Pharmacological cardioprotection of the human myocardium in diseased states

• Main Author: Rees, P. S. C.
• Published: University College London (University of London) 2011
• Subjects: 616.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.587618

Background: Coronary artery disease is the leading worldwide cause of death. Even despite restoration of blood flow following acute myocardial infarction, further myocardial damage is seen during the reperfusion phase. Pharmacological strategies to induce resistance to ischaemia reperfusion injury have been shown to share common pathways. The most important common signalling pathway involved is the Reperfusion Injury Salvage Kinase pathway, and in animal models this can be pharmacologically activated, resulting in inhibition of the opening of the mitochondrial permeability transition pore, with a resultant cardioprotective effect. Atorvastatin has been shown to act in this way in animal models of ischaemia-reperfusion injury, although this has not been demonstrated in humans. This thesis examines (a) the role of atorvastatin in acute protection from ischaemia-reperfusion injury in human myocardium, (b) the ability of high-dose atorvastatin to recapture cardioprotection in human myocardium in the setting of chronic statin therapy, and (c) the functionality of the mitochondrial permeability transition pore in human hypertrophic cardiomyopathy, and the role of atorvastatin in inhibiting pore opening following oxidative stress. Methods and Results: Using human models to simulate ischaemia-reperfusion injury we have demonstrated: (1) Human atrial myocardium can be protected from simulated ischaemia-reperfusion injury by treatment with atorvastatin at the time of reperfusion; (2) Cardioprotection against simulated ischaemia-reperfusion injury can be recaptured with high-dose atorvastatin; (3) The mitochondrial permeability transition pore is a critical determinant in cell death in hypertrophic cardiomyopathy, and its inhibition can be achieved using atorvastatin. Conclusion: The key aim of emergency reperfusion therapy in the setting of myocardial infarction is salvage of myocardium and preservation of cardiac function. These studies contribute to the field by exploring the cardioprotective effects of atorvastatin in human myocardium and delineating protective cascades involved. They offer a key translational step in our understanding of statin cardioprotection, and an insight into cardioprotection in hypertrophic cardiomyopathy.