Copyright © 2007, European Society of Cardiology
Impaired perfusion after myocardial infarction is due to reperfusion-induced 
PKC-mediated myocardial damage
aDivision of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States
bDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, United States
* Corresponding author. Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR, Rm 3145A, 269 Campus Drive, Stanford, CA 94305-5174, United States. Tel.: +1 650 725 7720; fax: +1 650 723 2253. Email address: mochly{at}stanford.edu
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 
PKC (protein kinase C) inhibitor, V1-1, in their myocytes only were treated with or without the PKC inhibitor after ischemia in an ex vivo AMI model. 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: 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 PKC-selective inhibitor, V1-1 (
250 ng/kg), and was completely corrected by 24 h. Myocardial contrast echocardiography, electron microscopy studies, and TUNEL staining demonstrated PKC-mediated microvascular damage. 
PKC-induced preconditioning, which also reduces infarct size by >60%, did not improve microvascular function.
Conclusions: These data suggest that 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 PKC inhibitor given in conjunction with removal of the coronary occlusion.
KEYWORDS No-reflow; Coronary flow reserve; Reperfusion; protein kinase C; Myocardial infarction
1 These authors contributed equally to the study.
Time for primary review 28 days
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