The role of the mitochondrial permeability transition pore in human myocardial protection

Background: Coronary artery disease is set to be the world’s leading cause of mortality by 2020. Hence novel treatment strategies are urgently required to protect the human myocardium against ischemia-reperfusion injury. This thesis examines the role of the mitochondrial permeability transition pore (MPTP) as a novel target for myocardial protection by interventions applied solely at the time of reperfusion, which can protect the human heart against lethal reperfusion injury. Methods and Results: Using human atrial tissue (harvested at the time of routine cardiac bypass surgery), subjected to simulated ischemia and reperfusion injury model, we have demonstrated that the opening of the MPTP at the time of reperfusion is a critical determinant of cardiomyocyte death. We also show that inhibiting MPTP opening, by administering known pharmacological inhibitors of MPTP at the onset of reperfusion, is cardio-protective. Using experimental models in adult human atrial trabeculae, we demonstrate that inhibiting MPTP opening at the time of reperfusion improves myocardial contractile function. Also using human atrial cardiomyocytes we demonstrate that inhibiting MPTP opening at the time of reperfusion improves cellular viability. Finally using the human atrial cardiomyocyte model for inducing and detecting the MPTP opening, we demonstrate the opening of MPTP and also the inhibitory effect of known MPTP inhibitors on MPTP opening. Conclusion: We find that MPTP opening does occur in the human atrial cardiomyocyte following ischemia-reperfusion injury, and that inhibiting the opening of the MPTP at the time of reperfusion, provides a potential target for human myocardial protection, when the intervention is applied at the time of reperfusion. Therefore, interventions, which target and inhibit MPTP opening, at the time of reperfusion, can protect the myocardium from lethal reperfusion injury and may improve morbidity and mortality from coronary artery disease. This is useful in the clinical settings of ischemia-reperfusion injury such as thrombolysis following an acute myocardial infarction, heart surgery and percutaneous transluminal coronary angioplasty.