PO-01-172 METABOLIC SHIFT CONTRIBUTES TO SINOATRIAL NODE DYSFUNCTION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

Abstract

Cardiometabolic alterations are frequent in patients with heart failure with preserved ejection fraction (HFpEF). We recently demonstrated sinoatrial node (SAN) dysfunction limits the chronotropic response in two distinct animal models of HFpEF; however, our new findings suggest a relationship between metabolism and SAN dysfunction. To identify metabolically-driven changes that facilitate SAN dysfunction in HFpEF. Male C57Bl6 mice fed with high fat (HFD) plus nitric oxide inhibitor (L-NAME) diet or regular chow served as HFpEF and controls, respectively. Transcriptomics, metabolomics, targeted quantitative proteomics of mitochondria, and optical mapping of SAN preparations from control and HFpEF-verified mice were performed. SAN from HFpEF-verified animals after 20 weeks of HFD+LNAME exhibited prolonged SAN recovery time (100%; P<0.05). A combination of multi-omics studies revealed changes in metabolic gene clusters suggesting a metabolic shift towards glycolysis as a source of energy. Supporting these findings, isolated mitochondria from HFpEF SANs showed depressed maximal mitochondrial respiration compared to controls (-42%; P<0.05). In addition, isolated pacemaker cells from HFpEF animals showed increased mitochondrial reactive oxygen species production compared to controls (+70%; P<0.05). Moreover, acute mitochondrial uncoupling induced by FCCP elicited a pronounced prolongation of SAN recovery time in HFpEF compared to controls (165%; P<0.05). Our results suggest that SAN dysfunction in HFpEF is closely associated with metabolic remodeling and energetic substrate shift. However, further studies are needed to establish the causality between metabolic changes and SAN dysfunction in HFpEF.