Apoptosis-related mitochondrial dysfunction in the early postoperative neonatal lamb heart

Christopher A. Caldarone, Elesa W. Barner, Lixing Wang, Mohsen Karimi, Christopher E. Mascio, James M. Hammel, Jeffrey L. Segar, Changqing Du, Thomas D. Scholz

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Background In the early postoperative period, the neonatal myocardium undergoes sparse apoptotic cell loss (∼ 1% of myocytes). Because apoptosis is preceded by events associated with mitochondrial dysfunction, the fraction of myocytes with preapoptotic mitochondrial changes has important clinical implications (eg, postoperative myocardial dysfunction). My colleagues and I therefore hypothesized that postoperative apoptotic myocytes represent a tip of the iceberg, with more myocytes upstream with apoptosis-related mitochondrial dysfunction (ARMD). Methods Neonatal lambs underwent cardiopulmonary bypass, 60 minutes of cardioplegic arrest, and 6 hours of recovery (cardiopulmonary bypass with cardioplegic arrest [CPB+CP]; n = 5) and were compared with nonbypass controls (non-CPB; n = 5). Myocardium (left ventricle [LV] and right ventricle [RV]) was examined by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, electron microscopy, immunohistochemistry, Western blot, and isolated mitochondrial oxygen consumption measurement. Results TUNEL-positive nuclei and electron microscopy-confirmed mitochondrial structural changes were more common in CPB+CP than non-CPB myocardium and were more common in the LV than RV (p = 0.0016). Bax (a proapoptotic mediator) translocated from the cytosol to the mitochondria (LV > RV; p < 0.05). Immunohistochemistry demonstrated diffuse mitochondrial loss of cytochrome c that was consistent with outer mitochondrial membrane permeabilization (LV > RV > non-CPB). Permeabilization was further demonstrated by augmentation of oxygen consumption in isolated mitochondria after administration of exogenous cytochrome c. The mitochondrial oxygen consumption boost was 57% for CPB+CP:LV; 23% for CPB+CP:RV; and 18% and 17% for non-CPB:LV and non-CPB:RV, respectively (p < 0.01, CPB+CP:LV vs other groups). Conclusions ARMD is much greater than the prevalence of TUNEL-positive myocytes in postoperative neonatal myocardium. Greater LV vulnerability may represent a relationship between increased afterload and ARMD. These changes are consistent with the early postoperative myocardial dysfunction commonly reported after neonatal cardiac operations.

Original languageEnglish (US)
Pages (from-to)948-955
Number of pages8
JournalAnnals of Thoracic Surgery
Volume78
Issue number3
DOIs
StatePublished - Sep 2004

Keywords

  • 31

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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