wire advancement.

This technique may represent a feasible endovascular option to avoid more invasive, timeconsuming or riskier procedures.

Fig. 6. Case 2. Diabetic patient with amputation of the II and V toes, previously undergone to endovascular treatment with poor outcome and guide-wire fracture at the origin of the dorsalis pedis artery with loss the rest of the wire in a subintimal lumen. TcPO2: 6 mmHg.

Angioplasty, Various Techniques and Challenges in 222 Treatment of Congenital and Acquired Vascular Stenoses

In our experience it could also be used to recanalize foot arteries, using a natural anastomoses in the foot, such as the so-called "Deep arch" of the foot, that communicate medial plantar artery with lateral tarsal branch and can be tracking in each other sense, to recanalize anterior or posterior tibial artery or in order to arrive to the Pedal arch, through the tarsal branch. In the same way, there is a natural anastomoses between peroneal artery and the "Deep arch" of the foot (Palena LM, et al. 2011), through a perforating deep branch and tracking this way is possible to retrogradely racanalize the other tibial arteries, via peroneal artery,

There are another collateral ways or natural anastomoses between tibial and foot arteries that allows to perform retrograde-antegrade recanalization of the tibial and the foot arteries,

However, the use of this technique may be considered selectively, even in last-attempt efforts, when other options are not possible or are contraindicated. This technique may be of value specifically when a proximal occlusion stump is not evident, when a dissection flap or a perforation in the proximal tract of the target vessel impairs guide-wire advancement. This technique may represent a feasible endovascular option to avoid more invasive, time-

Fig. 6. Case 2. Diabetic patient with amputation of the II and V toes, previously undergone to endovascular treatment with poor outcome and guide-wire fracture at the origin of the dorsalis pedis artery with loss the rest of the wire in a subintimal lumen. TcPO2: 6 mmHg.

The vessels are finally recanalized by antegrade PTA (Fig. 6 and 7).

and its represent an alternative option to recanalize the target vessel.

using a "Deep arch" of the foot.

consuming or riskier procedures.

(A-D) Diagnostic angiography shown patency of the posterior tibial artery and obstruction of the peroneal and anterior tibial arteries. On the foot patency of the first tract of the medial plantar artery and tarsal branch, obstruction of the lateral plantar and dorsalis pedis arteries.

Fig. 6. (cont). (F-H) recanalization of the peroneal artery and, through the "deep arch", retrogradely recanalization of the anterior tibial artery. After antegrade catheterization of the anterior tibial artery, (I) injection of the contrast material shown patency of the lateral tarsal branch. (J-K) PTA of the lateral tarsal branch (2 x 40 mm / FlexeCTO – Clearstream) and PTA of the anterior tibial artery (2.5 x 220 mm catheter balloon / Bantam-– Clearstream).

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 225

pedal artery and then of the anterior tibial artery. After successfully crossing the target lesion with the guide-wire, usually 0.014"-in (Pilot® 200 - Abbott), a dedicated low-profile over-the-wire catheter balloon should be deployed for PTA and the check to confirm the position of the tip of the catheter in the distal true lumen should be done, injecting contrast

Pedal-Plantar LOOP technique is based on the creation of a loop with the guide-wire from the anterior tibial to the posterior tibial arteries (or vice versa) by means of guide-wire

Clearly, this strategy can be adapted case by case and a combination of other technical possibilities, such as subintimal recanalization of the tibial vessel recanalized antegradely, followed by a re-entry on the foot artery or a subintimal recanalization of the foot and tibial artery recanalized retrogradely, followed by a re-entry at the origin of the tibial vessel, could

This technique may be of particular value whenever a proximal occlusion stump is unavailable, when dissection flap or a perforation in the proximal tract of the target vessel impairs the guide-wire advancement, as well as when distal disease makes retrograde

In our opinion this should be the last technical strategy, considered when the possible

It is intended as a direct percutaneous retrograde puncture of the distal tract of the tibial vessel or foot arteries, in order to retrogradely recanalization of the target vessel

This approach has been described as a solution for the re-entry in a subintimal recanalization (Gandini R, et al. 2007; Spinosa DJ, et al 2003, 2005), that in a small percentage of patients in whom antegrade subintimal recanalization is unsuccessful or there is a limited distal target vessel "landing" zone, a retrograde distal puncture can be performed and a retrograde recanalization, following by antegrade PTA and haemostasis

The possible retrograde access site may be different, such as distal tract of the posterior tibial artery, pedal artery (Fusaro M, et al. 2006, 2007) or peroneal artery, but the difficulties to perform the puncture increase from each other site and the risk to damage the distal patent vessel, compromising the possibility to perform a distal by-pass, should

In our experience, in selected and very challenging cases in whom a distal by pass is contraindicated, antegrade revascularization attempts failed and retrograde percutaneous distal access on the target vessel is not possible or failed too, an antegrade percutaneous distal access on the Pedal artery or in the common plantar artery, followed by antegrade recanalization of the foot artery, pedal arch and retrograde recanalization of the target vessel, is possible, but should be considered as indication in cases in whom every other

Endovascular recanalization of the tibial vessels and foot arteries, especially in diabetics with CLI is actually an excellent treatment option and, in our experience, should be considered as the first treatment option for revascularization. Different clinical studies and registries show that technical success rate is between 80% and 90% and clinical

endovascular or surgical strategy failed or are contraindicated.

media through the catheter.

tracking through the pedal arch of the foot.

help to reach both, technical and clinical success.

**5.3.3 Retrograde percutaneous revascularization** 

percutaneous puncture impossible.

solutions before described failed.

(Fig. 8 and 9).

may be a solution.

be considered.

Fig. 7. Angiographic results. (A-B) Recanalization of the anterior and peroneal arteries, patency of the posterior tibial artery. (C-D) Recanalization of the lateral tarsal branch and plantar arch, with good blood flow for the foot and the toes.

Clinical follow up. TcPO2 increased to 37 mmHg with healing the surgical treatment.

#### **5.3.2 Pedal-Plantar LOOP technique**

In a high percentage of cases the success rate of PTA remains suboptimal, particularly when the atherosclerotic disease involving also the distal run-off. In these cases the support of Pedal-Plantar LOOP technique could be necessary.

This technical approach, intended for the recanalization of challenging below-the-knee and below-the-ankle lesions, has been already described (Fusaro M, et al 2007) and the clinical results of its application in revascularization of tibial and foot vessels has thoroughly been described in a recent paper (Manzi M, et al. 2009).

Specifically, this technique consist in either one or both the following two approaches: antegrade recanalization of the anterior tibial artery and the pedal artery, including the pedal arch, followed by retrograde recanalization of the lateral plantar artery and then of the posterior tibial artery; or antegrade recanalization of the posterior tibial artery and the lateral plantar artery, including pedal arch, followed by retrograde recanalization of the pedal artery and then of the anterior tibial artery. After successfully crossing the target lesion with the guide-wire, usually 0.014"-in (Pilot® 200 - Abbott), a dedicated low-profile over-the-wire catheter balloon should be deployed for PTA and the check to confirm the position of the tip of the catheter in the distal true lumen should be done, injecting contrast media through the catheter.

Pedal-Plantar LOOP technique is based on the creation of a loop with the guide-wire from the anterior tibial to the posterior tibial arteries (or vice versa) by means of guide-wire tracking through the pedal arch of the foot.

Clearly, this strategy can be adapted case by case and a combination of other technical possibilities, such as subintimal recanalization of the tibial vessel recanalized antegradely, followed by a re-entry on the foot artery or a subintimal recanalization of the foot and tibial artery recanalized retrogradely, followed by a re-entry at the origin of the tibial vessel, could help to reach both, technical and clinical success.

This technique may be of particular value whenever a proximal occlusion stump is unavailable, when dissection flap or a perforation in the proximal tract of the target vessel impairs the guide-wire advancement, as well as when distal disease makes retrograde percutaneous puncture impossible.

#### **5.3.3 Retrograde percutaneous revascularization**

Angioplasty, Various Techniques and Challenges in 224 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 7. Angiographic results. (A-B) Recanalization of the anterior and peroneal arteries, patency of the posterior tibial artery. (C-D) Recanalization of the lateral tarsal branch and

Clinical follow up. TcPO2 increased to 37 mmHg with healing the surgical treatment.

In a high percentage of cases the success rate of PTA remains suboptimal, particularly when the atherosclerotic disease involving also the distal run-off. In these cases the support of

This technical approach, intended for the recanalization of challenging below-the-knee and below-the-ankle lesions, has been already described (Fusaro M, et al 2007) and the clinical results of its application in revascularization of tibial and foot vessels has thoroughly been

Specifically, this technique consist in either one or both the following two approaches: antegrade recanalization of the anterior tibial artery and the pedal artery, including the pedal arch, followed by retrograde recanalization of the lateral plantar artery and then of the posterior tibial artery; or antegrade recanalization of the posterior tibial artery and the lateral plantar artery, including pedal arch, followed by retrograde recanalization of the

plantar arch, with good blood flow for the foot and the toes.

**5.3.2 Pedal-Plantar LOOP technique**

Pedal-Plantar LOOP technique could be necessary.

described in a recent paper (Manzi M, et al. 2009).

In our opinion this should be the last technical strategy, considered when the possible solutions before described failed.

It is intended as a direct percutaneous retrograde puncture of the distal tract of the tibial vessel or foot arteries, in order to retrogradely recanalization of the target vessel (Fig. 8 and 9).

This approach has been described as a solution for the re-entry in a subintimal recanalization (Gandini R, et al. 2007; Spinosa DJ, et al 2003, 2005), that in a small percentage of patients in whom antegrade subintimal recanalization is unsuccessful or there is a limited distal target vessel "landing" zone, a retrograde distal puncture can be performed and a retrograde recanalization, following by antegrade PTA and haemostasis may be a solution.

The possible retrograde access site may be different, such as distal tract of the posterior tibial artery, pedal artery (Fusaro M, et al. 2006, 2007) or peroneal artery, but the difficulties to perform the puncture increase from each other site and the risk to damage the distal patent vessel, compromising the possibility to perform a distal by-pass, should be considered.

In our experience, in selected and very challenging cases in whom a distal by pass is contraindicated, antegrade revascularization attempts failed and retrograde percutaneous distal access on the target vessel is not possible or failed too, an antegrade percutaneous distal access on the Pedal artery or in the common plantar artery, followed by antegrade recanalization of the foot artery, pedal arch and retrograde recanalization of the target vessel, is possible, but should be considered as indication in cases in whom every other endovascular or surgical strategy failed or are contraindicated.

Endovascular recanalization of the tibial vessels and foot arteries, especially in diabetics with CLI is actually an excellent treatment option and, in our experience, should be considered as the first treatment option for revascularization. Different clinical studies and registries show that technical success rate is between 80% and 90% and clinical

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 227

Fig. 8. Case 3. Diabetics patient, previously underwent to TMA, with apical ischemic wound. The patient was underwent to endovascular treatment and stenting in the tibioperoneal trunk, without any stump of the posterior tibial artery origin. TcPO2: 4 mmHg. (A-E) Oclussione of the SFA with stent, occluded in the distal tract. Patency of the popliteal artery and the tibio-peronel trunk, with in-stent re-stenosis and patency of the peroneal artery and the distal truck of the posterior tibial artery. On the foot patency of the plantar arteries. (F-I) Retrograde puncture of the distal tract of the posterior tibial artery and retrograde recanalization. Antegrade long balloon PTA (2.5 x 220 mm catheter balloon /

Bantam-

– Clearstream).

success rate, intended as limb salvage, is about 70% at 12 months. These technical and clinical outcomes are obtained in a dedicated centers, combining all technical strategies described before.

Stent deployment in the below-the-knee district, in our opinion, should be considered as the last treatment option, because in-stent re-stenosis and occlusion related to neointimal hyperplasia or struts fractures, is a frequent complication and the presence of occluded stent represent a foreign body that makes new endovascular treatment very difficult.

Angioplasty, Various Techniques and Challenges in 226 Treatment of Congenital and Acquired Vascular Stenoses

success rate, intended as limb salvage, is about 70% at 12 months. These technical and clinical outcomes are obtained in a dedicated centers, combining all technical strategies

Stent deployment in the below-the-knee district, in our opinion, should be considered as the last treatment option, because in-stent re-stenosis and occlusion related to neointimal hyperplasia or struts fractures, is a frequent complication and the presence of occluded stent represent a foreign body that makes new endovascular treatment very

described before.

difficult.

Fig. 8. Case 3. Diabetics patient, previously underwent to TMA, with apical ischemic wound. The patient was underwent to endovascular treatment and stenting in the tibioperoneal trunk, without any stump of the posterior tibial artery origin. TcPO2: 4 mmHg. (A-E) Oclussione of the SFA with stent, occluded in the distal tract. Patency of the popliteal artery and the tibio-peronel trunk, with in-stent re-stenosis and patency of the peroneal artery and the distal truck of the posterior tibial artery. On the foot patency of the plantar arteries. (F-I) Retrograde puncture of the distal tract of the posterior tibial artery and retrograde recanalization. Antegrade long balloon PTA (2.5 x 220 mm catheter balloon / Bantam-– Clearstream).

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 229

In the same context, a lot of dedicated catheter balloons are actually available, from long balloons such as 22 cm or longer, to short and coronary-like such as 2 cm; and from 1.25 mm

The selection of the guide-wire and the catheter balloons should be done on the personal preferences and experience, but the availability of different materials, from different

Current results of minimally invasive endovascular techniques, with 2-years patency rate between 40 and 60%, low primary patency and increased repeat intervention rates, has

Percutaneous angioplasty of below-the-knee arteries is an accepted therapy for patients with critical limb ischemia (Buckenham TM, et al. 1993; Hanna GP, et al. 1997; Saab MH, et al.

However, below-the-knee interventions are limited by a considerable number of re-stenosis, especially in lesions with heavy calcified plaque. Directional atherectomy may be an alternative option to improve the procedural success and reduce the re-stenosis rate and the

In our opinion this debulking device is indicated especially in cases of re-stenosis, but also is an excellent option to treat bifurcations and could be used to treat in-stent re-stenosis,

Atherectomy should be prefer to traditional PTA in the popliteal artery, because of excellent

New dedicated BTK devices, with range from 2 to 4 mm in diameter, very small caliber design and excellent push-ability allow the recanalization of long occlusion, involving tibial

The atherectomy cutter catheter usually need a 6F sheath and is designed to track over a 0.014"-in guide-wire. Is recommended to use atherectomy crossing the lesion intraluminally, because of the potential risk of perforation during subintimal debulking. Cases of stenosis can be treated with primary atherectomy whereas occlusions should be pre-dilated with an undersized catheter balloon, to be sure that the guide-wire crosses the occlusion intraluminally and to guaranty the progression of the cutter catheter through the occlusion. Rotational atherectomy is also a useful technical strategy for calcified vessels. The limits of this technique is the push-ability of the device, that usually require long sheath deployment

After atherectomy, usually, is not necessary perform catheter balloon dilatation, because the atherectomy results are satisfactory when the debulking procedure is performed correctly,

This technique present low rate of complications and could be the option to avoid stent deployment with significant advantage in cases of re-stenosis, allowing the endovascular re-

Promising acute and long-term clinical results, with a high rate of limb salvage and high rate of primary and secondary patency (McKinsey, et al. 2008), makes this technical strategy an

excellent option for endovascular treatment in the below-the-knee district.

despite this indication (in-stent treatment) is contraindicated by the manufacturer.

re-intervention rate (McKinseyJF, et al. 2008; Zeller T, et al. 2004, 2007).

technical results, avoiding dissection and stenting (Fig. 10).

manufacturer would be useful and necessary to perform very challenging cases.

in diameter to 3 mm.

**7.1 Atherectomy** 

1992; Soder HK, et al. 2000).

vessels and/or foot arteries.

into the tibial vessel.

intervention.

cutting in the four faces of the artery wall.

**7. New frontiers and devices** 

oriented toward new alternative techniques.

Fig. 9. (A-F) After PTA of the SFA and Popliteal arteries, the angiographic study show patency of the femoro-popliteal tract, patency of the tibio-peroneal trunk and posterior tibial artery with excellent flow for the plantar arteries and for the apical lesion on the foot. Clinical follow up. TcPO2 increased to 33 mmHg with wound healing.

#### **6. Materials**

During the last years the development of the BTK techniques and the increasing rate of BTK interventionists have led a continuous expansion of the dedicated materials.

Actually, there are a huge different type of dedicated guide-wire, from 0.014"-in and 0,018" in to the 0,035"-in or CTO guide-wire, from different manufacturers, all usefully and necessary in the interventional suite.

In the same context, a lot of dedicated catheter balloons are actually available, from long balloons such as 22 cm or longer, to short and coronary-like such as 2 cm; and from 1.25 mm in diameter to 3 mm.

The selection of the guide-wire and the catheter balloons should be done on the personal preferences and experience, but the availability of different materials, from different manufacturer would be useful and necessary to perform very challenging cases.

#### **7. New frontiers and devices**

Current results of minimally invasive endovascular techniques, with 2-years patency rate between 40 and 60%, low primary patency and increased repeat intervention rates, has oriented toward new alternative techniques.

#### **7.1 Atherectomy**

Angioplasty, Various Techniques and Challenges in 228 Treatment of Congenital and Acquired Vascular Stenoses

Fig. 9. (A-F) After PTA of the SFA and Popliteal arteries, the angiographic study show patency of the femoro-popliteal tract, patency of the tibio-peroneal trunk and posterior tibial artery with excellent flow for the plantar arteries and for the apical lesion on the foot.

During the last years the development of the BTK techniques and the increasing rate of BTK

Actually, there are a huge different type of dedicated guide-wire, from 0.014"-in and 0,018" in to the 0,035"-in or CTO guide-wire, from different manufacturers, all usefully and

Clinical follow up. TcPO2 increased to 33 mmHg with wound healing.

interventionists have led a continuous expansion of the dedicated materials.

**6. Materials** 

necessary in the interventional suite.

Percutaneous angioplasty of below-the-knee arteries is an accepted therapy for patients with critical limb ischemia (Buckenham TM, et al. 1993; Hanna GP, et al. 1997; Saab MH, et al. 1992; Soder HK, et al. 2000).

However, below-the-knee interventions are limited by a considerable number of re-stenosis, especially in lesions with heavy calcified plaque. Directional atherectomy may be an alternative option to improve the procedural success and reduce the re-stenosis rate and the re-intervention rate (McKinseyJF, et al. 2008; Zeller T, et al. 2004, 2007).

In our opinion this debulking device is indicated especially in cases of re-stenosis, but also is an excellent option to treat bifurcations and could be used to treat in-stent re-stenosis, despite this indication (in-stent treatment) is contraindicated by the manufacturer.

Atherectomy should be prefer to traditional PTA in the popliteal artery, because of excellent technical results, avoiding dissection and stenting (Fig. 10).

New dedicated BTK devices, with range from 2 to 4 mm in diameter, very small caliber design and excellent push-ability allow the recanalization of long occlusion, involving tibial vessels and/or foot arteries.

The atherectomy cutter catheter usually need a 6F sheath and is designed to track over a 0.014"-in guide-wire. Is recommended to use atherectomy crossing the lesion intraluminally, because of the potential risk of perforation during subintimal debulking. Cases of stenosis can be treated with primary atherectomy whereas occlusions should be pre-dilated with an undersized catheter balloon, to be sure that the guide-wire crosses the occlusion intraluminally and to guaranty the progression of the cutter catheter through the occlusion.

Rotational atherectomy is also a useful technical strategy for calcified vessels. The limits of this technique is the push-ability of the device, that usually require long sheath deployment into the tibial vessel.

After atherectomy, usually, is not necessary perform catheter balloon dilatation, because the atherectomy results are satisfactory when the debulking procedure is performed correctly, cutting in the four faces of the artery wall.

This technique present low rate of complications and could be the option to avoid stent deployment with significant advantage in cases of re-stenosis, allowing the endovascular reintervention.

Promising acute and long-term clinical results, with a high rate of limb salvage and high rate of primary and secondary patency (McKinsey, et al. 2008), makes this technical strategy an excellent option for endovascular treatment in the below-the-knee district.

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 231

Fig. 10. Case 4. Diabetic patient with claudication intermittens (50 m). (A-B) Diagnostic angiography shows occlusion in the popliteal artery. (C) shows directional atherectomy of the occluded tract. (D-F) angiographic result shows excellent recanalization of the popliteal

Finally, we want to express our opinion about stent deployment in the BTK district. In literature is reported the use of stent for various indications such as dissections, calcified restenosis, recoiling and thrombus formation ( Tepe G, et al. 2007), with good clinical results. We are in accord with the concept that stent use translates in acute high technical success and good short-term patency rate, but the re-stenosis rate related to neo-intimal hyperplasia is very high and the presence of stent appear as a foreign body in the true or in a subintimal lumen, that makes re-intervention more complex or, sometimes, impossible. Our stent deployment rate in the BTK district in the last year, was less than 3% and it was related to very flow limiting dissection, especially in the bifurcations, thrombus formation with unsuccessful attempts to perform thrombus-aspiration and in 1 case the stent deployment

artery, without dissection, avoiding stenting and patency in flexion position.

was related to artery perforation with acute bleeding.

**8. Stent deployment** 

#### **7.2 DEB's**

The other possible solution to fight re-stenosis in the BTK district could be Drug eluting balloons. This new technology, Paclitaxel-coated balloons should be a potential role in the peripheral district (Manzi M, et al. 2010; Sharma S, et al. 2010; Waksman P, et al. 2009) to avoid re-stenosis due to the antiproliferative effect. The use of DEB is not technically complex and there are, actually, a wide range of different devices. Despite the encouraging data on coronary arteries where drug eluting devices have shown promising antirestenotic effects in experimental and clinical trials, a clinical results in BTK district, early experimental and clinical data are promising but a randomized controlled trials, comparing DEB and traditional angioplasty or DEB and atherectomy must be produced.

The limits of DEB's, in our experience, is the use of this device in a subintimal recanalization. DEB's are preferred to be used in intraluminal recanalization, due to the risk of pseudo-aneurism formation during subintimal recanalization.

#### **7.3 Cryoplasty**

The rational to use this technology is based in the presumed more uniform and less traumatic immediate performance of cryoplasty, in synergy with the induction of the apoptotic effect , that would result in less neo-intimal hyperplasia and, as consequence, better immediate and long-term angiographic and clinical results (Sipiliopoulos S, et al. 2010).

The data about 12-months follow-up from the BTK Chill trial (Das TS, et al. 2009), which evaluated cryoplasty in the infra-popliteal district of CLI patients, reported high rates of acute technical success and major amputation-free interval (97.3% and 78.5%, respectively) followed by a low percentage of repeated procedure due to clinically deterioration (21% at 12 months).

We simply report the data published in the actual literature, because we do not have experience with this technical strategy, but the technical and clinical result are encouraging. It seem to avoids stent deployment, with the mentioned benefits in the BTK district. However, more experience are expected and could be useful more data about bigger cohort of patients.

#### **7.4 Laser**

The excimer laser technology is based on a cold-tipped laser that delivers intense bursts of energy in the ultraviolet range (308 nm) carried out in ultra-short pulse duration (0.05 nm per pulse vs 0.3-2.0 mm per pulse in the hot-tip laser). The energy delivered elicits photochemical, photothermal and photomechanical actions, which break molecular bonds, and produce vapor bubbles that generate kinetic energy (Serino F, et al. 2010).

This technology has been studied in below-the-knee lesions, with improved results over standard PTA alone and exhibited excellent limb salvage rate (Bosier M, et al 2005; Laird JR, et al.2006). The use of the excimer laser represents a great opportunity to pursue a true endoluminal recanalization with potential long-term efficacy and decreased need for stenting. The LACI and LACI Belgium study have both proven that laser-assisted angioplasty is a low risk, successful treatment strategy in CLI patients. Primary patency rate range from 83% at 6-months to 97.6% at 12-months and the limb salvage rate range from 92.5% at 6-months to 94% at 12-months. However, the reported rate of stent deployment in the mentioned study was in a range from 21% to 52.9%, and this seem to be a contradiction between the opportunity to pursue the reduction of stent deployment that is at the bases of the use of this device and the real data reported about stent placement.

Fig. 10. Case 4. Diabetic patient with claudication intermittens (50 m). (A-B) Diagnostic angiography shows occlusion in the popliteal artery. (C) shows directional atherectomy of the occluded tract. (D-F) angiographic result shows excellent recanalization of the popliteal artery, without dissection, avoiding stenting and patency in flexion position.

#### **8. Stent deployment**

Angioplasty, Various Techniques and Challenges in 230 Treatment of Congenital and Acquired Vascular Stenoses

The other possible solution to fight re-stenosis in the BTK district could be Drug eluting balloons. This new technology, Paclitaxel-coated balloons should be a potential role in the peripheral district (Manzi M, et al. 2010; Sharma S, et al. 2010; Waksman P, et al. 2009) to avoid re-stenosis due to the antiproliferative effect. The use of DEB is not technically complex and there are, actually, a wide range of different devices. Despite the encouraging data on coronary arteries where drug eluting devices have shown promising antirestenotic effects in experimental and clinical trials, a clinical results in BTK district, early experimental and clinical data are promising but a randomized controlled trials, comparing DEB and

The limits of DEB's, in our experience, is the use of this device in a subintimal recanalization. DEB's are preferred to be used in intraluminal recanalization, due to the risk

The rational to use this technology is based in the presumed more uniform and less traumatic immediate performance of cryoplasty, in synergy with the induction of the apoptotic effect , that would result in less neo-intimal hyperplasia and, as consequence, better immediate and long-term angiographic and clinical results (Sipiliopoulos S, et

The data about 12-months follow-up from the BTK Chill trial (Das TS, et al. 2009), which evaluated cryoplasty in the infra-popliteal district of CLI patients, reported high rates of acute technical success and major amputation-free interval (97.3% and 78.5%, respectively) followed by a low percentage of repeated procedure due to clinically deterioration (21% at 12 months). We simply report the data published in the actual literature, because we do not have experience with this technical strategy, but the technical and clinical result are encouraging. It seem to avoids stent deployment, with the mentioned benefits in the BTK district. However, more experience are expected and could be useful more data about bigger cohort

The excimer laser technology is based on a cold-tipped laser that delivers intense bursts of energy in the ultraviolet range (308 nm) carried out in ultra-short pulse duration (0.05 nm per pulse vs 0.3-2.0 mm per pulse in the hot-tip laser). The energy delivered elicits photochemical, photothermal and photomechanical actions, which break molecular bonds,

This technology has been studied in below-the-knee lesions, with improved results over standard PTA alone and exhibited excellent limb salvage rate (Bosier M, et al 2005; Laird JR, et al.2006). The use of the excimer laser represents a great opportunity to pursue a true endoluminal recanalization with potential long-term efficacy and decreased need for stenting. The LACI and LACI Belgium study have both proven that laser-assisted angioplasty is a low risk, successful treatment strategy in CLI patients. Primary patency rate range from 83% at 6-months to 97.6% at 12-months and the limb salvage rate range from 92.5% at 6-months to 94% at 12-months. However, the reported rate of stent deployment in the mentioned study was in a range from 21% to 52.9%, and this seem to be a contradiction between the opportunity to pursue the reduction of stent deployment that is at the bases of

and produce vapor bubbles that generate kinetic energy (Serino F, et al. 2010).

the use of this device and the real data reported about stent placement.

traditional angioplasty or DEB and atherectomy must be produced.

of pseudo-aneurism formation during subintimal recanalization.

**7.2 DEB's** 

**7.3 Cryoplasty**

al. 2010).

of patients.

**7.4 Laser** 

Finally, we want to express our opinion about stent deployment in the BTK district. In literature is reported the use of stent for various indications such as dissections, calcified restenosis, recoiling and thrombus formation ( Tepe G, et al. 2007), with good clinical results. We are in accord with the concept that stent use translates in acute high technical success and good short-term patency rate, but the re-stenosis rate related to neo-intimal hyperplasia is very high and the presence of stent appear as a foreign body in the true or in a subintimal lumen, that makes re-intervention more complex or, sometimes, impossible. Our stent deployment rate in the BTK district in the last year, was less than 3% and it was related to very flow limiting dissection, especially in the bifurcations, thrombus formation with unsuccessful attempts to perform thrombus-aspiration and in 1 case the stent deployment was related to artery perforation with acute bleeding.

Revascularization of Tibial and Foot Arteries: Below the Knee Angioplasty for Limb Salvage 233

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The fear that early thrombosis and late luminal loss due to intimal hyperplasia formation potentially leads to insufficient long-term patency rates can explain the reluctance on implanting stents in small diameter below-the-knee (BTK) arteries. Drug-eluting stent (DES) technology was developed to prevent early thrombosis and late luminal loss to potentially improve long-term patency rates (Bosier M, et al. 2011).

Currently, the first level 1 evidence from prospective, randomized, controlled DESTINY and ACHILLES studies indicate that the implantation of DES in short lesion in the infrapopliteal arteries leads to favorable outcomes with high primary patency rates and a published paper (Rosales OR, et al. 2008.) conclude that DES is a safe and effective long-term option for CLI due to severe infrapopliteal arterial disease. Long-term vascular patency led to a high rate of limb preservation and low amputation rate.

May be in the future, a resorbable dedicated stent conceived for the BTK district will change the indications for stent deployment in tibial arteries.

#### **9. Conclusions**

Endovascular treatment of critical limb ischemia in diabetics with crural and pedal disease can be an exceedingly challenging and complex problem. Technical success rate and clinical outcomes, with a high rate of limb salvage and amputation-free survival are encouraging, support the endovascular revascularization as the first treatment option and demonstrate that is a reasonable and effective approach. The rapid pace of development of various endovascular devices and techniques often allow the interventionalist to treat increasingly complex and diffuse patterns of disease.

Is essential for endovascular specialist, in order to reach these technical and clinical success, a thorough knowledge of the wide range of endovascular techniques and options.

Usually only one technical strategy is not enough to treat crural and foot arteries and a combination of the previously described techniques improve the results of the procedures and allow to achieve excellent clinical outcomes.

#### **10. References**


Angioplasty, Various Techniques and Challenges in 232 Treatment of Congenital and Acquired Vascular Stenoses

The fear that early thrombosis and late luminal loss due to intimal hyperplasia formation potentially leads to insufficient long-term patency rates can explain the reluctance on implanting stents in small diameter below-the-knee (BTK) arteries. Drug-eluting stent (DES) technology was developed to prevent early thrombosis and late luminal loss to potentially

Currently, the first level 1 evidence from prospective, randomized, controlled DESTINY and ACHILLES studies indicate that the implantation of DES in short lesion in the infrapopliteal arteries leads to favorable outcomes with high primary patency rates and a published paper (Rosales OR, et al. 2008.) conclude that DES is a safe and effective long-term option for CLI due to severe infrapopliteal arterial disease. Long-term vascular patency led to a high rate of

May be in the future, a resorbable dedicated stent conceived for the BTK district will change

Endovascular treatment of critical limb ischemia in diabetics with crural and pedal disease can be an exceedingly challenging and complex problem. Technical success rate and clinical outcomes, with a high rate of limb salvage and amputation-free survival are encouraging, support the endovascular revascularization as the first treatment option and demonstrate that is a reasonable and effective approach. The rapid pace of development of various endovascular devices and techniques often allow the interventionalist to treat increasingly

Is essential for endovascular specialist, in order to reach these technical and clinical success,

Usually only one technical strategy is not enough to treat crural and foot arteries and a combination of the previously described techniques improve the results of the procedures

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**9. Conclusions** 

**10. References** 

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### *Edited by Thomas Forbes*

The field of performing transcatheter interventions to treat vascular lesions has exploded over the past 20 years. Not only has the technology changed, especially in the arena of balloon/stent devices, but the techniques of approaching complex lesions has evolved over the past decade. Lesions that no one would have imagined treating back in the 1990's are now being done routinely in the catheterization suite. This book provides an update on the current techniques and devices used to treat a wide variety of lesions. Though, at first, the outward appearance of the topics appears to be varied, they are all related by the common thread of treating vascular lesions. We hope, by publishing this book, to accomplish two things: First, to offer insight from experts in their field to treat, both medically and procedurally, complex vascular lesions that we frequently encounter. Secondly, we hope to promote increased communication between areas of medicine that frequently don't communicate, between adult interventional cardiologists, pediatric interventional cardiologists, interventional radiologists, and neurosurgeons. Much can be learned from our respective colleagues in these areas which can further our own world of interventions.

Angioplasty, Various Techniques and Challenges in Treatment of Congenital and Acquired

Vascular Stenoses

Angioplasty, Various

Techniques and Challenges in

Treatment of Congenital and

Acquired Vascular Stenoses

*Edited by Thomas Forbes*

Photo by HYWARDS / iStock