Seung-Jin Lee

*Soonchunhyang University Cheonan Hospital South Korea* 

#### **1. Introduction**

46 Coronary Interventions

Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, van den Brand M,

Singh M, Lennon RJ, Holmes DR, Jr., Bell MR, Rihal CS. Correlates of procedural

Vickers AJ, Cronin AM. Everything you always wanted to know about evaluating prediction models (but were too afraid to ask). *Urology.*76(6):1298-1301. Wu C, Hannan EL, Walford G, Ambrose JA, Holmes DR, Jr., King SB, 3rd, Clark LT, Katz S,

discussion 1864-1855.

*EuroIntervention.* 2005;1(2):219-227.

intervention. *J Am Coll Cardiol.* 2002;40(3):387-393.

coronary interventions. *J Am Coll Cardiol.* 2006;47(3):654-660.

mortality and morbidity risk models. *Ann Thorac Surg.* 2003;75(6):1856-1864;

Van Dyck N, Russell ME, Mohr FW, Serruys PW. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease.

complications and a simple integer risk score for percutaneous coronary

Sharma S, Jones RH. A risk score to predict in-hospital mortality for percutaneous

Drug-eluting stents (DES) substantially reduce restenosis compared with bare metal stents and represent a significant advance in percutaneous coronary interventions (PCIs). Accordingly, DES have been rapidly adopted into practice and are currently used in the vast majority of PCI procedures. As PCIs for more complicated lesions increase, various complications, such as stent thrombosis, fracture, dissection or perforation, are also increase. For example, PCIs for patients who have chronic total occlusion increase and these patients tend to have more risk factors like diabetes mellitus, hypertension, dyslipidemia, and previous myocardial infarction and also have multi-vessel diseases and have decreased left ventricular ejection fraction. If major procedure-related complications were developed in these high risk patients, it may leads to fatal results. So it is important to understand possible complications of PCIs and eliminate potential risk factors before procedures.

#### **1.1 Stent fracture**

Drug-eluting stents (DES) have proven very effective in reducing restenosis by suppressing neointimal hyperplasia. However, potentially serious complications such as in-stent restenosis and thrombus still occur. Stent fracture has been identified as a possible contributor to these adverse outcomes. A number of risk factors for the development of stent fracture have been described, although a detailed analysis of the angiographic factors predisposing to stent fracture is lacking.

#### **1.2 Incidence and definition**

Stent fracture is defined as the cases where the linear or curvilinear connections of stent struts are interrupted and areas of the stented segment are uncovered by stent struts visible on coronary angiography. The incidence of stent fracture is reported in 0.8-7.7% of cases.1-8 However, because of limited sensitivity of angiography to detect fracture, its true incidence is still unknown. In a recent report analyzed from autopsy findings, stent fracture was observed in 29% of total patients.9 So, the real incidence of stent fracture is assumed to be a little higher than what has been clinically reported. Stent fracture from patients treated with Cypher stents is more frequently observed than in cases of Taxus stents. The incidence of stent fracture of Cypher stent was 1.3% in the SIRIUS trial,9 compared to 0.58% incidence with the Taxus stent is in the Taxus IV/V/VI trials. Stent fracture has previously been recognized in noncoronary vessels, especially in the superficial femoral and popliteal arteries

Complications of Coronary Intervention 49

only

The complications observed with DES fracture include in-stent restenosis, target lesion revascularization, stent thrombosis, myocardial infarction, stent-related aneurysm, and sudden death. Lee et al. observed binary restenosis in six out of 10 patients (60%) with stent fracture and one patient had stent thrombosis.5 Local mechanical irritation of the vessel can occur from fractured stent struts, which may result in inflammation and neointimal hyperplasia. Restenosis could also reflect decreased local drug availability secondary to distortion of the stent architecture and polymer coating.13 Exposure of a free metal strut protruding into the vessel lumen could trigger platelet activation and resultant stent thrombosis. Acute myocardial infarction and sudden death can develop from fracture-

Usually stent fracture can be diagnosed by conventional fluoroscopy or follow-up coronary angiography. If the diagnosis is obscure, Intravascular Ultrasound (IVUS), Multi-Detector Computed Tomography (MDCT), or Optical Coherence Tomography (OCT) can be helpful. Because recently developed stents tend to have thinner struts and less radiopacity, the diagnosis of stent fracture tends to difficult. Unfortunately, there is no consensus of the treatment of stent fracture. It depends on whether or not there is restenosis and its related

Single strut fracture

Multiple single stent fractures occurring at

Multiple single stent fractures resulting in complete transverse linear fracture but without stent displacement

Complete transverse linear type III fracture with stent displacement -

different sites

Minor-single strut

Moderate-fracture >1

Severe-complete separation of stent

segments

fracture

strut

Classification Current report Allie et el Scheinert et al

Type 0 No strut fracture - -

gap between struts greater than 2 times expanded cell diameter

with V-form division of

stent fracture without displacement of fractured fragments more than 1 mm during the cardiac cycle

stent fracture with abundant movement and displacement of fractured fragments of more than 1 mm during the cardiac cycle

Type I Single strut fracture or

Type II Multiple strut fracture

Type III Complete transverse

Type IV Complete transverse

Table 1. Definitions used for stent fracture12

**1.4 Clinical implications** 

related stent thrombosis.

symptoms.

**1.5 Diagnosis and treatment** 

the stent

and with bare-metal stents in saphenous vein grafts.10,11 Because old classifications of stent fracture are originated from in cases of femoropopliteal arteries, Popma *et al.* suggested a more detailed new classification specially designed for coronary arteries (Figure 1, Table 1).12

#### **1.3 Predictors and possible mechanisms**

Stent fractures in the bare-metal stent era might be overlooked and masked due to the diffuse tissue overgrowth within the stented segment. Because drug-eluting stents can suppress neointimal hyperplasia more effectively thereby stent fracture may now be more obvious in the very localized lesions bordered by segments with no evidence of neointima.13 As already mentioned, among DESs, Cypher stents showed more frequent stent fractures compared to Taxus stents. The inter-strut angles of the Cypher stent which has a closed-cell design, were significantly smaller than Taxus stent which has an open-cell design.14 The different stent strut design should be considered as a key mechanism of Cypher stent fracture. To maintain smaller inter-strut angles and a more regular strut distribution, there must be higher shear forces on the struts of Cypher stent. Therefore the closed-cell designed Cypher stent may be more prone to fracture when shear forces are beyond its flexibility. It seems that stent fractures are rare in newer generation stents such as Xience V or Eendeavor stents. Stent fractures most frequently occur in the right coronary artery followed by the left anterior descending artery and finally the left circumflex artery. The predisposition of the right coronary artery for stent fracture is possibly attributed to the vessel anatomy, due to the excessive tortuosity, angulation, or change of angulation after stent implantation. Vessel movement throughout the cardiac cycle creates flexion, stretching, and torsion forces, creating hinge points and can lead to mechanical fatigue and fracture.2 Procedure related contributing factors are longer and more angulated lesions, lesions that are ostial in location with more proximal tortuosity, calcification, total occlusion, stent overlap, stenting in saphenous vein grafts, and overstretching of the stents with high pressure.12

Fig. 1. Definitions used for stent fracture

and with bare-metal stents in saphenous vein grafts.10,11 Because old classifications of stent fracture are originated from in cases of femoropopliteal arteries, Popma *et al.* suggested a more

Stent fractures in the bare-metal stent era might be overlooked and masked due to the diffuse tissue overgrowth within the stented segment. Because drug-eluting stents can suppress neointimal hyperplasia more effectively thereby stent fracture may now be more obvious in the very localized lesions bordered by segments with no evidence of neointima.13 As already mentioned, among DESs, Cypher stents showed more frequent stent fractures compared to Taxus stents. The inter-strut angles of the Cypher stent which has a closed-cell design, were significantly smaller than Taxus stent which has an open-cell design.14 The different stent strut design should be considered as a key mechanism of Cypher stent fracture. To maintain smaller inter-strut angles and a more regular strut distribution, there must be higher shear forces on the struts of Cypher stent. Therefore the closed-cell designed Cypher stent may be more prone to fracture when shear forces are beyond its flexibility. It seems that stent fractures are rare in newer generation stents such as Xience V or Eendeavor stents. Stent fractures most frequently occur in the right coronary artery followed by the left anterior descending artery and finally the left circumflex artery. The predisposition of the right coronary artery for stent fracture is possibly attributed to the vessel anatomy, due to the excessive tortuosity, angulation, or change of angulation after stent implantation. Vessel movement throughout the cardiac cycle creates flexion, stretching, and torsion forces, creating hinge points and can lead to mechanical fatigue and fracture.2 Procedure related contributing factors are longer and more angulated lesions, lesions that are ostial in location with more proximal tortuosity, calcification, total occlusion, stent overlap, stenting in

detailed new classification specially designed for coronary arteries (Figure 1, Table 1).12

saphenous vein grafts, and overstretching of the stents with high pressure.12

**1.3 Predictors and possible mechanisms** 

Fig. 1. Definitions used for stent fracture


Table 1. Definitions used for stent fracture12

#### **1.4 Clinical implications**

The complications observed with DES fracture include in-stent restenosis, target lesion revascularization, stent thrombosis, myocardial infarction, stent-related aneurysm, and sudden death. Lee et al. observed binary restenosis in six out of 10 patients (60%) with stent fracture and one patient had stent thrombosis.5 Local mechanical irritation of the vessel can occur from fractured stent struts, which may result in inflammation and neointimal hyperplasia. Restenosis could also reflect decreased local drug availability secondary to distortion of the stent architecture and polymer coating.13 Exposure of a free metal strut protruding into the vessel lumen could trigger platelet activation and resultant stent thrombosis. Acute myocardial infarction and sudden death can develop from fracturerelated stent thrombosis.

#### **1.5 Diagnosis and treatment**

Usually stent fracture can be diagnosed by conventional fluoroscopy or follow-up coronary angiography. If the diagnosis is obscure, Intravascular Ultrasound (IVUS), Multi-Detector Computed Tomography (MDCT), or Optical Coherence Tomography (OCT) can be helpful. Because recently developed stents tend to have thinner struts and less radiopacity, the diagnosis of stent fracture tends to difficult. Unfortunately, there is no consensus of the treatment of stent fracture. It depends on whether or not there is restenosis and its related symptoms.

Complications of Coronary Intervention 51

Changes in endothelial cells, visible after prolonged ischemia, are represented by endothelial protrusions and membrane-bound bodies, which often fill the capillaries up to luminal obliteration. Furthermore, large endothelial gaps with extravascular erythrocytes

A massive infiltration of the coronary microcirculation by neutrophils and platelets occurs at the time of reperfusion.25,26 Reintroduction of neutrophils in post-ischemic myocardium results in their activation, with subsequent adhesion to the endothelial surface and migration in the surrounding tissue. Activated neutrophils, in turn, release oxygen free radicals, proteolytic enzymes, and pro-inflammatory mediators that can directly cause tissue and endothelial damage. Neutrophils also form aggregates with platelets that plug capillaries, thus mechanically blocking flow.27,28 Finally, vasoconstrictors released by damaged endothelial cells, neutrophils, and platelets contribute to sustained vasoconstriction of the coronary microcirculation.29 Tumor necrosis factor-alpha expression is induced by reperfusion, and can impair endothelium-dependent coronary flow reserve.30 Interleukin-1β also has recently been associated with ischemia-reperfusion injury, because interleukin-1β knockout animals exhibit marked reduction of ischemic induced inflammation.31 Selectin expression on cell surfaces is also important for mechanical plugging of the microcirculation.32 Finally, the balance between nitric oxide and superoxide is tipped in favor of superoxide within minutes of reperfusion of ischemic tissues, due to increased production of xanthine oxidase by neutrophils, endothelial cells, and cardiac

Reperfusion might also cause irreversible injury to myocytes.34 During ischemia there is an increase of the intracellular sodium (Na+) content due to accumulation of hydrogen (H+), which is exchanged by the Na+/H+ exchanger. The subsequent exchange of doubly charged positive calcium ion (Ca++) with Na+ by the sarcolemmal Na+/Ca++ exchanger produces a calcium overload that triggers uncontrolled hypercontraction and stimulates opening of the mitochondrial permeability transition pore (m0PTP), which further enhances calcium overload. Furthermore, Na+ extrusion trough Na+/potassium (K+) adenosine triphosphate (ATP)-ase is impaired and together with Ca++ accumulation leads to myocyte cell swelling, which contributes to subsequent rupture of the cell membrane when the extracellular osmolality is rapidly normalized by reperfusion. Of note, cyclosporine, which blocks the m-PTP, has been recently shown to reduce infarct size by 20% when administered intravenously in patients undergoing primary PCI.35 Finally, ischemic pre-conditioning

Natriuretic peptides might modulate ischemia-reperfusion injury. Atrial natriuretic peptide might suppress the rennin-angiotensin-aldosterone system and endothelin (ET)-1 that

In humans, no-reflow is occasionally observed during elective procedures,38 whereas it can be absent after primary PCI in patients with acute myocardial infarction. In particular, diabetes and hypercholesterolemia has been associated with impaired microvascular

increase infarct size, microvascular obstruction, and cardiac remodeling.37

**4. Individual predisposition of coronary microcirculation to injury** 

myocytes, which leads to an exacerbation of the inflammatory state.33

might also reduce infarct size by blockade of m-PTP.36

**2. Ischemia-related injury** 

**3. Reperfusion-related injury** 

are common.25

## **2. No-reflow phenomenon**

The phenomenon of no-reflow is defined as inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction.15 The underlying cause of no-reflow is microvascular obstruction, which may be produced by various mechanisms. The concept of no-reflow was first described in experimental models in 196616 and then in the clinical setting of reperfusion after myocardial infarction in 1985.17 No-reflow has been documented in ≥30% of patients after thrombolysis18 or mechanical intervention for acute myocardial infarction. The prevalence is variable, ranging from 5% up to 50%, according to the methods used to assess the phenomenon and to the population under study.

A series of consistent data has clearly shown that no-reflow has a strong negative impact on outcome, negating the potential benefit of primary percutaneous coronary intervention (PCI).19,20 Indeed, patients with no-reflow exhibit a higher prevalence of: 1) early postinfarction complications (arrhythmias, pericardial effusion, cardiac tamponade, early congestive heart failure); 2) left adverse ventricular remodeling; 3) late repeat hospital stays for heart failure; and 4) mortality.

Therefore, it is important to prevent and effectively treat the no-reflow phenomenon during PCI to achieve an optimal outcome.

#### **2.1 Historical overview**

The term no-reflow was first used by Majno and colleagues21 in the setting of vertebral ischemia in 1967. This phenomenon was initially described by Krug *et al.*<sup>16</sup> during induced myocardial infarction in the canine model in 1966 and again by Kloner *et al.*15 in 1974 in which it occurred for 90 min after temporary epicardial coronary artery occlusion followed by reperfusion. Electron microscopic examination showed severe myocardial capillary damage with loss of pinocytonic vesicles in the endothelial cells, endothelial blisters or blebs and endothelial gaps with neutrophil infiltration. Intraluminal capillary plugging by neutrophils and/or microthrombi with myocardial cell swelling was also noted. Galiuto *et al.*22 with sequential measurements of myocardial perfusion by myocardial contrast echocardiography, have recently shown that in humans no-refow detected 24 h after successful PCI spontaneously improves over time in approximately 50% of patients. Thus, noreflow can be categorized as sustained or reversible. Sustained no-reflow is probably the result of anatomical irreversible changes of the coronary microcirculation, whereas reversible noreflow is the result of functional and thus, reversible, changes of the microcirculation.

In humans, no-reflow is caused by the variable combination of 4 pathogenetic components: 1) distal atherothrombotic embolization; 2) ischemic injury; 3) reperfusion injury; and 4) susceptibility of the coronary microcirculation to injury.

#### **1. Distal embolization**

Emboli of different sizes can originate from epicardial coronary thrombus and from fissured atherosclerotic plaques, in particular during primary PCI.23 Large emboli (>200μm diameter) can obstruct pre-arterioles, causing infarctlets. Experimental observations have shown that myocardial blood flow decreases irreversibly when microspheres obstruct more than 50% of coronary capillaries.24

#### **2. Ischemia-related injury**

50 Coronary Interventions

The phenomenon of no-reflow is defined as inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction.15 The underlying cause of no-reflow is microvascular obstruction, which may be produced by various mechanisms. The concept of no-reflow was first described in experimental models in 196616 and then in the clinical setting of reperfusion after myocardial infarction in 1985.17 No-reflow has been documented in ≥30% of patients after thrombolysis18 or mechanical intervention for acute myocardial infarction. The prevalence is variable, ranging from 5% up to 50%, according to the methods used to assess the

A series of consistent data has clearly shown that no-reflow has a strong negative impact on outcome, negating the potential benefit of primary percutaneous coronary intervention (PCI).19,20 Indeed, patients with no-reflow exhibit a higher prevalence of: 1) early postinfarction complications (arrhythmias, pericardial effusion, cardiac tamponade, early congestive heart failure); 2) left adverse ventricular remodeling; 3) late repeat hospital stays

Therefore, it is important to prevent and effectively treat the no-reflow phenomenon during

The term no-reflow was first used by Majno and colleagues21 in the setting of vertebral ischemia in 1967. This phenomenon was initially described by Krug *et al.*<sup>16</sup> during induced myocardial infarction in the canine model in 1966 and again by Kloner *et al.*15 in 1974 in which it occurred for 90 min after temporary epicardial coronary artery occlusion followed by reperfusion. Electron microscopic examination showed severe myocardial capillary damage with loss of pinocytonic vesicles in the endothelial cells, endothelial blisters or blebs and endothelial gaps with neutrophil infiltration. Intraluminal capillary plugging by neutrophils and/or microthrombi with myocardial cell swelling was also noted. Galiuto *et al.*22 with sequential measurements of myocardial perfusion by myocardial contrast echocardiography, have recently shown that in humans no-refow detected 24 h after successful PCI spontaneously improves over time in approximately 50% of patients. Thus, noreflow can be categorized as sustained or reversible. Sustained no-reflow is probably the result of anatomical irreversible changes of the coronary microcirculation, whereas reversible no-

reflow is the result of functional and thus, reversible, changes of the microcirculation.

susceptibility of the coronary microcirculation to injury.

In humans, no-reflow is caused by the variable combination of 4 pathogenetic components: 1) distal atherothrombotic embolization; 2) ischemic injury; 3) reperfusion injury; and 4)

Emboli of different sizes can originate from epicardial coronary thrombus and from fissured atherosclerotic plaques, in particular during primary PCI.23 Large emboli (>200μm diameter) can obstruct pre-arterioles, causing infarctlets. Experimental observations have shown that myocardial blood flow decreases irreversibly when microspheres obstruct more than 50% of

**2. No-reflow phenomenon** 

for heart failure; and 4) mortality.

PCI to achieve an optimal outcome.

**2.1 Historical overview** 

**1. Distal embolization** 

coronary capillaries.24

phenomenon and to the population under study.

Changes in endothelial cells, visible after prolonged ischemia, are represented by endothelial protrusions and membrane-bound bodies, which often fill the capillaries up to luminal obliteration. Furthermore, large endothelial gaps with extravascular erythrocytes are common.25

#### **3. Reperfusion-related injury**

A massive infiltration of the coronary microcirculation by neutrophils and platelets occurs at the time of reperfusion.25,26 Reintroduction of neutrophils in post-ischemic myocardium results in their activation, with subsequent adhesion to the endothelial surface and migration in the surrounding tissue. Activated neutrophils, in turn, release oxygen free radicals, proteolytic enzymes, and pro-inflammatory mediators that can directly cause tissue and endothelial damage. Neutrophils also form aggregates with platelets that plug capillaries, thus mechanically blocking flow.27,28 Finally, vasoconstrictors released by damaged endothelial cells, neutrophils, and platelets contribute to sustained vasoconstriction of the coronary microcirculation.29 Tumor necrosis factor-alpha expression is induced by reperfusion, and can impair endothelium-dependent coronary flow reserve.30 Interleukin-1β also has recently been associated with ischemia-reperfusion injury, because interleukin-1β knockout animals exhibit marked reduction of ischemic induced inflammation.31 Selectin expression on cell surfaces is also important for mechanical plugging of the microcirculation.32 Finally, the balance between nitric oxide and superoxide is tipped in favor of superoxide within minutes of reperfusion of ischemic tissues, due to increased production of xanthine oxidase by neutrophils, endothelial cells, and cardiac myocytes, which leads to an exacerbation of the inflammatory state.33

Reperfusion might also cause irreversible injury to myocytes.34 During ischemia there is an increase of the intracellular sodium (Na+) content due to accumulation of hydrogen (H+), which is exchanged by the Na+/H+ exchanger. The subsequent exchange of doubly charged positive calcium ion (Ca++) with Na+ by the sarcolemmal Na+/Ca++ exchanger produces a calcium overload that triggers uncontrolled hypercontraction and stimulates opening of the mitochondrial permeability transition pore (m0PTP), which further enhances calcium overload. Furthermore, Na+ extrusion trough Na+/potassium (K+) adenosine triphosphate (ATP)-ase is impaired and together with Ca++ accumulation leads to myocyte cell swelling, which contributes to subsequent rupture of the cell membrane when the extracellular osmolality is rapidly normalized by reperfusion. Of note, cyclosporine, which blocks the m-PTP, has been recently shown to reduce infarct size by 20% when administered intravenously in patients undergoing primary PCI.35 Finally, ischemic pre-conditioning might also reduce infarct size by blockade of m-PTP.36

Natriuretic peptides might modulate ischemia-reperfusion injury. Atrial natriuretic peptide might suppress the rennin-angiotensin-aldosterone system and endothelin (ET)-1 that increase infarct size, microvascular obstruction, and cardiac remodeling.37

#### **4. Individual predisposition of coronary microcirculation to injury**

In humans, no-reflow is occasionally observed during elective procedures,38 whereas it can be absent after primary PCI in patients with acute myocardial infarction. In particular, diabetes and hypercholesterolemia has been associated with impaired microvascular

Complications of Coronary Intervention 53

by Svilaas *et al.*49 confirmed the improvement of reperfusion associated with manual thrombus-aspiration as compared with standard primary PCI showing a strikingly lower mortality at 12-month follow-up.50 So, it is suggested that manual thrombus aspiration should be used in the setting of primary PCI, particularly in patients with a high thrombus

Strategies aimed at reducing pain onset-to-balloon time might reduce no-reflow by decreasing total ischemic time. Drugs known to reduce myocardial oxygen consumption and consequently the severity of ischemia and improve myocardial perfusion include

Intracoronary nitroglycerin is usually suggested as the first-line agent, mainly to reverse epicardial vessel spasm, even if the blood pressure is reduced. Theoretically, nitroglycerin should have little impact on arteriolar tone and hence on no-reflow since physiologically it

Patients at high risk of no-reflow can be treated with drugs such as glycoprotein IIb/IIIa antagonists, adenosine, nicorandil, and nitroprusside aimed at counteracting endothelial,

Fig. 2. Therapies of no-reflow targeted to main pathogenetic mechanisms

burden.51

**2. Ischemia-related injury** 

**3. Reperfusion-related injury** 

platelet, and neutrophil activation.

carvedilol, fosinopril, and valsartan.52,53

produces little effect in the microvasculature.

reperfusion by enhancing endothelial oxidative stress.39,40 Pre-conditioning by using nicorandil seems to have a beneficial effect on microvascular function.41

#### **2.2 Diagnosis**

#### **1. Coronary angiography**

Reduced coronary flow after primary PCI (TIMI flow 0 to 2) is associated with worse outcome than normal (TIMI 3) flow, even when no significant epicardial obstruction remains.42 More sensitive markers of tissue perfusion have now been identified and provide prognostic information beyond that of TIMI flow grade. The TIMI frame count assesses the number of angiographic frames required for the contrast medium to reach standardized distal landmarks of the coronary tree, and the myocardial blush grade (MBG) is a quantitative assessment of myocardial contrast density. The MBG is scored on a scale of 0 to 3, with higher scores indicating better perfusion. An MBG 0 to 1, suggestive of no-reflow, is observed in as high as 50% of patients with TIMI flow grade 3.43 Taken together, angiographic no-reflow can be defined as a TIMI flow grade <3 or 3 with an MBG 0 to 1.

#### **2. Electrocardiography**

Rapid ST-segment resolution defined as a reduction of ≥50% in the ST-segment elevation index is highly specific (91%) for myocardial reperfusion (or the absence of no-reflow on myocardial contrast echocardiography) although less sensitive (77%).44

#### **3. Myocardial contrast echocardiography (MCE)**

Lack of intramyocardial contrast opacification is due to microvascular obstruction; thus, it represents the extent of no-reflow.45 In the AMICI study, the extent of no-reflow at MCE was demonstrated to be the best predictor of adverse left ventricular remodeling after acute myocardial infarction, being superior to ST-segment resolution and to MBG among patients exhibiting TIMI flow grade 3.20

#### **4. Cardiac magnetic resonance imaging**

No-reflow can be diagnosed as: 1) lack of gadolinium enhancement during first pass; and 2) lack of gadolinium enhancement within a necrotic region, identified by late gadolinium hyperenhancement.46

#### **2.3 Prevention and treatment (Figure 2)**

#### **1. Distal embolization**

No specific technique is currently recommended in guidelines to prevent distal embolization during primary PCI. Direct stent implantation, by avoiding balloon-induced thrombus fragmentation and by entrapping the atherothrombus under the stent struts, has been suggested as a possible technique to reduce distal embolization in a specific subset of patients i.e. those with good distal visualization of the infarct-related artery after guidewire passage.47

A more promising technique is the use of thrombectomy and distal filter devices. Although distal filter devices did not improve early or late prognosis compared with standard primary PCI, thrombectomy performed with a simple manual aspiration catheter revealed improved myocardial reperfusion and significantly reduced no-reflow.48 A recent large trial

reperfusion by enhancing endothelial oxidative stress.39,40 Pre-conditioning by using

Reduced coronary flow after primary PCI (TIMI flow 0 to 2) is associated with worse outcome than normal (TIMI 3) flow, even when no significant epicardial obstruction remains.42 More sensitive markers of tissue perfusion have now been identified and provide prognostic information beyond that of TIMI flow grade. The TIMI frame count assesses the number of angiographic frames required for the contrast medium to reach standardized distal landmarks of the coronary tree, and the myocardial blush grade (MBG) is a quantitative assessment of myocardial contrast density. The MBG is scored on a scale of 0 to 3, with higher scores indicating better perfusion. An MBG 0 to 1, suggestive of no-reflow, is observed in as high as 50% of patients with TIMI flow grade 3.43 Taken together, angiographic no-reflow can be defined as a TIMI flow grade <3 or 3 with an MBG 0 to 1.

Rapid ST-segment resolution defined as a reduction of ≥50% in the ST-segment elevation index is highly specific (91%) for myocardial reperfusion (or the absence of no-reflow on

Lack of intramyocardial contrast opacification is due to microvascular obstruction; thus, it represents the extent of no-reflow.45 In the AMICI study, the extent of no-reflow at MCE was demonstrated to be the best predictor of adverse left ventricular remodeling after acute myocardial infarction, being superior to ST-segment resolution and to MBG among patients

No-reflow can be diagnosed as: 1) lack of gadolinium enhancement during first pass; and 2) lack of gadolinium enhancement within a necrotic region, identified by late gadolinium

No specific technique is currently recommended in guidelines to prevent distal embolization during primary PCI. Direct stent implantation, by avoiding balloon-induced thrombus fragmentation and by entrapping the atherothrombus under the stent struts, has been suggested as a possible technique to reduce distal embolization in a specific subset of patients i.e. those with good distal visualization of the infarct-related artery after guidewire passage.47 A more promising technique is the use of thrombectomy and distal filter devices. Although distal filter devices did not improve early or late prognosis compared with standard primary PCI, thrombectomy performed with a simple manual aspiration catheter revealed improved myocardial reperfusion and significantly reduced no-reflow.48 A recent large trial

nicorandil seems to have a beneficial effect on microvascular function.41

myocardial contrast echocardiography) although less sensitive (77%).44

**3. Myocardial contrast echocardiography (MCE)** 

**2.2 Diagnosis** 

**1. Coronary angiography** 

**2. Electrocardiography** 

exhibiting TIMI flow grade 3.20

hyperenhancement.46

**1. Distal embolization** 

**4. Cardiac magnetic resonance imaging** 

**2.3 Prevention and treatment (Figure 2)** 

by Svilaas *et al.*49 confirmed the improvement of reperfusion associated with manual thrombus-aspiration as compared with standard primary PCI showing a strikingly lower mortality at 12-month follow-up.50 So, it is suggested that manual thrombus aspiration should be used in the setting of primary PCI, particularly in patients with a high thrombus burden.51

#### **2. Ischemia-related injury**

Strategies aimed at reducing pain onset-to-balloon time might reduce no-reflow by decreasing total ischemic time. Drugs known to reduce myocardial oxygen consumption and consequently the severity of ischemia and improve myocardial perfusion include carvedilol, fosinopril, and valsartan.52,53

#### **3. Reperfusion-related injury**

Intracoronary nitroglycerin is usually suggested as the first-line agent, mainly to reverse epicardial vessel spasm, even if the blood pressure is reduced. Theoretically, nitroglycerin should have little impact on arteriolar tone and hence on no-reflow since physiologically it produces little effect in the microvasculature.

Patients at high risk of no-reflow can be treated with drugs such as glycoprotein IIb/IIIa antagonists, adenosine, nicorandil, and nitroprusside aimed at counteracting endothelial, platelet, and neutrophil activation.

Fig. 2. Therapies of no-reflow targeted to main pathogenetic mechanisms

Complications of Coronary Intervention 55

myocardial infarction.57 Vessel-related factors are ACC/AHA type C lesions, calcified lesions, and chronic total occlusion lesions.3 Procedure-related factors include use of stiff hydrophilic wires, device oversizing, use of atheroablative devices. One observational study reports that 87% of perforation due to guidewires is attributed to hydrophilic wires.58 In case of rotational atherectomy use, if lesions are eccentric, lesion length are >10cm, or lesions are

If coronary perforation is develop, usually patients feel severe chest pain. In addition, nausea, dizziness, and vomiting can occur. The heart rate can rise suddenly, blood pressure can drop and if cardiac tamponade happens, an increase of central venous pressure with neck vein engorgement develops. Sustained ST-segment elevation or depression can be

The diagnosis of coronary artery perforation is not difficult by coronary angiography. If cardiac tamponade is suspected, then echocardiography is very useful. Sometimes perforation can occur 12-48 h later after PCI, if vital signs become unstable and serum hemoglobin and hematocrit levels decrease, cardiac tamponade must be suspected and

Complications related to coronary artery perforation are diverse and depend on the degree of perforation. It has been reported that in cases of perforation, myocardial infarction can occurs in 13-34%, emergency coronary artery bypass graft in 11-39%, cardiac tamponade in 12-31%, and mortality in 7.6-19%.59-61 The degree of perforation is a important marker to predict the late prognosis. Ellis classification type I perforation has a clinically good prognosis in 60% and it is rare that type II perforation has a poor prognosis. However, type

Generally, guidewire-related perforation does not cause grave results except with concomitant use of glycoprotein IIb/IIIa inhibitors. However, perforation due to balloon, atherectomy devices, or laser can produce hemopericardium or hemodynamic collapse.

The most important thing to stop bleeding is prolonged balloon inflation at the perforation site at least for 10-15 min at 2-6 atm. If bleeding does not stop, a perfusion balloon catheter can be used for 15-45 min inflated at low pressure. This prolonged balloon inflation and timely pericardiocentesis can avoid surgical treatment in patients with Ellis type I perforation.

In some cases, a polytetrafluoroethylene(PTFE)-covered stent is effective. Rarely, one or more conventional stent (bare metal or drug-eluting stent) implantation can be considered.

very tortuous, the risk of perforation is high.

observed even though coronary balloons are deflated.

urgent echocardiography should be performed.

III perforation reveals high major adverse events rate.55,62

**3.5 Clinical outcomes and prognosis** 

**3.3 Symptoms and signs** 

**3.4 Diagnosis** 

**3.6 Treatment** 

**2. Stent** 

**1. Prolonged balloon inflation** 

Among glycoprotein IIb/IIIa antagonists, abciximab has been found to improve myocardial perfusion when started during primary PCI and infused for 12 h thereafter. Interestingly, intracoronary abciximab has been proven to be superior to intravenous abciximab in patients treated by primary PCI.54 Adenosine is an endogenous purine nucleoside that decreases arteriolar resistance and activates intracellular cardioprotective signaling pathways. Its mechanism of action may involve opening ATP-sensitive potassium channels (KATP), inhibition of neutrophil migration, prevention of superoxide generation, or blockade of coronary endothelin release. Nitroprusside is a nitric oxide donor that does not depend on intracellular metabolism to derive nitric oxide, with potent vasodilator properties. Nicorandil is a hybrid of a KATP opener and nitrate and may prevent reperfusion injury by blocking the mitochondrial permeability transition pore. Verapamil is a calcium-channel blocker that has several beneficial effects in the setting of no-reflow in addition to attenuation of microvascular spasm. Varapamil may also inhibit platelet aggregation and thrombus formation in the microvasculature and may have a direct effect on calcium flux across the sarcolemmal membrane or within intracellular compartment that could protect reversibly injuried myocytes.

### **3. Coronary artery perforation and cardiac tamponade**

Coronary artery perforation complicating percutaneous coronary intervention (PCI) occurs in 0.1-3.0% of cases. Perforation with balloon angioplasty or stenting is rare, occurring in 0.1% of cases. However, when ablation devices, such as rotablator, directional coronary atherectomy, transluminal extraction catheter, and excimer laser, are used, the frequency is substantially higher than with balloon angioplasty or stents, occurring up to 3.0%.55 Recently, the use of ablation devices in PCI has tended to decline. Instead, procedures for more complex lesions including calcification, severe angulation, and chronic total occlusion have increased. To treat these complex lesions, stiffer and hydrophilic wires are necessary and high pressure for balloon dilatation is needed. Increasing numbers of procedures using glycoprotein IIb/IIIa inhibitors is also contributing to the fact that coronary artery perforation still occurs.

#### **3.1 Classification**

The Ellis classification depends on angiographic findings is most widely used (table 2).55


#### **3.2 Risk factors**

Many factors are involved in coronary perforation during PCI. Related risk factors can be divided into patient-related, vessel-related, and procedure-related factors.56 Patients-related factors are old age, hypertension, PCI for unstable angina or non-ST segment elevation myocardial infarction.57 Vessel-related factors are ACC/AHA type C lesions, calcified lesions, and chronic total occlusion lesions.3 Procedure-related factors include use of stiff hydrophilic wires, device oversizing, use of atheroablative devices. One observational study reports that 87% of perforation due to guidewires is attributed to hydrophilic wires.58 In case of rotational atherectomy use, if lesions are eccentric, lesion length are >10cm, or lesions are very tortuous, the risk of perforation is high.

#### **3.3 Symptoms and signs**

If coronary perforation is develop, usually patients feel severe chest pain. In addition, nausea, dizziness, and vomiting can occur. The heart rate can rise suddenly, blood pressure can drop and if cardiac tamponade happens, an increase of central venous pressure with neck vein engorgement develops. Sustained ST-segment elevation or depression can be observed even though coronary balloons are deflated.

#### **3.4 Diagnosis**

54 Coronary Interventions

Among glycoprotein IIb/IIIa antagonists, abciximab has been found to improve myocardial perfusion when started during primary PCI and infused for 12 h thereafter. Interestingly, intracoronary abciximab has been proven to be superior to intravenous abciximab in patients treated by primary PCI.54 Adenosine is an endogenous purine nucleoside that decreases arteriolar resistance and activates intracellular cardioprotective signaling pathways. Its mechanism of action may involve opening ATP-sensitive potassium channels (KATP), inhibition of neutrophil migration, prevention of superoxide generation, or blockade of coronary endothelin release. Nitroprusside is a nitric oxide donor that does not depend on intracellular metabolism to derive nitric oxide, with potent vasodilator properties. Nicorandil is a hybrid of a KATP opener and nitrate and may prevent reperfusion injury by blocking the mitochondrial permeability transition pore. Verapamil is a calcium-channel blocker that has several beneficial effects in the setting of no-reflow in addition to attenuation of microvascular spasm. Varapamil may also inhibit platelet aggregation and thrombus formation in the microvasculature and may have a direct effect on calcium flux across the sarcolemmal membrane or within intracellular compartment that could protect

Coronary artery perforation complicating percutaneous coronary intervention (PCI) occurs in 0.1-3.0% of cases. Perforation with balloon angioplasty or stenting is rare, occurring in 0.1% of cases. However, when ablation devices, such as rotablator, directional coronary atherectomy, transluminal extraction catheter, and excimer laser, are used, the frequency is substantially higher than with balloon angioplasty or stents, occurring up to 3.0%.55 Recently, the use of ablation devices in PCI has tended to decline. Instead, procedures for more complex lesions including calcification, severe angulation, and chronic total occlusion have increased. To treat these complex lesions, stiffer and hydrophilic wires are necessary and high pressure for balloon dilatation is needed. Increasing numbers of procedures using glycoprotein IIb/IIIa inhibitors is also contributing to the fact that coronary artery

The Ellis classification depends on angiographic findings is most widely used (table 2).55

Type II Pericardial or myocardial blush without contrast jet extravasation

Cavity Perforation into an anatomic cavity chamber, spilling coronary sinus, etc

Many factors are involved in coronary perforation during PCI. Related risk factors can be divided into patient-related, vessel-related, and procedure-related factors.56 Patients-related factors are old age, hypertension, PCI for unstable angina or non-ST segment elevation

reversibly injuried myocytes.

perforation still occurs.

Table 2. Perforation Classification

**3.1 Classification** 

**3.2 Risk factors** 

**3. Coronary artery perforation and cardiac tamponade** 

Type I Extraluminal crater without extravasation

Type III Extravasation through frank (>1 mm) perforation

The diagnosis of coronary artery perforation is not difficult by coronary angiography. If cardiac tamponade is suspected, then echocardiography is very useful. Sometimes perforation can occur 12-48 h later after PCI, if vital signs become unstable and serum hemoglobin and hematocrit levels decrease, cardiac tamponade must be suspected and urgent echocardiography should be performed.

#### **3.5 Clinical outcomes and prognosis**

Complications related to coronary artery perforation are diverse and depend on the degree of perforation. It has been reported that in cases of perforation, myocardial infarction can occurs in 13-34%, emergency coronary artery bypass graft in 11-39%, cardiac tamponade in 12-31%, and mortality in 7.6-19%.59-61 The degree of perforation is a important marker to predict the late prognosis. Ellis classification type I perforation has a clinically good prognosis in 60% and it is rare that type II perforation has a poor prognosis. However, type III perforation reveals high major adverse events rate.55,62

#### **3.6 Treatment**

Generally, guidewire-related perforation does not cause grave results except with concomitant use of glycoprotein IIb/IIIa inhibitors. However, perforation due to balloon, atherectomy devices, or laser can produce hemopericardium or hemodynamic collapse.

#### **1. Prolonged balloon inflation**

The most important thing to stop bleeding is prolonged balloon inflation at the perforation site at least for 10-15 min at 2-6 atm. If bleeding does not stop, a perfusion balloon catheter can be used for 15-45 min inflated at low pressure. This prolonged balloon inflation and timely pericardiocentesis can avoid surgical treatment in patients with Ellis type I perforation.

#### **2. Stent**

In some cases, a polytetrafluoroethylene(PTFE)-covered stent is effective. Rarely, one or more conventional stent (bare metal or drug-eluting stent) implantation can be considered.

Complications of Coronary Intervention 57

In case of small vessel size or distal location, limited involved myocardium, chronic total occlusion, or situation where surgery is unavailable, embolization using coils or gelfoam can

If the perforation is severe, with hemodynamic instability or perforation is sustained despite

Dissection is defined as disruption of an arterial wall resulting in splitting and separation of

Ectasia A lesion diameter greater than the reference diameter in one or more areas

Thrombus Discrete, mobile angiographic filling defect with or without contrast staining

Persistence of contrast within the dissection after washout of contrast

Intima-media cracks and medial dissection can be developed by balloon injury and if dissection involves the adventitia layer, narrowing of the lumen can occur.65 In NHLBI classification, coronary dissection occurs in 32-41% of total balloon procedures. If the lumen narrows >50% or the length of dissection is >10mm, the risk of abrupt vessel closure increases. In the modern PCI era, where coronary dissection can be promptly resolved by stent implantation, clinically significant dissection is reported only 1.7%. Residual dissection increases the risk of post procedure MI, emergency CABG, and stent thrombosis and

Arterial contour that has a saw-toothed pattern consisting of opacification but not fulfilling the criteria for dissection or intracoronary thrombus

Abrupt Obstruction of contrast flow (TIMI 0 or 1) in a dilated segment with

Intimal flap A discrete filling defect in apparent continuity with the arterial wall

A Small radiolucent area within the lumen of the vessel B Linear, nonpersisting extravasation of contrast material C Extraluminal, persisting extravasation of contrast material

E Persistent lumen defect with delayed anterograde flow F Filling defect accompanied by total coronary occlusion

length(mm) Measure end to end for type B through F dissections

Table 3. Standardized criteria for postprocedural lesion morphology63,64

**4.2 Pathogenesis and incidence of coronary dissection** 

material from the remaining portion of the vessel

**5. Embolization** 

**6. Surgical treatment** 

**4.1 Angiographic definition** 

**Feature Definition** 

Luminal irregularities

Dissection

Dissection,

Dissection, staining

the intimal (or subintimal) layers.

D Spiral-shaped filling defect

mortality also increases threefold.66

successfully occlude the perforation.

nonsurgical management, emergency surgery is necessary.

closure previously documented anterograde flow

**4. Coronary dissection and acute closure** 

#### **3. Pericardiocentesis**

If perforation is suspected, echocardiography should be performed and if hemopericardium is confirmed, pericardiocentesis should be performed immediately. An indwelling pericardial catheter should be maintained for 6-24 h and echocardiography should repeated every 6-12 h.

#### **4. Management of anticoagulation**

When perforation occurs, anticoagulation should be maintained to prevent thrombus formation. However, if perforation happens after use of atherectomy or laser, it is recommended that protamine sulfate should be administrated intravenously in order to partially reverse the effect of heparin. If contrast leakage is sustained despite prolonged balloon inflation, repeated balloon inflation should be performed; meanwhile the dosage of protamine sulfate should increase under activated clotting time monitoring.

Glycoprotein IIb/IIIa inhibitors must be stopped. The effect of abciximab can be reversed after platelet transfusion of 6-10 units, but there are not any known antidotes for eptifibatide or tirofiban.

Fig. 3. Management algorithm of coronary artery perforation

#### **5. Embolization**

56 Coronary Interventions

If perforation is suspected, echocardiography should be performed and if hemopericardium is confirmed, pericardiocentesis should be performed immediately. An indwelling pericardial catheter should be maintained for 6-24 h and echocardiography should repeated every 6-12 h.

When perforation occurs, anticoagulation should be maintained to prevent thrombus formation. However, if perforation happens after use of atherectomy or laser, it is recommended that protamine sulfate should be administrated intravenously in order to partially reverse the effect of heparin. If contrast leakage is sustained despite prolonged balloon inflation, repeated balloon inflation should be performed; meanwhile the dosage of

Glycoprotein IIb/IIIa inhibitors must be stopped. The effect of abciximab can be reversed after platelet transfusion of 6-10 units, but there are not any known antidotes for eptifibatide

protamine sulfate should increase under activated clotting time monitoring.

Fig. 3. Management algorithm of coronary artery perforation

**3. Pericardiocentesis** 

or tirofiban.

**4. Management of anticoagulation** 

In case of small vessel size or distal location, limited involved myocardium, chronic total occlusion, or situation where surgery is unavailable, embolization using coils or gelfoam can successfully occlude the perforation.

#### **6. Surgical treatment**

If the perforation is severe, with hemodynamic instability or perforation is sustained despite nonsurgical management, emergency surgery is necessary.
