EN-510-03 SINOATRIAL NODE DYSFUNCTION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

Abstract

Under normal conditions, the human heart beats over 2 billion times during an average lifetime due to rhythmic electrical impulses initiated in the sinoatrial node (SAN). In disease conditions, such as heart failure with preserved ejection fraction (HFpEF), failure to maintain and regulate the heart rate due to SAN dysfunction can occur. We recently identified latent SAN dysfunction in animal models of cardiometabolic HFpEF. However, little is known about the metabolic imbalances underlying SAN dysfunction in HFpEF. To identify metabolically-driven functional and transcriptomic changes in HFpEF SAN. Male C57Bl6 mice fed with high fat (HFD) plus nitric oxide inhibitor (L-NAME) diet or regular chow served as HFpEF and control, respectively. RNA sequencing and optical mapping of SAN preparations from control and HFpEF-verified mice were performed. After 20 weeks of HFD+L-NAME, the sinus node recovery time was significantly prolonged in HFpEF mice compared to controls (162 ± 25 vs 88 ± 19 ms; p<0.05). Transcriptome profiling of SAN tissue revealed a significant enhancement of multiple disease-associated genes, with striking changes in extracellular matrix genes and metabolic pathways. In concordance with the observed fibrotic remodeling, conduction velocity (CV) was significantly lower in SAN of HFpEF mice compared to controls (6.4 ± 0.5 vs 13.1 ± 1.7 cm/s; p<0.05). Moreover, although β-adrenergic receptor stimulation accelerated the CV in control SAN, failed to do so in HFpEF animals (20 ± 3.1 vs 10.2 ± 1.1 cm/s; p<0.05). Our results using a cardiometabolic HFpEF model indicate that SAN dysfunction is closely associated with molecular changes in metabolic pathways and extracellular matrix remodeling associated genes. Understanding the metabolic control of the SAN may open new therapeutic targets for HFpEF associated SAN dysfunction.