Myocardial protection by postconditioning vs. staged reperfusion
Zusammenfassung der Projektergebnisse
Impending myocardial infarction is the inevitable consequence of prolonged myocardial ischemia, e.g. after a thrombotic occlusion of a large coronary artery. The progression of the ischemic injury can only be interrupted by timely reperfusion. However, reperfusion itself induces additional injury and contributes to final infarct size. An attractive strategy to reduce such reperfusion injury and salvage myocardium from infarction is ischemic postconditioning, i.e. additional brief periods of ischemia/reperfusion induced immediately at the onset of reperfusion. Postconditioning is clinically feasible because of its easy application at the predictable onset of reperfusion in patients with acute myocardial infarction and interventional reperfusion. Based on recent studies on ischemic postconditioning in small rodent heart models, the activation of so called Reperfusion Injury Salvage Kinases (RISK) was proposed to be involved in the protection against infarction. However, apart from inherent species differences, the spatial and temporal evolution of infarction in small rodent hearts largely differs from that in larger mammals, including humans. We investigated the impact of ischemic postconditioning in pigs, a large mammal species which closely resembles the human heart with respect to size, coronary anatomy and spatial and temporal development of myocardial infarction. The analysis of the underlying signal transduction cascade of myocardial protection at reperfusion focused on the role of RISK in myocardial protection at reperfusion. In addition, we also investigated myocardial protection against infarction by gentle reperfusion, another modification of the reperfusion phase with gradually increasing blood flow at reperfusion. Both, ischemic postconditioning and gentle reperfusion protected the myocardium against infarction after ischemia/reperfusion, i.e. infarct size was smaller than in control animals subjected to immediate full reperfusion. Activation of RISK kinases was observed at reperfusion, but the RISK activation pattern was not different between ischemic postconditioning and immediate full reperfusion. With gentle reperfusion, RISK activation was actually lower than with immediate full reperfusion. The pharmacological blockade of two major upstream RISK components, AKT and ERK1/2, did not abrogate infarct size reduction by postconditioning or gentle reperfusion. Thus, our results refute that in pigs an activation of RISK kinases at reperfusion is causal for myocardial protection against infarction by ischemic postconditioning or gentle reperfusion. This is in strong contrast to results from small rodent heart models, in which RISK activation is mandatory for protection against infarction. This discrepancy stresses the notion that the choice of the experimental model is crucial, since our data challenge the extrapolation of findings on the signal transduction underlying postconditioning and gentle reperfusion from other, notably rodent hearts to humans.
Projektbezogene Publikationen (Auswahl)
- Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res 2009;104:15-18
Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G
- Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs. Cardiovasc Res 2010, 85:110-117
Judith Musiolik, Patrick van Caster, Andreas Skyschally, Kerstin Boengler, Petra Gres, Rainer Schulz, and Gerd Heusch
