Published online before print May 24, 2007, doi: 10.1161/STROKEAHA.106.479642
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(Stroke. 2007;38:2063.)
© 2007 American Heart Association, Inc.
Original Contributions |
Impact of Metabolic Syndrome on the Development of Cardiovascular Disease in a General Japanese Population
The Hisayama Study
From the Departments of Environmental Medicine (T.N., M.K., K.Y., H.A., Y.K.) and Medicine and Clinical Science (Y.D., Y.T., K.T., M.I.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and the Marshfield Clinic Research Foundation (M.R.), Marshfield, Wis.
Correspondence to Toshiharu Ninomiya, MD, PhD, Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582 Japan. E-mail nino{at}envmed.med.kyushu-u.ac.jp
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Abstract |
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Background and Purpose— The metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease (CVD) events in general populations. However, well-designed prospective studies in Asian populations are very limited.
Methods— We prospectively evaluated a total of 2452 community-dwelling Japanese individuals aged 40 years or older from 1988 to 2002 and examined the effects of MetS defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria on incident CVD.
Results— The prevalence of the MetS was 21% in men and 30% in women at baseline. During the follow up, 307 CVD events occurred. Compared with those without MetS, the age-adjusted incidence of CVD (per 1000 person-years) was significantly higher in subjects with the MetS in both men (21.8 versus 11.6, P<0.01) and women (12.9 versus 6.5, P<0.01). The risk of CVD events was significantly higher even after adjusting for the following confounding factors: age, proteinuria, electrocardiographic abnormalities, serum total cholesterol, smoking habits, alcohol intake, and regular exercise (hazard ratio, 1.86; 95% CI, 1.32 to 2.62 in men and hazard ratio, 1.70; 95% CI, 1.22 to 2.36 in women). The risk of incident CVD was found to increase with the number of components of MetS and became significantly predictive when the number of components reached 3. Similar associations were also observed when CVD was divided into coronary heart disease and stroke.
Conclusions— Our findings suggest that MetS is a significant risk factor for the development of CVD in the Japanese middle-aged population.
Key Words: cardiovascular disease • epidemiology • metabolic syndrome • myocardial infarction • stroke
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Introduction |
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Metabolic syndrome (MetS), also known as syndrome X,1 the insulin resistance syndrome,2 and deadly quartet,3 is a constellation of dyslipidemia, central obesity, elevated blood pressure, and impaired glucose tolerance. It is associated with high risk for the development of type 2 diabetes mellitus and cardiovascular disease (CVD).4–7 In the past several years, a great deal of attention has been directed to it attributable to increases in its prevalence worldwide6 and its association with CVD morbidity and mortality. Although each of the components of MetS has been shown to increase CVD risk,8–12 the presence of MetS has been reported to identify additional risk.7 Different prospective studies7,13–25 based on the definitions from the National Cholesterol Education Program’s (NCEP) Third Adult Treatment Panel Report III5 and World Health Organization26 showed that subjects with MetS are at increased risk of incident CVD, CVD mortality, and all-cause mortality in the general population with or without diabetes mellitus. However, most of these studies were based on Western populations, and well-designed prospective studies in Asian populations are very limited.27–29 Thus, there is a dearth of literature regarding the relationship of MetS with incident CVD based on general population cohorts with a reasonable length of follow-up time in ethnic groups other than whites. In this study, we examined the impact of MetS on CVD events in a general Japanese population cohort based on 14-year prospective follow-up data.
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Materials and Methods |
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Study Population
The Hisayama Study, an epidemiological study of cerebro- and cardiovascular diseases, was established in 1961 in Hisayama Town, a suburban community adjacent to Fukuoka City, a metropolitan area of Kyushu Island in southern Japan. The population of the town is approximately 7500, and full community surveys of the residents have been repeated since 1961.30 In 1988, a screening survey for the present study was performed in the town. A detailed description of this survey was published previously.31 Briefly, a total of 2736 residents aged 40 years or over (80.7% of the total population of this age group) consented to participate in the examination and underwent a comprehensive assessment. After excluding 102 subjects with a history of coronary heart disease or stroke, as determined by a questionnaire and medical records, one subject for whom no blood sample was obtained, 120 subjects with postprandial blood sample, and 61 subjects without the measurements of their waist circumferences, the remaining 2452 subjects (1050 men and 1402 women) were enrolled in this study.
Follow-Up Survey
The subjects were followed prospectively from December 1988 to November 2002 by repeated health examinations. Health status was checked yearly by mail or telephone for any subjects who did not undergo a regular examination or who had moved out of town. We also established a daily monitoring system among the study team and local physicians or members of the town’s health and welfare office. When a subject died, an autopsy was performed at the Department of Pathology of Kyushu University. During the follow-up period, only one subject was lost to follow up and 479 subjects died, of whom 362 (75.6%) underwent autopsy.
Definition of Cardiovascular Events
CVD was defined as first-ever development of coronary heart disease (CHD) or stroke. The criteria for a diagnosis of CHD included first-ever acute myocardial infarction, silent myocardial infarction, sudden cardiac death within 1 hour after the onset of acute illness, or coronary artery disease followed by coronary artery bypass surgery or angioplasty.32 Acute myocardial infarction was diagnosed when a subject met at least 2 of the following criteria: (1) typical symptoms, including prolonged severe anterior chest pain; (2) abnormal cardiac enzymes more than twice the upper limit of the normal range; (3) evolving diagnostic electrocardiographic changes; and (4) morphological changes, including local asynergy of cardiac wall motion on electrocardiography, persistent perfusion defect on cardiac scintigraphy, or myocardial necrosis or scars >1 cm long accompanied by coronary atherosclerosis at autopsy. Silent myocardial infarction was defined as myocardial scarring without any historical indication of clinical symptoms or abnormal cardiac enzyme changes. Stroke was defined as a sudden onset of nonconvulsive and focal neurological deficit persisting for >24 hours. The diagnosis of stroke and the determination of its pathological type were based on the clinical history, neurological examination, and all available clinical data, including brain CT/MRI and autopsy findings. Stroke was classified as either ischemic or hemorrhagic.32
Risk Factor Measurement
At the baseline examination, each participant completed a self-administered questionnaire covering medical history, exercise, treatment for hypertension or diabetes, smoking habits, and alcohol intake. The questionnaire was checked by trained interviewers at the screening. The subjects engaging in sports or other forms of exertion 
3 times a week during their leisure time made up a regular exercise group. Smoking habits and alcohol intake were classified into currently habitual or not.
Blood pressure was measured 3 times using a standard mercury sphygmomanometer in the sitting position after rest for at least 5 minutes. The mean of the 3 measurements was used for the analysis. Hypertension was defined as blood pressure 140/90 mm Hg and/or current use of antihypertensive agents. The waist circumference was measured at the umbilical level in a standing position by a trained staff member. Body height and weight were measured in light clothing without shoes and the body mass index (kg/m2) was calculated. Electrocardiographic abnormalities were defined as left ventricular hypertrophy (Minnesota code, 3 to 1) and/or ST depression (Minnesota code, 4 to 1, 2, or 3).
Blood samples were collected from an antecubital vein after an overnight fast for the determination of lipids and blood glucose levels. Serum total cholesterol, triglycerides, and high-density lipoprotein cholesterol concentrations were determined enzymatically. Fasting blood glucose levels were measured by the glucose oxidase method. Diabetes was defined as fasting blood glucose 126 mg/dL (7.0 mmol/L) and/or current use of insulin or oral medication for diabetes. Fresh voided urine samples were collected at the examination and proteinuria was defined as 1+ or more using a reagent strip.
Definition of Metabolic Syndrome
MetS was defined by using criteria recommended in the NCEP Adult Treatment Panel III guideline5 with a modification. Specifically, abdominal obesity was defined as a waist circumference >90 cm in men and >80 cm in women according to International Obesity Task Force central obesity criteria for Asia.33 Elevated blood pressure was defined as average systolic/diastolic blood pressures of 130/85 mm Hg and/or current use of antihypertensive medicine. Hypertriglyceridemia was defined as serum triglycerides of 1.69 mmol/L. Low high-density lipoprotein cholesterol was defined as serum high-density lipoprotein cholesterol levels of <1.03 mmol/L in men and of <1.29 mmol/L in women. Elevated blood glucose level was defined as fasting blood glucose of 6.10 mmol/L and/or current use of insulin or oral medication for diabetes. MetS was defined as the presence of 3 or more of these components.5
Statistical Analysis
The SAS software package (SAS Institute, Inc, Cary, NC) was used to perform all statistical analyses. Serum triglycerides were transformed into logarithms to improve the skewed distribution. The statistical significance of differences in mean values of continuous variables and frequencies of categorical variables was examined using the Student t test and 
2 test as appropriate. The incidences were calculated by the person-year method. Differences in incidences between MetS status were tested by the Cox proportional hazards regression analysis after adjustment for age. The age- or multivariate-adjusted hazard ratios (HRs) and 95% CIs were also estimated with the use of the Cox proportional hazards model. P<0.05 was considered statistically significant in all analyses.
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Results |
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The overall prevalence of MetS at baseline was 25.9%. The baseline characteristics on the basis of sex and MetS are shown in Table 1. Men with MetS had significantly higher mean values of blood pressures, waist circumference, body mass index, fasting blood glucose, and serum triglycerides and lower mean values of serum high-density lipoprotein cholesterol compared with those without MetS. Moreover, the frequencies of antihypertensive medication, hypertension, proteinuria, diabetes, and alcohol intake were higher in men with MetS than in those without MetS. A similar distribution was observed in women with MetS in terms of the previously mentioned variables except for alcohol intake. In addition, women with Mets were significantly older and had higher serum total cholesterol compared with those without MetS.
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During the 14-year follow up, 307 first-ever CVD events (158 men and 149 women) occurred. Of these, there were 125 CHD (78 men and 47 women) and 209 stroke events (94 men and 115 women). The age-adjusted incidences of CVD were significantly higher in subjects with MetS compared with those without MetS for both sexes (men: 21.8 versus 11.6 per 1000 person-years, P<0.01; women: 12.9 versus 6.5, P<0.01) (Table 2). The same was true for CHD incidence in both sexes (men: 9.2 versus 5.7, P<0.01; women: 5.1 versus 1.5, P<0.01) and for stroke in men (14.1 versus 6.4, P<0.01). When we divided strokes into ischemic and hemorrhagic type, the age-adjusted incidences of ischemic stroke were significantly higher in subjects with MetS than in those without MetS for both sexes (men: 9.0 versus 4.8, P=0.03; women: 6.2 versus 3.4, P=0.01). The similar tendency was observed for hemorrhagic stroke only in men (5.1 versus 1.6, P=0.01).
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Age- and multivariate-adjusted hazard ratios of MetS for the development of CVD were estimated for both sexes (Table 3). The age-adjusted analysis showed that MetS was a significant risk factor for CVD in men and women. These relationships remained substantially unchanged even after adjustment for the following confounding factors: age, proteinuria, electrocardiographic abnormalities, serum total cholesterol, smoking habits, alcohol intake, and regular exercise. Furthermore, MetS was found to be an independent risk factor for the development of CHD and stroke after adjustment for the confounding factors in men and women. When strokes were divided into ischemic and hemorrhagic type, multivariate-adjusted HR of MetS for ischemic stroke was marginally higher in men and significantly higher in women, whereas MetS is an independent risk factor for hemorrhagic stroke only in men.
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The age- and sex-adjusted cumulative incidences of CVD, CHD, and stroke according to the number of MetS components are shown in the Figure. Because the cumulative incidence curves for one and 2 components overlapped, we combined these components. The incidences of CVD, CHD, and stroke were significantly higher among the subjects with 3 or more MetS components compared with those without any MetS component. A significant graded relationship between the number of components of MetS and the HR for developing CVD was identified from 3 MetS components and onward (Table 4). Compared with individuals with no MetS component, individuals with one, 2, 3, and 4 or more components had gradually increased HRs, respectively, for developing CVD after adjusting the confounding factors. A similar relationship was found when CVD was divided into CHD and stroke.
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Because hypertension and diabetes are strong risk factors for CVD, we examined the combined as well as separate effects of MetS and hypertension or diabetes on the development of CVD. As shown in Table 5, the age- and sex-adjusted HR of CVD was significantly higher in normotensive subjects with MetS, hypertensive subjects without MetS, and hypertensive subjects with MetS compared with those without hypertension and MetS. Furthermore, there was a significant excess risk of CVD in hypertensives with MetS than in those without MetS. Similarly, the age- and sex-adjusted HR of CVD was significantly higher in nondiabetic subjects with MetS and diabetic subjects with MetS compared with those without diabetes and MetS. However, no significant difference was found in the risk of CVD in diabetic subjects without MetS. Among diabetic subjects, the risk of CVD was significantly higher in subjects with MetS than in those without MetS. These relationships remained substantially unchanged even after adjusting for the confounding factors. Furthermore, we examined the association of MetS with CVD by the multivariate analysis using hypertension and diabetes in addition to the previously mentioned risk factors as confounding factors. As a result, MetS remained a significantly independent risk factor for the development of CVD (HR, 1.38; 95% CI, 1.07 to 1.78, P=0.01). The risks of other risk factors were as follows: age (HR, 2.00 [per increment of 10 years]; 95% CI, 1.79 to 2.26, P<0.01), male sex (1.45; 1.07 to 1.97, P=0.02), hypertension (1.64; 1.26 to 2.12, P<0.01), diabetes (1.55; 1.14 to 2.13, P<0.01), smoking habits (1.69; 1.28 to 2.23, P<0.01), regular exercise (0.58; 0.39 to 0.87, P<0.01), proteinuria (1.64; 1.13 to 2.38, P<0.01), electrocardiographic abnormalities (1.29; 0.98 to 1.69, P=0.07), serum total cholesterol (0.99 [per increment of 1 mmol/L]; 0.89 to 1.11, P=0.92), and alcohol intake (0.97; 0.73 to 1.30, P=0.84).
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Discussion |
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To our knowledge, our study is the first prospective cohort study of a general Japanese population with a long duration of follow up reporting the association of MetS with incident CVD using the modified NCEP definition. The sole study from Japan, which examined a similar association, was based on a diabetic population.27 We found a clearly increased incidence of CVD during 14 years of follow up in both men and women with MetS compared with those without MetS. Besides, the risk of MetS for the development of CVD remained significant even after adjustment for hypertension, diabetes, and other potentially confounding factors.
In our study, subjects with MetS had little over 70% increases in CVD risk compared with those without MetS. Similar or higher HRs (1.4- to 5.0-fold) of MetS for CVD/CHD were reported from different European and American studies.7,13–25 Differences in the study populations, prevalence of individual components of MetS, follow-up length, and MetS definition used seem to be the main causes behind the variation in the HRs. In our study, CHD risk related to MetS is higher in women than in men, which is consistent with the studies from the Western world.17
Our study showed that the risk of incident combined CVD, and CHD and stroke separately, was found to increase with the number of components of MetS and increased by 3-fold or more in those with 4 or more MetS components compared with those without any component. It also revealed that the risk of CVD increased in incremental fashion with the number of components of MetS and became predictive of CVD (also CHD and stroke separately) when the number of components reached 3. This phenomenon gives credence to the requirement of 3 components in the NCEP definition for establishing the diagnosis of MetS. Thereby, it can be assumed that the modified NCEP definition of MetS is well predictive for CVD in the general Japanese population.
One prospective study based on a Japanese diabetic population mentioned that MetS based on the NCEP definition was predictive for CVD in men and was not in women.27 The same authors again reported that the new International Diabetes Federation definition34 was not predictive for CVD in either male or female patients with diabetes.35 On the other hand, in our study, MetS based on the NCEP definition was consistently predictive of CVD not only in both men and women, but also in subjects with diabetes. We speculate that this discrepancy resulted from the difference in the cutoff point of the waist circumference between the 2 studies. The former used the waist circumference definition for abdominal obesity proposed by the Japan Society for the Study of Obesity (85 cm for men and 90 cm for women),36 whereas in our study, we used the waist circumference definition for Asian populations (90 cm for men and 80 cm for women), which was recommend by the International Diabetes Federation to use for the Japanese population.37 Further research is needed to refine the MetS definition, which would be applicable to various populations, including Japanese.
There was a possibility that the increased risk of MetS for CVD resulted from the influences of hypertension or diabetes, which are components of MetS and major risk factors for developing CVD. However, our stratified analysis showed that the MetS was a significant risk factor for CVD in normotensive subjects as well as in nondiabetic individuals and has a similar risk for CVD as hypertension; the risk is even higher than that of diabetes. Moreover, in the multivariate analysis, MetS was found to be a significant risk factor for CVD independent of hypertension, diabetes, and other confounding risk factors. These results imply the significant roles of MetS in the development of CVD and the need for prevention and early management of the MetS components. In addition, diabetes is not predictive of CVD in subjects without MetS in our study. This finding might suggest that good diabetic control is useful. However, because the number of our diabetic subjects without MetS is small, further studies are necessary to elucidate this issue in detail.
The strengths of our study include its longitudinal population-based study design, long duration of follow up, sufficient number of CVD events and almost perfect follow up of subjects, examining the data in men and women separately, and exclusion of patients with CVD at baseline. Moreover, it is the first study to examine prospectively CVD in relation to MetS based on a general Japanese population. One limitation of our study is that the diagnosis of MetS was based on a single measurement of its components at baseline as was the case in other epidemiological studies.13–25,27–29 During the follow up, risk factor levels could be changed attributable to modification of lifestyle or medication, and misclassification of the MetS is possible. Thus, it would weaken the association found in this study, biasing the results toward the null hypothesis. Therefore, the true association may be stronger than that shown in our findings.
In conclusion, we have shown that the prevalence of MetS is sizeable in Japanese middle-aged men and women and it is predictive of future CVD in both sexes based on a prospective study with 14 years of follow up. Our findings suggest that early identification of MetS and appropriate behavioral and therapeutic intervention may reduce the burden of CVD in the long run.
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Acknowledgments |
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We thank the residents of Hisayama Town for their participation in the survey and the staff of the Division of Health and Welfare of Hisayama for their cooperation in this study.
Sources of Funding
This study was supported in part by a Grant-in-Aid for Scientific Research A (No. 18209024), a grant from the Special Coordination Fund for Promoting Science, and a grant from the Technology and Innovative Development Project in Life Sciences from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Disclosures
None.
Received December 6, 2006; revision received January 10, 2007; accepted February 2, 2007.
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