Preconditioning the human myocardium: Recent advances and aspirations for the development of a new means of cardioprotection in clinical practice

Abstract

Ischemic preconditioning has been shown to be one of the most powerful means of protecting the myocardium from ischemic injury in experimental animal models, although the mechanism is incompletely understood. In this review we discuss the evidence for preconditioning occurring in ischemic syndromes in humans, whether the human myocardium can be preconditioned, and whether preconditioning would have a place as a therapeutic tool in clinical practice. Some studies evaluating patients after acute myocardial infarction have shown a better outcome in patients reporting angina before the onset of the infarction, but this is not a universal finding, and it is difficult to exclude other confounding factors, such as collateral flow, from influencing the results. More controlled prospective studies have evaluated patients undergoing percutaneous transluminal coronary angioplasty and have found less ST-segment change and less reported angina during the second balloon inflation when compared with the first. Again, it is impossible to completely exclude other causes for this effect, but the dependence on mechanisms that are known to be important for preconditioning in animal models does suggest the phenomena are the same. Further experiments using isolated human atrial muscle have shown that human myocardium can be preconditioned and that the mechanisms involved are similar to those elucidated in animal models (adenosine, protein kinase C, and ATP-dependent potassium channels). In clinical medicine preconditioning is most likely to benefit patients when it is used to protect against the ischemia induced by cardiac surgery. In this respect, a study has shown that in patients undergoing coronary artery bypass grafts, the reduction in ATP occurring during the first ischemic period is attenuated in those given an ischemic preconditioning protocol beforehand. Despite these advances, it is likely that the full potential of preconditioning in clinical practice will not be realized until the whole mechanism of protection is understood and a safe pharmacological "preconditioning" agent becomes available.

‘Warm-up’ phenomenon in diabetic patients with stable angina treated with diet or sulfonylureas

“…In the clinical setting there is some evidence to suggest that preconditioning occurs in human myocardium. An example may be the phenomenon of warm-up angina, in which patients complain that their anginal symptoms are worse in the morning but improve during the course of the day, and percutaneous transluminal coronary angioplasty studies in which repeated balloon inflation induces sequential brief periods of myocardial ischaemia [3][4][5]. More direct evidence for ischaemic preconditioning in man has emerged from a study in patients undergoing coronary artery bypass grafting using the cross-clamp fibrillation technique, in which the heart is subjected to repeated episodes of global ischaemia [6,7].…”

Controversies in preconditioning

“…The involvement of KAT P channels in the preconditioning of larger animals seems clear but may not be essential in rabbits and rats [for review, see [24]. The involvement of KAT P channels in the preconditioning of larger animals seems clear but may not be essential in rabbits and rats [for review, see [24].…”

“…The arteriovenous difference in both metabolites did not change significantly as a result of the repeated occlusions (Fig. We believe that the angioplasty times of balloon inflations, often lasting less than 2 minutes, are insufficient to induce ischemic preconditioning in humans [24]. The biochemical markers used provided no evidence for preconditioning during coronary angioplasty [11].…”

Preconditioning does not attenuate cardiac dysfunction after global ischaemia in the guinea‐pig

“…Although preconditioning has primarily been studied in models of experimental infarcts where infarct size is reduced in all species, increasing evidence suggests that it also improves cardiac performance during reperfusion after global ischaemia (Cave et al 1993, Moolman et al 1995, Weselcough et al 1995, Takeshima et al 1997. Despite intensive search for determining the underlying mechanisms of myocardial protection, these remain controversial and appear to differ between species (Mitchell et al 1993, Reimer et al 1994, Downey et al 1994, Downey & Cohen 1995, Jenkins et al 1995b. Some evidence suggests that endogenous cardiopro-tective substances such as adenosine may activate protein kinase C (PKC) through G-protein linked receptors, which through an unknown second effector may exert the cardioprotective actions.…”

“…Some evidence suggests that endogenous cardiopro-tective substances such as adenosine may activate protein kinase C (PKC) through G-protein linked receptors, which through an unknown second effector may exert the cardioprotective actions. Although PKC activation seems to be a mechanism in rats and rabbits, it is more controversial in pigs and dogs (Mitchell et al 1993, Reimer et al 1994, Downey et al 1994, Downey & Cohen 1995, Jenkins et al 1995b). The second effector, or possibly a mechanism on its own, is suggested to be the opening of ATP-dependent potassium channels ± this may be the case in big animals, but is not consistently shown in smaller animals (Mitchell et al 1993, Reimer et al 1994, Downey et al 1994, Downey & Cohen 1995, Jenkins et al 1995b).…”