Abnormal or paradoxical constriction of the coronary arteries contributes to the pathogenesis of myocardial ischemia in patients with both stable and unstable angina. The underlying disturbance in vascular tone is directly related to the atherosclerotic process and the attending impairment of endothelium-dependent vasodilation. Elevations of and oxidized LDL cholesterol have been shown to impair endothelium-dependent relaxation and evidence from experimental models of atherosclerosis suggests that this impairment can be reversed by therapeutic lowering of LDL and possibly oxidized LDL cholesterol. The reversibility of endothelial dysfunction, however, has not been addressed in the clinical setting. The applicants therefore plan to test the hypothesis that therapeutic lowering of LDL cholesterol or the combination of LDL and oxidized LDL cholesterol will reverse abnormal constriction and improve endothelium-dependent vasodilation in coronary arteries in patients with atherosclerosis. Utilizing an open label, prospective, randomized parallel design, the coronary vasomotor responses to the intracoronary infusions of the endothelium-dependent vasodilator, acetylcholine, and the endothelium-independent dilator, nitroglycerin, will be compared at baseline and after 12 months of therapy with, i) lovastatin and cholestyramine (LDL lowering group), ii) lovastatin and probucol (LDL and oxidized LDL group), or iii) diet therapy (control group). The vasomotor responses will be assessed by a previously well validated quantitative angiographic technique. This project aims to apply knowledge derived from basic biology to the clinical setting. It examines atherosclerosis from the point of view of functional behavior. Insights derived from this study may have important implications for the future management of myocardial ischemia and may lead to new strategies aimed at improving the functional rather than structural aspects of atherosclerotic arteries, thereby avoiding subsequent clinical events.
| Kohara, K; Brosnihan, K B; Ferrario, C M (1993) Angiotensin(1-7) in the spontaneously hypertensive rat. Peptides 14:883-91 |
