Heart Failure with Preserved Ejection Fraction (HFpEF), also known as “stiff” heart failure, is a common yet inadequately treated form of heart failure. In metabolic alteration-driven HFpEF (also referred to as cardiometabolic HFpEF, where risk factors such as obesity, hypertension, and diabetes are prevalent), the heart is exposed to metabolic insults that limit its ability to use glucose as a fuel source due to cardiac insulin resistance. This removes a major fuel source in the heart, creating significant energy deficiency. The recent success of Sodium glucose co-transporter 2 inhibitors (SGLT2i), a "metabolic intervention," in HFpEF trials suggests that increased ketone supply and myocardial utilization may underlie the benefits of SGLT2i in HFpEF. However, our study has revealed a potentially more effective approach to targeting both the ketogenic and ketolytic machinery in HFpEF myocardium. Our findings show that the mammalian heart has an intrinsic capacity to generate ketones via the mitochondrial enzyme 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2). However, HMGCS2 activity is impaired in HFpEF hearts, leading to reduced ketone body production and utilization as a fuel source for the heart. We have demonstrated that restoring myocardial NAD+ levels can rescue HMGCS2 activity and rescue the HFpEF phenotype, providing a promising therapeutic approach for this widely prevalent disease. These findings contribute to a better understanding of HFpEF and reveal a new therapeutic avenue with the potential to improve heart failure patient outcomes.