Abstract 17042: Altered Myocardial Energy Substrate Utilization in Metabolic Syndrome May Impact Pathways Involved in Contractile Dysfunction in Ischemic Myocardium

Abstract

Introduction: Metabolic syndrome (MetS) is increasingly prevalent and an independent risk factor for ischemic heart disease (IHD). MetS favors lipids over glucose as the predominant myocardial energy substrate. Similarly, in IHD, energy utilization is dependent on ketone bodies. Evidence is emerging that such changes in cardiac energy metabolism may drive contractile dysfunction, but the underlying processes have not been clarified in the context of coincident MetS and ischemia. Aims: The purpose of this multiomics study was to define the global metabolic state of ischemic myocardium in the setting of MetS, with a focus on energy metabolism and pathways modulating myocardial function and contractility. We hypothesized MetS would further shift substrate utilization away from glycolysis to favor ketone bodies, contributing to pathways of contractile dysfunction in injured myocardium. Methods: We used our well-established porcine model of diet-induced MetS and chronic myocardial ischemia to study effects on left ventricular tissue. Tissue samples from MetS swine and controls were analyzed using targeted LC-MS/MS for polar metabolites, RNA-seq, proteomics, and computational nonnegative matrix factorization. Results: MetS swine had altered bioavailability of 302 polar metabolites together with changes in gene expression of enzymes involved in glycolysis, fatty acid metabolism, ketone body utilization, and abnormal activation of renin-angiotensin-aldosterone system (RAAS). MetS swine also had reduced expression of Apelin protein, a potent stimulator of cardiac contractility (Figure). Conclusions: Our data show MetS enzymatically downregulates glycolysis and upregulates ketone body utilization together with derangement in RAAS in injured myocardium. Decreased Apelin expression may contribute to lipid-induced cardiac dysfunction through maladaptive effects on contractility and remodeling, and thus may serve as a future therapeutic target.