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Ann Thorac Surg 2004;78:948-955
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

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

Christopher A. Caldarone, MDa,b,*, Elesa W. Barner, MATa, Lixing Wang, MD, PhDb, Mohsen Karimi, MDa, Christopher E. Mascio, MDa, James M. Hammel, MDa, Jeffrey L. Segar, MDc, Changqing Du, MDb, Thomas D. Scholz, MDc

a Division of Cardiovascular Surgery, University of Iowa College of Medicine, Iowa City, Iowa, USA
c Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa, USA
b Division of Cardiothoracic Surgery, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Accepted for publication April 5, 2004.

* Address reprint requests to Dr Caldarone, Division of Cardiovascular Surgery, The Hospital for Sick Children, 555 University Ave, Ste 1525, Toronto, Ontario, Canada, M5G 1X8, Canada
christopher.caldarone{at}sickkids.ca

Presented at the Poster Session of the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.

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.




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