Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology

Abstract

The phenomenon of ischemic preconditioning, in which a period of sublethal ischemia can profoundly protect the cell from infarction during a subsequent ischemic insult, has been responsible for an enormous amount of research over the last 15 years. Ischemic preconditioning is associated with two forms of protection: a classical form lasting approximately 2 h after the preconditioning ischemia followed a day later by a second window of protection lasting approximately 3 days. Both types of preconditioning share similarities in that the preconditioning ischemia provokes the release of several autacoids that trigger protection by occupying cell surface receptors. Receptor occupancy activates complex signaling cascades which during the lethal ischemia converge on one or more end-effectors to mediate the protection. The end-effectors so far have eluded identification, although a number have been proposed. A range of different pharmacological agents that activate the signaling cascades at the various levels can mimic ischemic preconditioning leading to the hope that specific therapeutic agents can be designed to exploit the profound protection seen with ischemic preconditioning. This review examines, in detail, the complex mechanisms associated with both forms of preconditioning as well as discusses the possibility to exploit this phenomenon in the clinical setting. As our understanding of the mechanisms associated with preconditioning are unravelled, we believe we can look forward to the development of new therapeutic agents with novel mechanisms of action that can supplement current treatment options for patients threatened with acute myocardial infarction.

Mild exercise training, cardioprotection and stress genes profile

“…Recent studies have clearly shown that training at >60% VO 2max increases myocardial tolerance to ischemia-reperfusion (I-R) (Strøm et al 2005), improves cardiac performance and ameliorates the cell defence capacity against stress (Powers et al 2002;Freimann et al 2005). Most probably, the mechanisms underlying training-induced cardioprotection resemble those elicited by ischemic preconditioning (IP), e.g., the phenomenon whereby short ischemic episodes given before a major ischemic insult lead to into endogenous cardioprotection (Yellon and Downey 2003). Training may induce IP by emulating minor local ischemic episodes, where ischemia is intended as short periods of time during which the supply of blood and oxygen to tissues is limited with respect to the tissue needs (Hearse 1994).…”

Vasopressors for cardiopulmonary resuscitation

“…Secondly, the tissues inevitably become ischaemic whilst they are being removed from the animal and prior to set up. This ischaemia may be sufficient to activate ischaemic preconditioning, a cardioprotective phenomenon whereby short periods of ischaemia initiate pro-survival signalling within cells and protect against the damage caused by subsequent ischaemic episodes (Murry et al 1986;Awan et al 1999;Yellon and Downey 2003). Thirdly, isolated cardiac preparations are rarely viable for long enough to determine whether any myocardial dysfunction is due to permanent cell death or reversible stunning.…”

Comment utiliser le paradigme de préconditionnement ischémique pour protéger le myocarde ?

“…La protéine kinase C (PKC) semble participer à la médiation du pré-conditionnement [12]: des antagonistes de la PKC (ché-léréthryne, staurosporine…) abolissent la limitation de taille de l'infarctus consécutive au préconditionnement, tandis que les activateurs de la PKC (PMA…) reproduisent cet effet bénéfique. Selon l'espèce animale considérée, seules certaines isoformes sont impliquées [13]. Les tyrosine kinases (TK) et les mitogen-activated protein kinases (MAPK) (en particulier p38MAPK, mais aussi ERK et JNK) peuvent également participer à la signalisation du préconditionnement [13].…”

“…Selon l'espèce animale considérée, seules certaines isoformes sont impliquées [13]. Les tyrosine kinases (TK) et les mitogen-activated protein kinases (MAPK) (en particulier p38MAPK, mais aussi ERK et JNK) peuvent également participer à la signalisation du préconditionnement [13]. montrer que l'activation des canaux K + ATP est impliquée dans le préconditionnement; mais ils s'intéressaient alors aux canaux K + ATP localisés dans le sarcolemme [15].…”