Abstract 9485: Role of Fatty Acid Oxidation in Heart Function

• Published in: Circulation (New York, N.Y.) Vol. 146; no. Suppl_1; p. A9485
• Main Author: Kim, Chai-wan
• Format: Journal Article
• Language: English
• Published: Lippincott Williams & Wilkins 08.11.2022
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.9485

IntroductionMore than 70% of the energy used by myocardial cells is from fatty acid oxidation (FAO), but excessive FAO may also cause cardiac dysfunction due to increased cardiac oxygen consumption. Inhibition of cardiac FAO has been tested in animal models and human subjects with chronic heart failure, but its absolute benefit is still unclear. Here, we generated myocyte-specific ACC1 and 2 knockout mice (ACC dHKO) to investigate the role of FAO in cardiac function. MethodsACC dHKO were generated by crossing ACC1 and ACC2 floxed mice with Myh6-CRE transgenic mice. Cardiac FAO was measured by Langendorff perfusion. Etomoxir was administered to inhibit FA oxidation. FA composition and cardiolipins were measured by LC/MS and mitochondrial electron transport chain (mETC) was assessed using Seahorse. ResultsACC dHKO mice developed a dilated cardiomyopathy at 7-8 weeks, which progressed with age (A, B). Perfusion studies demonstrated that hearts from ACC mice exhibit increased FA oxidation. Cardiac fatty acid composition analysis showed a severe deficiency of cardiolipin due to a significant decrease in linoleic acid, presumably due to excessive FA oxidation (C). Cardiac mETC in ACC dHKO was significantly compromised compared to control mouse (D). Etomoxir, which blocks FAO, normalized levels of cardiac linoleic acid and cardiolipins, and prevented the development of the dilated cardiomyopathy in ACC dHKO (E). ConclusionsDeletion of ACCs in heart led to unrestrained FAO, mitochondrial dysfunction, and a dilated cardiomyopathy., which could be prevented by administration of drugs that suppress FA oxidation. This study provides evidence that elevated rates of mitochondrial FA oxidation can be detrimental and suggests that efforts to further increase FA oxidation in a failing heart may not enhance function.