Ischaemic preconditioning: is it clinically relevant?

Abstract

Direct clinical evidence for the classical preconditioning phenomenon, with infarct size limitation as an endpoint, cannot be obtained. However, a number of patient groups have been identified in which adaptation to ischaemia has been demonstrated by enhanced recovery of function or preservation of high energy phosphates in models of repeated ischaemia, such as atrial pacing stress tests, percutaneous transluminal coronary angioplasty and aortic cross-clamping during cardiac surgery. Evidence is accumulating that mechanisms which are operative in experimental ischaemic preconditioning (infarct size limitation) are also operative in these clinical models of repeated reversible ischaemia. Insight into the mechanisms responsible for ischaemic preconditioning could potentially help to develop pharmacological agents which mimic preconditioning. This is especially attractive as several of the ischaemic episodes maybe too short or insufficiently severe to trigger preconditioning. By a synergistic or additive action, the combination of such a stimulus with a low dose of pharmacological agent might result in protective action. If these agents were also to be used for treating cardiovascular conditions, such as the K+ATP channel activator nicorandil for the treatment of angina pectoris, the cardioprotective effect could be a beneficial side effect. The currently available protein kinase C activators are oncogenic, but with the recognition and better understanding of the different subtypes possibly involved in preconditioning, new protein kinase C activators may become available without these side-effects. On the other hand, hearts of patients who regularly experience episodes of ischaemia may be in a more or less permanent state of preconditioning afforded by one of these stimuli or have developed tolerance. In this situation it is likely that (additional) protection by a pharmacological agent cannot be accomplished at that time. It is reassuring, however, that in the animal, preconditioning can be reinstated immediately after the cardioprotection is lost and that it can also be demonstrated in hearts with pathological conditions such as hypertrophy. Finally, in view of the observations that cardioprotection may also be produced by transient ischaemia in other organs, and even by some forms of stress which do not lead to myocardial ischaemia, it could be envisioned that ischaemic preconditioning is only one component of a general form of adaptation.