Toward the heart of ischemic preconditioning

Time for primary review 1 day. In 1986 Murry and co-workers introduced the term ‘Ischemic Preconditioning’ [1]. In this classical paper the authors referred to ischemic preconditioning as an adaptation to ischemic stress induced by repetitive short periods of ischemia and reperfusion. The protective effect comprised a reduction of energy consumption and a delay of the onset of lethal cell injury during ischemia resulting in a limitation of infarct size after 40 minutes, but not after three hours of sustained ischemia [1]. The fascination for this intrinsic protective property of the myocardium has led to a still expanding gamut of research, which was comprehensively reviewed by Yellon and co-workers in this issue of Cardiovascular Research [2]. Three aspects can be distinguished in the process of ischemic preconditioning. The initial trigger (1), that is included in the short periods of ischemia and reperfusion, activates signalling pathways (2), which in their turn act upon an end-effector inducing the delay of lethal ischemic damage during sustained ischemia (3). All three facets have been extensively studied, although the vast majority of the investigations focuses on the signalling pathways. In spite of this, the central mechanism, which results in the delay of necrosis, remains unclear. Therefore, it can be questioned whether the apparently centrifugal expansion of triggers, mediators and salutary endpoints of ischemic preconditioning [2, 3]will at any time lead us to clarify a central effector mechanism. This paper aims at expounding the concept of the central mechanism and critically reviews the still increasing number of proposed signalling pathways and salutary endpoints of preconditioning. Obviously, the factor initiating protection is operative during the short periods of ischemia or reperfusion of ischemic preconditioning. However, this factor remains obscure. The majority of evidence suggests that it is the ischemia and not the reperfusion … * Corresponding author.