title: Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload.
abstract: OBJECTIVE
  Development of heart failure is known to be associated with changes in energy substrate metabolism. Information on the changes in energy substrate metabolism that occur in heart failure is limited and results vary depending on the methods employed. Our aim is to characterize the changes in energy substrate metabolism associated with pressure overload and ischaemia-reperfusion (I/R) injury.
  
  
  RESULTS
  We used transverse aortic constriction (TAC) in mice to induce pressure overload-induced heart failure. Metabolic rates were measured in isolated working hearts perfused at physiological afterload (80 mmHg) using (3)H- or (14)C-labelled substrates. As a result of pressure-overload injury, murine hearts exhibited: (i) hypertrophy, systolic, and diastolic dysfunctions; (ii) reduction in LV work, (iii) reduced rates of glucose and lactate oxidations, with no change in glycolysis or fatty acid oxidation and a small decrease in triacylglycerol oxidation, and (iv) increased phosphorylation of AMPK and a reduction in malonyl-CoA levels. Sham hearts produced more acetyl CoA from carbohydrates than from fats, whereas TAC hearts showed a reverse trend. I/R in sham group produced a metabolic switch analogous to the TAC-induced shift to fatty acid oxidation, whereas I/R in TAC hearts greatly exacerbated the existing imbalance, and was associated with a poorer recovery during reperfusion.
  
  
  CONCLUSIONS
  Pressure overload-induced heart failure and I/R shift the preference of substrate oxidation from glucose and lactate to fatty acid due to a selective reduction in carbohydrate oxidation. Normalizing the balance between metabolic substrate utilization may alleviate pressure-overload-induced heart failure and ischaemia.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, 8440 112 Street NW, Edmonton, AB, Canada T6G 2B7.
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.forename: Jun
authors.initials: J
authors.lastname: Mori
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Alexander
authors.initials: A
authors.lastname: Clanachan
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000105:Acetyl Coenzyme A / Q000096:biosynthesis; D000818:Animals; D004452:Echocardiography; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000032:analysis; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D006973:Hypertension / Q000150:complications*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D013599:Systole
chemical_list: D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D019344:Lactic Acid; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D005947:Glucose