Acute elevation of plasma β-hydroxybutyrate restores myocardial perfusion in aged mice
Authors: Nystoriak Matthew , Nong Yibing , Kurlawala Zimple , Hill Bradford 
Published: May 2023

Sustained cardiac health throughout the lifespan requires continuous blood delivery to supply the myocardium with adequate oxygen and nutrients. Myocardial perfusion is intrinsically linked to cardiac metabolism and oxygen consumption, which fluctuate with systolic parameters of heart rate, contractile force generation, and wall stress. Advanced age is associated with changes in myocardial nutrient utilization, lower perfusion reserve, and impaired mechanical performance. Nonetheless, how age-dependent metabolic remodeling impacts the physiological coupling between cardiac workload and myocardial perfusion is poorly understood. We hypothesize that age-related impairment of coupling between myocardial perfusion and cardiac workload is caused by compromised β-hydroxybutyrate (βHB) utilization. Protein abundance of βHB dehydrogenase (Bdh1) was significantly elevated (~6-fold) in the hearts, but was reduced (0.5-fold) in the livers of aged mice (25 mo.) relative to those from sex-matched young mice (5 mo.). Aged male mice had significantly lower plasma βHB after fasting relative to young adult mice. Using simultaneous contrast echocardiography and left ventricular pressure-volume measurements, we observed suppression of myocardial perfusion relative to cardiac workload (product of heart rate and stroke work) in aged mice of both sexes. Aged mice had modest systolic dysfunction, showing reductions in ejection fraction, global longitudinal strain, and dP/dt­max. Relative to young controls, aged male mice also showed significant changes in diastolic measures including elevated end-diastolic volume and pressure, relaxation time constants, and stiffness (slope of end-diastolic pressure-volume relationship), and reduced dP/dtmin. These data indicate associations between reduced βHB availability and metabolism, suppressed myocardial perfusion, and ventricular diastolic dysfunction. In a separate cohort of mice, we tested whether altered energetic substrate availability via elevation of βHB impacts myocardial perfusion. Consistent with this, intravenous bolus delivery of βHB (1 g/kg body wt.) increased plasma ketone body levels and enhanced resting perfusion by ~2.5-fold. We observed no significant change in heart rate upon βHB infusion, suggesting that enhanced perfusion in the presence of elevated βHB was independent of changes in cardiac workload. Moreover, infusion of βHB in aged mice restored resting myocardial perfusion to levels comparable with those observed in sex-matched young mice. Together, our data indicate that circulating ketone bodies influence resting myocardial perfusion, and low βHB availability may contribute to cardiac dysfunction in aged mice via an imbalance of metabolic demand and blood flow. This work was supported by the National Institutes of Health (HL142710 to M.A.N. and HL147844 to B.G.H.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.