miological studies have reported positive associations between the risk of coronary heart disease (CHD) and plasma fibrinogen levels. Fibrinogen is the major coagulation protein in blood by mass, the precursor of fibrin, and an important determinant of blood viscosity and platelet aggregation. [38][39][40][41] Because fibrinogen levels can be reduced considerably by lifestyle interventions that also affect levels of established risk factors (such as regular exercise, smoking cessation, and moderate alcohol consumption), there is interest in the possibility that measurement (or modification) of fibrinogen may help in disease prediction or prevention. [38][39][40]42 A meta-analysis of published data from 18 such studies, involving about 4000 CHD cases, indicated a relative risk of 1.8 (95% confidence interval [CI], 1.6-2.0) per 1-g/L increase in plasma fibrinogen level. 43 However, such analyses are not able to provide detailed assessments of the nature of any independent association of fibrinogen level with CHD or with other vascular and nonvascular outcomes. [43][44][45] This meta-analysis differs from previous analyses in several ways that should increase its reliability and scientific value. First, it is large and comprehensive: the data comprise 6944 first nonfatal myocardial infarction (MI) or stroke events and 13 210 deaths (cause-*The Authors/Writing Committee, Authors/Members, and Other Members of the Fibrinogen Studies Collaboration are listed at the end of this article.
Background-Oxidized LDL (oxLDL) is thought to play a key role in the inflammatory response in the arterial vessel wall. Methods and Results-In a prospective, nested, case-control study, the association between plasma oxLDL and risk of an acute coronary heart disease (CHD) event was investigated in men without prevalent CHD or diabetes mellitus at baseline. Subjects came from 2 population-based MONICA/KORA Augsburg surveys conducted in the years 1989 -1990 and 1994 -1995 with follow-up in 1998 (meanϮSD follow-up time, 5.6Ϯ2.6 years). OxLDL was determined by ELISA in 88 men with incident CHD and in 258 age-and survey-matched controls. Hazard ratios (HRs) were estimated from conditional logistic-regression models with matching for age and survey. Baseline mean plasma oxLDL concentrations were significantly higher in subjects who subsequently experienced an event compared with controls (meanϮSD, 110Ϯ32 versus 93Ϯ28 U/L; PՅ0.001). After adjustment for smoking, hypertension, obesity, physical activity, education, and alcohol consumption, the HR for a future CHD event in a comparison of the upper tertile of the oxLDL distribution with the lower tertile was 4.25 (95% confidence interval, 2.09 to 8.63; PϽ0.001). Plasma oxLDL was the strongest predictor of CHD events compared with a conventional lipoprotein profile and other traditional risk factors for CHD. When both oxLDL and C-reactive protein were simultaneously assessed in the same model, they still predicted future CHD events even after multivariable adjustment. Conclusions-Elevated
Objectives-We performed a prospective case-cohort study in initially healthy, middle-aged men and women from the MONICA/KORA Augsburg studies conducted between 1984 and 2002 to assess the role of IL-18 in comparison with IL-6 and CRP in the prediction of incident coronary heart disease (CHD). Methods and Results-Concentrations of IL-18 were measured in 382 case subjects with incident CHD and 1980 noncases.Mean follow-up was 11 years. Baseline concentrations of IL-18 were slightly higher in cases than in noncases (172.4 [1.0] versus 161.3 [1.0] pg/mL, respectively; Pϭ0.114), but were clearly elevated for C-reactive protein (CRP) and IL-6 in cases compared with noncases. In multivariable analyses, accounting for classical cardiovascular risk factors and inflammatory markers, no statistically significant association was seen between increased concentrations of IL-18 and incident CHD both in men (hazard ratio [HR] and 95% confidence intervals [CIs] comparing extreme tertiles, 1.20; 95% CI, 0.85 to 1.69), and in women (HR, 1.25; 95% CI, 0.67 to 2.34). However, in this population increased concentrations of CRP and IL-6 were found to be independent predictors of future CHD events, even after multivariable adjustment. Conclusions-Elevated concentrations of CRP and IL-6, but not IL-18, were independently associated with risk of CHD in subjects from an area with moderate absolute risk. Key Words: case-cohort study Ⅲ coronary heart disease Ⅲ IL-18 Ⅲ inflammation Ⅲ risk factors C ytokine-mediated inflammation accompanies atherosclerosis from its initiation to the occurrence of clinical endpoints. 1 Recently IL-18, a member of the IL-1 family of cytokines, has been suggested to play a central role in the regulation of both innate and adaptive immunity. 2-3 IL-18 is widely expressed in monocytes/macrophages, dendritic cells, Kupffer cells, adipocytes, colon carcinoma cells, keratinocytes, and osteoblasts. [3][4] It is synthesized as a 23-kDa biologically inert precursor, which is further cleaved by caspase 1 (or IL-1-converting enzyme) to yield the mature and active 18.3-kDa glycoprotein. 3,5 IL-18 induces interferon-␥ with subsequent promotion of the Th1 immune response; it also enhances the expression of matrix metalloproteases. 6 -7 These 2 abilities of IL-18 characterize it as a crucial and potent mediator of atherosclerotic plaque destabilization and vulnerability. Indeed, some experimental studies demonstrated significantly increased expression of in human atheroma, especially in lesions prone to rupture, where it is localized mainly in plaque macrophages. 6,8 Animal models further support the proatherogenic role of IL-18, demonstrating that endogenous inhibition of IL-18 by IL-18 binding protein reduced atherosclerotic plaque development and progression in apolipoprotein (apo) E-deficient mice. 9 Similarly, IL-18/apoE double knockout mice exhibited reduced lesion size. 10 In contrast, direct administration of IL-18 enhanced atherogenesis in an interferon-␥-dependent manner, 11 even in the absence of T cells 1...
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