Methods and Results. The two studies have a common core protocol and are based on a combined cohort of 4,860 middle-aged men from the general population. The first follow-up was at a nearly constant interval of 5.1 years in Caerphilly and 3.2 years in Speedwell; 251 major IHD events had occurred. Age-adjusted relative odds of IHD for men in the top 20% of the distribution compared with the bottom 20% were 4.1 (95% confidence interval, 2.6-6.5) for fibrinogen, 4.5 (95% confidence interval, 2.8-7.4) for viscosity, and 3.2 (95% confidence interval, 2.0-4.9) for white blood cell count. Associations with IHD were similar in men who had never smoked, exsmokers, and current smokers, and the results suggest that at least part of the effect of smoking on IHD is mediated through fibrinogen, viscosity, and white blood cell count.Multivariate analysis shows that white blood cell count is an independent risk factor for IHD as is either fibrinogen or viscosity, or possibly both. Jointly, these three variables significantly improve the fit of a logistic regression model containing all the main conventional risk factors. Further, a model including age, smoking habits, fibrinogen, viscosity, and white blood cell count predicts IHD as well as one in which the three hemostatic/rheological variables are replaced by total cholesterol, diastolic pressure, and body mass index.Conclusion. Jointly, fibrinogen, viscosity, and white blood cell count are important risk factors for IHD. (Circulation 1991;83:836-844) N mumerous epidemiological studies1'2 have found raised blood pressure, elevated total cholesterol, and smoking to be major factors associated with an increased risk of ischemic heart disease (IHD). Nevertheless, on an individual basis, the prediction of the risk of IHD from levels of blood pressure, lipids, and smoking is poor.3 There is evidence4,5 that occlusive thrombi are to be found in almost all cases of acute myocardial infarction and in

Abstract-Plasma levels of C-reactive protein (CRP, a marker of the reactant plasma protein component of the inflammatory response) and of fibrin D-dimer (a marker of cross-linked fibrin turnover) have each been associated in recent studies with the risk of future ischemic heart disease (IHD). Previous experimental studies have shown that fibrin degradation products, including D-dimer, have effects on inflammatory processes and acute-phase protein responses. In the Speedwell Prospective Study, we therefore measured CRP and D-dimer levels in stored plasma samples from 1690 men aged 49 to 67 years who were followed-up for incident IHD for an average of 75Ϯ4 months (meanϮSD) and studied their associations with each other, with baseline and incident IHD, and with IHD risk factors. CRP and D-dimer levels were each associated with age, plasma fibrinogen, smoking habit, and baseline evidence of IHD. Key Words: C-reactive protein Ⅲ fibrin D-dimer Ⅲ ischemic heart disease C -reactive protein (CRP), a marker of the reactant plasma protein component of the inflammatory response, has been associated with the risk of future ischemic heart disease (IHD), not only among patients with stable and unstable angina 1,2 and high-risk subjects 3 but also among population samples of apparently healthy middle-aged men 4,5 and elderly men and women. 6 A recent meta-analysis 7 of these prospective studies found a combined risk ratio for IHD of 1.7 (95% confidence interval [CI], 1.4 to 2.1) for subjects in the top third of the distribution of CRP compared with the bottom third. There was no evidence of heterogeneity between these studies.Fibrin D-dimer, a marker of cross-linked fibrin turnover, has also been shown in recent studies to be associated with the risk of future IHD in persons with and without baseline evidence of vascular disease. 8 -16 Local fibrin formation and lysis are part of the inflammatory response, and fibrin degradation products, including D-dimer, have been shown to have diverse effects on inflammatory processes and acutephase responses, including neutrophil and monocyte activation; secretion of cytokines, including interleukin-6 and interleukin-1; and hepatic synthesis of acute-phase proteins, including fibrinogen and CRP. [17][18][19][20] We therefore hypothesized that (1) plasma levels of CRP and D-dimer and their associations with incident IHD in the general population might be linked; (2) linkage might result from focal, vessel wall-related fibrin formation and lysis and an inflammatory response associated with unstable atherosclerotic plaque activity 21,22 ; and (3) CRP and D-dimer might be related to IHD risk factors associated with thrombogenesis and inflammation, particularly cigarette smoking. We are unaware of previously published studies of CRP and D-dimer considered jointly. We tested these hypotheses by studying the mutual relationships of CRP, D-dimer, incident IHD, and risk factors (especially smoking habit) in the middle-aged men of the Speedwell population cohort. Methods Study PopulationThe Speedwe...