Chapter category: Heart
Away from Ischemic Preconditioning and Towards Pharmacological Preconditioning
Ischemia-Reperfusion Injury in Cardiac Surgery
Edited by: Friedhelm BeyersdorfISBN: 1-58706-002-7
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Chapter authors:
Louis P. Perrault and Philippe Menasché
Endogenous myocardial protection refers to the natural defense mechanisms available to the heart to withstand an ischemic injury. So far these mechanisms have been shown to encompass two phenomena most likely interrelated: ischemic preconditioning and stress protein synthesis. Ischemic PC can be defined as the adaptive mechanism induced by a brief period of reversible ischemia increasing the heart's resistance to a subsequent longer period of ischemia. Two different time frames are defined for preconditioning, one early or classical preconditioning and one late also called the second window of preconditioning. The therapeutic exploitation of these natural adaptive mechanisms in cardiac surgery is an appealing prospect. Preconditioning could be used before aortic cross-clamping to enhance the current methods of myocardial protection. Two major conclusions emerge from the bulk of experimental data on preconditioning. First, the adaptive phenomenon reduces infarct size after regional ischemia in animal preparations across a wide variety of species but its effects on arrhythmias and on preservation of function after global ischemia are less consistent. This is relevant to cardiac surgery where postbypass pump failure is more often due to stunning than to discrete necrosis. Second, regardless of the various components of the intracellular signaling pathway elicited by the preconditioning stimulus, it seems that a major mechanism by which this pathway leads to a cardioprotective effect is a slowing of ATP depletion during the protracted period of ischemia. If the latter is true, then it can reasonably be predicted that this energy-sparing effect may become redundant to that of cardioplegia. These problems emphasize the importance of identifying the mechanisms underlying endogenous myocardial protection in an attempt to pharmacologically duplicate the protective action of ischemically induced preconditioning. Numerous triggers have been identified as being able to elicit and reproduce the effects of ischemic preconditioning. The role of ATP-sensitive potassium channels as mediators of the cardioprotective effects of preconditioning has been largely based on the observations that these effects could be duplicated by potassium channel openers (PCO) whereas they were abolished by potassium channel blockers. PCO given before potassium arrest have the ability to enhance functional recovery during reperfusion and may be independent of the temperature of the cardioplegia administered. Currently the application of these drugs is hampered by the fact that the anti-ischemic effects are obtained at much higher doses than those required for relaxation of smooth muscle and thus could cause important hemodynamic effects due to vasodilatation before the appearance of the cardioprotective effects. The modalities of pharmacologically-induced preconditioning,although intellectually appealing, remain to be determined including the choice of the optimal agents and regimens. The only clinical situation in which the ischemic preconditioning remains logical would be "off-pump" minimally invasive cardiac surgery as the occlusion of the target vessel during construction of the distal anastomosis most closely mimics the experimental scenario that has turned out to result in reduction of regionally-induced ischemic damage.
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