Abstract 17387: The Ketone Body Beta-Hydroxybutyrate Attenuates Cardiomyocyte Hypertrophy Independent of BDH1-Mediated Oxidation

Abstract

Previously, we and others identified evidence for increased myocardial ketone body oxidation in failing mouse and human hearts and demonstrated that increased levels of beta-hydroxybutyrate (ßOHB), the most abundant ketone body, reduced pathologic cardiac remodeling in preclinical models of heart failure. To better understand how ßOHB prevents pathologic cardiac hypertrophy, we sought to determine whether: 1) ßOHB has direct effects on cardiomyocyte (CM) hypertrophy; and 2) if ßOHB oxidation is required for this effect. CMs were isolated from hearts of adult male C57BL/6 cardiac-specific beta-hydroxybutyrate dehydrogenase 1 knockout (csBDH1KO) mice and wildtype (WT) littermate controls. csBDH1KO CMs are unable to oxidize ßOHB given that BDH1 catalyzes the first step of R-ßOHB oxidation. CMs were cultured in media containing 5.5mM glucose ± 3mM R-ßOHB in the presence or absence of the hypertrophic agonist phenylephrine (PE, 100μM). CM width and length were quantified to assess hypertrophic growth. Stimulation with PE increased CM width:length ratio compared to glucose control by 31% and 33% in WT and BDH1KO CMs, respectively. Addition of R-ßOHB in the absence of PE had no effect on CM morphology, whereas R-ßOHB limited PE-induced increases in width:length ratio to 2% and 4% in WT and BDH1KO CMs, respectively (p<0.01 vs PE without R-ßOHB). In addition, PE-induced hypertrophy was prevented in WT CMs treated with S-ßOHB (this stereoisomer cannot be oxidized). To confirm that the cultured CMs utilized ßOHB, WT and BDH1KO CMs were cultured in media containing [U- 13 C] R-ßOHB. Stable isotope tracing showed significant fractional enrichment of citrate by R-ßOHB in WT CMs with limited enrichment in BDH1KO CMs (17.8% vs 4.5%, p=0.02). These findings support a role for ßOHB-mediated attenuation of cardiac hypertrophy through direct action on CMs via a mechanism independent of BDH1-mediated oxidation. Taken together with our previous results, these findings strongly suggest that ketone bodies improve heart failure by providing both oxidation-dependent (fuel source) and oxidation-independent as yet undefined cardioprotective mechanisms.