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CARDIOVASCULAR |
Departments of
1 Biomedical Engineering
2 Physiology & Biophysics
3 Pediatrics
4 Nutrition
5 The Center for Modelling Integrated Metabolic Systems, Case Western Reserve University, Cleveland, OH 44106, USA
Steady state concentrations of ATP and ADP in vivo are similar at low and high cardiac workloads; however, the mechanisms that regulate the activation of substrate metabolism and oxidative phosphorylation that supports this stability are poorly understood. We tested the hypotheses that (1) there is parallel activation of mitochondrial and cytosolic dehydrogenases in the transition from low to high workload, which increases NADH/NAD+ ratio in both compartments, and (2) this response does not require an increase in fatty acid oxidation (FAO). Anaesthetized pigs were subjected to either sham treatment, or an abrupt increase in cardiac workload for 5 min with dobutamine infusion and aortic constriction. Myocardial oxygen consumption 
and FAO were increased 3- and 2-fold, respectively, but ATP and ADP concentrations did not change. NADH-generating pathways were rapidly activated in both the cytosol and mitochondria, as seen in a 40% depletion in glycogen stores, a 3.6-fold activation of pyruvate dehydrogenase, and a 50% increase in tissue NADH/NAD+. Simulations from a multicompartmental computational model of cardiac energy metabolism predicted that parallel activation of glycolysis and mitochondrial metabolism results in an increase in the NADH/NAD+ ratio in both cytosol and mitochondria. FAO was blocked by 75% in a third group of pigs, and a similar increase in 
and the NAHD/NAD+ ratio was observed. In conclusion, in the transition to a high cardiac workload there is rapid parallel activation of substrate oxidation that results in an increase in the NADH/NAD+ ratio.
(Received 27 October 2006;
accepted after revision 13 December 2006;
first published online 21 December 2006)
Corresponding author W. C. Stanley: Division of Cardiology, Department of Medicine, University of Maryland-Baltimore, 22 South Greene Street, Room S3B08, Baltimore, MD 21201, USA. Email: wstanley{at}medicine.umaryland.edu
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  M. S. Bray and M. E. Young Diurnal variations in myocardial metabolism Cardiovasc Res, July 15, 2008; 79(2): 228 - 237. [Abstract] [Full Text] [PDF]
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 L. Zhou, H. Huang, C. L. Yuan, W. Keung, G. D. Lopaschuk, and W. C. Stanley 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, February 1, 2008; 294(2): H954 - H960. [Abstract] [Full Text] [PDF]
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