Attenuation of Reperfusion Injury by Gliflozins During Cardiac Arrest Leading to Improved Post-Resuscitation Myocardial Function and Survival

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PROJECT SUMMARY Out-of-hospital sudden cardiac arrest is a leading cause of death worldwide affecting 1,000 cases every day in the United States. Many of these individuals are Veterans given their high prevalence of coronary artery disease and underlying risk factors. Despite cardiopulmonary resuscitation (CPR), less than 10% are successfully resus- citated and subsequently survive with good neurological function. Poor outcome is related to the damage that tissues suffer, especially the heart and the brain, consequent to the lack of blood flow during cardiac arrest. Additional tissue injury occurs when CPR is performed, and oxygenated blood is returned to organs that have been deprived of oxygenated blood. This injury is known as reperfusion injury and, as of today, there is no treatment available to reduce such injury during CPR. Our research lab for many years has shown that a group of drugs able to reduce sodium entry into cardiac cells during CPR can significantly reduce reperfusion injury. Yet, these drugs are not currently available for clinical use. However, a group of drugs known as gliflozins, originally developed for the treatment of type 2 diabetes mellitus, can also exert favorable effects on the cardio- vascular system. We conducted preliminary experiments in a swine model of cardiac arrest and found that em- pagliflozin given during CPR protected the heart from such injury resulting in a better cardiac function after re- suscitation. We now propose to conduct comprehensive studies in a swine model of cardiac arrest with high translational value examining whether empagliflozin could elicit (as our preliminary experiments suggest) cardiac effects during resuscitation of clinical value while understanding the mechanisms of these effects. The proposed studies are divided into two specific aims. Under Specific Aim 1, experiments will examine the direct effects of empagliflozin on the heart during cardiac resuscitation and after the return of cardiac activity. These studies will determine whether empagliflozin can elicit effects similar to those of the aforementioned drugs that limit sodium entry and will also examine the mechanisms by which empagliflozin elicits these effects. We will use an open- chest swine model of ventricular fibrillation and resuscitation with extracorporeal circulation. Under Specific Aim 2, experiments will examine the effects on a closed-chest swine model of cardiac arrest applying the same resuscitation protocols currently used for human resuscitation. We will examine the effects of empagliflozin on clinically relevant outcomes including the rate of return of spontaneous circulation, survival at 72 hours, and the recovery of neurological function. We will also examine the interaction of empagliflozin with vasopressor agents given during CPR and whether empagliflozin could minimize detrimental post-resuscitation effects elicited by epinephrine. In additional experiments, we will examine whether similar effects can be elicited by canagliflozin, suggesting a gliflozin class effect, and determine whether delayed administration during CPR may compromise the intended effect. If this project is successful, clinical translation of gliflozins for resuscitation will be greatly facilitated given their clinical availability and the existing 505(b)(2) FDA pathway for repurposing drugs.