Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Am J Physiol Heart Circ Physiol. 2008 Feb;294(2):H954-60. doi: 10.1152/ajpheart.00557.2007. Epub 2007 Dec 14.

Abstract

Inhibition of myocardial fatty acid oxidation can improve left ventricular (LV) mechanical efficiency by increasing LV power for a given rate of myocardial energy expenditure. This phenomenon has not been assessed at high workloads in nonischemic myocardium; therefore, we subjected in vivo pig hearts to a high workload for 5 min and assessed whether blocking mitochondrial fatty acid oxidation with the carnitine palmitoyltransferase-I inhibitor oxfenicine would improve LV mechanical efficiency. In addition, the cardiac content of malonyl-CoA (an endogenous inhibitor of carnitine palmitoyltransferase-I) and activity of acetyl-CoA carboxylase (which synthesizes malonyl-CoA) were assessed. Increased workload was induced by aortic constriction and dobutamine infusion, and LV efficiency was calculated from the LV pressure-volume loop and LV energy expenditure. In untreated pigs, the increase in LV power resulted in a 2.5-fold increase in fatty acid oxidation and cardiac malonyl-CoA content but did not affect the activation state of acetyl-CoA carboxylase. The activation state of the acetyl-CoA carboxylase inhibitory kinase AMP-activated protein kinase decreased by 40% with increased cardiac workload. Pretreatment with oxfenicine inhibited fatty acid oxidation by 75% and had no effect on cardiac energy expenditure but significantly increased LV power and LV efficiency (37 +/- 5% vs. 26 +/- 5%, P < 0.05) at high workload. In conclusion, 1) myocardial fatty acid oxidation increases with a short-term increase in cardiac workload, despite an increase in malonyl-CoA concentration, and 2) inhibition of fatty acid oxidation improves LV mechanical efficiency by increasing LV power without affecting cardiac energy expenditure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Blotting, Western
  • Cardiac Output / physiology
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Coronary Circulation
  • Energy Metabolism / physiology
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids / metabolism*
  • Female
  • Glucose / metabolism
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Heart / physiology*
  • Lactic Acid / metabolism
  • Male
  • Malonyl Coenzyme A / metabolism*
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Multienzyme Complexes / metabolism
  • Myocardial Contraction / physiology*
  • Myocardium / metabolism*
  • Oxidation-Reduction
  • Protein Serine-Threonine Kinases / metabolism
  • Stroke Volume / physiology
  • Swine
  • Ventricular Function, Left / physiology

Substances

  • Enzyme Inhibitors
  • Fatty Acids
  • Multienzyme Complexes
  • Lactic Acid
  • Malonyl Coenzyme A
  • 4-hydroxyphenylglycine
  • Carnitine O-Palmitoyltransferase
  • Protein Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • Glucose
  • Glycine