Abstract P3174: Loss Of Hmgcs2-mediated Ketogenesis Accelerates Cardiac Aging

Introduction: We have previously reported that the ketogenic enzyme HMGCS2 regulates metabolic changes to ameliorate cardiac damage by promoting adult cardiomyocyte dedifferentiation and proliferation after myocardial infarction (Cheng et al. Circulation , 2022). Intriguingly, ketogenic diet has been shown to prolong the lifespan of aged mice. However, whether the loss of HMGCS2 links to cardiac aging remains unclear. Hypothesis: We tested if loss of HMGCS2 results in metabolic change and heart dysfunction and leads to premature cardiac aging. Methods and Results: Conventional HMGCS2 knock-out (KO) mice were generated by inserting loxP sites flanking exon 2 of HMGCS2 to eliminate HMGCS2 protein production. HMGCS2 expression and β-hydroxybutyrate production were eliminated in the livers and hearts in HMGCS2 KO mice. Echocardiographic analysis and intraventricular catheterization did not display heart functional differences between wild-type and HMGCS2 KO mice at 3-month-old. However, growing with age, HMGCS2 KO mice revealed a declining survival rate, accompanied by worse diastolic and systolic functions including reduced left ventricle ejection fraction, myocardial performance index, fractional shortening, stroke volume, end-diastolic dimension, end-systolic dimension, isovolumic relaxation time, and left ventricular diastolic time constant (Tau) in HMGCS2 KO mice at 12-month-old. Histological analyses also exhibited aging-related phenotypes in the HMGCS2 KO heart at 12-month-old, including cardiac hypertrophy and fibrosis. Furthermore, mitochondrial analyses indicated mitochondrial impairments of function and structure. Conclusion: These results suggest that loss of HMGCS2 accelerates cardiac aging with declining cardiac and mitochondrial function.