title: Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy.
abstract: BACKGROUND
  Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear.
  
  
  RESULTS
  Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E'), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP.
  
  
  CONCLUSIONS
  The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.
authors.affiliation: Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Jagdip S
authors.initials: JS
authors.lastname: Jaswal
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.forename: Sowndramalingam
authors.initials: S
authors.lastname: Sankaralingam
authors.forename: Cory
authors.initials: C
authors.lastname: Wagg
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001012:Aorta, Abdominal / Q000503:physiopathology* / Q000601:surgery; D062186:Arterial Pressure; D001786:Blood Glucose / Q000378:metabolism; D006332:Cardiomegaly / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006019:Glycolysis; D054143:Heart Failure, Systolic / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D019344:Lactic Acid / Q000378:metabolism; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010725:Phosphocreatine / Q000378:metabolism; D013318:Stroke Volume; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D007328:Insulin; C495693:Slc2a4 protein, mouse; C021983:complex V (mitochondrial oxidative phosphorylation system); D010725:Phosphocreatine; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases
keywords: abdominal aortic constriction; cardiac insulin-resistance; cardiomegaly; electron transport chain; energy metabolism; myocardial lipid accumulation