The activity of myocardial ischemia is used to assess risk and manage patients with coronary artery disease. The presence and severity of ischemia raises fundamentally important questions about how to treat this problem and reduce the occurrence of adverse outcomes. Pilot studies are in progress evaluating the effectiveness of standard anti-anginal therapies (drugs and revascularization). however, in patients with coronary atherosclerosis, risk factors such as plasma LDL and oxidized LDL are now known to impair endothelial function leading to loss of vasodilation, abnormal vasoconstriction, a procoagulant surface, and adhesion of inflammatory cells. Clinical research has shown that these dysfunctions are important causes of myocardial ischemia in patients with obstructive coronary artery disease. Therefore, we plan to test the hypothesis that athe aggressive treatment of plasma LDL and oxidized LDL will; (a) result in important improvements in the activity of ischemia in patients with coronary artery disease, and (b) reverse characteristic cell/vessel wall dysfunctions in the arteries of these patients with atherosclerosis. We plan a prospective randomized, double-blind, placebo-controlled, parallel design trial in patients with coronary artery disease, active myocardial ischemia and raised plasma LDL. Ambulatory ECG monitoring and ultrasonic examination of endothelium-dependent vasomotion of the brachial artery will both be used to measure athe activity of ischemia and arterial dysfunction at base-line and after 12 months of therapy with (1) standard diet (Control Group), (ii) standard diet plus lovastatin (LDL lowering strategy), and (iii) standard diet, lovastatin and probucol (LDL and oxidized LDL lowering strategy). Pilot studies and preliminary data are presented in support of this proposal. The goals of this project are to test the value of new therapies aimed at treating the vascular dysfunctions that characterize coronary atherosclerosis in an attempt to control the ischemia that is associated with increased risk of adverse outcomes. If this alternative to the present massive use of standard anti-anginal drugs an revascularization proves effective, it would likely have important implications for strategies aimed at control of adverse events affecting patients with coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038780-09
Application #
6043748
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Project Start
1989-08-01
Project End
2001-07-31
Budget Start
1999-09-30
Budget End
2001-07-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Stone, Peter H; Lloyd-Jones, Donald M; Johnstone, Michael et al. (2004) Vascular basis for the treatment of myocardial ischemia study: trial design and baseline characteristics. Am Heart J 147:875-82
Kinlay, Scott; Timms, Tracy; Clark, Maureen et al. (2002) Comparison of effect of intensive lipid lowering with atorvastatin to less intensive lowering with lovastatin on C-reactive protein in patients with stable angina pectoris and inducible myocardial ischemia. Am J Cardiol 89:1205-7
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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
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; Gerhard, M D; Meredith, I T et al. (1995) Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol 75:71B-74B
Lieberman, E H; Gerhard, M D; Uehata, A et al. (1994) Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 121:936-41
Anderson, T J; Meredith, I T; Ganz, P et al. (1994) Nitric oxide and nitrovasodilators: similarities, differences and potential interactions. J Am Coll Cardiol 24:555-66

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