**2.6. Pharmacological treatment in the prevention of the cardiovascular complications of the MFS**

The pharmacological treatment in the prevention of the cardiovascular pathology in patients with MFS is based on the employment of β-adrenergic blocking agents and reninangiotensin system antagonists [8].

#### *Beta blockers*

Many studies have demonstrated that the employment of betablockers can slow down the aortic rate expansion and delay the moment of appearance of the aortic complications of the MFS, as the aortic regurgitation, the aortic dissection, the need of surgery, the congestive heart failure or the death, specially if they are use in the initial phases of the disease, as they can reduce the hemodynamic stress of the thoracic aorta wall.

These benefits are in all the groups of age, being more important in patients with not severe aortic dilatation.

Nowadays the clinical guidelines recommend the employment of betablockers at the right dose in all patients with MFS who tolerate them, independently from the degree of aortic dilatation.

Given that the aortic growth rate changes along the life, presenting a prepuberal peak, it is recommended the beginning of the treatment with betablockers in the infancy, and to support it forever, even in patients who have received aortic prophylactic surgery.

The effects of the pharmacological treatment must have a periodic review to assure an optimal management of the cardiac frequency and the arterial pressure of the patient (table 8).


**Table 8.** Pharmacological treatment in the MFS

442 Aneurysm

**CT or MRI:** 

**Anamnesis, physical examination, echocardiogram:**

registered an accelerated rate of growth (> 5 mm / year)

can reduce the hemodynamic stress of the thoracic aorta wall.

 **Later: every year, if the growth rate is stable and without complicationsa**

After the surgery, before the discharge, at 6 months, and then anually.

The evaluation will be more frequent as the aortic root approaches 45mm or if it is

**2.6. Pharmacological treatment in the prevention of the cardiovascular** 

b It is consider of utility to correct the aortic diameters in accordance with the age and the

The pharmacological treatment in the prevention of the cardiovascular pathology in patients with MFS is based on the employment of β-adrenergic blocking agents and renin-

Many studies have demonstrated that the employment of betablockers can slow down the aortic rate expansion and delay the moment of appearance of the aortic complications of the MFS, as the aortic regurgitation, the aortic dissection, the need of surgery, the congestive heart failure or the death, specially if they are use in the initial phases of the disease, as they

These benefits are in all the groups of age, being more important in patients with not severe

Nowadays the clinical guidelines recommend the employment of betablockers at the right dose in all patients with MFS who tolerate them, independently from the degree of aortic

Given that the aortic growth rate changes along the life, presenting a prepuberal peak, it is recommended the beginning of the treatment with betablockers in the infancy, and to support it forever, even in patients who have received aortic prophylactic

The effects of the pharmacological treatment must have a periodic review to assure an optimal management of the cardiac frequency and the arterial pressure of the patient

**At the beginning and at the 6 monthsa**

If there is aortic dilatation or dissection.

a Class I recommendation, level of evidence C.

**Table 7.** Cardiovascular follow-up in Marfan's syndrome

corporal size (class IIa, level of evidence C).

**complications of the MFS** 

*Beta blockers* 

aortic dilatation.

dilatation.

surgery.

(table 8).

angiotensin system antagonists [8].

#### *Renin-angiotensin-aldosterone system antagonists*

The influence of the renin-angiotensin-aldosterone system in the aortic wall degeneration of the MFS seems to be increasingly important. The angiotensin II (ATII) stimulates the expression of metalloproteases and promotes the apoptosis of the smooth muscle cells in the aortic wall. The experimental models have demonstrated that the deficiency of *FBN1* increases the TGF-β active, causing the detention of the cellular differentiation cicle, an increase of the apoptosis and deposit of extracelular matrix. The employment of reninangiotensin system antagonists by means of angiotensin-converting-enzyme inhibitors (ECAs) or with angiotensin II receptor antagonists (ARAII), produces beneficial effects at different levels. The ECAs contribute, apart from the control of the AP, to the decrease of the inflexibility of the aortic wall. The selective block of the type 1 receptor (AT1) of the angiotensin II might reduce the deleterious effects of the TGF-β, independently of the effects on the control of the AP. Though in animal models, losartan has demonstrated to stop and even to revert MFS manifestations, including the aortic aneurysm and its complications, we are waiting for the results of controlled clinical trials in human beings that are in process.

It is important to insist that the medical treatment, based fundamentally on betablockers, which is possible to associate to the renin-angiotensin system block, gets delaying the aortic expansion, but no medicament, up to the moment, has demonstrated either to avoid the development of aortic dissection or to avoid the need for surgery in human beings.

#### *Physical activity*

To reduce the hemodynamic stress in the MFS, the restriction of the physical activity complements the pharmacological therapy. The intense isometric exercise is contraindicated

due to the marked increases in the peripheral AP and the stress of the proximal aortic wall. Also competitive sports, contact sports and those that with marked changes in the atmospheric pressure are contraindicated, to prevent the arterial traumatism and the pneumothorax. Since the dynamic exercise is associated with minor aortic stress, for the decrease of the peripheral vascular resistance and of the diastolic AP, in patients without high risk, the practice of aerobic activity of moderate intensity is considered to be sure (table 9).

#### **2.7. Prophylactic surgery of the proximal aorta**

In the MFS, the prophylactic surgery of the aortic root and the ascending aorta is recommended, because of the high mortality of the emergency aortic replacement and because both, the type A aortic dissection and the aortic rupture, are the complications with major impact in the survival. Though technically more complex, the aortic valve conservation techniques, remodeling or reimplantation, are usually the ones preferred than the valvulated tubes, whenever they offer good results.

Provided that the dissection and mortality risk are proportional to the size of the proximal aorta, the guidelines recommend elective surgery in adults when the *external* diameter is ≥50mm. The surgery also must be considered in patients with diameter <50mm if they present additional risk factors: rapid growth of the aortic diameter (> 5mm/year), familial history of aortic dissection or rupture, or the presence of significant aortic regurgitation (table 10).

With regard to the *timing* of the elective surgery, some considerations must be done. According to the value of the threshold of the diameter, a more or less important proportion of patients will present complications without reaching this value or will surrender unjustibiably to the surgical risk of an elective procedure still being removed from complications. It turns out important to incorporate another information, as the growth rate, and indexing the diameters by body surface. The corporal surface, used in many nomograms on having contemplated the weight, can artificially modify the surgical risk. The current trend is to correct according to the stature, in order that in subjects of minor stature, specially women, but at risk of complication, surgery could be indicated even if their diameters were more near to 45 that to 50mm. In the clinical practice, the surgical indication starts beeing considered when the aorta is expanded (≥2 deviations over the average, Z-score≥2) or when its diameter comes closer to 45mm (before if the stature is lower than 170cm). The surgical results are determinant to indicate prophylactic surgery, preferably preserving the valve and with very low mortality, necessarily lower than 5%.

In *children and teenagers* with MFS, the establishment of a relation with the diameter of the aorta is more difficult than in adults, since the complications are infrequent before 12 years of age. The elective aortic surgery in this population, up to 18 years, is recommended when the aortic diameter exceeds 50mm, when there is a rapid aortic growth (> 10mm/year), when aortic regurgitation appears, or when there is simultaneous affectation of the mitral valve. As for the *timing,* it is necessary to weigh the risk of dissection and the delay of the surgical moment to avoid prosthetic *mismatch*, since the children will continue growing. The paediatric nomograms have been re-calculated to improve their correspondence with those of adults. The normalization for sex, age and corporal surface seems to be suitable, though it will be necessary to define better which is the dilatation of risk in which the benefits of the prophylactic surgery unequivocally overcome the risks.

444 Aneurysm

(table 10).

due to the marked increases in the peripheral AP and the stress of the proximal aortic wall. Also competitive sports, contact sports and those that with marked changes in the atmospheric pressure are contraindicated, to prevent the arterial traumatism and the pneumothorax. Since the dynamic exercise is associated with minor aortic stress, for the decrease of the peripheral vascular resistance and of the diastolic AP, in patients without high risk, the practice of aerobic

In the MFS, the prophylactic surgery of the aortic root and the ascending aorta is recommended, because of the high mortality of the emergency aortic replacement and because both, the type A aortic dissection and the aortic rupture, are the complications with major impact in the survival. Though technically more complex, the aortic valve conservation techniques, remodeling or reimplantation, are usually the ones preferred than

Provided that the dissection and mortality risk are proportional to the size of the proximal aorta, the guidelines recommend elective surgery in adults when the *external* diameter is ≥50mm. The surgery also must be considered in patients with diameter <50mm if they present additional risk factors: rapid growth of the aortic diameter (> 5mm/year), familial history of aortic dissection or rupture, or the presence of significant aortic regurgitation

With regard to the *timing* of the elective surgery, some considerations must be done. According to the value of the threshold of the diameter, a more or less important proportion of patients will present complications without reaching this value or will surrender unjustibiably to the surgical risk of an elective procedure still being removed from complications. It turns out important to incorporate another information, as the growth rate, and indexing the diameters by body surface. The corporal surface, used in many nomograms on having contemplated the weight, can artificially modify the surgical risk. The current trend is to correct according to the stature, in order that in subjects of minor stature, specially women, but at risk of complication, surgery could be indicated even if their diameters were more near to 45 that to 50mm. In the clinical practice, the surgical indication starts beeing considered when the aorta is expanded (≥2 deviations over the average, Z-score≥2) or when its diameter comes closer to 45mm (before if the stature is lower than 170cm). The surgical results are determinant to indicate prophylactic surgery, preferably preserving the valve and with very low mortality, necessarily lower than 5%.

In *children and teenagers* with MFS, the establishment of a relation with the diameter of the aorta is more difficult than in adults, since the complications are infrequent before 12 years of age. The elective aortic surgery in this population, up to 18 years, is recommended when the aortic diameter exceeds 50mm, when there is a rapid aortic growth (> 10mm/year), when aortic regurgitation appears, or when there is simultaneous affectation of the mitral valve. As for the *timing,* it is necessary to weigh the risk of dissection and the delay of the surgical moment to avoid prosthetic *mismatch*, since the children will continue growing. The

activity of moderate intensity is considered to be sure (table 9).

**2.7. Prophylactic surgery of the proximal aorta** 

the valvulated tubes, whenever they offer good results.


Treatment with betablokers is considered to be a standard for all patients.

a Maximum heart rate during activity <100 lpm (adults) and up to 110 lpm (children) with betablockers.

b If there is usual sport practice, it is suitable to follow-up the growth rate of the aortic root by a transthoracic echocardiogram each six months.

The presence of significant aortic regurgitation with aortic root dilatation makes inadvisable any type of sports practice.

**Table 9.** Recommendations for the physical activity in Marfan's syndrome

In what concerns the aspects of the *surgical techniques*, the Bono and Bentall procedure has been considered the *gold standard* for the treatment of these patients. It consists in replacing the root and the aortic valve with a composite graft by a dacron vascular graft (rectum or with morphology that imitates to Valsalva's sinus) and a prosthetic valve; the coronary arteries have to be reimplanted into the vascular graft. Diverse technical variations (inclusion vs interposition, *button technique,* Cabrol modification or Svensson) have emerged over the years trying to reduce the early complications (bleeding, coronary occlusion) and the late ones (anastomotic pseudoaneurysms) of the same one, being the most used nowadays the Bono-Bentall by interposition with anastomosis of the coronary arteries in tablets *(button technique).* In young patients, mechanical prosthetic valves are the most used, whereas in those of major age or with contraindications for anticoagulation, biological valves are usually used.

**Class I recommendations, level of evidence C External diameter of proximal aorta ≥ 50 mm External diameter <50mm with any of the following risk factors:** 


#### **Class IIa recommendations, level of evidence C**

In women with MFS who wish to get pregnancy, it looks reasonable the aortic root and ascending aorta replacement when the diameter is > 40 mm

Aortic surgery will be recommended when the quotient of the proximal aortic maximum area (in cm2) divided by the stature in meters is superior to 10, since the smallest patients and up to 15% of the MFS patients have aortic dissection with diameters <50 mm

**Table 10.** Criteria for the elective surgery of the aorta proximal in adults with MFS

The immediate and long-term results of this technique are very good, and the rates of the long-term survival are similar to those of the general population. Nevertheless, the results deteriorate considerably when the surgery is realized in an emergent form in the context of an aortic dissection. The long-term morbidity of these patients is in relation with the fact of being carriers of a valve prosthesis. This is the reason why in the last years some techniques have emerged to try to preserve the native aortic valve, which is re-implanted to the dacron vascular graft. They are the valve preserving techniques or *valve-sparing,* basically with two variants, the *reimplantation technique* or David procedure and the *remodeling technique* or Yacoub's surgery. In both cases, the aortic root is cut just above the aortic valve annulus and the coronary ostia; the diseased portion of aorta is removed and a collagen-coated polyester graft is used. In the modified David procedure, the sutures are placed just below the aortic valve, around the left ventricular outflow tract, and these sutures are then tied around a Hegar´s dilator to shape the bottom portion of the aort graft similar to a natural aortic root. Next, the valve is resuspendided within the graft, the aortic valve may be repaired or remodeled, and small holes are produced in the aorta graft for the coronary ostia, which are re-attached through the small holes.

In the Yacoub technique, the graft of dacron stands out imitating Valsalva's bosoms and the graft is sutured to the remnants of aortic fabric that stay close to the insertion of the veils.

David's technique is the one that more followers has inside the surgical community since theoretically it stabilizes better the valvular ring, though there are surgeons who praise the use of Yacoub's technique associated with maneuvers of stabilization to annul (anuloplastias with suture or with external rings), since this skill preserves better the functionality of the aortic root.

Those valve sparing methods can be realized either if the aortic valve is competent in the moment of the intervention or whenit is not, though in the latter case, specially if the regurgitación is very ancient, it maybe not possible to preserve the valve. This owes to the intense elongation that the leaflets can present, with very thin and friable tissue even with big fenestrations, on having been submitted to a great mechanical tension for a long time.

The immediate results of these procedures are similar to those of Bentall's surgery, though they are technically challenging, so they are used only in reference centres [9]. The long-term results also are excellent, remaining the patients free of significant degrees of aortic valve regurgitation and reoperation greater to 90% at 10 years [10].

Given these good long-term results, in many centers the valve sparing surgeries have turned into the new *gold standard* for the patients with Marfan syndrome.

#### **2.8. Elective surgery of the descending aorta**

446 Aneurysm

valves are usually used.

diameters <50 mm

small holes.

veils.

**Class I recommendations, level of evidence C External diameter of proximal aorta ≥ 50 mm** 

**Class IIa recommendations, level of evidence C**

**External diameter <50mm with any of the following risk factors:** 

**• Rapid progression of the aortic diameter (> 5 mm/year) • Significant aortic regurgitation (moderate or major)** 

ascending aorta replacement when the diameter is > 40 mm

**Table 10.** Criteria for the elective surgery of the aorta proximal in adults with MFS

**• Familial history of dissection or aortic rupture** 

whereas in those of major age or with contraindications for anticoagulation, biological

In women with MFS who wish to get pregnancy, it looks reasonable the aortic root and

maximum area (in cm2) divided by the stature in meters is superior to 10, since the smallest patients and up to 15% of the MFS patients have aortic dissection with

The immediate and long-term results of this technique are very good, and the rates of the long-term survival are similar to those of the general population. Nevertheless, the results deteriorate considerably when the surgery is realized in an emergent form in the context of an aortic dissection. The long-term morbidity of these patients is in relation with the fact of being carriers of a valve prosthesis. This is the reason why in the last years some techniques have emerged to try to preserve the native aortic valve, which is re-implanted to the dacron vascular graft. They are the valve preserving techniques or *valve-sparing,* basically with two variants, the *reimplantation technique* or David procedure and the *remodeling technique* or Yacoub's surgery. In both cases, the aortic root is cut just above the aortic valve annulus and the coronary ostia; the diseased portion of aorta is removed and a collagen-coated polyester graft is used. In the modified David procedure, the sutures are placed just below the aortic valve, around the left ventricular outflow tract, and these sutures are then tied around a Hegar´s dilator to shape the bottom portion of the aort graft similar to a natural aortic root. Next, the valve is resuspendided within the graft, the aortic valve may be repaired or remodeled, and small holes are produced in the aorta graft for the coronary ostia, which are re-attached through the

In the Yacoub technique, the graft of dacron stands out imitating Valsalva's bosoms and the graft is sutured to the remnants of aortic fabric that stay close to the insertion of the

David's technique is the one that more followers has inside the surgical community since theoretically it stabilizes better the valvular ring, though there are surgeons who praise the use of Yacoub's technique associated with maneuvers of stabilization to annul (anuloplastias

Aortic surgery will be recommended when the quotient of the proximal aortic

Though the elective surgery of the descending aorta is nowadays a safe procedure, the risk of paraplegia is still present (that should be lower than 5%) depending on the group experience, on the extension of the aortic segment to be replaced and on the spinal cord protection. Since the operative risk increases in the emergency cases (dissection or rupture), and given the limitation for the use of stents in these patients, it is recommended the prophylactic replacement of the aortic segment when the diameter is > 55mm (class I recommendation, level of evidence C).

#### **2.9. Treatment of the acute aortic complications**

The treatment of the acute aortic complications in patients with MFS includes the management of the type A and B ascending aortic dissection (table 11).

#### *Type A ascending aortic dissection*

Given that the unpredictable nature of the aortic dissection in the MFS, it is necessary to educate the patients on the symptoms of the acute aortic dissection. As in the general population, the type A aortic dissection in the MFS is a emergency surgery emergency in which there must be replaced the sinus and the sufficient extension of the ascending aorta.

#### *Type B descending aortic dissection*

The type B aortic dissection represents approximately 10% of the acute aortic dissections in the MFS. Like in other patients, the medical management is initially recommended, except complications or lack of response, in which case, the surgery must be considered. The routine accomplishment of CT or MRI is recommended if the descending aorta is large or if it has been dissected after the repair of a type A dissection. In the type B chronic aortic dissection it is recommended the open surgery when, in the absence of high comorbidity, the aorta diameter is >55mm.


b Later management: betablockers, additional medication if it is necessary for the control of the arterial pressure, and follow-up with MRI or CT according to the symptoms, the diameter and the aortic growth rate.

**Table 11.** Treatment of the aortic complications in Marfan's syndrome

#### **2.10. Therapy endovascular with stents**

Though the experience with endoprosthesis in the type B acute or chronic aortic dissection in the MFS is limited, it has been observed that in spite of the correct implantation of the stent, with total thrombosis of the false light, the aorta continues expanding. This is the reason for which it is not recommended to use aortic stents in the MFS, except high risk for the conventional surgery. The pseudoaneurysms after aortic replacement can be an exception when it is possible to fix to the previous graft the stent to seal the point of entry of the false aneurysm as an alternative to the surgical reintervention (table 12).


Class IIa recommendation, level of evidence C.

448 Aneurysm

the aorta diameter is >55mm.

**Type A ascending aortic** 

**Type B descending aortic** 

**Type B acute aortic** 

**Type B chronic aortic** 

reintervention (table 12).

a Class I recommendation, level of evidence B.

**Table 11.** Treatment of the aortic complications in Marfan's syndrome

diameter and the aortic growth rate.

**2.10. Therapy endovascular with stents** 

**dissection** 

**dissection**

**diseection**

**dissection**

complications or lack of response, in which case, the surgery must be considered. The routine accomplishment of CT or MRI is recommended if the descending aorta is large or if it has been dissected after the repair of a type A dissection. In the type B chronic aortic dissection it is recommended the open surgery when, in the absence of high comorbidity,

Initial management: medial treatmenta

• Mesenteric ischaemia, limbs or branches of the

• Inability to control the symptoms (pain...) or PA

In the absence of a elevated comorbidity, open surgery if

patients with MFS, except in those cases with conditions

**Emergency surgery**<sup>a</sup>

Surgery indicated ifb:

the diameter > 55 mma **Endovascular therapy** The stents of the descending aorta are not indicated in

b Later management: betablockers, additional medication if it is necessary for the control of the arterial pressure, and follow-up with MRI or CT according to the symptoms, the

Though the experience with endoprosthesis in the type B acute or chronic aortic dissection in the MFS is limited, it has been observed that in spite of the correct implantation of the stent, with total thrombosis of the false light, the aorta continues expanding. This is the reason for which it is not recommended to use aortic stents in the MFS, except high risk for the conventional surgery. The pseudoaneurysms after aortic replacement can be an exception when it is possible to fix to the previous graft the stent to seal the point of entry of the false aneurysm as an alternative to the surgical

• Progression of the dissection

• Accelerated rate of the aortic diameter

prohibiting the conventional open surgery

abdominal aorta

 a The aorta must be valued in its entirety, not only the ascending portion, since a great proportion (almost a third) of the aortic events that compromise the distal aorta happen during the follow-up of these patients.

**Table 12.** Follow-up after aortic surgery in Marfan's syndrome
