Effects of Losartan Versus Atenolol on Aortic and Cardiac Muscle Stiffness in Adults With Marfan Syndrome

Phase 3

Completed

Conditions: Marfan Syndrome

Interventions: Drug: Losartan
Drug: Atenolol

Registration Number: NCT00723801

Lead Sponsor: Brigham and Women's Hospital

Brief Summary: Marfan syndrome is an inherited connective tissue disorder with morbidity and mortality from aortic dilation and dissection. The degree of aortic dilation and response to beta-blockade (standard of care) vary in adults with Marfan syndrome. However, aortic stiffness is often present, and can be a predictor of aortic dilation and cardiovascular complications. In addition, adults with Marfan syndrome develop left ventricular diastolic dysfunction, which can progress to heart failure. Aortic stiffness and diastolic dysfunction are important and logical therapeutic targets in adults with Marfan syndrome.

TGF-beta mediates disease pathogenesis in Marfan syndrome and contributes to aortic stiffness. The angiotensin receptor blocker, losartan, inhibits TGF-beta activity and reverses aortic wall pathology in a Marfan mouse model. Losartan also decreases aortic stiffness and improves diastolic function in hypertension, renal disease and hypertrophic cardiomyopathy.

This trial is a randomized, double-blind trial of 50 adults with Marfan syndrome, treated with 6 months of atenolol vs. losartan. Arterial tonometry for aortic stiffness and echocardiography for diastolic function will be performed at the beginning and end of treatment. A blood draw for serum markers of extracellular matrix turnover and inflammation will also be performed at 0 and 6 months. We plan to determine whether losartan decreases aortic stiffness and left ventricular diastolic dysfunction significantly more than atenolol.

Detailed Description: Please See Summary.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Age greater than 25 years
Clinical Marfan Syndrome

Exclusion Criteria

Previous aortic or cardiac surgery
Pregnancy
Renal Insufficiency
Medication intolerance

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Subjects Randomized to Losartan	Losartan	Losartan: 100 mg PO QD
Subjects Randomized to Atenolol	Atenolol	Atenolol: 50 mg PO QD

Primary Outcome Measures

Name	Time	Method
Aortic Biophysical Properties - Pulse Wave Velocity	Baseline and 6 months	Aortic stiffness was assessed using applanation tonometry (SphygmoCor®, AtCor Medical, West Ryde, NSW, Sydney, Australia) to measure carotid to femoral artery pulse wave velocity (PWV). With the patient lying supine in a quiet environment, a handheld micromanometer-tipped probe was applied to the skin surface over the carotid and femoral arteries, compressing the vessel wall so that transmural forces within the vessel wall were perpendicular to the arterial surface. The distance from the sternal notch to the sites of carotid and femoral pulse acquisition were measured and inputted into the device to represent the relative distance from the carotid to femoral artery. The calculation of distance divided by time of pulse upstroke relative to the upstroke of the QRS on a 3 lead surface EKG was used by the device to calculate velocity. All recorded measurements met the manufacturer's quality control standards integrated into the software package.

Secondary Outcome Measures

Name	Time	Method
Diastolic Function - Ejection Fraction	Baseline and 6 months	Two-dimensional echocardiography was performed using a 3.0 MHz transducer (General Electric VIVID 7). Left ventricular and left atrial dimensions were determined in parasternal long axis views. Left ventricular ejection fraction was calculated using the modified Simpsons calculation in the apical two and four chamber views.