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Apoptosis-related mitochondrial dysfunction in the early postoperative neonatal lamb heart. Ann Thorac Surg 2004 Sep;78(3):948-55

Date

09/01/2004

Pubmed ID

15337026

DOI

10.1016/j.athoracsur.2004.04.031

Scopus ID

2-s2.0-4444367200   21 Citations

Abstract

BACKGROUND: In the early postoperative period, the neonatal myocardium undergoes sparse apoptotic cell loss ( approximately 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.

Author List

Caldarone CA, Barner EW, Wang L, Karimi M, Mascio CE, Hammel JM, Segar JL, Du C, Scholz TD

Author

Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Apoptosis
Disease Models, Animal
Immunohistochemistry
Mitochondria
Mitochondrial Diseases
Myocardium
Oxygen Consumption
Permeability
Proto-Oncogene Proteins c-bcl-2
Sheep
bcl-2-Associated X Protein
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75