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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.
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Abstract |
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Introduction |
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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.
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Patients and Methods |
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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 
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).
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Results |
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).
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).
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 1).
On multivariate analysis, plasma vWf was independently associated with the presence of metabolic syndrome, defined by either criteria at baseline (Table 2). 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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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 3).
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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 4). 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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) 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 5).
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Discussion |
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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.
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Footnotes |
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Received April 4, 2004.
Accepted August 5, 2004.
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References |
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