Published online before print July 31, 2006, doi: 10.1161/01.HYP.0000233466.24345.2e
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(Hypertension. 2006;48:411.)
© 2006 American Heart Association, Inc.
Original Articles |
Metabolic Syndrome May Not Associate With Carotid Plaque in Subjects With Optimal, Normal, or High-Normal Blood Pressure
From the Departments of Cardiovascular Medicine (N.I., R.N.) and Health Management and Policy (H.H.), University of Tokyo Graduate School of Medicine, and the Center for Multiphasic Health Testing and Services (Y.I., E.-I.T., M.Y.), Mitsui Memorial Hospital, Tokyo, Japan.
Correspondence to Nobukazu Ishizaka, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan. E-mail nobuishizka-tky{at}umin.ac.jp
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Abstract |
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Much evidence indicates that metabolic syndrome is a risk factor for the development of cardiovascular disease, but whether metabolic syndrome is an independent risk factor for early atherosclerosis in the individuals with only minor hemodynamic abnormalities, if any, is not well investigated. Here we have investigated the association between metabolic syndrome and carotid atherosclerosis in individuals with blood pressure of <140/90 mm Hg. Between 1994 and 2003, 8143 subjects underwent general health screening including carotid ultrasonography. Of 8143 individuals, 5661 individuals without antihypertensive medications who had blood pressure of <140/90 mm Hg were considered to have optimal, normal, or high-normal blood pressure. After adjustment for age, systolic blood pressure, body mass index, total and high-density lipoprotein cholesterol, triglycerides, fasting glucose, and smoking status, metabolic syndrome was not found to be an independent risk factor for carotid plaque (odds ratio: 1.65; 95% CI; 0.72 to 3.76 in women and odds ratio: 0.95; 95% CI: 0.70 to 1.28 in men) or for carotid intima-media thickening (odds ratio: 0.56; 95% CI: 0.18 to 1.72 in women and odds ratio: 0.93 95% CI: 0.62 to 1.38 in men) in these subjects. Thus, presence of metabolic syndrome may not increase the prevalence of carotid atherosclerosis independent of other cardiovascular risk factors in Japanese individuals with optimal, normal, or high-normal blood pressure.
Key Words: metabolism • carotid arteries • atherosclerosis • risk factor • hypertension, arterial
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Introduction |
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Metabolic syndrome (MetS) is a cluster of metabolic and hemodynamic abnormalities linked with insulin resistance.1–4 Several diagnostic criteria have been advocated for MetS, of which those proposed by the World Health Organization5 and the National Cholesterol Education Program1 are used most frequently. Epidemiological studies have shown that MetS is not a rare occurrence6 and is a risk factor for cardiovascular disease (CVD)7 and stroke.8 The coexistence of MetS in individuals with established CVD risk factors, such as diabetes and hypertension, has been shown to increase the risk of mortality and morbidity from CVD,9–11 and, thus, such individuals should undergo lifestyle advice and/or active treatment to dissolve the clustering of these abnormalities to reduce the risk of future cardiovascular events.
On the other hand, however, subjects with such established risk factors for CVD are already regarded to be at higher risk for CVD irrespective of the presence or absence of MetS. Therefore, it should be tested whether the concept of MetS can be used to identify individuals at higher risk for future CVD events when the extent of their hemodynamic and metabolic abnormalities is only mild, if present at all. Here, by analyzing the cross-sectional data from individuals who underwent general health screening, we have investigated the impact of MetS on carotid atherosclerosis in the subjects with optimal, normal, or high-normal blood pressure (BP). We also performed a similar analysis in the subpopulations that additionally had, if present, only mild abnormalities in glucose metabolism.
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Methods |
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Study Subjects
The study was approved by the Ethical Committee of Mitsui Memorial Hospital. Between September 1994 and December 2003, 8143 subjects underwent general health screening, including carotid ultrasonography at the Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital. BP, taken at the center, was classified according to the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure12: optimal BP: systolic BP (SBP) <120 mm Hg and diastolic BP (DBP) <80 DBP; normal BP: SBP 120 to 129 DBP or DBP 80 to 84 mm Hg; and high-normal BP: SBP 130 to 139 mm Hg or DBP 85 to 89 mm Hg. Fasting glucose levels were classified according to the American Diabetes Association criteria13: normal fasting glucose: FPG <100 mg/dL; and impaired fasting glucose: FPG
110 and <126 mg/dL. Individuals who were taking antidiabetic medication were not included.
Definition of MetS
We used a modified version of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII)1 and MetS was diagnosed when 3 of the following components were present: triglycerides 150 mg/dL; high-density lipoprotein cholesterol <40 mg/dL in men or <50 mg/dL in women; fasting plasma glucose (FPG) 110 mg/dL; SBP 130 mm Hg, DBP 85 mm Hg, or taking an antihypertensive medication; and body mass index (BMI) 25.0 kg/m2 (the waist circumference was not available in this study). This BMI cutoff point was chosen instead of other previously used values14 because of the discrepancy in BMI between white and Japanese populations in terms of morbidity.15
Selection of Subpopulation
We selected 3 types of target population as follows. Of the 8143 individuals, those with BP of <140/90 mm Hg were selected for target population 1 (n=6112). In addition, of the 6112 individuals in target population 1, those without antihypertensive medications (individuals with optimal, normal, and high-normal BP) were selected for target population 2 (n=5661). Furthermore, of the 5661 individuals in target population 2, those with either normal fasting glucose or impaired fasting glucose were selected for target population 3 (n=5398; Figure 1).
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Carotid Ultrasonography
Carotid artery status was studied using high-resolution B-mode ultrasonography (Sonolayer SSA270A, Toshiba) equipped with a 7.5-MHz transducer as described previously.16 Plaque was defined to be present when there is 1 clearly isolated focal thickening of the intima-media layer with thickness of 1.3 mm at the common or internal carotid artery or the carotid bulb. Carotid wall intima-media thickening was said to be present when intima-media thickness, which was measured at the far wall of the distal 10 mm of the common carotid artery, was 1.0 mm.16
Statistical Analysis
Comparisons of categorical and continuous variables were made by using 
2 and Student t tests, respectively. Logistic regression analysis was used to obtain adjusted odds ratios and their 95% CIs to predict the presence of carotid plaque or carotid intima-media thickening. Statistical analyses were carried out by using StatView (version 5.0; SAS Institute Inc). Results are expressed as mean±SD. A value of P<0.05 was taken to be statistically significant.
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Results |
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Association Between MetS and Carotid Atherosclerosis in Individuals With BP of <140/90 mm Hg (Target Population 1)
The age of the subjects ranged from 21 to 88 years (women, 22 to 87 years; men, 21 to 88 years). In this population, MetS was found in 81 (4%) of 2143 women and 511 (13%) of 3969 men (Table 1). In women, carotid plaque was found in 22 (27%) of the 81 MetS-positive subjects, which was significantly greater than that observed in the MetS-negative subjects (280 of 2062 [14%]; P<0.001 by
2 test). Similarly, in men, carotid plaque was found in 158 (31%) of the 511 MetS-positive subjects, which was significantly greater than that observed in the MetS-negative subjects (890 of 3458 [26%]; P=0.013 by 2 test; Figure 2; Table 2). When multivariate logistic regression analysis was performed after adjusting for age, the association between MetS and carotid plaque was statistically significant in both genders (Table 2). After full adjustment for additional CVD risk factors, including total cholesterol, smoking status, and components of the MetS (BMI, SBP, total cholesterol, high-density lipoprotein cholesterol, triglycerides, and FPG), however, this relationship was statistically significant in women, but not in men. After full adjustment, MetS was not significantly associated with carotid intima-media thickening in either gender (Table 3).
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Association Between MetS and Carotid Atherosclerosis in Individuals With Optimal, Normal, or High-Normal BP (Target Population 2)
Of the 6112 individuals in target population 1, 451 individuals were taking antihypertensive medication. To investigate the association between MetS and carotid atherosclerosis in individuals with optimal, normal, and high-normal BP, we omitted these individuals. In this population, the age of the subjects ranged from 21 to 88 years (women, 22 to 87 years; men, 21 to 88 years), and MetS was found in 64 (3%) of 2034 women and 410 (11%) of 3627 men (Table 4). Carotid plaque was found in 11 (17%) of the 64 MetS-positive female subjects and in 103 (25%) of the 410 MetS-positive male subjects. The carotid plaque prevalence was not significantly different from that observed in the MetS-negative subjects (249 of 1970 [13%] women; P=0.29; 769 of 3217 [24%] men; P=0.59; Figure 2 and Table 2). After full adjustment, MetS was not significantly associated with carotid plaque or carotid intima-media thickening in either gender (Table 3).
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Association Between MetS and Carotid Atherosclerosis in Individuals With Optimal, Normal, or High-Normal BP, Together With Normal or Impaired Fasting Glycemia (Target Population 3)
Of the 5661 individuals in target population 2, 263 individuals whose FPG levels were 126 mg/dL were omitted in the target population 3. In this population, the age of the subjects ranged from 21 to 88 years (women, 22 to 87 years; men, 21 to 88 years), and MetS was found in 57 (3%) of 2000 women and 315 (9%) of 3398 men (Table 5). Carotid plaque was found in 11 (19%) of the 57 MetS-positive female subjects and in 77 (24%) of the 315 MetS-positive male subjects. The carotid plaque prevalence was not significantly different from that observed in the MetS-negative subjects (244 of 1943 [13%] women; P=0.13; 723 of 3083 [23%] men; P=0.69; Figure 2 and Table 2). After full adjustment, MetS was not found to be significantly associated with carotid plaque or carotid intima-media thickening in either gender (Table 3).
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Discussion |
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Here, we have assessed whether MetS, as diagnosed by modified ATPIII criteria, is an independent risk factor for carotid atherosclerosis in the individuals with optimal, normal, or high-normal BP. Within this population, MetS was not found to be an independent risk factor for carotid atherosclerosis in either gender after the full-adjustment for age and other risk factors for CVD.
In several previous studies, the association between MetS and CVD has been assessed not only in individuals with diabetes17,18 but also in nondiabetic subjects. For example, in a prospective cohort study of Finnish men who did not have CVD or diabetes at enrollment, MetS was found to be associated with a 2.6- to 3.0-fold higher mortality from CVD.19 Another study found that MetS was associated with increased risk for CVD in middle-aged adults who did not have CVD or type 2 diabetes mellitus at enrollment.20 These findings indicate that MetS may increase the future risk for CVD and stroke irrespective of the presence or absence of diabetes. On the other hand, Juutilainen et al21 have reported that after adjusting for confounding factors, the presence of MetS predicted CVD mortality in nondiabetic women but not in nondiabetic men during the 18-year follow-up.
These studies may seem to substantiate the idea that MetS may be a risk for future CVD mortality, at least in women with low risk profiles. However, hypertension (defined as 160/95 mm Hg or on therapy) was prevalent in >65% of the women in the study by Juutilainen et al,21 but their results were not adjusted for BP. Similarly, Isomaa et al18 have reported that MetS is a predictor of cardiovascular mortality and morbidity in subjects with normal glucose tolerance. However, their results were adjusted for sex and age but not for BP, although 23% to 24% of their target population included subjects with hypertension (defined as >160/90 mm Hg or on therapy). Furthermore, Wilson et al have reported that in >8 years of follow-up, MetS was found to be associated with increased risk for CVD with odds ratios of 2.3 and 2.9 in middle-aged women and men, respectively, who lacked CVD or type 2 diabetes mellitus at baseline. Again, this result was adjusted only for age, although prevalence of hypertension (defined as 130/85 mm Hg or on therapy) was more prevalent in individuals with MetS (89% in women and 91% in men) than in those without MetS (34% in women and 43% in men).
It has been suggested recently by several investigators that clinicians should evaluate and treat all cardiovascular risk factors regardless of whether a patient meets the diagnosis criteria for MetS.22,23 In fact, individuals with established dyslipidemia, hypertension, and diabetes may be periodically followed-up at medical institutions and undergo medical therapy or lifestyle modification to ameliorate each of these disorders, regardless of the presence or absence of MetS. On the other hand, if individuals who do not have overt hemodynamic or metabolic abnormalities are at higher risk for atherosclerotic diseases when they have MetS, this concept may be useful for isolating individuals at higher risk for atherosclerotic diseases from those with low-risk profiles. For these reasons, we selected individuals with low-risk profiles to assess the usefulness of the MetS concept, and the odds ratio of MetS for carotid atherosclerosis has been calculated after adjusting for other conventional risk factors.
In the current study MetS was not found to be an independent predictor for either carotid plaque or carotid intima-media thickening in the individuals with optimal, normal, or high normal BP; however, we cannot jump to the conclusion that the concept of MetS is insignificant in such population. We may also have to investigate the possible association between MetS and other conditions, such as lacunar infarctions and arterial stiffness. These points should be analyzed in future studies.
The strength of our study is that we could abstract and analyze the data of individuals with optimal, normal, and high-normal BP from a large set of cross-sectional data of those who had undergone general health screening. On the other hand, our study has some limitations. For example, waist circumference data were not available in the study sample; thus, we used BMI as a surrogate of waist circumference, as has been done in several previous studies.24,25 Although the ability of MetS to predict CVD may differ according to the criteria used26 and ethnicity,27 waist circumference may be a more suitable risk factor component for the definition of MetS because of its strong correlation with computed tomography measurements of abdominal fat.28 In the near future, we are planning to validate the use of other MetS criteria, including waist circumference data, which have now been collected at our institute since 2005, in terms of isolating individuals with higher risk for early atherosclerosis from those with low-metabolic/hemodynamic risk profiles. Because our study was cross-sectional in nature, whether or not MetS, as defined here, would be useful in predicting future cardiovascular events cannot be determined. This point should also be assessed in future studies.
Perspectives
In the current study, by analyzing the cross-sectional data from individuals who had optimal, normal, or high-normal BP, we showed that MetS defined by modified ATPIII criteria was not an independent predictor for either carotid plaque or carotid intima-media thickening. A body of evidence exists that supports the notion that MetS is a risk factor for atherosclerotic disease. On the other hand, clinicians may have to evaluate and treat all of the atherogenic risk factors regardless of whether a patient meets the diagnosis criteria for MetS. If individuals with only mild hemodynamic and metabolic abnormalities are considered to be at substantially higher risk for CVDs when they have MetS, the concept of MetS would be useful in avoiding the underestimation of the cardiovascular risk in such subjects. Although our data did not support that MetS was an independent risk factor for carotid atherosclerosis in individuals without hypertension, whether the presence of MetS in such subjects would increase the possibility of the future development of CVD should be investigated in longitudinal studies.
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Acknowledgments |
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Disclosures
None.
Received February 19, 2006; first decision March 7, 2006; accepted June 14, 2006.
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