Radhakrishnan J, Wang S, Ayoub IM, Kolarova JD, Levine RF, Gazmuri RJ. Circulating levels of cytochrome c after resuscitation from cardiac arrest: a marker of mitochondrial injury and predictor of survival.

NHE-1 inhibition may represent a novel and remarkably effective intervention for resuscitation from VF.

overload yielding levels that corresponded to 77% and 71% of control hearts at VF/CC and PR, without differences among specific Na ϩ -limiting interventions. Limiting sarcolemmal Na ϩ entry attenuated reductions in left ventricular compliance during VF and prompted higher mean aortic pressure (110 Ϯ 7 vs. 95 Ϯ 11 mmHg, P Ͻ 0.001) and higher cardiac work index (159 Ϯ 34 vs. 126 Ϯ 29 g ⅐ m ⅐ min Ϫ1 ⅐ kg Ϫ1 , P Ͻ 0.05) with lesser increases in circulating cardiac troponin I at 60 min PR. Conclusions: Na ϩ -limiting interventions prevented excess Ca 2ϩ m accumulation induced by ischemia and reperfusion and ameliorated myocardial injury and dysfunction. calcium; cardiopulmonary resuscitation; myocardial ischemia; sodium

Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variables periods of time. However, reperfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as "reperfusion injury." At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Studies in animal models of ventricular fibrillation have shown that limiting myocardial cytosolic Na + overload attenuates mitochondrial Ca 2+ overload and maintains oxidative phosphorylation, which is the main bioenergetic function of mitochondria. This effect is associated with functional myocardial benefits such as preservation of myocardial compliance during chest compression and attenuation of myocardial dysfunction after return of spontaneous circulation. Additional studies in similar animal models of ventricular fibrillation have shown that mitochondrial injury leads to activation of the mitochondrial apoptotic pathway; characterized by the release of cytochrome c to the cytosol, reduction of caspase-9 levels, and activation of caspase-3 coincident with marked reduction in left ventricular function. Cytochrome c also "leaks" into the bloodstream attaining levels which are inversely proportional to survival. These data indicate that mitochondria play a key role during cardiac resuscitation by modulating energy metabolism and signaling apoptotic cascades and that targeting mitochondria could represent a promising strategy for cardiac resuscitation.