Plasma von Willebrand factor (VWF) levels have been shown to predict coronary heart disease in several large-scale epidemiological studies [1,2]. Circulating VWF is released from endothelial cells in response to a wide variety of agents, including prothrombotic and/or inflammatory mediators, vasoactive hormones, shear stress and oxidative stress . Plasma VWF levels are known to increase with age , and VWF (directly or via the state of endothelial activation it represents) could possibly contribute to the rise in cardiovascular events associated with age. However, the mechanisms of age-related increase in plasma VWF levels are largely unknown. Aging is also associated with increased arterial rigidity, which results in increased pulse wave velocity (PWV), systolic blood pressure and pulse pressure . There are several plausible mechanisms by which changes in arterial rigidity could induce endothelial activation and VWF secretion. We therefore hypothesized that VWF plasma levels could be associated with arterial rigidity.
We have previously studied the determinants of arterial rigidity in a 6-year longitudinal study . Normal, untreated and treated hypertensive subjects were examined at the ‘Center d’Investigations Préventives et Cliniques'. This medical center provides all working and retired persons and their families with a free medical examination every 5 years. Patients were studied twice, in 1992–1993 and in 1998–1999. Age, body mass index, supine blood pressure, smoking status, creatinine, C-reactive protein (CRP), blood glucose and lipid levels were determined. Aortic PWV was measured using an automated device (Complior; Colson, Artech Medical, France), recording the pulse waves at the base of the neck (common carotid artery) and over the right femoral artery; PWV was calculated as the distance between the two recording sites divided by the pulse wave transit time. We found that the progression of arterial rigidity is related to the presence of high blood pressure, fast heart rate and high serum creatinine.
We measured VWF plasma levels on the frozen stored plasma samples available from 219 patients, drawn at the second visit (1998–1999). The population included 92 women and 127 men, aged 59.3 ± 9.4 years (mean ± SD). Eighty-nine patients were normotensive and 130 patients were treated for hypertension. Blood was drawn under fasting conditions, in the morning after 10–15 min rest in sitting position. VWF was measured by ELISA on EDTA plasma, using normal pooled plasma as a standard. Since VWF levels are known to be influenced by ABO blood groups , blood grouping was performed serologically by the detection of anti-A/B antibodies on plasma tested with A1 and B red cells, using the gel microcolumn test, Diamed-ID Micro Typing System®. Measurements of intima-media thickness (IMT) were also performed on all these subjects with ultrasound examinations using the Aloka SSD-650, with a transducer frequency of 7.5 MHz. Acquisition, processing and storage of B-mode images were computer-assisted with the new version of software previously described (M'ATHS, Metris, France).
In univariate linear regression analysis, we observed a weak but significant correlation between VWF levels and age, PWV, and pulse pressure. When the analysis was restricted to 130 hypertensive subjects, VWF levels were more strongly related to age (Pearson's r = 0.27, P = 0.002), log (PWV) (0.24, r = 0.007), and the log (pulse pressure) (r = 0.18, P = 0.037). The stronger correlation between VWF levels and PWV in hypertensive subjects is possibly explained by the larger range of PWV values in this subgroup. There was no association between VWF levels and systolic, diastolic and mean blood pressure or any metabolic parameter; nor did we find any association between VWF and IMT. Plasma VWF levels were somewhat lower in group O subjects. Actually, a significant relationship between VWF and age was observed only among non-O subjects (VWF = 40.5 + (1.61 × age), r = 0.35, P < 0.001). As expected, the association between age and PWV was not influenced by blood group status.
To analyze further the relationship between VWF levels and PWV in the treated hypertensive patients, we performed a multivariate linear regression analysis including PWV, age, ABO blood group and CRP (see Table 1). After adjustment for age and CRP, the association between VWF levels and PWV was no longer significant. Including ABO blood group added little to the predictive power of the multivariate model. However, after inclusion of blood group, the relation of VWF to PWV improved, approaching statistical significance (coefficient 0.267, P = 0.067). Thus, our data show that in univariate analysis VWF plasma levels are associated with age, PWV and pulse pressure in hypertensive patients. Both age and blood group appear to be significant confounding factors. However, when both parameters are included, we still observe a possible association between PWV and VWF levels.
|Univariate analysis||Model A||Model B|
|Coeff. (95% CI)||P||r2||Coeff. (95% CI)||P (r2 = 9.8)||Coeff. (95% CI)||P (r2 = 11.5)|
|Age||0.011 (0.004, 0.017)||0.001||7.8||0.009 (0.002, 0.016)||0.018||0.008 ( 0.001, 0.015)||0.024|
|ln(PWV)||0.372 (0.103, 0.642)||0.007||5.5||0.241 (−0.045, 0.527)||0.097||0.267 (−0.019, 0.554)||0.067|
|ln(CRP)||0.018 (−0.040, 0.076)||0.548||0.3||0.007 (−0.050, 0.063)||0.813||0.011 (−0.045, 0.068)||0.689|
|Blood group O|
|− 0.080 (−0.197, 0.038)||0.182||1.4||−0.089 (−0.203, 0.025)||0.123|
Endothelial activation and VWF secretion could be related to arterial rigidity by several mechanisms. Oscillatory shear stress associated with arterial rigidity and/or increased pulse pressure could induce a local inflammatory state, increase superoxide anion generation or impair endothelial nitric oxide production ; all these changes could induce endothelial VWF secretion. In our study we found only weak associations among VWF, PWV and pulse pressure. There are several limitations in our study that may have underestimated this association. The most obvious is its small size. More importantly, hypertensive patients were treated; various antihypertensive drugs can modify neuroendocrine and/or hemodynamic parameters known to influence endothelial secretion and/or plasma VWF levels.
In conclusion, there is a possible association between VWF levels and arterial rigidity, but not intima-media thickness. This association deserves to be investigated in a larger study, preferably including untreated hypertensive subjects. Our data also provide a reminder that age and ABO blood group should always be taken into account when plasma VWF levels are used in epidemiological studies.