Abstract 9581: Bendavia, a Novel Mitochondrial-Targeted Cytoprotective Compound Reduces Ischemia/Reperfusion Injury: Experience in 3 Independent Laboratories

Abstract

Bendavia is a mitochondrial-targeting compound proposed to maintain cardiac mitochondrial function and decrease permeability transition pore (PTP) opening during ischemia/reperfusion (IR). Our labs assessed the cardioprotective effects of Bendavia using cellular and large animal models of IR when reactive oxygen species (ROS) generation is elevated. Left ventricular guinea pig cardiomyocytes were either untreated or incubated with 1nM Bendavia and exposed to 20 min of cellular anoxia plus 30 min of reoxygenation in a hypoxia chamber. Following reoxygenation 54% of control cells survived to the end of reoxygenation versus 93% of Bendavia-treated cells (p<0.05). Myocytes displayed bursts in ROS production immediately prior to cell death that were prevented by Bendavia. Similarly, Bendavia maintained mitochondrial membrane potential in cells exposed to oxidative challenge, suggesting that scavenging mitochondrial ROS with Bendavia sustained mitochondrial energetics by keeping PTP closed. A second study determined the effect of Bendavia on infarct size in anesthetized sheep (60 min coronary occlusion, 3 hr reperfusion). Bendavia infusions of 0.005, 0.05 and 0.5 mg/kg/hr were administered 30 min after occlusion and reduced mean infarct size by 25%, 16% and 17%, respectively (p≤0.05 versus vehicle). Cyclosporin A reduced infarct size by <10% in this same study (p=NS). In a third study anesthetized rabbits received 30 min of coronary artery occlusion plus 3 hr of reperfusion. Rabbits received placebo or Bendavia at 10 or 20 min after occlusion or immediately before reperfusion. At 3 hr of reperfusion, no reflow was assessed by Thioflavin S injection. For any size of ischemic risk zone, the no reflow zone was significantly smaller in the Bendavia group than control group (p=0.0085). There was an overall 21% reduction in no reflow and 11% reduction in infarct size in the Bendavia group. Cardiac hemodynamics were not influenced by Bendavia or Cyclosporin A in either the sheep or rabbit studies. In 3 separate labs studying IR injury, Bendavia protected cardiomyocytes along with reducing infarct size and limiting no reflow when given after ischemia, but prior to reperfusion, making the compound an attractive candidate for clinical studies in cardiac IR injury.