Abstract
In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury—and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.
Highlights
Despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results
The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury—and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man
Since the original description of ischaemic conditioning by Murry, Jennings and Reimer in 1986 [56], the understanding of the mechanisms of cell death arising from injurious ischaemia and reperfusion injury has been transformed: no longer a purely necrotic model, it is recognised as a complex, multifaceted pathophysiological process [37], involving necrosis, and cellular signalling, apoptosis, necroptosis [16] and the complex interaction of autophagy [15] through to inflammatory injury and pyroptosis [78] (Fig. 1)
Summary
Since the original description of ischaemic conditioning by Murry, Jennings and Reimer in 1986 [56], the understanding of the mechanisms of cell death arising from injurious ischaemia and reperfusion injury has been transformed: no longer a purely necrotic model, it is recognised as a complex, multifaceted pathophysiological process [37], involving necrosis, and cellular signalling, apoptosis, necroptosis [16] and the complex interaction of autophagy [15] through to inflammatory injury and pyroptosis [78] (Fig. 1). While the efforts of cardioprotective strategies such as primary PCI have led to reduced early cardiovascular mortality, the ‘‘cardioprotection paradox’’ has been the incremental increase in the number of patients living with the consequence of myocardial injury: ischaemic cardiomyopathy and heart failure [10, 55]. Remote Ischaemic Preconditioning for Heart Surgery (RIPHeart) [54] and Effect of Remote Ischaemic Preconditioning on Clinical Outcomes in CABG Surgery (ERICCA) [27] Both of these studies sought to determine the efficacy of remote ischaemic conditioning (four cycles of 5 min upper limb ischaemia wrought by inflation of a blood pressure cuff to 200 mmHg and 5 min reperfusion with cuff deflation) in patients undergoing open-heart surgery and on-pump cardio-pulmonary bypass. Optimisation of surgical and anaesthetic techniques may have led to a progressively smaller peri-procedural myocardial injury in patients undergoing CABG and valve surgery in recent years.
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