Spotlight on preconditioning.

The phenomenon of ischaemic preconditioning, in finally produce the profound protection, all attest to the which a period of sublethal ischemia can profoundly complexity of interrelated biological pathways. There is no protect the cell from subsequent lethal ischemic insult, has doubt that since the initial discovery of preconditioning we without doubt been responsible for an enormous amount of have learnt a huge amount with regard to the cellular research over the last 15 years. Since the original publiphysiology/molecular biology that was not appreciated cation in 1986 by Murry et al. [1] there have been in before. excess of 2000 publications directly attributed to this With ischemic preconditioning, nature has shown us that phenomenon. Furthermore it is virtually impossible to find cardioprotection is indeed possible. Over the last two a publication that fails to demonstrate the ability of decades there has been a concerted goal of trying to sublethal ischemia to protect the myocardium from a lethal understand the mechanism of this adaptive phenomenon. If ischemic insult thus attesting to the power of the phenomwe can grasp how cells are protected, as a consequence of enon of ischemic preconditioning. This early form of ischemic preconditioning, then the possibility of developprotection has become know as ‘‘classic or early precondiing pharmacological mimics that can be used clinically to tioning’’. This was followed in 1993 by the first descriphelp patients at risk of having a severe myocardial tion of the ‘‘Second Window of Protection’’ or delayed infarction, will be a major development. For the first time preconditioning (sometimes referred to as late precondiwe are gaining a real understanding of how a cell requires tioning) by Marber et al. [2] in which a second period of to protect itself from injury and based on this understandprotection was observed 24 h after a sublethal ischemic ing we may be truly at the brink of developing agents insult. For those interested in statistics it may be noted that capable of directly limiting cellular injury. What is amazthe original article in which this phenomenon was first ing however is how we can know so much about this described in 1986 is the most cited article that Circulation system and still be so ignorant of the fundamental mechahas ever published, with that describing the delayed or nism as to how preconditioning actually protects the heart. second window as the 15th most cited paper by that That lack of understanding probably stems from our not journal. knowing what the actual lethal event is in ischemic cell That a myocardial cell has an innate ability to protect death. Research must continue until a complete underitself from severe lethal ischemia based upon what it can standing of the preconditioning phenomenon has been ‘‘learn’’ from a prior sublethal ischemic insult has caught achieved. the imagination of basic and clinical scientists all over the This spotlight issue has been designed to both highlight world. What is believed to be so unique about this the amazing progress that has been made, to focus on new phenomenon is that it tells us how a cell tries to survive a and important discoveries that are taking place, and to severe ischemic insult. It is therefore important to try and spotlight the challenges that still lie ahead in this reunderstand the myriad of pathways that are associated with markably exciting time. this survival mechanism. From the initial receptor that This spotlight issue begins with four reviews each of triggers or initiates the complex and elaborate signalling which highlights new areas of interest that relate to the pathways to the incompletely understood end-effectors that potential mechanisms associated with ischemic preconditioning. Since the discovery that the mitochondrial KATP channel is pivotal to the mechanism of ischemic precondi*Corresponding author. Tel.: 144-207-380-0591; fax: 144-207-388tioning, controversy has existed as to whether this channel 5095. E-mail address: [email protected] (D.M. Yellon). is a trigger, a mediator, or the end effector of precondition-