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Right arrow Myocardial protection

Ann Thorac Surg 2006;81:1817-1823
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Preservation of Mitochondrial Structure and Function After Cardioplegic Arrest in the Neonate Using a Selective Mitochondrial KATP Channel Opener

Lixing Wang, MD, PhD, Caroline Kinnear, MS, James M. Hammel, MD, Wei Zhu, MD, Zhongdong Hua, MD, Wenyu Mi, MD, Christopher A. Caldarone, MD *

Division of Cardiovascular Surgery, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Accepted for publication November 4, 2005.

* Address correspondence to Dr Caldarone, Division of Cardiovascular Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada, M5G 1X8 (Email: christopher.caldarone{at}sickkids.ca).

BACKGROUND: Mitochondrial dysfunction may contribute to early postoperative neonatal heart dysfunction. Diazoxide, a mitochondrial-selective adenosine triphosphate–sensitive potassium-channel opener, is associated with mitochondrial preservation after cardioplegic arrest. We evaluated the mitochondrial-protective effect of diazoxide in terms of mitochondrial structure and function after neonatal cardioplegic arrest.

METHODS: Newborn piglets (age, approximately 14 days) underwent cardiopulmonary bypass and 60 minutes of cardioplegic arrest using cold crystalloid cardioplegic solution (CCP, n = 5) or cold crystalloid cardioplegic solution with diazoxide (CCP+D, n = 5). After 6 hours of recovery, myocardium was harvested. Control myocardium from piglets that did not undergo cardiopulmonary bypass (non-CPB, n = 5) was obtained.

RESULTS: Cardioplegic arrest was associated with translocation of Bax to the mitochondria, which was not prevented by diazoxide. Nevertheless, by electron microscopy, CCP-associated remodeling of mitochondrial structure was subjectively diminished in CCP+D hearts. In addition, CCP-associated mitochondrial permeabilization and cytochrome c release into the cytosol were prevented with CCP+D (p < 0.05). In vitro oxygen consumption of isolated mitochondria demonstrated deficient function of mitochondrial complex I in CCP, but it was preserved in the CCP+D myocardial mitochondria (p < 0.05). Complex II and IV activity was not different among groups. In parallel with impaired complex I function, the cardiac adenosine triphosphate content was diminished in CCP hearts, but well maintained in CCP+D hearts (p < 0.05).

CONCLUSIONS: Although early apoptotic signaling events (Bax translocation) are not prevented by diazoxide, addition of the mitochondrial-selective adenosine triphosphate–sensitive potassium-channel opener to the cardioplegic solution is associated with protection of mitochondrial structural and functional integrity in a clinically relevant model of neonatal cardiac surgery. The mitochondrial-protective effects of diazoxide may contribute to improved postoperative myocardial function in the neonate.




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