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

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 bhydroxybutyrate (beta-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 beta-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of beta-hydroxy-beta-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic b-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.

Automated summary

Under conditions of low-flow ischemia, the heart can generate ketones through pathways involving HMGCS2 and SCOT, impacting cardiac functional recovery.