Cardiomyocyte Ketone Metabolism Regulates Myocardial Hyperemia

Abstract

Myocardial perfusion is inextricably coupled to metabolism, with increases in physiologic cardiac demand promoting coronary vasodilation. Despite its wide acceptance, the hypothesis that cardiomyocyte metabolism autoregulates myocardial perfusion lacks mechanistic detail; however, clinical and preclinical studies suggest a signaling role for intermediary metabolites in the vasodilatory response. In particular, the ketone body precursor, β-hydroxybutyrate (3-OHB), enhances myocardial blood flow in humans, but the mechanism by which it does so remains unclear. Here, we determined the extent to which 3-OHB influences myocardial hyperemia in mice. Intravenous 3-OHB infusion (0.5 g/kg) in adult mice (12–24 wks) raised circulating 3-OHB levels (0.5 ± 0.1 to 5.1 ± 0.6 mM; p=0.005) and increased myocardial perfusion (18.6 ± 4.4 to 50.9 ± 10.4 mL/min/g; p=0.024), as measured by myocardial contrast echocardiography. Enhanced perfusion induced by 3-OHB occurred in the absence of changes in cardiac output or systolic performance. Next, to determine if 3-OHB directly dilates the coronary vasculature, we exposed pressurized (80 mmHg), small-diameter (100–260 μm) coronary arteries from mice (C57/Bl6J and 6N) to 3-OHB (0.1–5 mM) but found no significant changes in diameter. Based on these results, we tested whether cardiomyocyte metabolism of 3-OHB is required for the vasodilatory response. We deleted β-hydroxybutyrate dehydrogenase (BDH1) selectively in cardiomyocytes using Bdh1fl/fl mice crossed with tamoxifen-inducible Cre recombinase mice (csBDH1−/−). Although 3-OHB robustly enhanced myocardial perfusion (6.9 ± 1.4 to 21.3 ± 5.6 mL/min/g; p=0.031) at sustained cardiac workloads and peripheral vascular resistance in Cre-negative littermate (control) mice, csBDH1−/− mice completely lacked the 3-OHB-induced hyperemic response (8.0 ± 2.5 to 6.3 ± 2.8 mL/min/g; p>0.999). Together, these data indicate that 3-OHB evokes workload-independent enhancement of myocardial perfusion through a mechanism that requires cardiomyocyte metabolism of 3-OHB. Our results support the general concept that acute changes in metabolic substrate availability may influence oxygen delivery to cardiomyocytes via a cardiomyocyte-vascular signaling nexus. R01HL163818, R01HL142710, R01HL163003, P30GM127607, P30GM127607-05S1, Jewish Heritage Fund for Excellence (JHFE), S10OD025178. This is the full abstract presented at the American Physiology Summit 2024 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.