Dissecting the Ketone Metabolic Axis in Heart Failure with Reduced Ejection Fraction

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Despite significant advances in the treatment of patients with heart failure with reduced ejection fraction (HFrEF), substantial residual morbidity and mortality continues to plague the contemporary treatment era. The cardinal clinical feature of patients with HF is reduced exercise capacity, which is associated with substantially reduced quality of life. Even with insights into diverse mechanisms of myocardial dysfunction, most current medical treatment focuses on modulating the "neurohormonal axis", and orthogonal approaches are direly needed. Recent preclinical and clinical data from our team and others demonstrate that exogenous delivery of ketone therapy improves HF hemodynamics, suggesting potential ergogenic benefits. Our research has also highlighted the contribution of skeletal muscle abnormalities to impaired exercise tolerance in HF, and limited data suggest beneficial effects of ketones in reducing peripheral anaerobic carbohydrate metabolism in healthy volunteers. We therefore seek to understand the potential benefits of therapeutic ketosis in patients with HFrEF by performing deep phenotyping of myocardial, peripheral musculature, and metabolic contributions. Aim 1 will determine the acute effects of exogenous ketone ester administration on functional capacity and investigate potential myocardial and vascular mechanisms of benefit in a crossover, placebo-controlled trial. Aim 2 will compare whether ketone ester therapy alters systemic carbohydrate metabolism through targeted metabolomics, stable isotope infusions, and exercise measures of gas exchange. Aim 3 will investigate the effects of ketone therapy on peripheral intramuscular lactate production and perfusion using state-of-the-art magnetic resonance imaging protocols. Such studies will leverage the rich translational research environment at the University of Pennsylvania, including the Center for Human Phenomic Sciences, a Clinical and Translational Research Award (CTSA) initiative, and the Center for Magnetic Resonance and Optical Imaging. If beneficial, our results would add to the burgeoning literature, demonstrating the importance of targeting the "ketone metabolic axis" as a treatment strategy to help improve exercise capacity and quality of life, and would inspire larger, randomized trials of ketone therapy. Dr. Selvaraj, an early career investigator and a fellow in advanced heart failure, has a long-term goal of becoming an independently funded cardiovascular researcher with a focus on cardiovascular metabolic interventions in HF and using deep phenotyping techniques to define pathways of benefit. Thsese research aims are part of a comprehensive training plan and will be supervised by a mentorship team spanning the basic science, translational, and clinic spectrum with rich experience in cardiovascular metabolism in HF, metabolomic profiling, deep phenotyping during early stage studies of HF therapeutics, and molecular metabolic imaging. This diverse and collaborative team will guide Dr. Selvaraj's transition to an independently funded research career with extension of findings to low output HF syndromes.