Relationship between coronary atherosclerosis and "sudden cardiac death". Effects of age and calcium blockers in hypercholesterolemic mini-pigs.
Marked atherosclerosis was produced in the coronary arteries (c.a.) of full-grown ("old") mini-pigs by combination of protracted hypercholesterolemia with two repetitions of irradiation of the heart region. "Sudden cardiac death" with occlusion of some peripheral c.a. occurred to 40% of the pigs within 15 to 21 weeks from the last irradiation. Growing ("young") pigs, after the same treatment, developed more marked atherosclerotic lesions in the c.a. than "old" pigs. There was a trend to a situation in which mortality (58%; p = 0.2) in "young" pigs was higher than in "old". When "old" pigs were treated with the calcium-channel blocker nifedipine (2 x 20 mg/day; mean body weight 66 kg), there was some trend to reduced mortality from 40% to 25% (p = 0.25). If the effects of age and nifedipine were combined, the difference in mortality (58% or 25%) was significant (p less than 0.05). In pigs that had died a "sudden cardiac death", the content of cholesteryl esters in the c.a. rose to values of greater than 60 x 10(-6) mol/g prot. In age-matched control pigs, the mean ester content was 2.8 or 1.2 x 10(-6) mol/g prot. in "young" and "old" pigs. In nonirradiated hypercholesterolemic pigs, the mean ester content in "young" animals was 39 x 10(-6) mol/g prot. but in "old" pigs it came to 4.8 x 10(-6) mol/g prot. 12 months after the "sudden cardiac death" period had ended, the ester content in the surviving pigs was 25 x 10(-6) mol/g prot. in "young" and 3.5 x 10(-6) mol/g prot. in "old" animals. Irradiation had produced some kind of healing effect. This regress in cholesteryl ester content was significantly and moderately delayed by nifedipine treatment. It did not otherwise change the cholesterol metabolism of the arteries. A probable explanation for the partly marked and rapid changes in cholesterol metabolism of c.a. was that there had been a change in phenotype of vascular smooth muscle cells, mainly localised to the intima of the c.a. The vascular endothelial cells influence the phenotype of vascular smooth muscle cells by stimulating proliferation and accumulation of cholesterol by growth factors (PDGF) which act via thrombospondin. By releasing heparin and/or heparin-like glycosaminoglycans, endothelium may inhibit the effect of thrombospondin on vascular smooth muscle cells. An additional contribution is possibly made by cholesterol from high-lipid macrophages.
Lundholm
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Department of Pharmacology, University of Linköping, Sweden.
Sundbom
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Lundholm
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D000818:Animals; D002784:Cholesterol / Q000032:analysis / Q000097:blood; D003324:Coronary Artery Disease / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000401:mortality; D003331:Coronary Vessels / Q000032:analysis / Q000473:pathology; D003645:Death, Sudden / Q000209:etiology*; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications; D009543:Nifedipine / Q000627:therapeutic use; D013552:Swine; D013556:Swine, Miniature
D002784:Cholesterol; D009543:Nifedipine