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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5377-5381
Copyright © 2004 by The Endocrine Society

Plasma von Willebrand Factor and the Development of the Metabolic Syndrome in Patients with Hypertension

Hoong Sern Lim, Gregory Y. H. Lip and Andrew D. Blann

Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom

Address all correspondence and requests for reprints to: Dr. A. D. Blann, Ph.D., M.R.C.Path., Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom. E-mail: a.blann{at}bham.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Although the metabolic syndrome is associated with endothelial damage/dysfunction, the effect of risk factors and their relationship with the development of this condition are unclear. We hypothesized that plasma von Willebrand factor (vWf, marking endothelial damage/dysfunction) increases with the number of components of metabolic syndrome and that increased levels precede its development. To test this, fasting vWf, glucose and lipids were measured in 161 patients (mean age 63 ± 7 yr, 85% males) with hypertension. Using World Health Organization (WHO) criteria, 32 (19.9%), and using National Cholesterol Education Program (NCEP) criteria, 70 (43.5%) had metabolic syndrome. Plasma vWf was higher in these patients regardless of defining criteria and increased with the number of the components of metabolic syndrome (both P < 0.001). After 4 yr, patients who did not have metabolic syndrome at baseline were reassessed for the development of this condition. Of the 129 patients who did not meet the WHO criteria at baseline, 38 (29.5%) subsequently developed the condition, whereas 36 of the 91 (39.6%) who did not meet the NCEP criteria at baseline subsequently developed metabolic syndrome. Baseline vWf levels did not predict development of metabolic syndrome, regardless of criteria (P = 0.071 for WHO and P = 0.639 for NCEP). Our data suggest more severe endothelial damage/dysfunction with cumulative metabolic syndrome-related risk factors. The failure of plasma vWf to predict the development of metabolic syndrome suggests that endothelial damage/dysfunction is a consequence, not a cause, of these risk factors.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE METABOLIC SYNDROME is a common phenotype characterized by the coalition of multiple cardiovascular risk factors, particularly that of raised blood pressure, central obesity, abnormal glucose, and lipid metabolism (1, 2). This clinical syndrome is associated with the development of diabetes and increased cardiovascular mortality (3, 4). Whereas insulin resistance, broadly defined as impaired biological response to insulin, is widely regarded as the primary abnormality (5), others have proposed that the overt manifestations of this clinical syndrome may be consequences of endothelial damage/dysfunction in small vessels of different vascular beds (6). However, there are few data examining the temporal relationship between the development of components of metabolic syndrome and endothelial damage/dysfunction. Similarly, epidemiological studies indicated higher coronary heart disease (CHD) risk (as calculated from the Framingham equation) in patients with metabolic syndrome (7), but there are no prospective data examining the relationship between CHD risk and the development of metabolic syndrome.

Plasma von Willebrand factor (vWf) is a recognized circulating marker of endothelial damage/dysfunction (8, 9). Elevated in patients with hypertension (10), plasma vWf correlates with coronary risk (11) and has been associated with an adverse prognosis (12, 13). It has been shown to increase with increasing insulin levels (14), suggesting a relationship with insulin resistance and metabolic syndrome, but there are few data on vWf in relation to cumulative number of components of metabolic syndrome.

The present work tests the hypothesis that baseline plasma vWf levels and calculated CHD risk predict the subsequent development of metabolic syndrome in patients with essential hypertension. In addition, we hypothesize that vWf increases with increasing numbers of the components of metabolic syndrome in these patients. We tested our hypotheses in a cohort of patients attending the hypertension clinic followed up for 4 yr, using routinely available clinical and biochemical parameters to define metabolic syndrome [according to the World Health Organization (WHO) criteria (1)] to simulate routine clinical practice. We then compared these patients with those identified by a modified National Cholesterol Education Program (NCEP) criteria, recently adopted by Sattar et al. (15), which have been proposed as being more clinician friendly.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients were recruited from a specialist outpatient hypertension clinic. Inclusion criteria were age between 40 and 80 yr, either newly diagnosed untreated hypertension, systolic blood pressure (SBP) higher than 160 mm Hg and/or diastolic blood pressure (DBP) higher than 100 mm Hg, or treated hypertension with SBP higher than 140 and/or DBP higher than 90 mm Hg. Specific inquiries were made to elucidate a history of cardiovascular disease, i.e. stroke, transient ischemic attack, myocardial infarction, angina, claudication, and coronary or peripheral revascularization, and such patients were excluded. Other exclusion criteria included secondary or malignant-phase hypertension, significant hepatic and renal disease, diabetes mellitus, or raised fasting plasma glucose (>7.0 mmol/liter).

Blood pressure was measured after 10 min of rest in a quiet room. Three consecutive blood pressure readings were taken, and the average of the last two readings was used. Left ventricular hypertrophy was diagnosed according to the Cornell voltage duration product (>2440) or Sokolow-Lyon criteria (>38 mV) on electrocardiogram. Fasting plasma glucose and total serum cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were analyzed by standard techniques in the hospital laboratory. Using these data, the 10-yr CHD risk was calculated from the Framingham equation (16). Body weight was measured with a single layer of clothing and, with height, generated a body mass index (BMI). All these clinical and biochemical measurements were repeated annually over the 4-yr period. Treatment was at the discretion of the physician according to recommended practices (17). The study was approved by the West Birmingham Local Research Ethics Committee, and informed consent for all subjects was obtained.

Plasma vWf

Blood was drawn after an 8-h fast with minimal trauma from the antecubital vein into citrated tubes. Samples were put on ice for 5 min and then centrifuged at 2500 rpm (1000 x g) for 20 min at 4 C. The plasma was stored at –70 C until assayed. Levels of vWF were analyzed with a sandwich ELISA using commercially available reagents and standards (Dako Ltd., Ely, UK). The assay has an intraassay coefficient of less than 5% and an interassay coefficient of less than 10%.

Definition of metabolic syndrome

The threshold for the modified NCEP criteria used were fasting plasma glucose greater than 6.1 mmol/liter, triglycerides 1.7 mmol/liter or more, HDL cholesterol 1.1 mmol/liter or less, and BMI greater than 28.8 kg/m2, as described by Sattar et al. (15). Because all the study participants were hypertensive, these patients were classified as having metabolic syndrome if they fulfilled two or more of the above criteria. Similarly, because all these patients were hypertensive, the WHO criteria (1) were defined as impaired fasting glycemia plus any one of the following: fasting plasma triglycerides 1.7 mmol/liter or more, HDL cholesterol less than 0.9 mmol/liter in men and 1.0 mmol/liter in women, or BMI greater than 30 kg/m2.

Power calculations

At the time of the study, there were no data on plasma vWf in relation to cumulative number of components of metabolic syndrome. Therefore, we based our power calculations from a previous study of patients with hypertension and additional risk factors (10). Hypothesizing a difference of 0.5 SD, we would require a minimum of 32 patients for 2P < 0.05 and 1-ß = 0.80. With a prevalence of metabolic syndrome estimated at over 40% (over the age of 60 yr) from population studies (18), we would require a minimum of 80 patients for a cross-sectional comparison between patients with and without metabolic syndrome. Similarly, there were no data on the incidence of metabolic syndrome in patients with hypertension at the time of the study. In a study of elderly subjects, Hiltunen et al. (19) found a 36% conversion to impaired glucose tolerance over a 3- to 4-yr period. Using this as a reference, we hypothesized a more conservative incidence of developing metabolic syndrome of 25% over 4 yr. Therefore, we would need a minimum of 128 patients followed up for 4 yr to yield 32 patients, again hypothesizing a difference of 0.5 SD in baseline vWf between patients who subsequently developed metabolic syndrome, compared with those who did not.

Statistical analysis

Continuous data were subjected to the Anderson-Darling test to determine their distribution. Nonnormal data are presented as median and interquartile range. Normally distributed are presented as mean and SD and analyzed by t tests. Nonnormally distributed data were analyzed by Mann-Whitney U tests. Categorical data were analyzed by the {chi}2 test. Differences between multiple groups of normally distributed data were analyzed by ANOVA and Tukey’s post hoc test. Analyses and power calculations were performed using Minitab 13 (Minitab Inc., State College, PA).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
We recruited 161 patients from the outpatient hypertension clinic. Using fasting plasma glucose and the WHO criteria, 19.9% (n = 32) of patients fulfilled the WHO criteria for metabolic syndrome. Seventy patients (43.5%) fulfilled the modified NCEP criteria-defined metabolic syndrome (Table 1Go).


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  		TABLE 1. Baseline characteristics of patients with and without metabolic syndrome

 
As expected, the 32 patients who met the WHO criteria for metabolic syndrome had higher BMI, fasting plasma glucose, and serum triglycerides and were more likely to be from non-Caucasian ethnic groups (four of the seven non-Caucasians were South Asians). Plasma vWf levels were higher in these patients, compared with those who did not meet the criteria for metabolic syndrome, but the predicted 10-yr CHD risk was not significantly different (Table 1Go).

Similarly, the 70 patients with modified NCEP criteria-defined metabolic syndrome had higher BMI and serum triglycerides, but these patients also had lower serum HDL cholesterol and were more likely to be males. This was associated with higher predicted 10-yr CHD risk and plasma vWf (Table 1Go).

On multivariate analysis, plasma vWf was independently associated with the presence of metabolic syndrome, defined by either criteria at baseline (Table 2Go). Gender and BMI were not independently associated with metabolic syndrome after adjusting for differences in the metabolic profile and plasma vWf.


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  		TABLE 2. Multivariate analysis of factors associated with the presence of metabolic syndrome at baseline [only factors significantly different at baseline (Table 1Go) entered into analyses]

 
vWf and components of metabolic syndrome

vWf increased with increasing number of components of metabolic syndrome, either defined by the WHO or modified NCEP criteria [P (linear trend) of 0.021 and 0.039, respectively]. In particular, the presence of two or more components of metabolic syndrome, defined by either the WHO or modified NCEP criteria, in addition to hypertension, was associated with significantly elevated levels of plasma vWf (Table 3Go).


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  		TABLE 3. Relationship between plasma vWf and the number of components of the metabolic syndrome in 161 patients with hypertension

 
Plasma vWf and the development of metabolic syndrome

In the longitudinal study, all the patients completed 3 yr of follow-up with 117 of the 161 (72.7%) followed up for 4 yr. Thirty-eight (29.5%) of the 129 patients who did not meet the WHO criteria for metabolic syndrome at baseline fulfilled the criteria after 4 yr of follow-up. These patients had higher BMI, SBP, and serum triglycerides but lower HDL cholesterol at baseline and consistently at follow-up (P < 0.05). However, there were no significant differences in baseline-predicted CHD risk and plasma vWf levels (Table 4Go). Lipid-lowering therapy was used in 55% of patients who developed WHO-defined metabolic syndrome, compared with 52% in those who did not (P = 0.708) with no significant differences in total cholesterol levels over the 4 yr. The proportion of patients requiring at least three antihypertensive agents was not significantly different between the two groups (P = 0.187).


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  		TABLE 4. Baseline characteristics of patients who developed metabolic syndrome at follow-up

 
After 4 yr of follow-up, 36 of 91 patients (39.6%) who did not meet the modified NCEP criteria at baseline subsequently developed metabolic syndrome. As expected, these patients had higher BMI and lower HDL cholesterol. Unlike the WHO criteria, this was associated with higher predicted 10-year CHD risk at baseline (Table 4Go) but not significantly different baseline plasma vWf levels between patients who fulfilled the criteria for metabolic syndrome at follow-up, compared with those who did not. The proportion of patients on statin therapy (64% vs. 49%, P = 0.0165) was higher in patients who developed modified NCEP criteria-defined metabolic syndrome, compared with those who did not, but those requiring at least three antihypertensive therapy (58% vs. 64%, P = 0.611) was not different. There was no significant difference in SBP or DBP control and serum total cholesterol levels over the 4 yr. As in those patients identified by the WHO criteria, serum triglycerides levels were consistently higher, and HDL cholesterol lower, in patients who developed metabolic syndrome.

On multivariate analysis, BMI, HDL cholesterol, and in patients who developed metabolic syndrome by the WHO criteria, serum triglycerides were independently associated with the development of metabolic syndrome (Table 5Go).


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  		TABLE 5. Multivariate analysis of factors associated with the development of metabolic syndrome [only factors significantly different (Table 4Go) entered into analyses]

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this cohort study of patients with hypertension we have shown the following: 1) plasma vWf levels were higher and independently associated with the presence of established metabolic syndrome, identified by either the WHO or a modified NCEP criteria; 2) plasma vWf increased with the number of components of metabolic syndrome; 3) patients who developed metabolic syndrome did not have higher plasma levels of vWf at baseline, compared with patients who did not fulfill the criteria; and 4) baseline CHD risk (from the Framingham equation) was higher in patients who developed metabolic syndrome, compared with those who did not.

Metabolic syndrome describes the frequent association of multiple cardiovascular risk factors, but the precise pathophysiology of this clinical syndrome is not clear. Pinkney et al. (6) proposed that endothelial damage/dysfunction may be a central component of metabolic syndrome, possibly preceding or even causing its development. Whereas other studies have demonstrated the association between plasma indices of endothelial damage/dysfunction (including vWf) with features of the metabolic syndrome (20), a temporal relationship (with cause preceding effect) has not been defined. Indeed, the latter represents one of the most rigorous criteria in the judgment of causality (21). Hence, our data appear to refute the above hypothesis and suggest that endothelial damage/dysfunction may be a consequence, rather than the cause, of metabolic syndrome.

In contrast to plasma vWf, baseline BMI, (lower) HDL cholesterol, and higher triglycerides (in WHO-defined metabolic syndrome) were independently associated with the development of metabolic syndrome. Obesity and dyslipidemia (high serum triglycerides and low HDL cholesterol) correlate well with measures of insulin resistance (22). Therefore, our findings support current proposed pathogenetic mechanisms implicating obesity and insulin resistance in the development of metabolic syndrome (23).

Cross-sectional studies have indicated higher predicted CHD risk in patients with compared with those without metabolic syndrome, identified by either the NCEP or WHO criteria (7). However, it was not clear whether these patients were already at increased risk before fulfilling these criteria. Our data indicate that patients who developed metabolic syndrome (by modified NCEP criteria) had higher calculated CHD risk at baseline, suggesting higher risk even before all the criteria for the metabolic syndrome were met. There was no significant difference in CHD risk (using the Framingham equation) in patients with and without metabolic syndrome, as defined by the WHO criteria, probably because we used only fasting plasma glucose without any measures of insulin resistance, which may have underestimated the number of patients with this syndrome. However, the measurement of insulin resistance has not been widely adopted into clinical practice, and the use of oral glucose tolerance testing has only limited clinical uptake (24). In this regard, our study closely reflects routine everyday clinical practice, suggesting that the WHO criteria (with fasting plasma glucose) may have only limited utility in early identification of patients at increased risk of CHD or development of metabolic syndrome in contemporary clinical practice.

Our study suffers from some notable limitations. First, this is not a true population study, and so our data may not be applicable to other populations because we recruited only patients with hypertension, most of whom were of white European descent, and that primary therapy was aimed at this. The temporal relationship among obesity, insulin resistance, endothelial damage/dysfunction, and the development of metabolic syndrome further upstream (e.g. in apparently healthy individuals) should be explored in future studies. Second, we did not examine the relationship between specific combinations of components of metabolic syndrome with vWf. However, it was not our aim to interrogate the impact of specific risk factor combinations on the molecule because this would have demanded a larger study population. Each of the components of metabolic syndrome may not carry equal weight in influencing vWf levels and indeed do not in the Framingham calculation of CHD risk. Despite this, in a general population (although free of hyperglycemia and not on a basis of hypertension), vWf correlates with the Framingham CHD risk score (25), emphasizing the importance of risk factors, and our present data support the concept that increasing levels of vWf predict adverse events (12, 26). Because we used the modified NCEP criteria to diagnose metabolic syndrome, we cannot confirm whether our data are directly comparable with other studies using the conventional NCEP criteria. Nonetheless, these modified NCEP criteria have been shown to predict coronary events and diabetes (15). Finally, although the prospective component is limited by a rather small population studied over a limited time period, thus risking a possible type 2 statistical error, our power calculation is robust, and the recruitment number and proportion of patients with end points is comparable with other studies.

In conclusion, as expected, metabolic syndrome is associated with higher plasma vWf, which increases with the number of components of metabolic syndrome, probably indicating more severe endothelial damage/dysfunction. However, baseline plasma vWf did not predict the development of metabolic syndrome, suggesting that endothelial damage/dysfunction is a consequence and not a cause of metabolic syndrome. CHD risk may be raised in patients, even before fulfilling the criteria for metabolic syndrome. In this regard, the modified NCEP criteria may be more useful in identifying patients at increased risk of CHD in routine clinical practice, compared with the WHO criteria.


   Footnotes
 
Abbreviations: BMI, Body mass index; CHD, coronary heart disease; DBP, diastolic blood pressure; HDL, high-density lipoprotein; SBP, systolic blood pressure; vWf, von Willebrand factor.

Received April 4, 2004.

Accepted August 5, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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