Abstract P2015: Metabolic-epigenetic Coupling In High Fat Diet And Heart Failure With Reduced Ejection Fraction

Abstract

Given rising obesity rates, understanding how metabolic changes exacerbate other cardiovascular disease (CVD) risk factors will yield novel therapeutic targets for associated comorbidities, such as heart failure. We hypothesize that obesity-related metabolic syndrome induces transcriptional programs that engender cardiac pathology via mechanisms involving chromatin regulators, thereby perpetuating the pathology by epigenetic memory. C57BL/6J adult male mice were put on a high fat diet (HFD) for 24 weeks. After HFD, hearts were in hypertrophy, as defined by an increase in heart weight to tibia length ratio (24.67 ± 5.14 mg/mm in HFD versus 17.06 ± 0.98 mg/mm in regular chow controls, p=0.026). Examination of blood plasma revealed significant increase in LDL-C (74.37 ± 22.45 mg/dL in HFD versus 21.91 ± 5.98 mg/dL in controls, p=0.0005) and insulin (452.81 ± 224.77 uIU/mL in HFD versus 89.66 ± 45.60 uIU/mL in controls, p=0.0003), indicative of metabolic disorder. RNA-seq of isolated cardiomyocytes revealed distinct transcriptomic changes at 1 week, 6 weeks, and 24 weeks of HFD. At 1 week, HFD stimulus induced promotion of lipid metabolism ( Pdk4, Per2 ) and suppression of genes related to development and proliferation ( Sox4, Epha4 ). By 6 weeks, the cardiomyocytes underwent metabolic reprogramming (downregulation of Lpl and Irs2 ) and structural changes ( Acta2, Col8a1). At 24 weeks, we observed suppression of ketolytic machinery (downregulation of Abat, Bdh1, and Oxct1 ) in response to obesity-driven hyperglycemia, suggesting that cardiomyocytes transitioned to a pre-diabetic state. To test whether this metabolic disease state compounds with other CVD risk factors, we devised a two-hit model, where mice were fed HFD for 6 weeks and then underwent transverse aortic constriction as a model of pressure overload. Cardiomyocytes from this two-hit model exhibited an enhanced hypertrophic response ( Myh7, Nppa, Col1a1 mRNA levels) compared to pressure overload with regular chow, sham surgery with HFD, or sham surgery with chow. Thus, phenotypic and transcriptional data suggest that HFD reprograms cardiomyocytes to a pre-diabetic state characterized by insulin resistance which exacerbates the effects of other CVD risk factors like hypertrophy.