Grant: Project Grant

Heart failure is a debilitating disease that is very prevalent in the world. A problem in heart failure patients is that the heart can become "energy starved" and cannot produce the required energy to sustain proper contractile function. The very high energy demands of the heart are normally met by the mitochondrial oxidation of glucose, fatty acids, ketones, lactate, and amino acids. Normally, there is a balance between the use of these fuels by the heart. However, in heart failure the heart becomes "metabolically inflexible", and glucose oxidation is impaired. There are two main types of heart failure, heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). While cardiac glucose oxidation is impaired in both HFrEF and HFpEF, ketone oxidation is increased in HFrEF, but decreased in HFpEF. In addition, in HFpEF there is an increase in fatty acid oxidation, which is an oxygen costly source of fuel. We hypothesize that increasing cardiac glucose oxidation in both HFrEF and HFpEF, and/or increasing cardiac ketone oxidation in HFpEF, will increase cardiac energy production, thereby improving heart function. To address this hypothesis, we will use two established mouse models of HFrEF and HFpEF to examine whether increasing glucose oxidation or ketone oxidation can be used as a therapeutic approach to lessen the severity of heart failure. The HFpEF model will involve the use of aging female mice, as HFpEF is prevalent in older females. Studies will also be performed in human heart samples to examine what differences in glucose oxidation, ketone oxidation and fatty acid oxidation occur between patients with HFrEF or HFpEF. We propose that a better understanding of how energy metabolism can be optimized in heart failure could lead to the development of novel therapeutic strategies that can be used to treat both HFrEF and HFpEF patients.