Remote ischemic conditioning to protect the heart in myocardial infarction : therapeutic intervention and underlying mechanisms

Sammanfattning: Background Urgent reperfusion of the occluded coronary artery halts the ischemic insult to the myocardium and is the single most important action to limit infarct size in ST-elevation myocardial infarction. However, reperfusion itself introduces an additional threat to the recovering ischemic myocardium whereby still viable cardiomyocytes suffer additional irreversible damage. This is referred to as reperfusion injury and significantly contributes to final infarct size. As of yet there is no established treatment to avoid or limit reperfusion injury, but promising results have been presented from early clinical trials of remote ischemic conditioning, whereby short cycles of non-harmful ischemia and reperfusion performed in remote tissue during the late stages of myocardial ischemia or early stages of myocardial reperfusion elicits an innate mechanism that ultimately terminates in cardioprotection. However, the exact underlying mechanisms are not fully known and additional clinical trials are needed to decide the possible role for remote ischemic conditioning in the treatment of patients with ST-elevation myocardial infarction. This thesis was undertaken to determine the effects of remote ischemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction and to explore underlying mechanisms. Studies I and II The effect of remote ischemic conditioning performed during the late stages of ischemia and at reperfusion as an adjunct to primary percutaneous intervention was investigated in 115 patients with anterior ST-elevation myocardial infarction. Infarct size as evaluated by cardiac magnetic resonance imaging during the first week and six months after the myocardial infarction, as well as clinical outcomes up to three years of follow-up were not affected by remote ischemic conditioning. Study III The involvement of the glucagon-like peptide-1 receptor in the signaling pathway of remote ischemic conditioning was explored in twelve healthy males. Intravenous infusion of the glucagon-like peptide-1 receptor antagonist exendin(9-39) abolished the protection against endothelial ischemia-reperfusion injury provided by remote ischemic conditioning, as evaluated by ultrasound based measurement of flow mediated dilatation in the brachial artery. Study IV The effect of chronic ticagrelor treatment on endothelial function was evaluated in twenty male patients with a previous acute coronary syndrome. Chronic ticagrelor treatment was not associated with protection against endothelial ischemia-reperfusion injury or better basal endothelial function compared to after its discontinuation, as evaluated by ultrasound based measurement of flow mediated dilatation in the brachial artery. Conclusions Remote ischemic conditioning performed during the late stages of ischemia and at reperfusion as an adjunct to primary percutaneous coronary intervention in patients with anterior STelevation myocardial infarction does not lead to smaller myocardial infarct size or improved clinical outcomes. Remote ischemic conditioning utilizes a glucagon-like peptide-1 receptor dependent pathway to protect against endothelial ischemia-reperfusion injury. Chronic ticagrelor treatment does not provide protection against endothelial ischemia-reperfusion injury or improved basal endothelial function compared to after its discontinuation.