Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients

The major clinical problems in patients with Marfan Syndrome (MFS) are aortic root dilation (ARD), dissection and rupture. Although the available treatments (beta-blockers, BBs) improve the evolution of the disease, they do not protect MFS patients from progression of ARD and dissection. A key molecule that negatively influences cell growth, differentiation, survival and death in MFS is TGFb which is antagonised by existing drugs employed in the clinical practice, the Angiotensin II receptor blockers (ARB).

Marfan Syndrome is a rare disease (1:5000)(MIM#154700) caused by mutations of the Fibrillin 1 (FBN1) gene. The major clinical problem is aortic aneurysm with risk of dissection when root diameter is 5 cm.

The investigators designed a clinical trial in which a new generation Beta-Blocker Nebivolol with expected effects on shear stress, heart rate and potential anti-stiffness benefits is compared to Losartan, and Angiotensin receptor blocker anti TGF-beta effects, and to the association of both molecules in patients with Marfan Syndrome. Nebivolol is a patented drug that differs chemically, pharmacologically and therapeutically from all other BBs. Nebivolol shows the highest selectivity for ß1 receptors among the currently available BBs, influences the arterial stiffness through an agonistic effect on ß2-receptors and preserves the arterial compliance. We expect a significantly lower progression of the Aortic Root Dilation in the arm of Nebivolol plus Losartan vs. single drug (primary end-point).The investigators further expect: decrease of arterial stiffness higher in the arm treated with both drugs than in solely Nebivolol or Losartan; a decrease of serum levels of active TGFb in both Losartan arms, a drug \& age-dependant variation of the expression of the mutated FBN1 gene. As for other end-points, the potential results are the improvement of valve function, hard events \& delay of surgical timing for the aortic root. The enrolment period will last 12 months, while the overall follow-up period will be of 4 years. An interim analysis for the primary outcome is programmed at month 24.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of MFS: Ghent criteria and genetically proven defect of the FBN1 gene
* Age: 12 months to 55 years
* BSA-adjusted aortic z score = or \>2 measured at the level of the sinuses of Valsalva at baseline according to Roman's method, or absolute aortic root diameter \>38mm for females and \>40 mm for males

Exclusion Criteria:

* Prior aortic surgery and/or dissection
* Aortic root diameter at the level of the sinuses of Valsalva 5 cm
* Planned aortic surgery within 6 months of enrollment for a rate of ARD progression\>5 mm/year even in pts with ARD less than 5 cm
* Clinical or molecular diagnosis of non-MFS connective tissue diseases sharing some features with MFS (Shprintzen-Goldberg syndrome or Loeys-Dietz syndromes)
* Un-renounceable therapeutic (systemic hypertension, arrhythmia, ventricular dysfunction, valve regurgitation) use of drugs such as ACE inhibitors, BBs, or calcium-channel blockers
* Known side-effects while taking an ARB or a BB
* Intolerance to ARB that resulted in termination of therapy
* Intolerance to BB that resulted in termination of therapy
* Renal dysfunction (creatinine level more than upper limit of age-related normal values)
* Diabetes mellitus
* Pregnancy or planned pregnancy within 48 months of enrollment
* Technical limitations for the imaging studies including poor acoustic windows with limits the accurate measurement of aortic root
* Asthma.