Ischaemic conditioning: are we there yet?

1. To recognise that acute myocardial ischaemia/reperfusion injury is a neglected therapeutic target for cardioprotection that is responsible for the ongoing morbidity and mortality of patients with ischaemic heart disease. 2. To be aware that cardiac bypass surgery and STEMI are the major clinical settings in which the heart is subjected to acute ischaemia/reperfusion injury. 3. To be familiar with the concept of 'ischaemic conditioning', in which the heart is protected against acute ischaemia/reperfusion injury by subjecting it to cycles of brief ischaemia and reperfusion, a therapeutic strategy which has been demonstrated in proof-of-concept studies to be beneficial in patients with ischaemic heart disease. Ischaemic heart disease (IHD) is the leading cause of death and disability worldwide. Despite current therapies, patients still experience significant morbidity and mortality when undergoing cardiac bypass surgery or when presenting with an ST-segment elevation myocardial infarction (STEMI). This is partly attributed to the detrimental effects of acute ischaemia/reperfusion injury (IRI) on the heart, which in combination mediate cardiomyocyte death, resulting in impaired left ventricular (LV) systolic function and increased risk of heart failure. Although a number of strategies exist for reducing the ischaemic component of acute IRI injury in cardiac bypass surgery (such as cardioplegia and hypothermia) and STEMI (such as prompt reperfusion with primary percutaneous intervention-PPCI), paradoxically, reperfusing previously ischaemic myocardium leads to further cardiomyocyte death – termed 'myocardial reperfusion injury' and for which there is currently no effective therapy. Therefore, novel therapeutic interventions are required to protect the heart from acute IRI in these clinical settings in order to improve clinical outcomes. In this regard, 'ischaemic conditioning', in which the heart is rendered tolerant to acute IRI by subjecting it to cycles of brief ischaemia and reperfusion, provides an endogenous form of cardioprotection. In this article, we review the role for ischaemic conditioning as a therapeutic strategy for attenuating cardiomyocyte death, preserving myocardial function, and improving clinical outcomes in patients subjected to acute myocardial IRI. Although myocardial reperfusion is essential to salvage viable myocardium following the onset of acute myocardial ischaemia, the restoration of coronary blood flow comes at a price, paradoxically inducing myocardial injury and cardiomyocyte death – termed 4 'myocardial reperfusion injury'. Four types of myocardial reperfusion injury have been described: 1. Reperfusion-induced arrhythmias: These occur on reperfusing previously ischaemic myocardium and comprise idioventricular rhythm and ventricular arrhythmias, the majority of which are self-terminating or are easily treated. 2. Myocardial stunning: …