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

Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H767-75. doi: 10.1152/ajpheart.00468.2006. Epub 2006 Oct 13.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers / blood
  • Blotting, Western
  • Caspase 3 / metabolism
  • Chromatography, High Pressure Liquid / methods
  • Cytochromes c / blood*
  • Disease Models, Animal
  • Electric Stimulation
  • Heart Arrest / blood*
  • Heart Arrest / etiology
  • Heart Arrest / pathology
  • Heart Arrest / physiopathology
  • Heart Arrest / therapy
  • Heart Ventricles / metabolism
  • Leukocytes / metabolism
  • Male
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Heart / pathology
  • Predictive Value of Tests
  • Prognosis
  • Rats
  • Rats, Sprague-Dawley
  • Resuscitation*
  • Severity of Illness Index
  • Time Factors
  • Ventricular Fibrillation / complications
  • Ventricular Function, Left

Substances

  • Biomarkers
  • Cytochromes c
  • Caspase 3