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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Cooperative Clinical Research--Cooperative Agreements (U10)
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Special Emphasis Panel (ZHL1-CSR-K (O2))
Program Officer
Shah, Monica R
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University of Vermont & St Agric College
Internal Medicine/Medicine
Schools of Medicine
United States
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Kiernan, Michael S; Stevens, Susanna R; Tang, W H Wilson et al. (2018) Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials. J Card Fail 24:428-438
Borlaug, Barry A; Anstrom, Kevin J; Lewis, Gregory D et al. (2018) Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial. JAMA 320:1764-1773
Napier, Rebecca; McNulty, Steven E; Eton, David T et al. (2018) Comparing Measures to Assess Health-Related Quality of Life in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail 6:552-560
Butler, Javed; Kalogeropoulos, Andreas P; Anstrom, Kevin J et al. (2018) Diastolic Dysfunction in Individuals With Human Immunodeficiency Virus Infection: Literature Review, Rationale and Design of the Characterizing Heart Function on Antiretroviral Therapy (CHART) Study. J Card Fail 24:255-265
LeWinter, Martin M (2017) Pericardiectomy to Treat Heart Failure With Preserved Ejection Fraction: Unrestrained Enthusiasm? Circ Heart Fail 10:e003971
Lewis, Gregory D; Malhotra, Rajeev; Hernandez, Adrian F et al. (2017) Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA 317:1958-1966
LeWinter, Martin M; Zile, Michael R (2016) Could Modification of Titin Contribute to an Answer for Heart Failure With Preserved Ejection Fraction? Circulation 134:1100-1104
AbouEzzeddine, Omar F; Wong, Yee Weng; Mentz, Robert J et al. (2016) Evaluation of Novel Metrics of Symptom Relief in Acute Heart Failure: The Worst Symptom Score. J Card Fail 22:853-858
Margulies, Kenneth B; Hernandez, Adrian F; Redfield, Margaret M et al. (2016) Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA 316:500-8
AbouEzzeddine, Omar F; Lala, Anuradha; Khazanie, Prateeti P et al. (2016) Evaluation of a provocative dyspnea severity score in acute heart failure. Am Heart J 172:34-41

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