THE EFFECT OF BENDAVIA ON ISCHEMIA/REPERFUSION INJURY, LEFT VENTRICULAR REMODELING AND DYSFUNCTION
Robert A. Kloner, M.D., Ph.D., Good Samaritan Hospital/USC, Los Angeles, CA, USA
Background and Objectives: Bendavia is a small water soluble molecule that freely crosses cell membranes and localizes to the inner mitochondrial membrane where it associates with cardiolipin and reduces intracellular reactive oxygen species (ROS) production. Our objective was to determine Bendavia’s effect on myocardial infarction.
Methods and Results: In isolated guinea pig hearts exposed to 20 minutes of global ischemia and 2 hours of reperfusion, Bendavia, administered either throughout ischemia/reperfusion or given only at reperfusion, reduced myocardial infarct size by approximately 40%. In an in-vitro model Bendavia primarily reduced myocyte death that occurred with ROS burst at the time of reoxygenation, even though it is not a ROS scavenger. In an in-vivo rabbit model, there was a trend for Bendavia to reduce infarct size (by 18%) in rabbits with risk zones of greater than 20% (p=0.09); while for any given risk zone, the extent of no-reflow was reduced by Bendavia (p=0.0085). When administration of Bendavia was delayed by 10 minutes after reperfusion, it did not demonstrate a beneficial effect. 6-week administration of Bendavia starting 2 hours after permanent coronary artery occlusion in the rat model decreased scar circumference to 40% LV versus vehicle (47%; p=0.024), and reduced LV volumes. Bendavia improved ejection fraction by an absolute 6% (p=0.005) and fractional shortening by 21% (p=0.047). Bendavia preserved expression of mitochondrial function related genes in the non-infarcted border zone adjacent to the infarct and preserved expression of the SERCA 2a gene at the infarct border zone.
Conclusion: The mitochondria targeting peptide, Bendavia demonstrated a reduction in reperfusion injury when administered acutely in myocardial ischemia/reperfusion models. When administered chronically in a permanent coronary artery occlusion model, Bendavia improved post myocardial infarction remodeling and left ventricular dysfunction.