Post-ischemic myocardium exhibits a physiologic abnormality which is manifested by delayed recovery of ATP content and contractile function, and increased oxygen consumption per unit work. The mechanism responsible for the contractile dysfunction and for the higher oxygen consumption when stimulated to perform work is not understood. In order to test the hypothesis that post-ischemic cardiac dysfunction in the adult heart is due to impaired cytosolic calcium regulation associated with altered high energy phosphate energetics, we plan to measure free cytosolic calcium in the reperfused beating heart using calcium sensitive fluorescent dyes. 31P NMR spectroscopy will be used to measure high energy phosphate content and allow calculation of the free energy released from ATP hydrolysis. We plan to utilize the differences between newborn and adult hearts with respect to calcium regulation for excitation-contraction coupling in order to determine the cause and precise location of the regulatory defect in the adult. The role of the sarcoplasmic reticulum in post-ischemic contractile dysfunction will e determined by utilizing measurements of the phasic changes in cytosolic calcium concentration during the cardiac cycle. Because of the increased demand for oxygen per unit work in the post- ischemic adult heart, we plan to test the hypothesis that the energetic inefficiency in the """"""""stunned"""""""" heart is at least in part due to altered substrate utilization by the myocytes. We plan to analyze the effects of providing substrates that yield a higher ATP production per mole of oxygen consumed (P:O ratio) on post-ischemic energetic efficiency. We expect that by combining substrates that have high P:O ratios with metabolic inhibitors of other substrates, we will be able to correct the abnormality in the oxygen consumption to work relationship. Post-operative myocardial dysfunction leading to significant mortality and morbidity after cardiac surgery or transplantation remains an important clinical problem. Considerable information regarding the mechanisms for the energetic inefficiency and delayed metabolic and functional recovery of the post-ischemic heart should result from this project.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HL046207-01A1
Application #
3473454
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1992-02-24
Project End
1996-01-31
Budget Start
1992-02-24
Budget End
1993-01-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Choi, Yeong-Hoon; Cowan, Douglas B; Moran, Adrian M et al. (2009) Myocyte apoptosis occurs early during the development of pressure-overload hypertrophy in infant myocardium. J Thorac Cardiovasc Surg 137:1356-62, 1362.e1-3
Takeuchi, K; McGowan, F X; Danh, H C et al. (1995) Direct detrimental effects of L-arginine upon ischemia--reperfusion injury to myocardium. J Mol Cell Cardiol 27:1405-14
Ohkado, A; Cao-Danh, H; Sommers, K E et al. (1994) Evaluation of highly buffered low-calcium solution for long-term preservation of the heart. Comparison with University of Wisconsin solution. J Thorac Cardiovasc Surg 108:762-71
McGowan Jr, F X; Cao-Danh, H; Takeuchi, K et al. (1994) Prolonged neonatal myocardial preservation with a highly buffered low-calcium solution. J Thorac Cardiovasc Surg 108:772-9