Targeting Reperfusion Injury in the Era of Primary PCI
Introduction of reperfusion therapy by primary percutaneous coronary intervention (PCI) has resulted in improved outcomes for patients presenting with ST-segment elevation myocardial infarction. Despite the obvious advantages of primary PCI, acute restoration of blood flow paradoxically also jeopardises the myocardium in the first minutes of reperfusion—a phenomenon known as reperfusion injury. Prevention of reperfusion injury may help to improve outcome following primary PCI. This review focuses on the clinical evidence of potential therapeutic cardioprotective methods as adjuvant to primary PCI. Despite overall disappointing, there exists some promising strategies, including ischaemic postconditioning, remote ischaemic conditioning, pharmacological conditioning with focus on adenosine, cyclosporine A, glucose–insulin–potassium, exenatide, atrial natriuretic peptide and metoprolol and cooling. But hitherto no large randomised study has demonstrated any effect on outcome, and ongoing studies that address this issue are underway. Moreover, this review will discuss important clinical predictors associated with reperfusion injury during primary PCI that may interfere with a potential protective effect (pre-PCI thrombolysis in myocardial infarction flow, preinfarction angina, collateral flow, duration of ischaemia and hyperglycaemia). This paper will also provide a short overview of the technical issues related to surrogate endpoints in phase II trials. Based upon these discussions, the paper will provide factors that should be taken into account when designing future clinical studies.
During the last decades, dramatic changes in the management of patients with ST-segment elevation myocardial infarction (STEMI) have evolved, resulting in improved outcomes. The major advance has been the introduction of reperfusion therapy by fibrinolysis and subsequently primary percutaneous coronary intervention (PCI), which today is the recommended treatment. However, the mortality rate following a STEMI has reached a plateau with 1-year mortality of 10%, and a substantial amount of patients develop clinical heart failure. It is a fundamental dogma that the benefit of reperfusion therapy is exerted through increased myocardial salvage and thereby reduction in infarct size. Thus, there is a need for further improvement in the treatment of patients with STEMI to improve myocardial salvage and drive the event rates down.
Despite the obvious advantages of reperfusion by primary PCI, acute restoration of blood flow paradoxically also jeopardises the myocardium in the first minutes of reperfusion. This phenomenon is known as reperfusion injury, which encompasses several distinct pathophysiological components including reversible impaired myocardial contractility (stunning), arrhythmias, no-reflow and death of cardiomyocytes (lethal reperfusion injury). Experimental data implicate a number of factors contributing to lethal reperfusion injury independently of no-reflow such as opening of the mitochondrial permeability transition pore (mPTP), rapid normalisation of pH, intracellular calcium overload and generation of reactive oxygen species (ROS). The lethal reperfusion injury may account for 50% of the final myocardial damage following an acute myocardial infarction, and prevention of reperfusion injury is considered pivotal for improving outcomes in patients with STEMI. This review evaluates potential cardioprotective treatments and determinants of reperfusion injury during primary PCI.
Abstract and Introduction
Abstract
Introduction of reperfusion therapy by primary percutaneous coronary intervention (PCI) has resulted in improved outcomes for patients presenting with ST-segment elevation myocardial infarction. Despite the obvious advantages of primary PCI, acute restoration of blood flow paradoxically also jeopardises the myocardium in the first minutes of reperfusion—a phenomenon known as reperfusion injury. Prevention of reperfusion injury may help to improve outcome following primary PCI. This review focuses on the clinical evidence of potential therapeutic cardioprotective methods as adjuvant to primary PCI. Despite overall disappointing, there exists some promising strategies, including ischaemic postconditioning, remote ischaemic conditioning, pharmacological conditioning with focus on adenosine, cyclosporine A, glucose–insulin–potassium, exenatide, atrial natriuretic peptide and metoprolol and cooling. But hitherto no large randomised study has demonstrated any effect on outcome, and ongoing studies that address this issue are underway. Moreover, this review will discuss important clinical predictors associated with reperfusion injury during primary PCI that may interfere with a potential protective effect (pre-PCI thrombolysis in myocardial infarction flow, preinfarction angina, collateral flow, duration of ischaemia and hyperglycaemia). This paper will also provide a short overview of the technical issues related to surrogate endpoints in phase II trials. Based upon these discussions, the paper will provide factors that should be taken into account when designing future clinical studies.
Introduction
During the last decades, dramatic changes in the management of patients with ST-segment elevation myocardial infarction (STEMI) have evolved, resulting in improved outcomes. The major advance has been the introduction of reperfusion therapy by fibrinolysis and subsequently primary percutaneous coronary intervention (PCI), which today is the recommended treatment. However, the mortality rate following a STEMI has reached a plateau with 1-year mortality of 10%, and a substantial amount of patients develop clinical heart failure. It is a fundamental dogma that the benefit of reperfusion therapy is exerted through increased myocardial salvage and thereby reduction in infarct size. Thus, there is a need for further improvement in the treatment of patients with STEMI to improve myocardial salvage and drive the event rates down.
Despite the obvious advantages of reperfusion by primary PCI, acute restoration of blood flow paradoxically also jeopardises the myocardium in the first minutes of reperfusion. This phenomenon is known as reperfusion injury, which encompasses several distinct pathophysiological components including reversible impaired myocardial contractility (stunning), arrhythmias, no-reflow and death of cardiomyocytes (lethal reperfusion injury). Experimental data implicate a number of factors contributing to lethal reperfusion injury independently of no-reflow such as opening of the mitochondrial permeability transition pore (mPTP), rapid normalisation of pH, intracellular calcium overload and generation of reactive oxygen species (ROS). The lethal reperfusion injury may account for 50% of the final myocardial damage following an acute myocardial infarction, and prevention of reperfusion injury is considered pivotal for improving outcomes in patients with STEMI. This review evaluates potential cardioprotective treatments and determinants of reperfusion injury during primary PCI.
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