Ischemic preconditioning: a plea for rationally targeted clinical trials

Ischemic preconditioning has emerged as among the most promising approaches to reduce ischemic cell death. While tremendous effort has gone into the determination of mechanisms of both the early and delayed phases of this phenomenon, progress toward the direct application of PC-based therapies in cardiovascular medicine has been lacking. Initial screening of potential PC-mimetic candidates is highly feasible in isolated myocyte models and in the setting of angioplasty, while prophylactic treatment with PC-based strategies could most readily be evaluated in clinical trials of heart transplant and coronary artery bypass surgery. In contrast, the requirement for pretreatment will make therapeutic application of PC-mimetics in the unpredictable setting of acute MI considerably more challenging. It is important that all clinical studies of PC and PC-based therapies endeavor to include, as a primary endpoint, a direct or surrogate assessment of myocyte necrosis, the undisputed hallmark of PC-induced cardioprotection. Moreover, any large-scale clinical application of PC-based strategies will clearly require definitive evidence for the continued efficacy of ischemic preconditioning in the aged and diseased heart.