β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery

Abstract

Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.

Short‐term fasting of mice elevates circulating fibroblast growth factor 23 (FGF23)

“…60,61 Both conditions are associated with ketogenesis, 62 and particularly βhydroxybutyrate influences heart function, for example, in ischemia. 63 Enhanced cardiac FGF23 production in fasting-dependent ketogenesis is therefore in perfect line with the established up-regulation of cardiac FGF23 production in heart conditions that by the same token predispose for ketogenesis.…”

“…On the one hand, FGF23 induces left ventricular hypertrophy in mice, 59 on the other hand, the heart produces FGF23 under pathological conditions, for example, myocardial infarction or in heart failure in mice 60,61 . Both conditions are associated with ketogenesis, 62 and particularly β‐hydroxybutyrate influences heart function, for example, in ischemia 63 . Enhanced cardiac FGF23 production in fasting‐dependent ketogenesis is therefore in perfect line with the established up‐regulation of cardiac FGF23 production in heart conditions that by the same token predispose for ketogenesis.…”

Glucagon and exenatide improve contractile recovery following ischaemia/reperfusion in the isolated perfused rat heart

“…Rats were euthanized by rising CO 2 levels, with death confirmed by cervical dislocation. Hearts were excised and perfused in the Langendorff mode with Krebs–Henseleit buffer (118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO 4 , 11 mM glucose, 1.3 mM CaCl 2 , 0.5 mM EDTA, 25 mM NaHCO 3 , 1.2 mM KH 2 PO 4 ; pH 7.4) as previously described (Lindsay et al, 2021 ), and continually gassed with 95% O 2 /5% CO 2 . Hearts were perfused with 250 mL recirculating buffer under a constant pressure of 100 mmHg.…”

Ketone Body Metabolism in the Ischemic Heart

“…Consistent with this, a recent report demonstrated that ketone body utilization was suppressed by myocardial ischemia in patients presenting with chest pain ( 103 ). However, β-OHB has been shown to accumulate in rat hearts exposed to low-flow ischemia ( 104 ), and since the perfusate was devoid of ketone bodies, this suggests that ketogenesis was active in the ischemic heart. Supporting this, inhibition of Hmgcs2 decreased β-OHB accumulation and improved functional recovery during reperfusion ( 104 ).…”

“…However, β-OHB has been shown to accumulate in rat hearts exposed to low-flow ischemia ( 104 ), and since the perfusate was devoid of ketone bodies, this suggests that ketogenesis was active in the ischemic heart. Supporting this, inhibition of Hmgcs2 decreased β-OHB accumulation and improved functional recovery during reperfusion ( 104 ). This reported finding is somewhat curious, as extrahepatic tissues have been considered incapable of ketogenesis.…”