Submitted on May 13, 2007
Accepted on December 11, 2007
Metabolic Response to an Acute Jump in Cardiac Workload:
Effects on Malonyl-CoA, Mechanical Efficiency, and Fatty Acid Oxidation an Acute Jump in Cardiac Workload
Lufang Zhou1, Hazel Huang, Celvie L Yuan, Wendy Keung2, Gary D Lopaschuk3, and William C. Stanley4*
1 United States
2 Cardiovascular Research Group, University of Alberta, 423 Heritage Medical Research Center, Edmonton, T6G 2S2, Canada
3 Department of Pediatrics, University of Alberta, Edmonton, Alberta,, Canada
4 Division of Cardiology, Department of Medicine, University of Maryland-Baltimore, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: wstanley{at}medicine.umaryland.edu.
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 in normal and ischemic myocardium. This phenomenon has not been assessed at high workloads in non-ischemic myocardium, so we therefore 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 (CPT-I) inhibitor oxfenicine would improve LV mechanical efficiency. In addition, the cardiac content of malonyl-CoA, (an endogenous inhibitor of CPT-I) and acetyl-CoA carboxylase activity (which synthesizes malonyl-CoA) were assessed. Increased workload was induced by aorta 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 both fatty acid oxidation and cardiac malonyl-CoA content, but did not affect the activation state of acetyl-CoA carboxylase (ACC). The activation state of the ACC 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%, respectively, 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 effecting cardiac energy expenditure.
