The objectives of this proposal will be to characterize substrate metabolism in stunned and hibernating myocardium and describe the relationships among substrates for oxidation, regulation of fatty acid transfer, and energy resynthesis under prolonged states of reperfusion and chronic hypoperfusion. The proposed specific aims in part extend from work conducted in the present granting interval which detailed the metabolic- functional associations in acutely (35-60 min) reperfused heart muscle. It was determined that metabolic performance was in part restored and in part impaired. Normal patterns of fatty acid oxidation were re-established with reciprocal inhibitions of glucose, pyruvate, and lactate oxidations. Conversely, mitochrondrial ATP resynthesis and energy transfer were depressed. Taken together, these defects may contribute to mechanical stunning. Such observations will now be expanded to include reperfusion conditions of longer duration. The proposal also will take advantage of a new animal model of hibernating myocardium induced by chronic hypoperfusion in pigs. A progressive deterioration in regional shortening, partial restoration of reactive hyperemia, and largely preserved viable myocardium were observed. The largest database describing metabolism in chronically jeopardized myocardium is that derived clinically from positron emission tomography and suggests dependence on anaerobic glycolysis as the prime substrate for energy needs. In the applicant's opinion, this conclusion is flawed since it is dubious how heart muscle, even with impaired contraction, could survive long-term on such trivial ATP production. To resolve these controversies, a detailed survey of multiple substrate utilizations, energetics, and mitochrondrial performance is planned over longer periods of reperfusion 1) after sustained exposures to ischemia, non-Q wave infraction, and pre-conditioning and 2) in the hibernating heart model. It is also planned to test the regulatory importance of carnitine palmitoyltransferase (CPT I) as a rate-limiting control site in modulating fatty acid oxidation during prolonged reperfusion and hypoperfusion. Previous data suggested that the carnitine transferase-translocase sequence is rate-limiting in ischemia. Studies will be conducted in isolated and intact hearts and isolated and reconstituted membrane-enzyme systems. The health relatedness of this proposal is linked to the increasing use of clinical reperfusion protocols in patients with life-threatening coronary artery disease. The results of this proposal may reveal mechanisms to improve metabolic efficiency and reverse the mechanical dysfunction associated with reflow and chronic hypoperfusion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032350-11
Application #
2217016
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1984-01-01
Project End
1996-06-30
Budget Start
1995-01-01
Budget End
1996-06-30
Support Year
11
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Hacker, T A; Renstrom, B; Nellis, S H et al. (1998) The role of glucose metabolism in a pig heart model of short-term hibernation. Mol Cell Biochem 180:75-83
Hacker, T A; Renstrom, B; Nellis, S H et al. (1997) Effect of repetitive stunning on myocardial metabolism in pig hearts. Am J Physiol 273:H1395-402
Liedtke, A J; Hacker, T; Renstrom, B et al. (1996) Anaplerotic effects of propionate on oxidations of acetate and long-chain fatty acids. Am J Physiol 270:H2197-203
Renstrom, B; Liedtke, A J (1995) Adjustments in competitive substrate utilization in stunned myocardium during early reperfusion. Basic Res Cardiol 90:279-81
Liedtke, A J; Renstrom, B; Nellis, S H et al. (1995) Mechanical and metabolic functions in pig hearts after 4 days of chronic coronary stenosis. J Am Coll Cardiol 26:815-25
Liedtke, A J; Renstrom, B; Hacker, T A et al. (1995) Effects of moderate repetitive ischemia on myocardial substrate utilization. Am J Physiol 269:H246-53
Liedtke, A J; Renstrom, B; Nellis, S H et al. (1994) Myocardial function and metabolism in pig hearts after relief from chronic partial coronary stenosis. Am J Physiol 267:H1312-9
Bolukoglu, H; Liedtke, A J; Nellis, S H et al. (1992) An animal model of chronic coronary stenosis resulting in hibernating myocardium. Am J Physiol 263:H20-9
Bolukoglu, H; Eggleston, A M; Subramanian, R et al. (1991) Effects of propionyl-L-carnitine in chronically hypoperfused (""hibernating"") myocardium. Cardioscience 2:245-55
Molaparast-Saless, F; Shrago, E; Spennetta, T L et al. (1988) Determination of individual long-chain fatty acyl-CoA esters in heart and skeletal muscle. Lipids 23:490-2