Abstract P3182: Promoting Mitophagy By Enhanced Fatty Acid Oxidation Improves Phenotypes Of Heart Failure With Preserved Ejection Fraction

Abstract

Although metabolic remodeling is known to contribute to the development of heart failure with reduced ejection fraction (HFrEF), the role of energy metabolism in HF with preserved ejection fraction (HFpEF) is poorly understood. Here we assessed cardiac energy metabolism in both HFpEF and HFrEF mice by multi-nuclear NMR spectroscopy. HFpEF was induced by a 2-hit of high fat diet (HFD) and Nω-nitrol-arginine-methyl-ester (L-NAME, in drinking water) for 10 weeks. Mice fed with chow diet, HFD or L-NAME administration alone were used as controls. HFpEF phenotypes were assessed as the exercise intolerance, pulmonary congestion, high E/e’ by echocardiography and left shift of pressure-volume relationship obtained from isolated hearts. High energy phosphate content, assessed by 31P NMR spectroscopy of isolated perfused hearts, showed a lower phosphocreatine (PCr) content in HFpEF hearts while ATP level was unaltered compared to all the controls, resulting a reduced PCr/ATP ratio similar to that in HFrEF induced by TAC. Decreased respiratory function and increased ROS production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile, assessed by 13C-isotopmer analysis, showed a high dependency on fatty acid oxidation (FAO) in HFpEF hearts, which is opposite of HFrEF but similar to that in HFD hearts. However, PCr/ATP ratio and mitochondrial function were sustained in the HFD hearts with the same duration of treatment. We found that mitophagy was activated in HFD heart but did not change in HFpEF hearts despite similar extent of obesity suggesting that HFpEF heart is maladaptive to the metabolic stress. Promoting mitophagy by TAT-Beclin1 treatment improved mitochondrial function in HFpEF hearts and partially rescued cardiac diastolic dysfunction and lung congestion. Furthermore, enhancing FAO in HFpEF hearts by deleting acetyl-CoA carboxylase 2 stimulated mitophagy and improved HFpEF phenotypes. In summary, our results show that mitochondrial dysfunction is an important pathogenic mechanism for cardiac dysfunction in HFpEF. Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control which can be improved by stimulating FAO.