We hypothesized that the formation of foam cells and fatty streaks requires a postsecretory oxidative modification of lipoproteins that targets them for rapid uptake by macrophages. Lipid peroxidation may in part depend on the concentration of tissue iron, one of the major oxidants in vivo. We analyzed the relation between sonographically assessed carotid atherosclerosis and body iron stores in a population sample of 847 men and women aged 40 to 79 years. In a logistic regression analysis adjusting for age, sex, and all major vascular risk markers, ferritin emerged as one of the strongest indicators of carotid artery disease in both sexes (40 to 59 R ecent advances in understanding vascular lipid metabolism have yielded new insights into the mechanisms that determine endothelial injury and plaque development. In particular, the postseCTetory modification of lipoproteins has attracted increasing attention.1 Oxidative changes in the surface structure of low-density lipoproteins enhance the affinity to macrophage scavenger receptors, giving rise to the formation of foam cells and fatty streaks. -3 Prominent iron stores may promote lipid peroxidation and accelerate atherogenesis and cardiovascular disease. This hypothesis recently received empirical support from a large population study (Kuopio Ischaemic Heart Disease Risk Factor Study) that demonstrated an enhanced risk of myocardial infarction in middle-aged men with elevated concentrations of serum ferritin.4 These findings, however, do not necessarily imply a causal role of iron in atherogenesis. Enhanced reperfusion injury, direct cardiotoxicity of high myocardial iron deposits, vasospastic events, and increased blood viscosity may also be significant. 57 We designed the current study to investigate the relation between sonographically assessed carotid atherosclerosis and body iron stores as estimated by serum ferritin. 89 We also investigated physiologically normal iron status and addressed sex differences in the amount of body iron and the manifestation of atherosclerotic vascular disease.Received November 30, 1993; revision accepted June 29, 1994. From the Department of Neurology (S.K., F.A., F.G., F.S., J.W.) and Department of Laboratory Medicine (EJ.), University Ginic Innsbruck (Austria), and the Department of Internal Medicine, Hospital of Bruneck (G.E., A.M., G.R., F.O.) (Italy).Correspondence to Dr J. Willeit, Department of Neurology, University of Innsbruck, AnichstraBe 35, A-6020 Innsbruck, Austria.years; odds ratio, 1.54 per 100 /xg/L; P<.001). The predictive significance of ferritin was found to be synergistic with that of hypercholesterolemia. Variations in body iron stores between sexes may partly explain evident sex differences in the expression of carotid atherosclerosis. In the elderly (£60 years) the predictive significance of ferritin was found to decrease parallel to that of apolipoprotein B. The current study suggests a possible role of body iron in early atherogenesis. (ArUriosder Thromb. 1994;14:1625-1630 Key Words • carotid ...

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The present study demonstrates a strong and independent association between elevated Lp(a) levels and carotid atherosclerosis in a large randomized population and provides evidence of a potential role of Lp(a) in the evolution of carotid stenosis. Apart from atherogenicity of Lp(a) cholesterol, interference with fibrinolysis of atheroma-associated clots and fibrin deposits in the arterial wall may achieve pathophysiological significance.

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The LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase play primary roles in the regulation of cellular cholesterol metabolism. To investigate the transcriptional regulation of lipid metabolism under physiological conditions ex vivo and its alterations during aging, we analyzed both the activity and mRNA concentration of the LDL receptor and HMG-CoA reductase in freshly isolated lymphocytes from healthy young and elderly donors. Data from fluorescent reverse transcriptase-polymerase chain reaction indicated that not only plasma LDL but also plasma HDL downregulates lymphocyte LDL receptor mRNA. Downregulation by HDL was three times more effective than that by LDL and presumably involved specific HDL binding sites. There was coordinate regulation of HMG-CoA reductase mRNA with LDL receptor mRNA that was independent of plasma lipoprotein concentrations. Despite elevated plasma concentrations of LDL, lymphocytes from elderly donors paradoxically expressed increased levels of the LDL receptor (P = .030) and HMG-CoA reductase mRNA (P = .062). The age-related dysregulation of the LDL receptor was predominantly due to impaired downregulation by plasma LDL rather than by HDL. Thus, not only LDL but also HDL and age significantly influences the transcriptional regulation of the LDL receptor in extrahepatic cells in vivo.