We recently developed a murine model of insufficient ketogenesis by disrupting the rate-limiting enzyme of ketogenesis, HMG-CoA synthase 2 ( Hmgcs2 -/- ; Keto-less mice), and reported a mitochondrial protection by ketone body metabolism (Arima. et. al., Nature Metabolism 2021). While new evidence has suggested a cardiovascular-protective role by ketone bodies, the precise impact of ketone bodies on heart failure remains unknown. Using our new model in this study, we aimed to elucidate the role of ketone bodies in heart failure. We first generated a pressure-overload model using transverse aortic constriction and compared keto-less mice with wild-type mice. While Keto-less mice showed a tendency for increased cardiomyocytes size, there was no significant difference in mortality and heart weight. Our previous report revealed that fatty acid overload enhances ketogenesis. Therefore, we employed a dietary heart failure mouse model with preserved ejection fraction (HFpEF) using a high-fat diet and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). The HFpEF model confirmed increased ketogenesis and hyperacetylation of mitochondrial protein. We then tested the impact of ketone bodies by using hepatic-specific keto-less mice. Hepatic keto-less mice showed significantly decreased ketone body concentration, but did not show significant changes in body weight and blood pressure. However, cardiomyocyte hypertrophy was exacerbated in the HFpEF model with hepatic specific keto-less mice compared to wild-type mice (WT 325±90um2; hKL 402±110um2, p<0.0001). We examined the multifaceted effects of the ketone body, and addressed a significant reduction in sequential enzymatic reactions in the TCA cycle.These data suggested that ketone bodies have a protective role against heart failure by modulating cardiomyocyte energetics.