The pathophysiology of myocardial ischemia and its relationship to atherosclerosis is incompletely understood. The traditional view that coronary stenoses precipitate myocardial ischemia by limiting increases in blood flow is now thought to be incomplete. Experimental and clinical evidence has accumulated that dynamic biological processes in atherosclerotic coronary stenoses and resistance vessels both play an active role in causing ischemia by intermittently interfering with coronary blood flow. Subsequently, endothelial dysfunction has been shown to play a central role in this abnormal constrictor response. However, to date, the mechanisms of endothelial dysfunction in causing ischemia and the relationship of this dysfunction to the stages of atherosclerosis are not fully understood. The objectives of this study are: 1. To examine the temporal and spatial relationship between the extent of atherosclerosis, especially in the early phases of the disease and the development of endothelial vasodilator dysfunction. 2. To investigate whether atherosclerosis in large epicardial arteries is associated with the impairment of the endothelium-dependent vasodilator function in human coronary resistance vessels resulting in disturbed regulation of coronary flow. 3. To study if superoxide dismutase can reverse the loss of endothelium-dependent vasodilation in vivo in the atherosclerotic epicardial and resistance vessels, suggesting that excessive generation of superoxide radicals impairs normal endothelial function. 4. To assess the ability of therapeutic interventions (aggressive cholesterol lowering) to reverse signs of endothelial dysfunction and improve vasomotor responses in the coronary arteries of patients. this project aims to redefine coronary atherosclerosis in functional, in addition to structural terms and to treat endothelial dysfunction with the associated abnormal vasomotion as an essential component of atherosclerosis in the clinical setting.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08HL002787-02
Application #
3083207
Study Section
Research Training Review Committee (RTR)
Project Start
1992-07-01
Project End
1997-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Davis, S F; Yeung, A C; Meredith, I T et al. (1996) Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant. Circulation 93:457-62
Anderson, T J; Meredith, I T; Charbonneau, F et al. (1996) Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans. Circulation 93:1647-50
Lieberman, E H; Gerhard, M D; Uehata, A et al. (1996) Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol 78:1210-4
Liang, D H; Gao, S Z; Botas, J et al. (1996) Prediction of angiographic disease by intracoronary ultrasonographic findings in heart transplant recipients. J Heart Lung Transplant 15:980-7
Anderson, T J; Meredith, I T; Yeung, A C et al. (1995) The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 332:488-93
Anderson, T J; Uehata, A; Gerhard, M D et al. (1995) Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 26:1235-41

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