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J Thorac Cardiovasc Surg 2009;138:538-546
© 2009 The American Association for Thoracic Surgery

Congenital Heart Disease

Association of neonatal hypoxia with lasting changes in left ventricular gene expression: An animal model

Danny Del Duca, MDa, Guoruey Wong, BASch, Phan Trieu, BScg, Demetra Rodaros, BScb, Athanasios Kouremenos, BScg, Artavazd Tadevosyan, MScc,d,f, George Vaniotis, BScd,e,f, Louis R. Villeneuve, MScd, Christo I. Tchervenkov, MDa, Stanley Nattel, MDc,d,f,g, Bruce G. Allen, PhDd,e,f, Terence E. Hébert, PhDg,*, Charles V. Rohlicek, MD, PhDb,h,i,*

a Division of Cardiovascular Surgery, Montréal Children's Hospital—McGill University Health Centre, Montréal, Québec, Canada
b Division of Cardiology, Montréal Children's Hospital—McGill University Health Centre, Montréal, Québec, Canada
c Department of Medicine, Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, Canada
d Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, Canada
e Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada
f Université de Montréal, Montréal, Québec, Canada
g Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
h Department of Physiology, McGill University, Montréal, Québec, Canada
i Department of Pediatrics, McGill University, Montréal, Québec, Canada

Received for publication July 2, 2008; revisions received April 1, 2009; accepted for publication April 27, 2009.

* Address for reprints: Terence E. Hébert, PhD, Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Room 1303, Montréal, Québec, Canada H3G 1Y6 (Email: terence.hebert{at}mcgill.ca; charles.rohlicek{at}mcgill.ca).

* Charles V. Rohlicek, MD, PhD, Department of Cardiology, Montréal Children's Hospital, McGill University Health Centre, 2300 Tupper St, Room D-365, Montréal, Québec, Canada H3H 1P3. (Email: terence.hebert{at}mcgill.ca; charles.rohlicek{at}mcgill.ca).

Objective: Innovations in pediatric cardiovascular surgery have resulted in significant improvements in survival for children with congenital heart disease. In adults with such disease, however, surgical morbidity and mortality remain significant. We hypothesized that hypoxemia in early life causes lasting changes in gene expression in the developing heart and that such changes may persist into later life, affecting the physiology of the adult myocardium.

Methods: Microarray expression analyses were performed with left ventricular tissue from 10- and 90-day-old rats exposed to hypoxia (inspired oxygen fraction 0.12) for the first 10 days after birth then subsequently reared in ambient air and with tissue from age-matched rats reared entirely in ambient air. Changes in expression of selected genes were confirmed with real-time reverse transcriptase polymerase chain reaction. Left ventricular cardiomyocytes were isolated from adult animals in both groups, and cellular morphology and viability were compared.

Results: Microarray analyses revealed significant changes in 1945 and 422 genes in neonates and adults, respectively. Changes in genes associated with adaptive vascular remodeling and energy homeostasis, as well as regulation of apoptosis, were confirmed by real-time reverse transcriptase polymerase chain reaction. The viability of cardiomyocytes isolated from hypoxic animals was significantly lower than in those from control animals (36.7% ± 13.3% vs 85.0% ± 2.9%, P = .024).

Conclusions: Neonatal hypoxia is associated with significant changes in left ventricular gene expression in both neonatal and adult rats. This may have physiologic implications for the adult myocardium.

Abbreviations and Acronyms GO = gene ontology; RT-PCR = reverse transcriptase polymerase chain reaction






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