Ischaemic Preconditioning of the Human Heart: Mechanisms of Myocardial Protection

Ischaemic preconditioning (PC) describes the increased resistance to myocardial infarction that follows short sublethal periods of ischaemia. It has been shown to exist in all mammalian species investigated to date. In the early 90's, some evidence started to evolve which reported that this powerful cardioprotective phenomenon exists in man. After ischaemia that triggers preconditioning, there are 2 phases of protection: an early phase (short-lived) termed early of classic preconditioning and a late (more prolonged) phase termed a second window of protection. The evidence for this has primarily come from work on the rabbit and rat isolated hearts. There is no information related to the characteristics of this preconditioning phenomenon in humans. The study commenced with the development of an in vitro model of human myocardium to study the effects of ischaemia and reperfusion injury. The data provided evidence that the in vitro incubation of human atrial tissue is stable and slices are viable for at least 24 hr and that this permits the study of early and delayed consequences of ischaemia and reperfusion in the human myocardium. This model was also used to study the preconditioning phenomenon fully. There were some unanswered questions pertaining to the characteristics of the PC phenomenon. The results showed that maximal protection can be achieved with 4-6 min of ischaemic stimulus/5min reperfusion and beyond that, protection was abolished. It also reported that this early phase was protective for only 2 hours after the trigger and that in the atrium, a second window of protection existed although much less potent. Attention was then focussed on the mechanisms underlying this powerful event. The mechanisms have only been partly characterised in humans. It would appear that a trigger (e. g adenosine, bradykinin, adrenaline) activates a receptor-mediated Gi protein which activates a signalling pathway (Protein kinase C+ Mitogen activated Protein Kinase systems) which in turn open ATP-dependent K+ channels (end-effector), either at the sarcolemmal or mitochondrial membrane, which when activated leads to protection. The initial sets of experiments were performed to elucidate this effector via pharmacological means primarily. It showed that this putative effector in human preconditioning was the mitochondrial KATP channel and not the sarcolemmal channel, as previously described. There has been conflicting evidence suggesting that this phenomenon is a healthy heart phenomenon. In parallel studies, experiments were conducted to explore the impact of cardiac function and diabetes mellitus on the protection induced by PC. The data revealed that cardioprotection induced PC is abolished in the failing myocardiurn and also in diabetic hearts. This is a novel finding and the implications are far-reaching. It also demonstrated that the failure to precondition the diabetic heart is due to dysfunction of the mitochondrial KATP channels and the mechanism of failure in the failing heart lies in other elements of the signal transduction pathway different from the mitochondrial KATP channels. Despite intensive investigation into the phenomenon, clinical application is still controversial. Whether this powerful cardioprotective phenomenon has a role in clinical practice is still not established. The apparent discrepancy between clinical studies in the literature could be reconciled if one takes into account one possible hypothesis - that preconditioning and its salutary effects are only observed in situations of unprotected ischaemia. As a result, this led to the design of a prospective randomised clinical study with the following aims: (i) to investigate whether ischaemic preconditioning with 5 min ischaemia followed by 5 min reperfusion is protective in patients undergoing coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass using cardioplegia and ventricular fibrillation techniques and in patients undergoing CABG on the beating heart without cardiopulmonary bypass, and (ii) to elucidate the underlying cause of any protection. The results of the studies suggested that PC is protective in patients undergoing coronary artery surgery on the beating heart without the use of CPB but offers no additional benefit when associated to CPB regardless of the mode of cardioprotection used and the reason for this being that CPB per se induces preconditioning. What is clear, however, is that the unravelling of the mechanisms and phenomenon of PC may permit the development of methods to delay the onset of irreversible ischaemic injury, so providing a greater time window during which reperfusion may be achieved.