Pathogenesis of Coronary Artery Spasm
Although the relationship between coronary atherosclerosis and events of ischemic heart disease has been well accepted, the pathogenesis of ischemic events remained unanswered. Variant angina is a unique ischemic attack caused by coronary spasm, which suggests the importance of coronary vascular tone or responsiveness to vasoactive agents in the pathogenesis of ischemic heart disease. Clinical observation also suggests the intimate relationship between the site of a coronary lesion and coronary vasospasm. Accordingly, we developed an animal model of coronary spasm in atherosclerotic miniature swine, which have coronary anatomy similar to human and are also a preferential model of atherosclerosis. In the present study, effects of intimal thickening and hypercholesterolemia on coronary hypercontraction to autacoids such as histamine and serotonin were examined by angiography and ECG in Göttingen miniature pigs under anesthesia. In 36 consecutive pigs, coronary artery spasm was provoked before endothelial denudation in five pigs by the intracoronary administration of 10 μg/kg histamine after pretreatment with cimetidine, 60 mg/kg i.v., in which serum cholesterol was 51 ± 8 mg/dl. These pigs were sacrificed without denudation, and an intimate topological correlation between the site of intimal thickening and coronary artery spasm was confirmed by comparing histological and angiographic findings. Five pigs died during the denudation procedure; the other 26 pigs were randomly allotted to a high-cholesterol diet (2% cholesterol in regular laboratory chow) or a regular diet. Three months after denudation, serum cholesterol increased from 56 ± 6 to 270 ± 30 mg/dl (P < 0.01) in pigs fed the cholesterol-containing diet (n = 13) and was little changed from 48 ± 5 to 56 ± 6mg/dl in pigs with the regular diet (n = 13). In both groups coronary spasm was provoked, and percentage luminal narrowing at the denuded site was 78 ± 3 and 74 ± 4% at its maximum degree in cholesterol and regular diet, respectively. Serotonin also enhanced coronary constriction at the site of histamine-induced coronary spasm; however, phenylephrine, 1 μg/kg i.c., did not cause hypercontraction, suggesting the acquired hyperresponsiveness of the denuded coronary artery specific to autacoids. A similar degree of intimal thickening was noted histologically in both groups at the site of coronary spasm. There was a curvilinear relationship between the thickness of the intima and histamine-induced coronary narrowing (γ = 0.92, P < 0.01). A close topological correlation was noted between the site of angiographic spasm and that of intimal thickening. In addition, the diameter narrowing at the denuded site during histamine provocation was more extreme than the constriction predicted geometrically from the intimal thickening. Thus, the presence of spontaneous or artificially induced intimal thickening was a major pathogenetic factor in coronary artery spasm; however, hypercholesterolemia per se did not affect the provocation of coronary spasm.
KeywordsRegular Diet Intimal Thickening Coronary Spasm Coronary Artery Spasm Variant Angina
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