Impaired perfusion after myocardial infarction is due to reperfusion-induced delta PKC-mediated myocardial damage

Objective: To improve myocardial flow during reperfusion after acute myocardial infarction and to elucidate the molecular and cellular basis that impedes it. According to the AHA/ACC recommendation, an ideal reperfusion treatment in patients with acute myocardial infarction (AMI) should not only focus on restoring flow in the occluded artery, but should aim to reduce microvascular damage to improve blood flow in the infarcted myocardium. Methods: Transgenic mouse hearts expressing the delta PKC (protein kinase C) inhibitor, delta V1-1, in their myocytes only were treated with or without the delta PKC inhibitor after ischemia in an ex vivo AMI model. delta V1-1 or vehicle was also delivered at reperfusion in an in vivo porcine model of AMI. Microvascular dysfunction was assessed by physiological and histological measurements. Results: delta PKC inhibition in the endothelial cells improved myocardial perfusion in the transgenic mice. In the porcine in vivo AMI model, coronary flow reserve (CFR), which is impaired for 6 days following infarction, was improved immediately following a one-minute treatment at the end of the ischemic period with the delta PKC-selective inhibitor, delta V1-1 (similar to 250 ng/kg), and was completely corrected by 24 It. Myocardial contrast echocardiography, electron microscopy studies, and TUNEL staining demonstrated delta PKC-mediated microvascular damage. epsilon PKC-induced preconditioning, which also reduces infarct size by > 60%, did not improve microvascular function. Conclusions: These data suggest that delta PKC activation in the microvasculature impairs blood flow in the infarcted tissue after restoring flow in the occluded artery and that AMI patients with no-reflow may therefore benefit from treatment with a delta PKC inhibitor given in conjunction with removal of the coronary occlusion. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.