Randomized, Double-blind Study for the Evaluation of the Effect of Losartan Versus Placebo on Aortic Root Dilatation in Patients With Marfan Syndrome Under Treatment With Beta-blockers

• Comparative arterial stiffness [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Evaluation of progression of aortic regurgitation [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Aortic dissection incidence [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Aortic root surgery [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Progression of mitral regurgitation [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Left ventricular size and function [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Skeletal and somatic traits [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Quality of life [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: No ]
• Genetic polymorphisms affecting clinical symptoms and response to treatment [ Time Frame: End of study ] [ Designated as safety issue: No ]
• Death [ Time Frame: At baseline and after 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Aortic stiffness as assessed by MRI [ Time Frame: At baseline and after 1 year and 3 years follow-up ] [ Designated as safety issue: Yes ]

• Comparative arterial stiffness [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Evaluation of progression of aortic regurgitation [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Aortic dissection incidence [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Aortic root surgery [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Progression of mitral regurgitation [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Left ventricular size and function [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Skeletal and somatic traits [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]
• Quality of life [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: No ]
• Genetic polymorphisms affecting clinical symptoms and response to treatment [ Time Frame: End of study ] [ Designated as safety issue: No ]
• Death [ Time Frame: At 6 months, 1, 2 and 3 years follow-up ] [ Designated as safety issue: Yes ]

To study the effect of losartan (an angiotensin receptor blocker-ARB) on aortic root growth in patients with Marfan syndrome, already treated with beta-blockers (BB). The effect of losartan will be compared to placebo. Losartan or placebo will be added to the treatment regimen in a two-step up-titration scheme over 2 weeks. Start doses of Losartan will be 25 mg for subjects under 50kg of weight and 50mg if the weight is over 50kg. Uptitration will be guided by the tolerance of the drug by the patients. Patients will be contacted by phone call for assessment of side-effects before second step of uptitration.

Daily maximal doses of Losartan will be 50mg for subjects under 50kg of weight and 100mg if the weight is over 50kg

• Drug: Losartan
  Daily maximal doses of Losartan will be 50mg for subjects under 50kg of weight and 100mg if the weight is over 50kg
• Drug: Placebo
  Daily placebo capsule

• Experimental: 1
  Losartan
  Intervention: Drug: Losartan
• Placebo Comparator: 2
  Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Patients > 10 years
• Diagnosis of MFS, according to the Ghent criteria and/or genetically proven FBN1 mutations or linkage
• Consent obtained (written) either for the patient and for his/her parents (<18y
• Z-score of the aorta at the level of the sinus of Valsalva ≥2 (BSA adjusted)
• ARB naïve patients

Exclusion Criteria:

• Poor echocardiographic window,limiting the accurate measurement of the aortic root
• Contra-indication for ARB: Bilateral renal artery stenosis, renal function abnormalities (creatinine above normal for age), hyperkalemia
• Intolerance for ARB (eg angioedema)
• Pregnancy or breast feeding women
• Absence of effective contraception
• Liver function abnormalities
• Heart Failure
• Patients included in other clinical trial