Published online before print April 18, 2005, doi: 10.1161/01.HYP.0000165018.63523.8a
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(Hypertension. 2005;45:997.)
© 2005 American Heart Association, Inc.
Original Articles |
Elevated C-Reactive Protein Augments Increased Arterial Stiffness in Subjects With the Metabolic Syndrome
From the Second Department of Internal Medicine, Tokyo Medical University (Y.Y.) Health Care Center, Kajima Corporation, Tokyo, Japan.
Correspondence to Akira Yamashina, MD, Second Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan 160-0023. E-mail akyam{at}tokyo-med.ac.jp
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Abstract |
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We examined whether the presence of an increasing number of metabolic syndrome "disorders" was associated with an increasing pulse wave velocity, which is recognized as a marker of cardiovascular risk, and evaluated whether an elevated plasma C-reactive protein level augments this increasing pulse wave velocity. Using a cross-sectional study design, C-reactive protein, metabolic syndrome–related anthropometric parameters, and pulse wave velocity were measured in 5752 middle-aged Japanese men (44±10 years old). In linear regression analyses, all of the metabolic "disorders" and the logarithm of the C-reactive protein significantly correlated with pulse wave velocity. Multiple linear regression analysis demonstrated that triglycerides, HDL cholesterol, mean blood pressure, fasting glucose, and the logarithm of the C-reactive protein were significant independent positive predictors of pulse wave velocity (R-square=0.38). The presence of an increasing number of metabolic "disorders" in the subjects was associated with an increasing pulse wave velocity (no disorders 1228±139 cm/s
3 disorders 1437±250 cm/s; P<0.01). Among subjects with the metabolic syndrome, pulse wave velocity was higher in cases with (1508±278 cm/s) than in those without an elevated C-reactive protein (1427±243 cm/s; P<0.01). In conclusion, an increase in arterial stiffness may constitute a pathophysiological basis for the increased risk of cardiovascular disease in patients with the metabolic syndrome and that an elevated C-reactive protein level may aggravate this cardiovascular risk.
Key Words: arteriosclerosis • hypertension, obesity • immune systems • insulin resistance
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Introduction |
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The metabolic syndrome (MetS) is defined by the presence of a cluster of disorders that are associated with a marked increase in the risk of atherosclerotic cardiovascular disease.1–4 On the other hand, inflammation has a pivotal role in the initiation or progression of atherosclerosis,5 and the plasma level of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, has been reported as a simple predictor of future cardiovascular events.6 MetS is also associated with chronic subclinical inflammation,7,8 and an elevated hs-CRP level has been reported to worsen the prognosis of MetS.9–11 However, conflicting results in relation to this issue have also been reported;12 therefore, the pathophysiological basis that elevated levels of hs-CRP worsen the prognosis of MetS should be examined cautiously.
Pulse wave velocity (PWV), which reflects arterial stiffness, is related to the severity of atherosclerosis, and an increase in PWV is known to predict future cardiovascular events.13,14 In other words, an increase in a patient’s PWV may reflect a worsening of his/her prognosis. The present study examined whether an increasing number of MetS disorders was associated with an increasing PWV and evaluated whether an elevated hs-CRP level augments the increased PWV in middle-aged Japanese men.
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Methods |
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Design and Subjects
The present cross-sectional study was performed on the employees of a single large construction company, all of whom are required to undergo an annual routine health check-up. The employees were divided into 3 groups according to their employee identification number, with an almost equal number of employees in each group. Beginning in 2000, brachial-ankle PWV measurements were added to the annual routine health check-up at 3-year intervals (PWV was measured in the first group in 2000, in the second group in 2001, and in the third group in 2002). The second round of PWV examinations was started in 2003. Furthermore, measurement of the plasma CRP level every 3 years was added to the examination, beginning in 2002. In total, 5867 male employees underwent a health check-up during the period from May 2002 to July 2003. The ages of the subjects ranged from 29 to 76 years. Subjects who met the following criteria were excluded from the study: an ankle/brachial systolic blood pressure index (ABI) of <0.9, indicating a possible diagnosis of arteriosclerosis obliterans (n=9); atrial fibrillation (n=5); a serum creatinine concentration of
141 µmol/L (n=13);15 and an hs-CRP level 10.0 mg/L (n=88). Consequently, 5752 men were included in the final analysis of this study. Verbal informed consent was obtained from all participants. The study was approved by the ethical guidelines committee of Tokyo Medical University.
Measurements
Pulse Wave Velocity
The brachial-ankle PWV was measured using a volume-plethysmographic apparatus (Form/ABI; Colin Co. Ltd.), in accordance with a previously described methodology.16,17 Briefly, ECG electrodes were placed on both wrists, and cuffs were wrapped around both arms and ankles. The cuff, which was wrapped around both arms and ankles, was connected to a plethysmographic sensor to determine volume pulse form and to an oscillometric sensor to measure blood pressure, and the brachial and post-tibial arterial pressure waveforms thus obtained were stored for 10 s. Sufficient waveform data were obtained in this stored sample. The characteristic points of the waveforms were determined automatically according to the phase velocity theory.18 The components >5 Hz were stored using a pass filter, and the wave front was determined. The time interval between the wave front of the brachial waveform and that of ankle waveform was defined as time interval between brachium and ankle (
Tba). The distance between the sampling points of the brachial-ankle PWV was calculated automatically according to the height of the subject. The path length from the suprasternal notch to the brachium (Lb) was obtained from superficial measurements and was expressed using the equation: Lb=0.2195xheight of the patient (in centimeters)–2.0734. The path length from the suprasternal notch to the ankle (La) was obtained from superficial measurements and was expressed using the equation: La=(0.8129xheight of the patient (in centimeters)+12.328). Finally, the following equation was used to obtain the brachial-ankle PWV: brachial-ankle PWV=(La–Lb)/Tba.
The brachial-ankle PWV was measured after the subject had rested for 5 minutes. The above-described method of measurement of this parameter has been validated in a previous study.16,17 The interobserver and intraobserver coefficients of variation were 8.4% and 10.0%, respectively.17
Laboratory Measurements
The serum total cholesterol, HDL cholesterol, triglycerides, and fasting blood sugar levels were measured using enzymatic methods (Falco Biosystems Co. Ltd.). The interassay coefficients of variation of the laboratory measurements were as follows: total cholesterol 0.4%; HDL cholesterol 1.9%; triglycerides 1.5%; and blood sugar 0.8%. The hs-CRP level was determined using the latex-aggregation method (Eiken Co.),19 which is a high-sensitivity assay method with a detection threshold of <0.1 mg/L. The interassay coefficient of variation for this parameter was 2.9%. Subjects with hs-CRP levels >10.0 mg/L, which was considered to be a possible response to acute-phase exogenous stimuli, were excluded from the analysis.20 All the blood samples were obtained in the morning after the patients had fasted overnight.
Definitions
We used a modified version of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria,21 namely, HDL cholesterol <1.036 mmol/L, triglycerides 1.695 mmol/L, blood pressure 130/85 mm Hg, fasting glucose 6.105 mmol/L, and body mass index 27.522 (the waist circumference was not available in this study) for the clinical recognition of MetS in this study. Elevated hs-CRP was defined as a high–hs-CRP level 3.0 mg/L.23 Blood pressure was determined as the mean of 2 measurements obtained in an office setting by the conventional cuff method using a mercury sphygmomanometer.
Statistical Analysis
Data were expressed as mean±SD. A univariate linear regression analysis was performed to examine each association between brachial-ankle PWV and either the MetS disorders or the logarithm of the plasma hs-CRP level. A multivariate linear regression analysis was performed to assess the correlation and independent variables for brachial-ankle PWV with MetS disorders and the logarithm of the plasma hs-CRP level, adjusted for age, height, heart rate, and smoking status (model A), for model A plus total cholesterol (model B), and for model B plus the prevalence of subjects receiving drugs for hypertension, hypercholesterolemia, diabetes, and that for heart diseases (model C). These variables are noted as a factor influencing the PWV. In addition, total cholesterol has influences on triglycerides and HDL cholesterol. In these analyses, all variables were added together in a large multivariate equation.
Subjects were classified into 4 groups according to the number of metabolic disorders present: non-disorder, one-disorder, two-disorders, and 3 disorders. In addition, the subjects having 3 metabolic disorders were defined as those with MetS, and the subjects having 
2 metabolic disorders were defined as those without MetS. For the assessment of the differences of each variable among these 4 groups, a 1-way ANOVA with Scheffe’s adjustment was applied for continuous variables, and the 
2 test was applied for categorized variables. A general linear model (GLM) univariate analysis post hoc multiple comparison with Sidak’s adjustment was used to assess the differences in the brachial-ankle PWV among the 4 groups adjusted for the variables, which are noted as a factor influencing the PWV (age, body mass index, height, smoking status, mean blood pressure, heart rate, total cholesterol, HDL cholesterol, triglycerides, and fasting blood sugar) and the prevalence of subjects receiving drugs for hypertension, hypercholesterolemia, diabetes, and that for heart diseases (model D excluding mean blood pressure and model E including mean blood pressure).
In subjects either with or without MetS, the differences in each variable between the 2 study groups (with or without an elevated hs-CRP level) were evaluated using Welch’s t test for continuous variables and the 2 test for categorical variables. In subjects either with or without MetS, the difference in the brachial-ankle PWV of subjects with or without an elevated hs-CRP level was assessed using a GLM univariate analysis post hoc comparison adjusted for models D and E. These GLM analyses were conducted separately in the subjects without and with MetS. All analyses were conducted using SPSS software for Windows, version 11.0J (SPSS). P values <0.05 were considered to denote statistical significance.
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Results |
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Table 1 depicts the correlation coefficients in each univariate linear regression analysis between brachial-ankle PWV and either the MetS disorders or the logarithm of the plasma hs-CRP level. All the disorders and the logarithm of the plasma hs-CRP level showed significant correlation with the brachial-ankle PWV. Table 2 shows the results of a multivariate linear regression analysis to assess the correlation and independent variables for brachial-ankle PWV with MetS disorders and the logarithm of the plasma hs-CRP level. In the adjustments, total cholesterol and the prevalence of subjects receiving drugs did not have much influence on the coefficients. Therefore, Table 2 shows the results of the analysis without the adjustments and those of the adjustment of model C. Even after the adjustments, triglycerides, HDL cholesterol, mean blood pressure, fasting glucose, and the logarithm of hs-CRP were significantly positive independent variables for the brachial-ankle PWV.
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Table 3 shows the clinical characteristics in cases with and without the MetS and in cases with and without an elevated plasma level of hs-CRP in all subjects. After the adjustment of model E, the brachial-ankle PWV was higher in subjects with MetS than that in subjects without MetS.
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Table 4 shows the clinical characteristics among the 4 groups classified according to the number of metabolic disorders present. Most of the variables had a significant phased increase concomitant with an increase in the number of MetS disorders present. After the adjustment of model D (excluding mean blood pressure), the presence of an increasing number of MetS disorders was associated with a significantly increasing brachial-ankle PWV. After the adjustment of model E (including mean blood pressure), the brachial-ankle PWV in subjects with MetS was higher than that in subjects with either non-disorder or one-disorder.
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Table 5 shows the clinical characteristics in cases with and without an elevated hs-CRP in the subjects with and without MetS. After the adjustment including mean blood pressure (model E), the brachial-ankle PWV was higher in cases with than in those without an elevated hs-CRP in subjects with MetS but not in subjects without MetS.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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A phased increase in the brachial-ankle PWV with an increasing number of MetS disorders was observed. Among subjects with MetS, the brachial-ankle PWV was higher among cases with an elevated hs-CRP level (
3.0 mg/L) than among those without an elevated hs-CRP level. It has been demonstrated that the PWV is an independent prognostic factor in subjects with either hypertension or diabetes mellitus,24,25 both of which are MetS disorders. The proposed underlying mechanisms for this association are as follows: an increase in the PWV, which is related to the severity of atherosclerosis, results in an increased cardiac ventricular load, reduced ejection fraction, increase in the myocardial oxygen demand, impaired coronary blood flow, and a direct aggravation of atherosclerosis via increased stress on the arterial wall.13,14 The brachial-ankle PWV reflects the net arterial stiffness through the central and peripheral arteries; brachial-ankle PWV measurements are very simple to perform and can be performed even in large study populations. It is also strongly correlated with the aortic PWV.17 Thus, the brachial-ankle PWV can very reliably be used as a convenient marker of arterial stiffness in the central aorta. A phased increase in the brachial-ankle PWV with the presence of an increasing number of MetS disorders is consistent with the well-known marked increase in the risk of atherosclerotic cardiovascular disease in subjects with MetS.1,2 Therefore, increased arterial stiffness may serve as a marker for the pathophysiological basis for the increased risk of cardiovascular events in cases with MetS.
It is now well recognized that a high hs-CRP level is a predictor of the future risks of diabetes mellitus and atherosclerotic cardiovascular events.6,26 Furthermore, recent studies have demonstrated that elevated hs-CRP levels are an additive prognostic factor in subjects with MetS.9,10 Ridker et al have proposed the inclusion of elevated hs-CRP levels as a clinical criterion of MetS for the global prediction of atherosclerotic cardiovascular disease risk.11 On the other hand, Rutter et al reported that the inclusion of the hs-CRP level among the conventional MetS disorders adds little to the overall risk prediction.12 Some studies have reported an association between hs-CRP levels and the PWV;19,27 our previous study also demonstrated an association between hs-CRP levels and the brachial-ankle PWV, independent of conventional atherosclerotic risk factors.19 The increase in the brachial-ankle PWV in subjects with an elevated hs-CRP level was augmented in subjects with MetS, and a multiple linear regression analysis demonstrated that the hs-CRP level was a significant indicator of the brachial-ankle PWV independent of the conventional MetS disorders. Thus, this augmentation might, at least in part, indicate a poorer prognosis for subjects with MetS.
The plasma levels of hs-CRP were higher in subjects with than without MetS. Ford et al reported similar findings,8 and the results are also consistent with some experimental results indicating that adipokines (eg, leptin, adiponectin, and resistin) and cytokines (eg, tumor necrosis factor-
and interleukin-6) are related to central obesity,28,29 and that HDL cholesterol has a direct anti-inflammatory effect.30 On the other hand, Reilly et al proposed a hypothesis for the high prevalence of subclinical inflammation in subjects with MetS; they suggested that the cluster of MetS disorders has a common proximal inflammatory basis (eg, innate immunity).31 Further study is proposed to evaluate whether low-grade inflammation is an epiphenomenon of MetS disorders, especially central obesity, or whether there is a common proximal pathophysiological basis.
There were several limitations to this study. A prospective study to confirm that an increasing brachial-ankle PWV is a marker to predict future cardiovascular events in cases with MetS is required. We used modified criteria for the clinical recognition of MetS, in accordance with Satter’s or Lee’s report,10,32 because the waist circumference was not available in this study. The prevalence of MetS in middle-aged Japanese men of 8% was lower than that in Western populations. It has been reported that the prevalence of MetS may be lower in Asian people, even after adjustment for the body mass index,32 and ethnic differences in the hs-CRP levels have also been reported.33 Therefore, our findings in this study in relation to the prevalence of MetS must be confirmed in other ethnic groups, including women.
Perspectives
In the present study, the presence of an increasing number of metabolic disorders in the subjects was associated with an increasing PWV, and this increase was augmented in cases with an elevated hs-CRP level among subjects with MetS. When adjusted for mean blood pressure, a further effect of MetS (although much diminished) and that of an elevated hs-CRP level remained significant. These results offer evidence for a degree of structural stiffening of the arterial architecture and not just a functional stiffening related to the elevation of blood pressure. Further studies are proposed to examine the underlying mechanisms of those factors associated with structural stiffening. Whereas an elevated hs-CRP level has been reported to worsen the prognosis of MetS, the pathophysiological basis for this effect remains unclear. The present study suggested that an increase in arterial stiffness may serve as a marker for a pathophysiological basis for the increased risk of cardiovascular disease in patients with MetS and that an elevated hs-CRP level may aggravate this cardiovascular risk.
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Acknowledgments |
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This study was supported in part by a grant-in-aid from the Japanese Atherosclerosis Prevention Fund (A.Y.) and a grant from the Research Fund of Mitsukoshi Health and Welfare Foundation (H.T.).
Received January 15, 2005; first decision January 29, 2005; accepted March 9, 2005.
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