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Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:3071-3078

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:3071.)
© 1999 American Heart Association, Inc.

Thrombosis

von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects

The Hoorn Study

Agnes Jager; Victor W. M. van Hinsbergh; Piet J. Kostense; Jef J. Emeis; John S. Yudkin; Giel Nijpels; Jacqueline M. Dekker; Robert J. Heine; Lex M. Bouter; Coen D. A. Stehouwer

From the Institute for Research in Extramural Medicine (A.J., P.J.K., G.N., J.M.D., R.J.H., L.M.B., C.D.A.S.), the Institute for Cardiovascular Research (V.W.M.v.H., C.D.A.S.), and the Department of Epidemiology and Biostatistics (P.J.K., L.M.B.), Vrije Universiteit, Amsterdam, Netherlands; Gaubius Laboratory (V.W.M.v.H., J.J.E.), TNO Prevention and Health, Leiden, the Netherlands; the Centre for Diabetes and Cardiovascular Risk (J.S.Y.), Department of Medicine, University College London Medical School, London, UK; and the Department of Internal Medicine (R.J.H., C.D.A.S.), University Hospital Vrije Universiteit, Amsterdam, the Netherlands.

Correspondence to Dr Coen D.A. Stehouwer, Department of Internal Medicine, University Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, Netherlands. E-mail cda.stehouwer{at}azvu.nl


*    Abstract
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Abstract—Increased levels of von Willebrand factor (vWf) and C-reactive protein (CRP) predict cardiovascular mortality in selected populations. It is uncertain whether vWf and CRP predict mortality in a general population and whether vWf and CRP predict mortality through similar pathways. This study investigated the association of vWf and CRP with cardiovascular and all-cause mortality among diabetic and nondiabetic subjects. An age-, sex-, and glucose tolerance–stratified sample (n=631) of a population-based cohort aged 50 to 75 years was followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). vWf (>1.56 IU/mL) and CRP (>2.84 mg/L) levels in the upper tertile were associated with, respectively, a 3- and 2-fold increase in cardiovascular mortality after adjustment for age, sex, and glucose tolerance status. Analyses in nondiabetic and diabetic subjects separately gave similar results. After further adjustment for hypertension, levels of HDL cholesterol and triglyceride, smoking habits, ischemic heart disease, and peripheral arterial disease, the relative risks (RRs) were 3.0 (95% CI 1.2 to 7.9) for vWf and 1.4 (95% CI 0.6 to 3.5) for CRP. When both vWf and CRP were included in the latter multivariate analysis, the RRs were 3.0 (95% CI 1.1 to 7.9) for vWf and 1.3 (95% CI 0.5 to 3.4) for CRP. The association between vWf and risk of cardiovascular mortality was independent of blood group (O versus non-O) and, moreover, similar among subjects with different blood groups. Repeating the analyses for all-cause mortality gave similar results for CRP. For vWf, the RR was 2.0 (95% CI 1.1 to 3.5) after adjustment for all other risk factors. Increased levels of vWf are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects. The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors. Mutual adjustment of vWf and CRP did not markedly change the results, favoring the hypothesis that vWf and CRP predict mortality through different pathways.


Key Words: von Willebrand factor • C-reactive protein • cardiovascular mortality • non–insulin-dependent diabetes mellitus • acute phase reactant


*    Introduction
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Accumulating evidence indicates that endothelial dysfunction and chronic low-grade inflammation play a pivotal role in the pathogenesis of atherothrombotic disease.1 2 3

Increased levels of von Willebrand factor (vWf) have been proposed to reflect generalized endothelial dysfunction.4 5 Indeed, subjects with peripheral,6 cerebral,7 and coronary artery atherosclerotic disease8 have increased levels of vWf compared with control subjects. Furthermore, high levels of vWf have been shown to predict cardiovascular mortality in patients recently presenting with cardiovascular disease.7 8 9 10 11 However, 2 population-based studies showed no significant association of high vWf levels with cardiovascular mortality.12 13

C-reactive protein (CRP), an acute-phase reactant, is a marker of inflammation. In healthy subjects, its concentration is generally low, rising 5-fold to >100-fold in acute illness. Slightly increased, but conventionally normal, CRP levels may reflect a chronic low-grade inflammatory state and have been found to be an independent predictor of cardiovascular mortality among subjects at high risk of atherothrombotic events,8 14 15 16 as well as among healthy subjects.17 18 19

Levels of both vWf20 21 and CRP22 are increased in non–insulin-dependent diabetes mellitus (NIDDM) compared with levels in control subjects. NIDDM is associated with a 2- to 4-fold increased cardiovascular mortality,23 but there are few prospective data for vWf and cardiovascular disease in NIDDM21 24 and none for CRP.

We performed a prospective population-based cohort study among nondiabetic and diabetic subjects to investigate the relation between vWf and CRP concentrations on one hand and cardiovascular and all-cause mortality on the other. A further aim of the present study was to investigate whether vWf and CRP affect the risk of mortality through similar pathways. We reasoned that if vWf and CRP confer mutually independent excess risks of mortality, this would argue in favor of the idea that vWf and CRP affect mortality risk through substantially different pathways.


*    Methods
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General Study Design
The Hoorn study is a population-based cohort study of disturbances of glucose tolerance in a white population aged 50 to 75 years conducted from 1989 to 1992 (n=2484 subjects; response rate 71%).25 An extensive investigation was performed in an age-, sex-, and glucose tolerance–stratified random sample (n=631, response rate 89%).25 26 27

From these subjects, we obtained an ankle-brachial blood pressure index (n=631) and a resting ECG (n=625). Subjects were classified as having (1) peripheral arterial disease (PAD) when they had an ankle-brachial pressure index <0.9 in either leg and/or when they had undergone a peripheral arterial bypass or amputation,28 (2) ischemic heart disease (IHD) when they had an ECG with a Minnesota code 1.1 to 1.3, 4.1 to 4.3, 5.1 to 5.3, or 7.1 and/or had undergone coronary bypass surgery or angioplasty, and (3) cerebrovascular disease when they had evidence of a past transient ischemic attack or stroke according to the World Health Organization (WHO) cardiovascular questionnaire.29

vWf and CRP
Concentrations of vWf and CRP were assessed in deep frozen (-70°C) heparin plasma samples. No plasma samples were available for 21 subjects. vWf antigen levels were estimated in duplicate by ELISA, essentially as described,30 with the use of polyclonal antibodies from Dako (Glostrup, Denmark), and they were expressed as percentage of vWf detected in pooled citrated plasma of healthy volunteers. According to the 4th International Standard for vWf in plasma (NIBSC code 97/586), the pooled citrated plasma contained 1.03 IU/mL of vWf antigen. CRP levels were measured in duplicate with an enzyme immune assay that used rabbit antibodies against CRP (Dako) as both the capture and tagging antibody, with a sensitivity of 0.2 mg/L.31 CRP standard serum (Behring Diagnostics GmbH) was used for calibration. In 11 subjects, the CRP level was undetectable and therefore set at 0.2 mg/L.

Other Measurements
Data on blood pressure, weight, height, body mass index, glycated hemoglobin, fasting specific plasma insulin, serum total cholesterol, HDL cholesterol, and triglyceride levels were obtained.25 ABO blood groups were determined by standard agglutination techniques using commercial test erythrocytes. LDL cholesterol was calculated by the Friedewald formula,32 except when the triglyceride level was >4.55 mmol/L (n=23). Hypertension was defined as diastolic pressure >=95 mm Hg, systolic pressure >=160 mm Hg, and/or the use of antihypertensive drugs.33 Current smoking was defined as currently smoking cigarettes and/or cigars.

Follow-Up
Data on the vital status of the subjects on April 1, 1997, were collected from the mortality register of the municipality of Hoorn. Of 49 subjects who moved out of town, information on vital status was obtained from the new local municipalities. For each subject, we determined whether or not death had occurred in the first 5 years of follow-up and, if so, the date at which death occurred. For all subjects who had died, the cause of death was classified according to the 9th edition of the International Classification of Diseases.26 Cardiovascular mortality was defined as codes 390 to 459; cancer mortality, as codes 140 to 240. Information on cause of death could not be obtained for 6 (10%) of the deceased subjects.

All participants gave informed consent for the present study, which was approved by the local ethics committee.

Statistical Analyses
All analyses were performed with SPSS 7.5 for Windows 95. Survival over 5 years of follow-up was calculated by Kaplan-Meier curves for different groups, and differences were tested by the log rank test. Differences between groups in continuous variables that had a normal distribution were tested by Student t tests; in continuous variables that had a skewed distribution, by Mann-Whitney tests; and in percentage of subjects with versus without the presence of dichotomous variables, by {chi}2 tests. The correlation between vWf and log-transformed CRP was assessed with the Pearson correlation coefficient. Predictors of 5-year cardiovascular and all-cause mortality were determined by Cox proportional hazards multiple regression analysis (in all cases, because of the stratification procedure) with adjustment for age, sex, and glucose tolerance status. Results are described as relative risks (RRs [hazard ratios]) with 95% CIs.

Potential risk factors measured on a continuous scale were used as such in the regression models, except for HDL cholesterol and body mass index, because the association of these variables with all-cause mortality was nonlinear. Therefore, a low HDL cholesterol level was defined as a level <0.9 mmol/L34 ; obesity, as a body mass index >27 kg/m2 for men and >26 kg/m2 for women.35 Levels of fasting insulin and triglyceride were log-transformed because of a better fit of the regression model. Subjects were grouped according to levels of vWf and CRP. Subjects with levels in the highest tertile were compared with those with levels in the 2 lower tertiles. vWf and CRP were thus entered into the regression models as dichotomized variables, ie, upper tertile versus lower tertiles. (The lowest and middle tertiles were taken together because preliminary analyses showed that the RRs of mortality for these 2 lower tertiles of vWf and CRP were similar, whereas the RR for the upper tertile of vWf and CRP was increased.) To evaluate a possible effect-modifying role of potential risk factors with regard to cardiovascular or all-cause mortality, Cox regression analyses were performed with the risk factor of interest, vWf (or CRP), their product term, age, sex, and glucose tolerance status in the model. A significant RR for the product term was considered effect modification by that risk factor. To assess whether the associations of vWf and CRP with mortality were independent, regression analyses were primarily adjusted for all risk factors that were statistically significant in initial analyses, secondarily adjusted for the presence of cardiovascular morbidity, and finally adjusted for other potential risk factors of interest that showed no significant association in the initial analyses.

To investigate whether vWf and CRP affected risk of mortality through similar pathways, regression analyses were performed that included both vWf and CRP as independent variables. A 2-sided probability value of P<0.05 was considered statistically significant.


*    Results
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Figures 1Down and 2Down (insets) show the distribution of vWf and CRP. The ranges of vWf and CRP levels were 0.24 to 3.89 IU/mL and 0.2 to 35.2 mg/L, respectively. Thirty-three (5.4%) of the subjects had a CRP level >10.0 mg/L. Table 1Down shows the baseline characteristics of the study population. Levels of vWf and CRP in the upper tertile compared with the lower tertiles were significantly associated with higher age, higher levels of fasting glucose, glycated hemoglobin, and insulin, and higher body mass index, systolic blood pressure, and prevalence of NIDDM, hypertension, and PAD. CRP levels in the upper tertile were, in addition, significantly associated with higher levels of triglycerides, higher waist-to-hip ratio, and a higher prevalence of women, current smoking status, and IHD compared with CRP levels in the lower tertiles (data not shown).



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  		Figure 1. Cardiovascular survival (Kaplan-Meier method) according to plasma vWf levels in the upper tertile (>1.56 IU/mL) vs the lower 2 tertiles. Inset shows percentage of vWf >1.56 IU/mL per glucose tolerance status.



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  		Figure 2. Cardiovascular survival (Kaplan-Meier method) according to plasma CRP levels in the upper tertile (>2.84 mg/L) vs the lower 2 tertiles. Inset shows percentage of CRP >2.84 mg/L per glucose tolerance status.


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  		Table 1. Baseline characteristics and RR of 5-Year Cardiovascular and All-Cause Mortality Associated With Potential Risk Factors

After 5 years of follow-up, 58 of the 631 subjects had died, of whom 24 (41%) had died of cardiovascular disease. Subjects who died had higher levels of vWf (mean±SD) and CRP (median interquartile range) compared with those that survived: 1.76±0.72 versus 1.33±0.68 IU/mL and 3.33 (1.36 to 6.88) versus 1.68 (0.79 to 3.35) mg/L, respectively. Table 1Up shows RRs of mortality associated with potential risk factors.

von Willebrand Factor
In the entire group, vWf levels in the upper tertile were associated with an {approx}4-fold increased risk of cardiovascular mortality (Figure 1Up) and, after adjustment for age, sex, and glucose tolerance status, with an {approx}3-fold increased risk (Table 2Down). After further adjustment for hypertension, current smoking, low level of HDL cholesterol, level of triglyceride, IHD, and PAD, the RR associated with vWf was 3.04 (Table 2Down). Subgroup analyses in nondiabetic and diabetic subjects showed that vWf was associated with a 4-fold and 2-fold increased risk of cardiovascular death, respectively, after correction for age, sex, and impaired glucose tolerance (Table 2Down). Further adjustment increased the RR associated with vWf to 11.83 among nondiabetic subjects, whereas the RR among diabetic subjects remained 2.51 (Table 2Down).


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  		Table 2. Relative Risk of 5-Year Cardiovascular and All-Cause Mortality Associated With Presence of vWF Highest Tertile (>1.56 IU/mL) After Adjustment for Potentially Confounding Risk Factors

The RR of all-cause mortality associated with vWf in the upper tertile was 2.03, which was not affected by adjustment (Table 2Up).

To investigate whether the RR of vWf was similar among different risk groups, we performed analyses with interaction terms added (see Methods). Impaired glucose tolerance, NIDDM, current smoking, levels of triglyceride and total cholesterol, body mass index, IHD, and PAD showed no significant interaction (for interaction term, P>0.2). The RRs of cardiovascular mortality associated with vWf in the upper tertile among women, in subjects >65 years of age, and in the presence of hypertension or low levels of HDL cholesterol were 12.3 (P=0.03), 6.5 (P=0.07), 5.0 (P=0.12), and 4.5 (P=0.10) times higher, respectively, than when these factors were absent (data not shown).

The hypothesis has been advanced that the ABO blood group could be the explanation for the association between vWf level and cardiovascular mortality, because blood groups are associated with both cardiovascular disease and levels of vWf.36 The prevalences of blood groups O, A, B, and AB were 45%, 39%, 11%, and 6%. After adjustment for age, sex, and glucose tolerance status, blood group non-O was associated with a 2-fold increased cardiovascular mortality compared with blood group O (RR 2.08 [95% CI 0.85 to 5.07] among all subjects). Additional adjustment for risk factors mentioned in Table 2Up did not materially change this result (data not shown). The levels of vWf were significantly lower in blood group O compared with blood group non-O (mean±SD 1.16±0.58 and 1.49±0.72 IU/mL, respectively; P<0.05). The RRs of cardiovascular mortality associated with vWf level and blood group non-O were not importantly affected by mutual adjustment (eg, for model 1 in Table 2Up, RRs 3.02 [1.22 to 7.53] and 1.77 [0.72 to 4.38], respectively). Further adjustment for risk factors mentioned in Table 2Up gave similar results (data not shown). Analyses performed among blood group O and blood group non-O separately gave similar results (eg, for model 1 in Table 2Up, RRs 2.01 [0.42 to 9.51] and 3.28 [1.05 to 10.25] among all subjects, respectively).

C-Reactive Protein
In the entire group, CRP levels in the upper tertile were associated with an {approx}3-fold increased risk of cardiovascular mortality (Figure 2Up) and, after adjustment for age, sex, and glucose tolerance status, with an {approx}2-fold increased risk (Table 3Down). After further adjustment for hypertension, current smoking, low level of HDL cholesterol, triglyceride level, IHD, and PAD, the RR associated with CRP was 1.41 (Table 3Down). The RRs of cardiovascular mortality associated with CRP in the upper tertile were similar among nondiabetic and diabetic subjects ({approx}2-fold). After further adjustment, the RR of CRP decreased to 0.83 among nondiabetic and to 1.34 among diabetic subjects (Table 3Down).


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  		Table 3. Relative Risk of 5-Year Cardiovascular and All-Cause Mortality Associated With Presence of CRP in Highest Tertile (>2.84 mg/L) After Adjustment for Potentially Confounding Risk Factors

CRP was a significant predictor of all-cause mortality after adjustment for age, sex, and glucose tolerance status in the entire group (Table 3Up). After adjustment for other risk factors, the RR decreased from 1.88 to 1.33 (Table 3Up).

Impaired glucose tolerance, NIDDM, hypertension, current smoking, low levels of HDL cholesterol, levels of triglyceride and total cholesterol, body mass index, IHD, and PAD showed no significant interaction (for interaction term, P>0.2). The RRs of cardiovascular mortality associated with CRP in the upper tertile among women and subjects older than 65 years were, respectively, 3.6 (P=0.18) and 6.5 (P=0.13) times higher than those among men and subjects aged <65 years (data not shown).

Additional Analyses
The correlation between vWf and log-transformed CRP in the entire group was 0.10 (P=0.014). The RRs of cardiovascular mortality associated with vWf and CRP in their respective upper tertiles were not importantly affected by mutual adjustment (Table 4Down). Further adjustment also did not materially affect the results (Table 4Down). vWf and CRP showed no mutual interaction (for interaction term, P=0.99).


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  		Table 4. Relative Risk of 5-Year Cardiovascular and All-Cause Mortality Associated With Plasma Concentration of vWf and CRP in Upper Tertile After Mutual Adjustment

Twenty-six (45%) of the subjects died of cancer. After adjustment for age, sex, and glucose tolerance status, both vWf and CRP were not significantly associated with risk of cancer mortality (RRs 1.50 [0.67 to 3.34] and 1.23 [0.54 to 2.82], respectively).

Because the RRs of mortality were similar in the lower tertiles of either vWf or CRP and increased in the upper tertile only, we further investigated whether there was a threshold value of vWf and CRP for predicting mortality by changing the definitions of a "high" vWf and CRP concentration. When vWf was dichotomized as with 1.22 IU/mL (median) or 1.74 IU/mL (highest quartile) as cutoffs, the risk estimates for cardiovascular mortality were slightly lower (eg, for model 1 in Table 2Up, RRs 2.36 [0.93 to 5.99] and 2.63 [1.16 to 5.98] compared with 2.80 [1.18 to 6.66], respectively). When CRP was dichotomized with 2.11 mg/L (used in Reference 1818 ), 3.20 mg/L (used in Reference 1717 ), or 3.60 mg/L (used in Reference 1515 ) as cutoffs, the RR of cardiovascular mortality was lower (eg, for model 1 in Table 3Up, RRs 1.35 [0.56 to 3.22], 1.93 [0.85 to 4.41], and 1.58 [0.68 to 3.64] compared with 2.23 [0.95 to 5.21], respectively). Exclusion of subjects with vWf level <0.50 IU/mL (n=39) or of subjects with CRP level >10.0 mg/L gave similar results (data not shown). Analyses with a shorter follow-up duration showed higher RRs of cardiovascular mortality associated with vWf and CRP levels in their respective upper tertiles. For example, after adjustment for age, sex, and glucose tolerance status, the RRs for vWf and CRP in the first 3 years of follow-up were 4.02 (1.09 to 14.93) and 4.46 (1.14 to 17.41); for 3 to 5 years of follow-up, the values were 1.86 (0.55 to 6.37) and 1.15 (0.32 to 4.10), respectively. The difference between these risk estimates (the first 3 years compared with 3 to 5 years of follow-up) was not significant (P=0.40 and P=0.15, respectively).


*    Discussion
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 *Discussion
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This prospective study showed that higher levels of vWf are associated with 5-year cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects. This association is independent of conventional risk factors and blood groups. The level of CRP is a predictor of all-cause mortality, which, however, is not independent of other risk factors. Mutual adjustment of vWf and CRP did not markedly affect the RRs of mortality. These results, together with the weak correlation between vWf and CRP at baseline (r=0.10), argue in favor of the idea that vWf and CRP predict mortality through different pathways.

Our finding that vWf is an independent predictor of cardiovascular mortality is in line with results of some7 8 9 10 11 but not all studies.11 12 13 37 38 39 To the best of our knowledge, this is the first study that provides evidence for an independent association of vWf with cardiovascular mortality in the general population. The precise mechanism by which vWf increases cardiovascular risk is unclear. It has been suggested that vWf is a marker of generalized endothelial dysfunction,4 5 which is an important feature of atherothrombotic disease.1 2 3 Alternatively, it has been hypothesized that vWf, as an acute-phase reactant,40 reflects endothelial activation and stimulation (without necessarily implying endothelial dysfunction) and, as such, is a marker of more severe disease in general. Accordingly, the ECAT study (Juhan-Vague et al41 ) showed that among subjects with angina pectoris, the independent RR of cardiovascular mortality associated with vWf disappeared after adjustment for variables related to inflammation, ie, CRP and/or fibrinogen. In other words, the risk predicted by vWf was explained by the risk predicted by CRP and/or fibrinogen. In contrast, we found that mutual adjustment of vWf and CRP did not materially change the risk estimates, suggesting different mechanisms through which vWf and CRP predict mortality. Finally, vWf plays an important role not only in platelet adhesion and aggregation but also in coagulation42 43 and may thus enhance the risk of thrombogenesis. Accordingly, the increase of vWf within 48 hours after a myocardial infarction was a predictor of the rate of restenotic cardiovascular events within 14 days, whereas the increase of CRP, as a marker of acute-phase response, was not.44 Our finding that the RR of mortality associated with vWf is strongest in the first few years of follow-up is compatible with the view that vWf is related more to atherothrombotic than to atherosclerotic disease. In sum, our data are consistent with the concept that a high vWf level, in the general diabetic and nondiabetic population, is a marker of generalized endothelial dysfunction and/or a prothrombotic state but not with the view that a high vWf level reflects an acute-phase response.

Slightly increased levels of CRP have been found to be associated with increased cardiovascular risk in subjects with angina pectoris8 14 15 and in healthy subjects.17 18 19 It has been hypothesized that a chronic low-grade bacterial infection, which can cause raised CRP levels within the normal range and is associated with coronary heart disease,45 46 is the mechanism through which CRP predicts cardiovascular mortality.18 19 On the other hand, CRP itself has bioactive properties that may counterregulate the inflammatory response.46 47 48 Nevertheless, these anti-inflammatory properties have been found only in studies using concentrations of CRP above the conventional normal range and may thus be less important for slightly increased levels of CRP. We found that high CRP levels were associated with a 2-fold increased risk of cardiovascular mortality. This result is in partial agreement with previous studies among apparently healthy subjects.16 17 18 19 First, in contrast to previous studies,17 18 19 we showed that the association of CRP with cardiovascular mortality was to a large extent explained by other risk factors (Table 5). Second, we found that the RR of mortality for CRP was stronger in the first few years of follow-up, whereas Ridker et al18 found that this risk was stable in time, at least up to 8 years of follow-up. Third, we did not find a linear association of CRP level with mortality, whereas others did.18 19 Fourth, although we did find evidence for a stronger association of CRP with mortality risk among women and among subjects aged >65 years, we could not demonstrate interactions, with regard to mortality risk, between CRP and current smoking,16 49 total cholesterol levels,50 or IHD.16 Fifth, the determinants of CRP that we found (Table 1Up) were in line with some51 but not all previous studies.17 Taken together, these data suggest that the association between CRP and cardiovascular mortality differs between populations. This hypothesis requires further study.

We observed similar associations of vWf and CRP with RR of cardiovascular mortality among nondiabetic and diabetic subjects. NIDDM is associated with a 2- to 4-fold increase of cardiovascular mortality.23 Various hypotheses have been put forward to explain the mechanism through which diabetes accelerates atherothrombosis. Potential glucose-mediated mechanisms include increased oxidative stress, increased concentrations of advanced glycation end products, and activation of the diacylglycerol–protein kinase C pathway,5 52 which can directly or indirectly induce endothelial dysfunction, an acute phase response, and a procoagulant state.5 52 In other words, the associations of vWf and CRP with cardiovascular mortality could be different between diabetic and nondiabetic subjects, because the underlying pathophysiological conditions that cause increased levels of vWf and CRP might be dissimilar. However, from our data, it seems that once levels of vWf and CRP are increased, their associations with cardiovascular mortality are similar among diabetic and nondiabetic subjects.

As has been shown previously, we found higher RRs of mortality associated with vWf12 53 among women than among men. Furthermore, vWf was a stronger predictor in subjects aged >65 years and in the presence of hypertension or a low level of HDL cholesterol. We could neither prove nor disprove the presence of interaction between vWf and these last 3 variables; therefore, more comprehensive studies are necessary to address these issues.

The levels of vWf and CRP were both measured once, which may have led to nondifferential misclassification and, therefore, an underestimation of the RRs associated with mortality. The present study was too limited to assess, with much precision, above what threshold vWf and CRP are associated with mortality. Furthermore, a longer follow-up duration is necessary to establish or exclude definitively the existence of time dependence in the associations of vWf and CRP with mortality risk. Although our data support the concept that levels of vWf and CRP predict cardiovascular mortality through different pathophysiological mechanisms, we did not investigate these possible mechanisms.

We have shown that the level of vWf is a strong independent predictor of cardiovascular and all-cause mortality in the general population, whereas the association of CRP with mortality is confounded by other risk factors. The risk estimates of cardiovascular mortality associated with vWf and CRP were mutually independent, suggesting that vWf and CRP predict mortality through different pathways. This, along with our finding that the risk predicted by vWf seems time dependent (stronger in the first few years of follow-up), gives support to the hypothesis that vWf is more likely to be a marker of risk for atherothrombotic than for atherosclerotic disease. From a therapeutic point of view, this is of clinical relevance, because antithrombotic agents have been shown to reduce the risk of a first myocardial infarction54 and to provide a favorable outcome after a myocardial infarction.44 Therefore, we suggest that the use of antithrombotic agents among subjects with high vWf levels might be particularly effective in reducing the risk of myocardial infarction. Randomized clinical trials are necessary to investigate this hypothesis.


*    Acknowledgments
 
Prof Dr van Hinsbergh and Dr Emeis were supported by a grant from the Praeventiefonds (28-1622-1), and Dr Stehouwer was supported by a Clinical Research Fellowship from the Diabetes Fonds Nederland and the Netherlands Organization for Scientific Research (NWO). We are indebted to J.W.G. Geerdink for her excellent laboratory assistance.

Received February 18, 1999; accepted May 28, 1999.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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