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Abstract 15489: Adipose Tissue Lipolysis Modifies the Cardiac Lipidome in Chronic Heart Failure

Introduction: Adipose tissue lipolysis often occurs during the development of heart failure as a consequence of chronic adrenergic stimulation and increased natriuretic peptide levels. However, the impact of enhanced adipose triacylglycerol hydrolysis on cardiac function is mainly unknown. Hypothesis: Adipose tissue lipolysis regulates cardiac function and the cardiac lipidome. Methods: To investigate the role of fat tissue lipolysis during heart failure development we generated mice with impaired lipolytic capacity. Mice deficient for adipose triglyceride lipase (ATGL) (atATGL-KO) were subjected to transverse aortic constriction (TAC) and phenotyped after 11 weeks. The cardiac mouse lipidome was analyzed by shotgun lipidomics using a Q Exactive mass spectrometer in quadrupole-Orbitrap configuration. The profiling encompassed 542 lipid species from 16 different classes. Results: We have recently shown that TAC-induced cardiac dysfunction was attenuated in atATGL-KO compared to wild-type (wt) mice. In particular, pressure-induced increases in left ventricular mass (LVM) and diastolic LV inner diameter were significantly reduced in atATGL-KO mice. In addition, atATGL-KO mice were completely protected against TAC-induced systolic LV-failure. Perturbation of lipolysis in adipose tissue in atATGL-KO mice resulted in the prevention of major cardiac lipidome changes observed after TAC in wt mice. Major changes occurred in the lipid class of phosphatidylethanolamines (PE) in which multiple PE-species (PE18:0-20:4; PE16:0-18:1; PE16:0-18:2; PE16:0-20:4; PE17:0-20:4; PE18:0-22:4; PE18:1-18:1; PE18:2-18:0; PE18:2-19:0) were markedly induced in failing wt-hearts. This was attenuated in atATGL-KO hearts. TAC-induced cardiac PE induction resulted in a lipid species-specific decrease of PC/ PE-ratios almost exclusively in failing wt-hearts, a process previously associated with enhanced apoptosis. Conclusions: Perturbation of adipose tissue lipolysis leads to an improvement of pressure-induced heart failure accompanied with the prevention of deleterious cardiac lipidome changes. Non-cardiac mediated-modulation of the cardiac lipidome may play an important role in the pathogenesis of chronic heart failure.