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J Thorac Cardiovasc Surg 2003;125:1268-1275
© 2003 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Myocardial apoptosis after cardioplegic arrest in the neonatal lamb

From the Departments of Surgery,^a Pediatrics,^b Biochemistry,^c and Internal Medicine,^d the University of Iowa College of Medicine, Iowa City, Iowa.

Supported in part by a Scientist Development Grant from the American Heart Association (C.A.C.), a grant from the National Institutes of Health (RO1 HO64770; C.A.C., T.D.S., and J.L.S.), a Grant In Aid from the American Heart Association (W.G.L.), and a grant from the Children's Miracle Network (C.A.C.).

Received for publication June 16, 2002. Revisions requested July 23, 2002; revisions received Aug 12, 2002. Accepted for publication Sept 13, 2002. Address for reprints: Christopher A. Caldarone, MD, Division of Cardiovascular Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada, (E-mail: christopher.caldarone{at}sickkids.ca).

Objective: Myocardial apoptosis is observed after various cardiac injuries and is also a normal part of fetal cardiac development and early postnatal maturation. Cardioplegic arrest and reperfusion result in ischemic injury and oxidative stress, known triggers of apoptosis. Because the neonatal heart is in a proapoptotic state, we hypothesize that apoptosis is triggered after cardioplegic arrest in neonatal myocardium.
Methods: We started neonatal lambs (6-8 days old, n = 5) on cardiopulmonary bypass and administered cold crystalloid cardioplegia at 20-minute intervals. Total crossclamp time was 70 minutes, and bypass time was 90 minutes. After a six-hour recovery period, the hearts were excised and examined by using TdT-mediated dUTP nick-end labeling; radiolabeled DNA electrophoresis; fluorimetric caspase 3, 8, and 9 activity assay; mRNA microarray; and Western immunoblotting. Control lambs were anesthetized but did not undergo operation (n = 5) or were started on cardiopulmonary bypass for 90 minutes but not arrested (n = 5).
Results: Lambs subjected to cardioplegia had 5-fold more TdT-mediated dUTP nick-end labeling-positive nuclei compared with that seen in unoperated control animals (P = .007) and bypass-only control animals (P = .008). DNA laddering was present in all postcardioplegia hearts but absent among control hearts. Bad and Bcl-X mRNA transcription increased significantly. Caspase 3, 8, and 9 activities were slightly greater than those seen in control animals, but the differences were not significant. No change was detected in Bcl-2, Bax, or Bcl-xL proteins.
Conclusions: In a clinically relevant model of neonatal cardioplegic arrest, increased apoptotic cell death is present 6 hours after reperfusion, and both proapoptotic and antiapoptotic responses are triggered. The clinical implications of apoptosis after cardioplegic arrest remain undetermined.

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