New England, New York and Quebec Regional Clinical Center

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DESCRIPTION (provided by applicant): This application is a renewal of the New England, New York and Quebec Regional Clinical Center of the NHLBI Heart Failure Research Network, under the direction of Dr. Martin LeWinter of the University of Vermont and Fletcher Allen Health Care (UVM/FAHC). With this application we propose a new leadership structure, a multiple PI/PD partnership with Tufts Medical Center (Tufts MC) under the direction of Dr. Marvin Konstam, and a major expansion of the RCC. We believe that this expansion will markedly enhance both our scientific contribution to the Network and our enrollment capabilities. As our clinical trial, we propose to study the effects of ranolazine in patients with heart failure with normal ejection fraction (HFNEF). About 50% of HF patients have a normal EF. There are currently no evidence-based treatments for HFNEF. We have published in vitro studies using excitable left ventricular (LV) myocardial strips obtained from patients undergoing coronary bypass grafting which show that the presence of concentric LV hypertrophy (LVH), which is common in patients with HFNEF, is associated with the appearance of increasing diastolic tension at abnormally low stimulation frequencies. We have also shown that the anti-anginal drug ranolazine, which inhibits the late sarcolemmal Na current, normalizes this rate-dependent diastolic dysfunction. Accordingly, we propose a 24 week randomized trial of ranolazine versus placebo in patients with HFNEF and LVH to test the hypothesis that ranolazine improves exercise performance, assessed as peak V02 during either treadmill or cycle exercise. Secondary outcome variables include results of a symptom questionnaire, submaximal exercise performance, and changes in LV mass, diastolic function, and serum biomarkers of neurohumoral activation. A positive result of this trial would lay the foundation for a larger, mor definitive trial of ranolazine in treating the very difficult problem of HFNEF. RELEVANCE (See instructions): HF has become a problem of major proportions over the last two decades. Important strides have been made in improving functional capacity and survival in HF with reduced ejection fraction. However, progress in the approximately 50% of patients with normal ejection fraction has been disappointing. The proposed trial, along with expansion of our RCC, has the potential to positively impact this major clinical problem.