ANGIOTENSIN-II BLOCKADE IN MITRAL REGURGITATION

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DESCRIPTION (the applicant's description verbatim): Background: Mitral regurgitation (MR) is frequent and its prevalence is increasing with aging of the population. Organic MR, due to primary valvular lesions has severe consequences determined by its degree, with left ventricular (LV) remodeling and dysfunction, left atrial (LA) enlargement, leading to poor clinical outcome. Surgery can eliminate MR, but carries notable risks and is not applicable to all patients. Therefore, chronically decreasing MR, protecting LV and LA with vasoactive treatment are major goals of medical therapy. However, effects of chronic oral vasoactive treatment of MR are controversial and uncertain and recent practice guidelines underscored these gaps in knowledge and did not recommend vasoactive treatment of MR. Hence, a trial of treatment of organic MR is needed. A large trial with mortality-morbidity end-points is desirable but premature without knowledge of magnitude of mechanistic effects of vasoactive treatment. Our pilot studies suggest that sustained improvement of degree of' MR, LV remodeling and LA enlargement can be achieved with tissue angiotensin blockade. The improvement of these intermediate endpoints, mechanistically linked to outcome, is measurable with non-invasive quantitative techniques and forms the basis of the present clinical trial proposal. Hypothesis: Chronic tissue angiotensin blockade therapy using either angiotensin-II receptor blocker (Candesartan Cilexetil) or tissue angiotensin-converting enzyme inhibition (Ramipril) in two arms, weighed against placebo produces a sustained reduction of the consequences of organic MR. Specific aims are that treatment improves a) degree of MR (decreases regurgitant volume, primary end-point), b) LV remodeling (decreases LV end-diastolic volume index, second end-point), and c) LA enlargement (decreases LA volume, third end-point) as compared to placebo. Population: Patients with MR organic (intrinsic valve disease), isolated (no other valve disease), equal to or greater than moderate (regurgitant volume equal to or greater than 30 mL/beat). Methods: A randomized clinical trial, placebo controlled, double-blind, without crossover, of 1 year oral treatment with potent tissue angiotensin blockade (with one arm using Candesartan and one arm using Ramipril) titrated to the maximally tolerated dose. The trial is preceded by an acute study to determine tolerance. End-points are measured by Doppler-Echocardiography for quantitation of MR (regurgitant volume) using combination of 3 simultaneous methods (quantitative Doppler, two-dimensional echocardiography, proximal flow convergence) and combination of echocardiography and electron beam computed tomography for LV and LA volume measurement. This single center study seeks to enroll a total of 135 patients. The analysis will be based on intention to treat and compare changes in regurgitant volume, LV end-diastolic volume index and LA volume measured after one year of treatment with active drugs or placebo. The results of this clinical trial should provide strong evidence regarding medical treatment of patients with organic MR and define future strategies to minimize mortality and morbidity of organic MR.