Metabolic Syndrome and the Risk of Ischemic Heart Disease and Stroke Among Japanese Men and Women
Background and Purpose— Limited evidence was available on the metabolic syndrome and risk of cardiovascular disease in Asia. The purpose of this study is to examine the association of the metabolic syndrome and risk of ischemic cardiovascular disease in Japanese men and women.
Methods— We conducted an 18-year prospective study of 9087 Japanese people aged 40 to 69 years (3595 men and 5492 women), initially free of ischemic heart disease or stroke. During follow-up, there were 116 (74 men and 42 women) cases of ischemic heart disease and 256 (144 men and 112 women) ischemic strokes. Metabolic syndrome was defined by the modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII), with the presence of ≥3 of the following factors: (1) serum triglycerides ≥1.69 mmol/L (150 mg/dL); (2) HDL-cholesterol <1.03 mmol/L (40 mg/dL) for men and <1.29 mmol/L (50 mg/dL) for women; (3) glucose ≥6.11 mmol/L (110 mg/dL) fasting or ≥7.77 mmol/L (140 mg/dL) nonfasting, or on treatment; (4) blood pressure ≥130/85 mm Hg or medication use, and (5) body mass index ≥25.0 kg/m2.
Results— For both sexes, high blood pressure, high triglycerides and low HDL cholesterol were associated with increased risks of ischemic heart disease or stroke after adjustment for cardiovascular risk factors. A dose-response relationship was found between the number of metabolic risk factors and incidence of these cardiovascular end points. The multivariable hazard ratio (95% CI) associated with metabolic syndrome was 2.4 (1.4 to 4.0) in men and 2.3 (1.2 to 4.3) in women for ischemic heart disease, and 2.0 (1.3 to 3.1) and 1.5 (1.0 to 2.3), respectively, for ischemic stroke. The contribution of metabolic syndrome to the risks was independent of serum total cholesterol levels but stronger among smokers.
Conclusions— The metabolic syndrome is a major determinant of ischemic cardiovascular disease among middle-aged Japanese men and women, in particular among smokers.
Metabolic syndrome is defined by a condition of high-risk for ischemic heart disease and cardiovascular disease in Western populations.1–3 However, the impact of the metabolic syndrome has not been thoroughly examined among Asian populations, probably because of the lower prevalence of obesity, low HDL cholesterol and abnormal glucose levels compared with Western populations.4–6 It is uncertain whether the metabolic syndrome can define a high-risk subgroup among Japanese people who have low mortality from ischemic heart disease and high mortality from stroke, and who have different profiles of other cardiovascular risk factors, eg, lower serum cholesterol levels for men and women and higher prevalence of smoking for men, compared with Western populations.7
Previous prospective studies of Asians showed that high triglycerides,8 low HDL-cholesterol9 and hypertension10 are risk factors for ischemic heart disease, and that low HDL-cholesterol,11 diabetes6 and hypertension12 are risk factors for ischemic stroke. However, no studies have comprehensively examined the role of the metabolic syndrome and its components on the risk of ischemic cardiovascular disease among Japanese people living in Japan.
To examine the impact of the metabolic syndrome on the risk of ischemic heart disease and stroke among Asians, we explored data from an 18-year prospective study of 9087 persons (3595 men and 5492 women) in 5 Japanese communities. We also examined whether the contribution of metabolic syndrome was modified by other major cardiovascular risk factors, such as serum total cholesterol levels and smoking.
Materials and Methods
The surveyed population comprised residents aged 40 to 69 years in 5 communities who participated in cardiovascular risk surveys between 1975 and 1980 in northeast rural communities, Ikawa, Ishizawa and Kitautetsu, and in a southwest rural community, Noichi, and between 1981 and 1987 in a central rural community, Kyowa, and between 1975 and 1984 in a southwest urban suburb, Yao. The participants in the baseline survey numbered 12 982 (5326 men and 7656 women), and the overall participation rate was 70%. Individuals with a history of ischemic heart disease (n=80) or stroke (n=211), or with missing values of serum HDL cholesterol or triglycerides (n=3604) were excluded, and the data for 9087 individuals (3595 men and 5492 women) were used for the analyses. Compared with individuals included in the analyses, those with missing serum lipids were 4 years older, had a 4% higher prevalence of hypertension (defined below) and 6% higher prevalence of current smoking. There was, however, no difference in mean levels of body mass index (BMI) or serum total cholesterol or the proportion with blood glucose abnormality between individuals with and without serum lipid values. Therefore, potential selection bias may be small.
The subjects were followed-up to determine incidence of ischemic heart disease and stroke occurring by the end of 2001. Persons who moved out of the communities during the follow-up period, determined by the municipal office records on emigration, numbered 343 (4%), and 1001 (11%) persons died during the follow-up. These cases were censored at the date of moving out or the date of death, respectively. The median follow-up period was 18.3 years. The study was approved by the Ethics Committee in the University of Tsukuba.
End Point Determination
The follow-up was conducted by annual cardiovascular risk surveys to obtain histories of incident ischemic heart diseases and strokes for the participants. For nonparticipants in any survey, these end points were ascertained by a mailed questionnaire and by the use of death certificates as an underlying cause of death (International Classification for Diseases, 9th edition: 410 to 414, 428, 429 and 430 to 438, respectively). We also used national insurance claims, ambulance records, reports by local physicians and public health nurses for case ascertainment. To confirm the diagnosis, all living patients were telephoned or visited to obtain medical history, and their medical records were reviewed. For deaths, we obtained histories from families and reviewed medical records.
The criteria for ischemic heart disease were modified from those of the World Health Organization (WHO) Expert Committee.13 Definite myocardial infarction was indicated by typical chest pain, lasting for ≥30 minutes with the appearance of abnormal and persistent Q or QS waves, or changes in cardiac enzyme activity or both. Probable myocardial infarction was indicated by typical chest pain in which the findings of ECG or enzyme activity were not available. Angina pectoris was defined as repeated episodes of chest pain during effort, especially when walking, usually disappearing rapidly after the cessation of effort or by use of sublingual nitroglycerin. Sudden cardiac death was defined as death within 1 hour of onset, a witnessed cardiac arrest, or abrupt collapse not preceded by >1 hour of symptoms. Ischemic heart disease included definite or probable myocardial infarction, angina pectoris, and sudden cardiac death.
Stroke was defined as a focal neurological disorder with rapid onset, which persisted at least 24 hours or until death. The determination of incident strokes was conducted based on the clinical criteria.12 Stroke events were further subclassified as subarachnoid hemorrhage, intraparenchymal hemorrhage, ischemic stroke (nonembolic or embolic) primarily based on CT or MRI.14 Stroke cases without the imaging studies were subclassified according the clinical criteria12 as subarachnoid hemorrhage, intraparenchymal hemorrhage, ischemic stroke (nonembolic or embolic) and stroke of undetermined type. In the present study, the stroke end point of interest was nonembolic ischemic stroke. Embolic infarction was not included because atrial fibrillation, which is relevant to chronic hypertension but not to abnormalities of lipids or glucose, was the embolic source in the majority.6 The proportion of stroke cases confirmed by CT or MRI was 87% for total stroke, 96% for subarachnoid hemorrhage, 94% for intraparenchymal hemorrhage, 87% for nonembolic ischemic stroke and 100% for embolic infarction.
A panel of 3 or 4 physician-epidemiologists made the final diagnoses for ischemic heart disease and stroke, blinded to the data of risk factor surveys.
At baseline survey, blood was drawn from seated participants into a plain, siliconized glass tube and the serum was separated. Fasting was not required. The distribution of time since the last meal was <2 hours (39%), 2 hours (43%), 3 to 7 hours (9%) and ≥8 hours (9%). Serum glucose was measured by the cupric-neocuproine method between 1975 and September 1986, and by the hexokinase method thereafter. Glucose values from the cupric-neocuproine method were adjusted to make the hexokinase-method values comparable, using a formula from a regression line estimated from 60 random samples of blood: 0.855×glucose−0.541 (mmol/L), R2=0.93.
Serum total cholesterol and HDL cholesterol after heparin-manganese precipitation were measured by the Liebermann-Burchard direct method using the Autoanalyzer II (Technicon) at the Osaka Medical Center for Health Science and Promotion. The laboratory has been standardized by CDC-NHLBI Lipid Standardization Program, Centers for Disease Control and Prevention, Atlanta, and successfully met the criteria for precision and accuracy of triglycerides, and total- and HDL-cholesterol measurements as an international member of the US National Cholesterol Reference Method Laboratory Network (CRMLN).15
Trained technicians measured blood pressure using standard mercury sphygmomanometers on the right arm of seated participants after a 5-minute rest. Height in stockinged feet and weight in light clothing were measured. BMI was calculated as weight (kg) divided by the square of height in meters (m2).
An interview was conducted to ascertain the smoking status, the number of cigarettes smoked per day, and usual weekly intake of alcohol in go units (a Japanese traditional unit of volume corresponding to 23 g ethanol). Women were asked their menopausal status.
A modified definition by the Adult Treatment Panel III guideline of the National Cholesterol Education Program16 was used to categorize the subjects according to the number of components of the metabolic syndrome. Because waist circumference was not measured in the present study, BMI ≥25.0 kg/m2 was used as the criterion for obesity for the analysis; this BMI level was reported to correspond well to the Asian criterion for high waist circumference ≥90 cm in men and ≥80 cm in women.17 The metabolic syndrome was defined as the presence of 3 or more of the following components: (1) serum triglycerides ≥1.69 mmol/L (150 mg/dL); (2) HDL cholesterol <1.03 mmol/L (40 mg/dL) for men and <1.29 mmol/L (50 mg/dL) for women; (3) glucose ≥6.11 mmol/L (110 mg/dL) fasting or ≥7.77 mmol/L (140 mg/dL) nonfasting, or on treatment; (4) blood pressure ≥130/85 mm Hg or medication use, and (5) overweight: BMI ≥25.0 kg/m2.
Age-adjusted mean values or prevalences of metabolic syndrome, its components and other cardiovascular risk factors were compared between incident cases of ischemic heart disease and stroke and noncases by analysis of covariance or χ2 tests.
Person-years were calculated as the sum of individual follow-up time until the occurrence of incident ischemic heart disease, stroke, death, emigration, or the end of 2001. The hazard ratios of ischemic heart disease and stroke and the respective 95% CI were calculated with reference to the risk of individuals without the metabolic syndrome, or without each of its components, or with none of the components, using the Cox proportional hazards model. We adjusted for age (years) and community, and for other potential confounding variables including serum total cholesterol (mmol/L), smoking status (never, former and current smokers), alcohol intake category (never, former and current <46, 46 to 68 and ≥69 g/d ethanol), time since last meal (<2, 2, 3 to 7 and 8 hours or more), and menopausal status (pre- and postmenopause) for women. We conducted tests for trend across the categories of the number of metabolic risk factors by assigning median values for each category (0, 1, 2, 3 and 4) and testing the significance of this variable. Test for effect modification by sex was conducted using an interaction term generated by multiplying the median values for each category by sex.
The multivariable-adjusted associations of ischemic heart disease and stroke were examined overall and stratified by serum total cholesterol levels, ie, <5.69 mmol/L (220 mg/dL) and ≥5.69 mmol/L and the current smoking status. The significance of the interaction of metabolic syndrome with serum total cholesterol levels and smoking status was tested using cross-product terms of these variables in multivariable models. Probability values for statistical tests were 2-tailed and P<0.05 was regarded as statistically significant. The SAS statistical package (version 8, SAS Institute Inc) was used for the analyses.
After 167 045 person-years of follow-up, we documented 116 incident cases of ischemic heart disease (74 in men and 42 in women) and 256 incident cases of ischemic stroke (144 in men and 112 in women). Ischemic heart disease composed of 43 (29 in men and 14 in women) defined and 33 (21 in men and 12 in women) probable myocardial infarctions, 25 (19 in men and 6 in women) angina pectoris, and 19 (8 in men and 11 in women) sudden cardiac deaths with 4 cases (3 in men and 1 in women) of both myocardial infarction and angina pectoris. Absolute risk of ischemic heart disease was 0.7 per 1000 person-years for total subjects, 1.2 per 1000 person-years for men and 0.4 per 1000 person-years for women. The respective risk of ischemic stroke was 1.6, 2.3 and 1.1 per 1000 person-years.
Table 1 compares age-adjusted values and proportions of components of the metabolic syndrome and other cardiovascular risk factors between incident cases and noncases of ischemic heart disease and stroke. Compared with noncases, cases with ischemic heart disease were older, more hypertensive, smoked more, and had higher mean serum total cholesterol levels, serum triglycerides, and lower HDL-cholesterol levels among both men and women. Compared with noncases, cases with ischemic stroke were older and more hypertensive among both men and women, and cases smoked more and had lower HDL-cholesterol levels only among men.
Age- and community-adjusted risks of ischemic heart disease were ≈2-fold higher in the presence of each component of the metabolic syndrome among men, except there was no association with glucose abnormality (Table 2). For women, similar associations were found but the associations with high blood pressure and overweight were weak and insignificant. Age- and community-adjusted risks of ischemic stroke were 3- to 4-fold higher in the presence of high blood pressure and 1.5- to 2-fold higher in the presence of other components of the metabolic syndrome among men. Similar associations were found among women except for no association with low HDL-cholesterol levels. High total cholesterol levels were, and smoking tended to be, associated with increased risk of ischemic heart disease but not ischemic stroke for both men and women. These significant associations were somewhat attenuated after adjustment for metabolic factors and other confounding variables, but the associations with blood pressure and total cholesterol levels remained statistically significant; those with triglycerides, HDL-cholesterol and smoking remained statistically significant or of borderline significance.
Risks of ischemic heart disease and stroke were positively associated with the number of metabolic syndrome components for both men and women with no interaction with sex (P for interaction >0.05; Table 3). For men and women combined, adjusting for sex, the dose-response relationship was more pronounced for ischemic heart disease than for ischemic stroke where the risk plateaued for 3 or more risk factors. The multivariable hazard ratio (95% CI) for 3 or more components versus 0 component in the total group was 2.9 (1.5 to 5.5) for ischemic heart disease and 7.6 (3.9 to 15.0) for ischemic stroke, and that for 4 or more components versus 0 component was 4.0 (1.9 to 8.5) and 7.6 (3.5 to 16.4), respectively. The respective multivariable hazard ratio (95% CI) associated with metabolic syndrome (≥3 components versus <3) was 2.4 (1.6 to 3.6) and 1.8 (1.3 to 2.4). This hazard ratio for ischemic stroke did not change materially when we excluded clinically diagnosed stroke cases (n=33): 1.7 (1.2 to 2.3; not shown in the tables). Trends were similar for both men and women.
The associations between the metabolic syndrome and risks of ischemic heart disease and stroke were examined for the total group, stratified by serum total cholesterol levels and smoking status (Table 4). The excess risk of ischemic heart disease associated with the metabolic syndrome was larger for persons with serum cholesterol levels <5.69 mmol/L than for those with higher cholesterol levels, whereas that of ischemic stroke was similar according to total cholesterol levels. The excess risk associated with the metabolic syndrome was more evident among current smokers than among nonsmokers (P for interaction=0.09 for ischemic heart disease and 0.04 for ischemic stroke). These results did not alter substantially when the clinically diagnosed cases (n=33) were excluded. The multivariable hazard ratio of ischemic stroke was 1.6 (1.2 to 2.3) for serum total cholesterol <5.69 mmol/L and 2.1 (0.9 to 4.9) for the higher cholesterol levels (P for interaction=0.50), and 1.4 (0.9 to 2.0) for nonsmokers and 2.3 (1.4 to 3.9) for smokers (P for interaction=0.08; not shown in the tables).
The metabolic syndrome was associated with ≈1.5- to 2.5-fold increase in the risk of ischemic heart disease and stroke among Japanese men and women aged 40 to 69 years where the incidence rate of ischemic stroke was 2 to 3 times higher than that of ischemic heart disease. The higher incidence rate for ischemic stroke compared with coronary heart disease was expected as a characteristic for Japanese people because another community-based cohort study reported a similar finding.18
Each component of metabolic syndrome contributed to the increased risk of these end points except for glucose abnormality in men and women and an overweight status in women. There was a dose-response relationship between the number of metabolic risk factors and incidence of these end points for both sexes. The risk of ischemic heart disease was 4-fold higher for persons with 4 or more metabolic risk factors, compared with those without any risk factors, whereas the respective risk of ischemic stroke was 8-fold higher. The excess risk for persons with 1 or 2 metabolic risk factors compared with those without any risk factors was also large (4- to 6-fold) for ischemic stroke, because high blood pressure was a strong risk factor and was present in 65% to 80% of persons with 1 or 2 metabolic risk factors. The other metabolic risk factors were present in <40% of these subgroups. For persons with 3 or more risk factors, the risk of ischemic stroke plateaued according to the number of risk factors. Therefore, the multivariable hazard ratios associated with metabolic syndrome per se were not so different between ischemic heart disease and stroke: 2.4 (1.6 to 3.6) and 1.8 (1.3 to 2.4), respectively.
Our results are consistent with the findings from previous prospective studies, showing that the metabolic syndrome was associated with the increased mortality and incidence of ischemic heart disease or cardiovascular disease,1–3 and ischemic stroke.3 The present study extended these findings to cardiovascular disease in Asian populations. The lack of significant association between glucose abnormality and risks of ischemic cardiovascular disease may be in part attributable to the inclusion of mild to moderate glucose abnormalities because we found a significant excess risk of ischemic stroke associated with diabetes but not borderline glucose abnormality.6
The associations between the metabolic syndrome and risks of cardiovascular disease remained statistically significant after adjustment for total cholesterol levels and other cardiovascular risk factors. Also, there was the larger hazard ratio among current smokers than among nonsmokers, suggesting a synergistic effect of smoking and metabolic syndrome on the risk of ischemic cardiovascular disease. Because smoking enhances insulin resistance,19 the synergistic effect is biologically plausible. Our finding also implies that smokers with the metabolic syndrome are a subpopulation worthy of targeting for control of the metabolic syndrome in the prevention of ischemic cardiovascular disease.
The population levels of components of metabolic syndrome have changed over time in Japan. Mean BMI has increased consistently among men aged 40 to 69 (from 22.6 to 23.6 kg/m2) but not among women (from 23.1 to 23.1 kg/m2) between 1980 and 2000 according to a national survey,4,20 and the prevalence of diabetes has increased from 3% to 13% in men and from 1% to 8% in women according to several population-based surveys.21 The proportion of fasting triglycerides ≥1.69 mmol/L (150 mg/dL) increased among men aged 40 to 69 (from 24% to 35%) but not among women (from 19% to 21%), whereas mean HDL cholesterol increased for both sexes (from 1.30 to 1.37 mmol/L in men and from 1.47 to 1.58 mmol/L in women) between 1990 and 2000.20 On the other hand, blood pressure levels and the prevalence of hypertension decreased for both sexes between 1980 and 2000.20 In Ikawa, one of our survey communities, the age-adjusted prevalence of metabolic syndrome has increased more for men than for women aged 40 to 69 from 1994–1999 to 2000–2005: 18 (95% CI, 16% to 21%) to 35 (32% to 39%) for men and 11 (9% to 13%) to 17 (15% to 19%) for women, which suggests an increased public health issue among Japanese men.
The strengths of the present study included the large population-based sample of middle-aged men and women, and the use of standardized methods for the measurement of serum lipids and risk characteristics. The stroke surveillance was almost complete and a high percentage of the events was confirmed using imaging studies.
The limitations of the study were, first, that we did not measure waist circumference at the baseline survey. However, the contribution of high waist circumference per se to the prediction for risk of cardiovascular disease has been inconsistent; high waist circumference was associated with mortality from cardiovascular disease other than stroke,22 but not with the incidence of ischemic heart disease.3 Second, we used nonfasting data, in particular nonfasting serum triglycerides ≥1.69 mmol/L (150 mg/dL) as a component of metabolic syndrome. Although the justification of the use for the same cut point as fasting status is under debate, the data of nonfasting triglycerides can be used because of the significant predictor for ischemic heart disease.8 Third, the definition of metabolic syndrome has not been established, and the different definitions may lead to the different results on the contribution to the risk of cardiovascular disease.23 The multivariable hazard ratios (95% CI) of coronary heart disease for the metabolic syndrome among men and women were 1.5 (0.7 to 3.2), P=0.34, according to the modified criteria of WHO1 and 1.9 (1.2 to 2.9), P=0.008, according to the modified criteria of International Diabetes Federation24 in which high waist circumference was substituted by BMI ≥25.0 kg/m2. The respective hazard ratios of ischemic stroke were 1.7 (1.0 to 3.0), P=0.05, and 1.4 (1.0 to 2.0), P=0.04. Thus, these criteria may provide less prognostic information than do the present ATIII criteria as a previous study indicated.25
In summary, metabolic syndrome is a major determinant of ischemic heart disease and stroke among middle-aged Japanese men and women. The excess risk associated with the metabolic syndrome was larger among smokers than among nonsmokers.
The authors thank Professor Aaron R. Folsom, University of Minnesota, USA for valuable comments, and Dr Masakazu Nakamura for excellent achievement in quality control for lipid measurements.
Sources of Funding
This study was supported in part by a contract from the Japanese Ministry of Education (Grant-in-Aid for Research A:04304036).
- Received August 24, 2006.
- Revision received November 12, 2006.
- Accepted November 15, 2006.
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