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Neonatal vulnerability to ischemia and reperfusion: Cardioplegic arrest causes greater myocardial apoptosis in neonatal lambs than in mature lambs. J Thorac Cardiovasc Surg 2004 Feb;127(2):490-7



Pubmed ID




Scopus ID

2-s2.0-10744225976   35 Citations


OBJECTIVES: Apoptosis is a mechanism for deletion of injured or obsolete cells that is distinct from necrosis and mediated by mitochondrial release of cytochrome c caspase activation. Because myocardial apoptosis is a part of normal fetal and postnatal maturation, we hypothesize that neonatal myocardium is more vulnerable to undergo myocardial apoptosis than mature myocardium after cardioplegic arrest.

METHODS: Newborn and mature lambs (n = 5 in each group) underwent cardiopulmonary bypass, antegrade crystalloid hyperkalemic cardioplegic arrest for 60 minutes, and a 6-hour recovery period. Myocardium was examined by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL), Western blotting, in vitro kinase assays, and fluorometric assays of the activity of caspases 3, 8, and 9. Myocardium from nonoperated control subjects (n = 5 in each age group) was also obtained.

RESULTS: More TUNEL-positive nuclei were present in the newborn postcardioplegic myocardium (P =.04). Caspase 3, 8, and 9 activities were 1.6-fold, 1.5-fold, and 1.4-fold greater in the newborn postcardioplegic myocardium (P =.04, P =.01, and P =.01, respectively). The Bax/Bcl-2 ratio was higher in the newborn postcardioplegic myocardium (P =.04). Apoptosis signal-regulating kinase 1 activity and cleaved caspase 3 levels were higher in the newborn postcardioplegic myocardium (P =.02 and P =.009). Mitochondrial release of cytochrome c was greater in the newborn postcardioplegic myocardium (P =.009).

CONCLUSIONS: The increased Bax/Bcl-2 ratio in the newborn myocardium suggests a proapoptotic state that is manifested by greater TUNEL staining, cytochrome c release, and cleavage of caspase 3. Increased apoptosis signal-regulating kinase 1 activity suggests greater oxidative stress, immature mechanisms to ameliorate oxidative stress, or both in the neonatal myocardium. Mitochondrial release of cytochrome c suggests that apoptosis-related mitochondrial dysfunction might contribute to early postoperative myocardial dysfunction in the neonate.

Author List

Karimi M, Wang LX, Hammel JM, Mascio CE, Abdulhamid M, Barner EW, Scholz TD, Segar JL, Li WG, Niles SD, Caldarone CA


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, Newborn
Blotting, Western
Cytochrome c Group
Disease Models, Animal
Electron Transport Complex IV
Enzyme Activation
Fluorescent Dyes
Heart Arrest, Induced
Heart Ventricles
In Situ Nick-End Labeling
MAP Kinase Kinase Kinase 5
MAP Kinase Kinase Kinases
Models, Cardiovascular
Myocardial Reperfusion Injury
Myocytes, Cardiac
Oxidative Stress
Proto-Oncogene Proteins
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75