Cardiac Energy Metabolism is Disrupted in Older Females with Heart Failure

Background: Heart failure with preserved ejection fraction (HFpEF) is a debilitating disease that is prevalent in our society. HFpEF is prevalent in older women with coexisting obesity, diabetes, and hypertension. Unfortunately, there are few effective pharmacotherapies to treat HFpEF. As such, it is urgent to find new therapeutic targets and to understand the complex pathophysiology of HFpEF. While it is well-accepted that changes in myocardial energetics are involved in heart failure progression, it remains unknown whether alterations in cardiac energetics contribute to HFpEF severity. Therefore, the objectives of this study were to define the cardiac energy metabolic profile in HFpEF using aged female mice and then attempt to lessen the severity of HFpEF by improving cardiac energetics. Methods: Obesity and hypertension were produced in 13-month-old female C57BL/6J mice by subjecting them to 10 weeks of 60% high fat diet (HFD) and 0.5g/L of Nω-nitro-L-arginine methyl ester (L-NAME) in the drinking water. Control mice were fed with regular chow diet. At the end of the study protocol, echocardiography, pressure volume (PV) loops, and glucose tolerance (GTT) test were performed. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of glucose oxidation and fatty acid oxidation. A third intervention group of mice were treated with 40mg/kg/day of pyruvate dehydrogenase inhibitor (PDKi) MMR013 while receiving the HFpEF protocol. Results: HFpEF mice exhibited a significant increase in body weight, glucose intolerance, and elevated blood pressure. Echocardiography revealed that HFpEF mice developed diastolic dysfunction and concentric hypertrophy. In HFpEF mice hearts, glucose oxidation was significantly suppressed, whereas fatty acid oxidation was not decreased. Total cardiac ATP production was reduced in HFpEF hearts compared to healthy control hearts. Acute addition of PDKi to the perfusate increased glucose oxidation rates. PDKi treated mice had improved systolic and diastolic function compared to vehicle treated mice. PDKi treatment also improved vascular function, ameliorated hypertension, and improved overall survival rates. Conclusion: The aged female heart becomes metabolically inflexible and energy deficient in HFpEF, as characterized by a prominent decrease in glucose oxidation with a simultaneous increase in fatty acid oxidation. Stimulation of cardiac glucose oxidation using PDKi lessens the severity of HFpEF and exerts functional benefits. Therefore, targeting cardiac energy metabolism could be a promising therapeutic target for treating HFpEF in older females.