Marfan syndrome is an autosomal dominant disorder of connective tissue in which cardiovascular, skeletal, and ocular abnormalities may be present to a highly variable degree. Prevalence has been estimated at 2 to 3 in 10,000, and 25% to 30% of cases represent new mutations. Prognosis is mainly determined by progressive dilatation of the aorta, potentially leading to aortic dissection and death at a young age ( Fig. 67.1 ). Prophylactic surgery can prevent aortic dissection, and early identification of patients with Marfan syndrome is therefore of considerable importance.
Genetics
Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15q21 encoding a large glycoprotein in the extracellular matrix called fibrillin-1. FBN1 mutations induce abnormal or deficient fibrillin-1 protein synthesis, affecting the structural integrity of the extracellular matrix, and thereby weakening the supporting tissues. Besides being a structural protein, fibrillin-1 normally binds to a large latent complex, which comprises the inactive form of transforming growth factor-β (TGF-β).
In a mouse model of Marfan syndrome, increased TGF-β signaling appeared to play a causal role in progressive aortic root dilatation. Furthermore, increased TGF-β signaling provides an explanation for changes in the architecture of the aortic wall, such as aberrant thickening of the aortic media with increased collagen deposition that cannot be explained only by structural weakness of the wall. Indeed, elevated plasma TGF-β levels were correlated with a larger aortic root diameter and a faster aortic dilatation rate.
More than 3000 mutations in the FBN1 gene have been identified, and almost all are unique to an affected individual or family. In approximately 10% of patients with a definite diagnosis of Marfan syndrome, an FBN1 mutation is not identified. Genotype-phenotype correlations in Marfan syndrome have been complicated by the large number of unique mutations reported and by clinical heterogeneity among individuals with the same mutation. However, clinical phenotype seems to be influenced by the effect of the FBN1 mutations on the fibrillin-1 protein. FBN1 mutations can be classified as dominant negative mutations or haploinsufficient mutations. Dominant negative mutations such as cysteine substitutions lead to a disturbed function or folding of the protein and generally more ectopia lentis. On the other hand, haploinsufficient mutations, such as whole gene deletions and stop codon mutations, lead to lower production of normal fibrillin-1 protein, and generally more often to skeletal features and cardiovascular involvement. Prospective research is needed to confirm the influence of this classification on aortic dilatation rate and clinical endpoints.
Clinical Presentation and Natural History
Diagnosis
Early identification and establishment of the diagnosis in patients with Marfan syndrome is of considerable importance because prophylactic surgery can prevent aortic dissection and rupture. Elucidation of the molecular mechanisms behind Marfan syndrome will allow improvement in diagnostic testing, but so far the diagnosis of Marfan syndrome has to be made on clinical grounds, following the revised Ghent criteria ( Table 67.1 ).
| Criteria for Diagnosis of Marfan Syndrome | ||||
|---|---|---|---|---|
| Family History | Aortic Dilatation (Z ≥2) or Dissection | Ectopia Lentis | Systemic Score ≥7/20 Points | FBN1 Mutation |
| x | x | |||
| x | x | |||
| x | x | |||
| x | x ∗ | |||
| x | x | |||
| x | x | |||
| x | x | |||
| Scoring of Systemic Features | ||||
| ||||
A definite diagnosis requires the coexistence of aortic root aneurysm or aortic dissection together with a lens dislocation, a pathogenic FBN1 mutation, or a positive family history. The remaining cardinal manifestations of Marfan syndrome are incorporated in a systemic score; a systemic score greater than 7 also contributes to the diagnosis (see Table 67.1 ). Marfan syndrome can be confused with other heritable connective tissue disorders that closely mimic some Marfan syndrome manifestations, such as Loeys-Dietz syndrome, familial aortic aneurysm, bicuspid aortic valve with aortic dilatation, familial ectopia lentis, mitral valve prolapse, aortic enlargement, skin and skeletal findings (MASS) phenotype, and Ehlers-Danlos syndrome, because of the considerable clinical overlap among the various syndromes. The variability in clinical expression and the presence of FBN1 mutations in patients with other fibrillinopathies require a multidisciplinary approach in a Marfan screening center for complete evaluation and screening of a patient and his or her relatives.
Clinical Findings
Prognosis of patients with Marfan syndrome is mainly determined by progressive dilatation of the aorta, potentially leading to aortic dissection and aortic rupture, which are the major causes of death. Mean survival of untreated patients is 40 years, but the variance is large. Dilatation of the sinus of Valsalva is found in 60% to 80% of adults with Marfan syndrome ( Figs. 67.2 and 67.3 ). The rate of dilatation is heterogeneous and unpredictable. The risk of type A dissection clearly increases with increasing aortic root diameter, but dissection may occasionally occur in patients with no or only mild aortic dilatation. The aortic root and other parts of the aorta may be dilated. As an additional potential predictor for aortic dissection, noninvasive aortic elasticity has been investigated in patients with Marfan syndrome. Decreased aortic elasticity, determined by measurement of local distensibility and flow wave velocity with magnetic resonance imaging (MRI), has been demonstrated in many but not all unoperated patients with Marfan syndrome. Aortic elasticity of the descending thoracic aorta has been identified as an independent predictor of progressive descending aortic dilatation.
Besides gradual expansion of the aortic diameter, the aorta also elongates, which forces the anatomically fixed aorta to curve and become tortuous. The aortic tortuosity index has been found to correlate with age and aortic diameter, and to independently predict aortic dissections in patients with Marfan syndrome.
Although not included in the diagnostic criteria for Marfan syndrome, it has been speculated that a fibrillin defect in the myocardium may predispose patients with Marfan syndrome to left ventricular dilatation and reduced left ventricular function. In an MRI study of 144 patients with Marfan syndrome without significant valvular regurgitation, the left and right ventricular ejection fractions were slightly impaired. However, in an echocardiographic study of 234 patients with Marfan syndrome without significant valvular regurgitation, left ventricular dimensions and systolic function were normal in most patients, and none of the patients fulfilled the criteria for dilated cardiomyopathy.
Patients with a dilated aorta are usually asymptomatic. The presence of significant aortic, tricuspid, or mitral regurgitation may lead to symptoms of ventricular volume overload. Patients with Marfan syndrome tend to feel fatigued, which may be explained, at least partly, by orthostatic hypotension. The combination of increased height and a structural abnormality of the blood vessels may cause impaired orthostatic tolerance. In Marfan patients, fatigue and low orthostatic tolerance have been correlated. Patients can be educated in physical counterpressure maneuvers, such as leg crossing and muscle tensing, to counteract orthostatic drops in blood pressure. Adequate muscle mass is, however, a prerequisite for these maneuvers.
Treatment
Medical Treatment
Both medical and surgical therapies have improved life expectancy substantially up to a median survival of 60 to 70 years. β-Adrenergic blockers may reduce the rate of aortic dilatation and improve survival in patients with Marfan syndrome. Rigorous antihypertensive medical treatment aimed at systolic blood pressure of less than 120 mm Hg (110 mm Hg in patients with aortic dissection) is important. β-Blocker therapy may be protective, independent of its effects on blood pressure, by reducing the force of left ventricular ejection. Losartan, an angiotensin II receptor 1 blocker, might be an alternative or complementary therapy to β-blockers, since losartan reduces arterial pressure and potentially interferes with the pathophysiology of Marfan syndrome by TGF-β antagonism. Based on evidence of the effectiveness of losartan in a mouse model of Marfan syndrome, eight randomized clinical trials were initiated to test losartan effectiveness, and so far four studies have been published.
First, a small pilot study in children and adults demonstrated a beneficial effect of losartan combined with β-blockers ( n = 15) on aortic dilatation rate compared with β-blockers alone ( n = 13) after 35 months of echocardiographic follow-up. The COMPARE trial confirmed these results in a larger cohort ( n = 145) as measured using MRI, and additionally demonstrated a beneficial effect of losartan on the distal part of the aorta after aortic root surgery in 63 patients. The Marfan Sartan trial evaluated the benefit of adding losartan to a high dose of β-blockers. Remarkably, in this cohort of 292 children and adults, aortic dilatation rate was similar for the losartan- and placebo-treated group after 3.5 years of echocardiographic follow-up. Finally, the investigators in the Pediatric Heart Network Study compared losartan with atenolol in a large blinded trial including 608 children during 36 months of echocardiographic follow-up. This trial showed that losartan and atenolol were equally effective in reducing aortic dilatation rate, without superiority. The discrepancies in outcome between the studies may be explained by the different study designs. Until the results of the four ongoing trials and meta-analysis are known, we can conclude that losartan does not seem to be more effective in reducing the rate of aortic dilatation than a high dosage of β-blockers, but that losartan can safely be administered as an alternative or as an additive to β-blocker therapy.
Surgical Treatment
Indications for aortic surgery are shown in Box 67.1 . Composite replacement of the aortic valve and ascending aorta has been the standard operation for aortic root aneurysm in patients with Marfan syndrome for a long time. Over the past 30 years, the composite valve graft or Bentall procedure has become a low-risk operation and a very durable one for these patients. In a large series of aortic root surgery in 675 patients with Marfan syndrome, the operative mortality was 1.5% for elective operations and 11.7% for emergency operations. In patients with initially normal aortic valves, in whom aortic insufficiency is due to the dilated annulus or dissection, valve-sparing operations with root replacement by a Dacron prosthesis and with reimplantation of the coronary arteries into the prosthesis (the David procedure) or remodeling of the aortic root (the Yacoub procedure) have now become the preferred surgical choice ( Fig. 67.4 ). Both types of valve-sparing aortic root replacement and their modifications appear to be safe, reproducible, and associated with excellent 5- to 10-year results. Freedom from reoperation of the aortic valve after the David procedure was 94.8%, with a slow progressive deterioration of aortic valve function after 18 years of follow-up.
