Cardioprotective effect of empagliflozin in acute myocardial infarction: the role of ketone bodies availability

Abstract

Background: The cardio-renal benefits of SGLT2i have been clearly established by clinical trials. Of interest, despite not having any effect on the incidence of classic atherothrombotic events (MI and strokes), patients receiving SGLT2i treatment had a higher chance of surviving myocardial infarction (MI). Purpose(s): We aim to evaluate the cardioprotective potential of empagliflozin on acute myocardial infarction. We postulate that the benefits of SGLT2-I are mediated via an increase in circulating ketone bodies (KBs) induced by SGLT2i, and its preferential myocardial utilization energetically benefits the heart to better withstand an ischemic event. Method(s): The study was undertaken in our non-diabetic porcine model of ischemia/reperfusion. Animals were allocated to either one-week pretreatment with empagliflozin or placebo before MI-induction. A third group received IV infusion of KBs at the time of the MI- induction to serve as positive-control. The acute effects of the treatments were studied 24 hours after MI-induction by Cardiac Magnetic Resonance (CMR). Immediately post-CMR, animals were sacrificed and heart samples collected for molecular analysis. Results (see Table and Figure): Despite similar initial ischemic injury (area at risk) in all groups, empagliflozin was associated with a significantly higher myocardial salvage (MSI 23.7+/-9.7 vs 4.5+/-3.6%, p<0.001) and better preserved cardiac function (LVEF 41.3+/-3.1 vs 33+/-5.5%, p<0.009) compared with placebo. The infusion of KBs replicated in part the beneficial profile of the empagliflozin group (MSI 16.7+/-8.8 and LVEF 39.1+/-3.6%). Histological analysis showed less cardiomyocyte apoptosis and less oxidative stress Conclusion(s): To the best of our knowledge, this is the first study evaluating in vivo the cardioprotective potential of a SGLT2 inhibitor in a wellstablished porcine translational model. Furthermore, effects are evaluated using the gold standard for visualization and quantification of MI, Cardiac Magnetic Resonance (CMR). Three are the main conclusions: 1. One-week treatment with empagliflozin raises circulating KBs levels and confers significant cardio-protection during a myocardial infarction. Acute post-MI benefits (greater myocardial salvage and better preserved cardiac function) are already seen within 24 hours as compared with placebo. 2. Periprocedural IV infusion of KBs induces similar benefits than the SGLT2-I group. 3. These observations strongly support our hypothesis that SGLT2 inhibition is associated with increased circulating KBs and its selective use as preferential myocardial source of energy as a potential mechanism of action involved in the cardio-renal benefits observed with SGLT2i. (Figure Presented).