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TRANSLATIONAL PHYSIOLOGY

Circulating levels of cytochrome c after resuscitation from cardiac arrest: a marker of mitochondrial injury and predictor of survival

¹Division of Critical Care Medicine, Department of Medicine, and Department of Physiology and Biophysics, and ³Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, and ²Section of Critical Care Medicine, Medical Service, North Chicago Veterans Affairs Medical Center, North Chicago, Illinois

Submitted 8 May 2006 ; accepted in final form 3 October 2006

Ca²⁺ overload and reactive oxygen species can injure mitochondria during ischemia and reperfusion. We hypothesized that mitochondrial injury occurs during cardiac resuscitation, causing release of cytochrome c to the cytosol and bloodstream while activating apoptotic pathways. Plasma cytochrome c was measured using reverse-phase HPLC and Western immunoblotting in rats subjected to 4 or 8 min of untreated ventricular fibrillation and 8 min of closed-chest resuscitation followed by 240 min of postresuscitation hemodynamic observation. A sham group served as control. Plasma cytochrome c rose progressively to levels 10-fold higher than in sham rats 240 min after resuscitation (P < 0.01), despite reversal of whole body ischemia (decreases in arterial lactate). Cytochrome c levels were inversely correlated with left ventricular stroke work (r = –0.40, P = 0.02). Western immunoblotting of left ventricular tissue demonstrated increased levels of 17-kDa cleaved caspase-3 fragments in the cytosol. Plasma cytochrome c was then serially measured in 12 resuscitated rats until the rat died or cytochrome c returned to baseline. In three survivors, cytochrome c rose slightly to 2 µg/ml and returned to baseline within 96 h. In nine nonsurvivors, cytochrome c rose progressively to significantly higher maximal levels [4.6 (SD 2.0) vs. 1.6 (SD 0.3) µg/ml, P = 0.029] and at faster rates [0.7 (SD 0.5) vs. 0.1 (SD 0.1) µg·ml^–1·h^–1, P = 0.046] than in survivors. Plasma cytochrome c may represent a novel in vivo marker of mitochondrial injury after resuscitation from cardiac arrest that relates inversely with survival outcome.

apoptosis; biological markers; cardiopulmonary resuscitation; myocardial ischemia; ventricular fibrillation