title: Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation.
abstract: Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,10-(3)H]oleate, [U-(14)C]glucose, and [1-(13)C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity for malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomenon.
authors.affiliation: Dept. of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA.
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Janos
authors.initials: J
authors.lastname: Kerner
authors.forename: Hazel
authors.initials: H
authors.lastname: Huang
authors.forename: Edwin
authors.initials: E
authors.lastname: Vazquez
authors.forename: Aneta
authors.initials: A
authors.lastname: Reszko
authors.forename: Wenjun Z
authors.initials: WZ
authors.lastname: Martini
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Makoto
authors.initials: M
authors.lastname: Imai
authors.forename: Sharad
authors.initials: S
authors.lastname: Rastogi
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004285:Dogs; D015536:Down-Regulation; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000493:pharmacokinetics*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate; D019344:Lactic Acid / Q000097:blood; D008316:Malonyl Coenzyme A / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D019301:Oleic Acid / Q000493:pharmacokinetics; D010084:Oxidation-Reduction; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012720:Severity of Illness Index; D017725:Ventricular Pressure
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D011768:Pyruvate Dehydrogenase Complex; D019301:Oleic Acid; D019344:Lactic Acid; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase