IN VIVO ENDOTHELIAL INJURY AND DEPENDENT VASOMOTION

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The impairment of endothelial-dependent vascular relaxation (EDVR) in vivo in coronary arteries is probably related to the amount of endothelial injury induced in part by coronary risk factors and atherosclerosis in pigs and patients and may be reduced by risk factor reduction. Vasoconstriction in arteries can reduce blood flow, increase arterial wall-shear forces which increases platelet deposition in injured arteries, and may precipitate rupture of atherosclerotic plaques. The endothelium can metabolize and reduce the intramural diffusion of intraluminal vasoconstrictive substances (platelet products and catecholamines), prevent platelet activation and subsequent release of platelet vasoconstrictive substances, and promote vasodilation via the production and release of prostacyclin and endothelial-derived relaxing factor (EDRF). In the pig, we will test the hypothesis that the segmental coronary arterial impairment of EDVR (measured by quantitative angiography) to graded infusions of acetycholine (an EDRF- releasing agent) correlates with the extent of endothelial injury (quantitated by the degree of 111 In-labeled autologous platelet deposition (no. of platelets/cubic cm.) and the percent of surface area stained by Evans blue) (a) induced by mild balloon dilatation, (b, c) following regrowth of endothelial-like cells 4 and 8 days after balloon injury, (d) induced by 4 mo of 2% cholesterol feeding (e) following healing or regrowth of endothelium after 4 mo withdrawal of cholesterol feeding, (f) induced by 8 mo of 4% cholesterol feeding, in locations proximal, overlying, and distal to a greater than 50% atherosclerotic lesion, and (g) 4 mo after withdrawal from 4% cholesterol feeding. In patients segmental coronary arterial impairment of EDVR (measured by quantitative coronary angiography) to graded infusions of acetylcholine can be a probe to investigate the severity of endothelial injury (and the extent and timing of healing or regrowth) in minimally diseased coronary arteries before and after (a) reduction of elevated triglycerides and cholesterol, (b) reduction of elevated cholesterol, and (c) cessation of smoking. Segmental coronary arterial impairment of EDVR can also be a probe for measuring the timing and degree of endothelial healing just proximal and distal to the site of balloon angioplasty (where there is endothelial damage but no smooth muscle cell necrosis), in the symptom-producing artery after myocardial infarction or unstable angina, and for determining the level of coronary risk factor reduction necessary for optimal healing of the endothelium.