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Faraz Kerendi
Paul M. Kirshbom
Michael E. Halkos
Zhi-Qing Zhao
Kirk R. Kanter
Robert A. Guyton
Jakob Vinten-Johansen
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Ann Thorac Surg 2006;81:2055-2062
© 2006 The Society of Thoracic Surgeons

Thoracic Surgery Directors Association Award

Cobalt Chloride Pretreatment Attenuates Myocardial Apoptosis After Hypothermic Circulatory Arrest

Faraz Kerendi, MD, Paul M. Kirshbom, MD, Michael E. Halkos, MD, Ning-Ping Wang, PhD, Hajime Kin, MD, Rong Jiang, PhD, Zhi-Qing Zhao, PhD, Kirk R. Kanter, MD, Robert A. Guyton, MD, Jakob Vinten-Johansen, PhD *

Division of Cardiothoracic Surgery and the Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, Georgia

Accepted for publication January 4, 2006.

* Address correspondence to Dr Vinten-Johansen, Cardiothoracic Research Lab, 550 Peachtree St NE, Atlanta, GA 30308 (Email: jvinten{at}emory.edu).

Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) causes myocyte injury as a consequence of ischemia and reperfusion. Previous studies have shown that hypoxia or hypoxia-mimetic agents (cobalt chloride [CoCl2] or deferoxamine [DFX]) limit myocyte necrosis by upregulating the transcription factor hypoxia-inducible factor. However, it remains unknown whether these agents attenuate myocardial apoptosis after DHCA. This study tested the hypotheses (1) that hypoxia, DFX, or CoCl2 preconditioning attenuates myocardial apoptosis during DHCA; and (2) that the protective mechanism involves the altered expression of apoptosis regulatory proteins pAkt (antiapoptotic), Bcl-2 (antiapoptotic), and Bax (proapoptotic).

METHODS: Anesthetized neonatal piglets were randomly assigned to four groups (n = 6 in a group): control (NaCl injection); hypoxia (pO2 of 30 to 40 mm Hg for 3 hours); DFX injection; or CoCl2 injection. Twenty-four hours later, the animals underwent cardiopulmonary bypass (CPB) and 110 minutes of DHCA. One week after CPB, percentage of apoptotic myocytes (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling [TUNEL] assay) and expression of the pAKT, Bcl-2, and Bax were assessed by Western blot.

RESULTS: Although preconditioning with hypoxia and DFX failed to show a protective benefit, CoCl2 pretreatment significantly attenuated myocardial apoptosis (9.3% ± 4.1%) versus controls (33.8% ± 9.7%, p = 0.042). That was associated with increased myocardial pAkt expression (0.19 ± 0.006 in CoCl2 versus 0.12 ± 0.008 in control, p < 0.001). The expression of Bcl-2 was also significantly higher in the CoCl2 group (0.15 ± 0.02) versus control (0.11 ± 0.01, p = 0.007), whereas Bax expression was lower (0.34 ± 0.04 versus 0.54 ± 0.03 for control, p < 0.001).

CONCLUSIONS: Preconditioning with CoCl2 before prolonged DHCA in neonatal piglets attenuates myocardial apoptosis by mechanisms involving phosphorylation of Akt, upregulation of the antiapoptotic protein Bcl-2, and decreased expression of the proapoptotic protein Bax.






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