Ketone Body Metabolism in the Ischemic Heart

Figure 1. Ketone body pathways in the liver and heart. Ketogenesis occurs primarily in the liver from fatty acids obtained from the blood. Acetyl CoA is formed from hepatic beta-oxidation and ultimately converted to beta-hydroxybutyrate (β-OHB) via multiple enzymatic reactions. Once β-OHB enters the heart, a series of reactions forms Acetyl CoA for entry into Kreb's Cycle. AcAc, acetoacetate; Acac CoA, acetoacetyl CoA; ACAT1, acetyl-coenzyme A acetyltransferase 1, βOHB, beta-hydroxybutyrate; BDH1, mitochondrial beta-hydroxybutyrate dehydrogenase; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; HMGCL, HMGC-CoA lyase; SCOT, succinyl-CoA:3-oxoacid-CoA transferase. Created with BioRender.com.

Figure 2. Summary of studies investigating ketone body metabolism in the ischemic heart. Various strategies to target ketone body metabolism in models of cardiac ischemia have been attempted including short-term ketogenic diets (KD, 2–4 weeks), long-term KD (19 weeks), infusion of beta-hydroxybutyrate (β-OHB), ketone ester (KE) supplementation, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. The observed outcomes of these various interventions are presented as impaired, improved, or no effect. The current literature is limited on the effectiveness of these specific strategies: short-term KD (five studies), long-term KD (1 study), β-OHB infusion (four studies), KE supplementation (1 study), SGLT2 inhibitors (three studies). Created with BioRender.com.