Abstract P169: A Novel Mitochondrial Permeability Transition Pore Inhibitor, Bendavia, Reduces Microvascular Obstruction (No-Reflow) due to Myocardial Ischemia/Reperfusion Injury in the Rabbit

Abstract

Background: The no-reflow phenomenon is an important detrimental component of reperfusion injury with clinical implications, as it is an independent predictor of outcome after myocardial infarction. Whether the mitochondrial permeability transition pore (MPTP) is involved in vascular integrity and no-reflow post reperfusion is unknown. Therefore, we tested Bendavia, a compound that is known to inhibit the MPTP, for its effects on no-reflow. Methods: Anesthetized rabbits were subjected to 30 min coronary artery occlusion and 3 hrs reperfusion. Treated animals (n=49) received Bendavia (0.05 mg/kg/hr) after the onset of ischemia, 1, 10 or 20 min before reperfusion. Control animals (n=15) received saline. Risk zone was measured by Unisperse blue staining, anatomic no-reflow area using thioflavin S and necrosis by triphenyltetrazolium chloride. Results: The ischemic insult was similar in both groups (31% of left ventricle (LV) in Bendavia and 30% in control). Bendavia treatment resulted in a non-significant 11% reduction in necrosis, expressed as a percentage of the risk zone. However for any given risk zone size, no-reflow was significantly reduced by Bendavia, as there was a significant group effect on the relationship between the extent of the no-reflow zone and that of the risk zone (ANCOVA, p = 0.0085). Overall, the no-reflow zone, expressed as a % of the risk zone was 22 ± 2% in treated hearts vs. 28 ± 3% in controls (p=0.07). In hearts with less severe risk zones (below the mean value of 31% of LV), Bendavia treatment significantly reduced the no-reflow zone by 35% (17±2 vs. 26±4% of risk zone, p <0.05); in hearts with large risk zone, Bendavia non-significantly reduced no-reflow by 17%. Bendavia treatment had no effect on hemodynamic parameters or regional myocardial blood flow during the ischemic period. Conclusion: These data suggest that the MPTP may play a role in the pathophysiology of no-reflow after myocardial ischemia/reperfusion. Bendavia reduced the extent of the no-reflow zone for any given risk zone size, suggesting that it helped prevent microvascular obstruction.