Clinical and therapeutic implications of fibrosis in hypertrophic cardiomyopathy

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DESCRIPTION (provided by applicant): The main objective of this proposal is to develop the scientific and clinical research skills of Dr. Martin Maron, so that he may become an independent clinical investigator. The hypertrophic cardiomyopathy (HCM) center, Molecular Cardiology Research Institute (MCRI), advanced cardiac imaging department and echocardiographic laboratory at Tufts-New England Medical Center will provide Dr. Maron with an appropriate environment in which to study whether an aldosterone antagonist drug can favorable alter the magnitude of myocardial fibrosis in patients with HCM and thereby improve clinical and morphologic markers of disease. Through collaboration with the clinical mentor, Dr. James Udelson, as well as an extensive network of other experienced scientific and clinical investigators, Dr. Maron will acquire the skills necessary to mature into an independent clinical investigator. HCM is the most common genetic cardiomyopathy and remains the leading cause of sudden cardiac death in young people and an important cause of heart failure symptoms and death at any age. In HCM, pathological remodeling of the left ventricle involving myocardial fibrosis is likely a major contributor to cardiac dysfunction and also a nidus for the generation of ventricular arrhythmias. Serum markers of collagen turnover have been shown to reliably reflect the magnitude of myocardial fibrosis in a variety of cardiovascular diseases. In addition, aldosterone antagonist drugs have been shown to decrease fibrous tissue formation in the myocardium in certain pathologic cardiovascular states in which aldosterone production is increased. In HCM, aldosterone production is up-regulated and has been implicated in the formation of myocardial fibrosis. Therefore, the specific aims of this proposal are to: 1) assess serum markers of collagen turnover at baseline and correlate these findings with a variety of clinical and morphologic disease parameters 2) examine the effects of a 12-month treatment with the aldosterone antagonist spironolactone on magnitude of fibrosis as measured by serum markers of collagen turnover as well as changes in clinical and morphologic disease parameters. The results of this proposal will offer important insights into the clinical significance of myocardial fibrosis in this primary genetic cardiomyopathy. The demonstration that spironolactone decreases fibrosis and improves clinical course would provide the rational for a larger multicenter clinical trial evaluating this novel therapy for improving clinical outcome in patients with HCM. (End of Abstract)