title: Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery.
abstract: During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower (P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% (P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemia-reperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia.
authors.affiliation: Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Departments of Pediatrics and Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Tatsujiro
authors.initials: T
authors.lastname: Oka
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Lam
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Wendy
authors.initials: W
authors.lastname: Keung
authors.forename: Virgilio J J
authors.initials: VJ
authors.lastname: Cadete
authors.forename: Victor
authors.initials: V
authors.lastname: Samokhvalov
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Tanner
authors.forename: Donna L
authors.initials: DL
authors.lastname: Beker
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.forename: Alda
authors.initials: A
authors.lastname: Huqi
authors.forename: Jagdip S
authors.initials: JS
authors.lastname: Jaswal
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Rebeyka
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006019:Glycolysis / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D011817:Rabbits
chemical_list: D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047493:PPAR alpha; D000255:Adenosine Triphosphate