Circulating levels of cytochrome c after resuscitation from cardiac arrest: a marker of mitochondrial injury and predictor of survival.
Ca(2+) 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 <or=2 microg/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) microg/ml, P = 0.029] and at faster rates [0.7 (SD 0.5) vs. 0.1 (SD 0.1) microg.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.
Radhakrishnan
Jeejabai
J
Division of Critical Care Medicine, Department of Medicine, Rosalind Franklin University of Medicine and Science, and North Chicago Veterans Affairs Medical Center, North Chicago, Illinois, USA.
Wang
Sufen
S
Ayoub
Iyad M
IM
Kolarova
Julieta D
JD
Levine
Rita F
RF
Gazmuri
Raúl J
RJ
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D045304:Cytochromes c / Q000097:blood*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006323:Heart Arrest / Q000097:blood* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D006352:Heart Ventricles / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012720:Severity of Illness Index; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000150:complications; D016277:Ventricular Function, Left
D015415:Biomarkers; D045304:Cytochromes c; D053148:Caspase 3