The United States has a higher prevalence of metabolic syndrome (MS) and cardiovascular disease (CVD) mortality than Japan, but it is unknown how much of the difference in MS accounts for the mortality difference. The aim of this study was to examine the impact of MS on the excess CVD mortality in the United States compared with that in Japan. Data from the United States Third National Health and Nutrition Examination Survey (NHANES III; n = 12,561) and the Japanese National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in Aged (NIPPON DATA; n = 7,453) were analyzed. MS was defined as ≥3 of 5 risk factors (obesity, high blood pressure, decreased high-density lipoprotein cholesterol, elevated glycosylated hemoglobin, and elevated triglycerides). The results show that after a median of 13.8 years of follow-up in the United States, 1,683 patients died from CVD (11.75 per 1,000 person-years), and after a median of 15 years of follow-up in Japan, 369 patients died from CVD (3.56 per 1,000 person-years). The age-adjusted prevalence of MS was 26.7% in the United States and 19.3% in Japan. Of 5 MS factors, obesity, high blood pressure, elevated triglycerides, and glycosylated hemoglobin in the United States, and high blood pressure and elevated glycosylated hemoglobin in Japan were significant risk factors for CVD mortality. Estimates of 13.3% and 44% of the excess CVD mortality for the United States could be explained by the higher prevalence of MS and MS plus baseline CVD history than in Japan. In conclusion, the present study is the first to quantitatively demonstrate that MS and MS plus baseline CVD history may significantly contribute to the explanation of excess CVD mortality in the United States compared with Japan.
Cardiovascular disease (CVD) has been established as a clear threat to human health. A number of studies have reported that metabolic risk factors, a group of cofactors, increase the risk for CVD. The United States has higher CVD mortality than most developed countries, including Japan. However, few internationally comparative studies have been conducted to examine the impact of metabolic factors on the risk for CVD mortality across countries. Given the differences in the burden of CVD and potential differences in the risk factors, a comparative study of the outcome and risk factors, using nationally representative samples, may add new insights into the studies of CVD. In the present study, we hypothesized that the prevalence of metabolic risk factors was significantly higher in the United States and that the difference is a significant contributor to the excess CVD mortality for the United States compared with Japan. To test these hypotheses, we used data from the United States Third National Health and Nutrition Examination Survey (NHANES III) and the Japanese National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in Aged (NIPPON DATA).
Methods
NHANES III (1988 to 1994) is a nationwide survey conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention in the United States, which gathers information representing the health and nutritional status of the noninstitutionalized civilian United States population aged ≥2 months. The study consists of interviews, physical examinations, and data from blood sample analyses. A detailed description of the survey and its sampling procedures is available at the NHANES III Web site. The NHANES III mortality follow-up study was conducted and linked with the National Death Index. This linked study provides mortality follow-up from the date of baseline NHANES III participants (1988 to 1994) through December 31, 2006. In the study, we included participants aged ≥30 years because CVD mortality is substantially lower in those aged <30 years. Of 15,042 participants aged ≥30 years, we excluded 22 who had ineligible measurements on their vital statistics and 2,459 who did not complete all measurements of 5 metabolic factors (body mass index [BMI], blood pressure [BP], serum high-density lipoprotein cholesterol, triglyceride [TG], and/or glycemia). The remaining 12,561 subjects (83.5% of 15,042) were included in the study sample (5,896 male, 6,665 female). Data from NIPPON DATA90 used in the present study were approved by the NIPPON DATA steering committee and the institutional review board of Shiga University of Medical Science.
NIPPON DATA90, supported by the Ministry of Health and Welfare of Japan, is a cohort study of representative Japanese subjects aged ≥30 years at baseline surveys (1990). Participants in the study were randomly selected from 300 districts throughout Japan. Data from physical examinations, blood tests, and a self-administered questionnaire on lifestyle were collected in person at individual districts’ health care centers. Mortality follow-up was conducted for all participants from baseline to November 2005. For the purpose of the comparison, we used NIPPON DATA90 because it was conducted approximately in the same time period (1990 to 2005) and had the same measures and standardizations as NHANES III (1988 to 2006). Of 8,383 baseline participants aged ≥30 years, we excluded 284 who had invalid follow-up data and 646 who had no measurements of 5 metabolic risk factors. The remaining 7,453 patients (88.9% of 8,383) were included in the study. NHANES III was approved by the institutional review board of the National Center for Health Statistics.
Several criteria for the definition of metabolic syndrome (MS) have been proposed. In the present study, we used the World Health Organization and the American Heart Association criteria by including 5 factors: (1) Obesity was defined using the World Health Organization criteria of BMI ≥30 kg/m 2 . When doing data analysis for Japanese patients only, we also defined obesity using a cut-off point of BMI ≥25 kg/m 2 , according to the criteria of the Japan Society for the Study of Obesity. (2) High BP was defined as systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg or current use of antihypertensive medication. (3) Decreased high-density lipoprotein (HDL) cholesterol was defined as HDL cholesterol <40 mg/dl (<1.0 mmol/L) for male subjects and HDL cholesterol <50 mg/dl (<1.3 mmol/L) for female subjects. (4) Elevated glucose was defined as serum glycosylated hemoglobin (HbA 1c ) ≥5.7%. We used HbA 1c because it does not require a fasting blood sample. HbA 1c level has been shown to be a highly reliable and correlated marker of fasting glucose in several studies when fasting sample is not available. Participants with previous diagnoses of diabetes or those using antidiabetic medications (insulin or oral agents) were classified as having elevated glucose. (5) Elevated serum TG was defined as serum TG ≥150 mg/dl (≥1.7 mmol/L) for a fasting sample or TG ≥200 mg/dl (≥2.3 mmol/L) for a nonfasting sample. Subjects with ≥3 of 5 MS components were classified having MS.
The 2 countries’ CVD deaths were classified using the International Classification of Diseases, 10th Revision as CVD (codes I00 to I99), coronary heart disease (codes I20 to I25), and cerebrovascular disease (codes I60 to I69).
A serial analysis was conducted. First, we described baseline characteristics of participants by gender and country. Analysis of covariance and chi-square tests were used in the descriptive analysis. The age-adjusted prevalence of MS was estimated by the direct method using the World Standard Population. Second, we used a Cox proportional-hazards regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of individual MS factors and MS for the risk for CVD mortality. To verify the Cox proportional-hazards assumptions, we used plots of the log (−log) survival curves and Schoenfeld residuals. Third, we examined the impact of MS on the excess CVD mortality of the United States compared with Japan by conducting 8 multivariate models. Model 1 estimated the HR of the United States versus Japan for CVD mortality and was adjusted for 5 covariates (age, gender, smoking status, alcohol consumption, and total cholesterol). Model 1 served as the base model. Models 2 to 6 adjusted for the same 5 covariates used in model 1 along with each of 5 MS components separately in a step-by-step manner. Model 7 examined the total impact of MS on CVD mortality, and model 8 included adjustment for baseline CVD conditions (coronary heart disease and stroke). The magnitudes of the impact of each MS component and MS on the excess CVD mortality of the United States compared with Japan were expressed using the formula (HR 1 − HR 2 )/(HR 1 − 1.0) × 100%, where HR 1 represents then HR derived from model 1, HR 2 represents the HR after adjusting for additional covariates (i.e., models 2 to 8), and 1.0 represents the HR when there was no excess risk. Finally, survival functions of participants who had MS for the risk for CVD mortality were estimated and depicted by country and by the number of exposures to MS components. A repeated data analysis was conducted for participants who were free of baseline CVD conditions to examine whether the MS-CVD mortality associations remained observed.
All data analyses were conducted using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). We used sampling weights and accounted for the complex sampling design using “SAS Procedures for Analysis of Sample Survey Data.” Two-sided p values ≤0.05 were considered as having statistical significance.
Results
Table 1 shows that the United States participants had significantly higher means of BMI, total cholesterol, TG and HbA 1c and lower HDL cholesterol than the Japanese participants. Differences in smoking and other risk factors between male and female participants were also observed in the U.S. and Japan.
| Variable | Men | Women | ||||
|---|---|---|---|---|---|---|
| United States (n = 5,896) | Japan (n = 3,129) | p Value ∗ | United States (n = 6,665) | Japan (n = 4,324) | p Value ∗ | |
| Continuous variables | ||||||
| Age (yrs) | 49.48 ± 0.36 | 53.36 ± 0.24 | <0.001 | 51.32 ± 0.52 | 52.48 ± 0.21 | 0.03 |
| BMI (kg/m 2 ) | 27.00 ± 0.11 | 22.96 ± 0.05 | <0.001 | 26.98 ± 0.17 | 22.86 ± 0.05 | <0.001 |
| Systolic BP (mm Hg) | 126.83 ± 0.43 | 138.01 ± 0.36 | <0.001 | 123.86 ± 0.54 | 133.72 ± 0.32 | <0.001 |
| Diastolic BP (mm Hg) | 78.01 ± 0.22 | 83.78 ± 0.21 | <0.001 | 73.27 ± 0.22 | 79.62 ± 0.18 | <0.001 |
| Total cholesterol (mg/dl) | 208.83 ± 1.03 | 198.58 ± 0.66 | <0.001 | 212.64 ± 0.94 | 206.82 ± 0.59 | <0.001 |
| HDL cholesterol (mg/dl) | 45.32 ± 0.38 | 50.37 ± 0.27 | <0.001 | 55.34 ± 0.42 | 56.73 ± 0.23 | 0.002 |
| TG (mg/dl) † | 165.73 ± 3.10 | 147.62 ± 1.88 | <0.001 | 139.33 ± 3.09 | 121.12 ± 1.20 | <0.001 |
| HbA 1c (%) | 5.49 ± 0.02 | 5.37 ± 0.01 | <0.001 | 5.45 ± 0.03 | 5.25 ± 0.01 | <0.001 |
| Categorical variables | ||||||
| Smoking status | <0.001 | <0.001 | ||||
| Never | 53.77% | 20.29% | 71.63% | 88.32% | ||
| Former | 8.76% | 24.32% | 4.77% | 2.52% | ||
| Current | 37.47% | 55.39% | 23.60% | 9.16% | ||
| Current alcohol use ‡ | 62.00% | 65.10% | <0.001 | 39.16% | 7.54% | <0.001 |
| Hypertension § | 37.47% | 53.563% | <0.001 | 37.15% | 46.21% | <0.001 |
| Hypercholesterolemia || | 35.31% | 17.034% | <0.001 | 36.92% | 22.94% | <0.001 |
| Diabetes mellitus ¶ | 9.14% | 8.69% | 0.35 | 9.57% | 5.20% | <0.001 |
| Coronary heart disease # | 6.13% | 3.10% | <0.001 | 3.27% | 2.61% | 0.10 |
| Stroke # | 2.49% | 2.52% | 0.13 | 2.49% | 1.36% | <0.001 |
∗ For age-adjusted tests using analysis of covariance for continuous variables and chi-square tests for categorical variables, expect for testing difference in age between countries.
† Nonfasting in Japanese data.
‡ Defined by self-report, if a subject had consumed ≥1 drink of any type (beer, wine, or liquor) per month.
§ Defined as self-report of physician diagnosis of hypertension, systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, or use of antihypertensive medication.
|| Defined as self-report of physician diagnosis of hyperlipidemia or total cholesterol ≥240 mg/dl (6.2 mmol/L).
¶ Defined as self-report of physician diagnosis of diabetes mellitus or serum HbA 1c ≥6.5% or use of medication to treat diabetes.
# Defined as self-report of physician diagnosis of each disease.
The mean follow-up period was 12.7 years (median 13.8) for the NHANES III participants and 13.9 years (median 15) for the Japanese participants. Of 12,561 United States participants, 1,683 died from CVD. Of CVD deaths, 1,058 patients (62.9%) died from coronary heart disease, 315 (18.7%) from cerebrovascular disease, and 310 (18.4%) from other CVD subtypes. Of 7,453 Japanese participants, 369 died from CVD. Of CVD deaths, 81 patients (22.0%) died from coronary heart disease, 160 (43.4%) from cerebrovascular disease, and 128 (34.6%) from other CVD subtypes. Figure 1 shows that the United States had significantly higher CVD mortality than Japan (11.75% vs 3.56%, p <0.001).
Table 2 shows that the United States had significantly higher age-adjusted prevalence rates for individual MS factors, except for having a significantly lower prevalence of high BP than Japan (p <0.01 or p <0.05). The United States had significantly higher prevalence of MS than Japan (26.7% vs 19.3%, p <0.01), when obesity was defined as BMI ≥30 kg/m 2 and BMI ≥25 kg/m 2 for the United States and Japanese samples, respectively. Obesity, high BP, elevated TG, and elevated HbA 1c significantly predicted CVD mortality in the United States population, and high BP and elevated HbA 1c predicted CVD mortality in Japan (p <0.001 for all). The HR of MS for CVD mortality was 22.9% higher ([1.43 − 1.35]/[1.35 − 1]) in the United States than in Japan (p <0.001) when obesity was defined as BMI ≥30 kg/m 2 for the United States and BMI ≥25 kg/m 2 for Japan. However, the HR was 23.3% higher in Japan than in the United States (p <0.001) when obesity was classified as BMI ≥30 kg/m 2 for the 2 populations. Similar associations were observed for participants without baseline CVD conditions.
| MS Relation to CVD Mortality | United States | Japan | |||||
|---|---|---|---|---|---|---|---|
| Rate ∗ | HR (95% CI) | p Value | Rate ∗ | HR (95% CI) | p Value | ||
| In total participants | |||||||
| 1a | BMI ≥30 kg/m 2 (U.S.), BMI ≥25 kg/m 2 (Japan) † | 25.3% | 1.27 (1.05–1.55) | 0.017 | 23.7% | 0.80 (0.62–1.04) | 0.09 |
| 1b | BMI ≥30 kg/m 2 (both countries) † | 25.3% | 1.27 (1.05–1.55) | 0.017 | 2.4% | 0.89 (0.39–2.06) | 0.79 |
| 2 | High BP ‡ | 43.9% | 1.51 (1.18–1.93) | <0.001 | 60.5% | 2.62 (1.74–3.96) | <0.001 |
| 3 | Low HDL cholesterol § | 38.0% | 1.18 (1.00–1.40) | 0.06 | 29.1% | 1.06 (0.85–1.33) | 0.59 |
| 4 | Elevated triglycerides || | 35.8% | 1.17 (1.02–1.35) | 0.028 | 19.1% | 1.21 (0.95–1.54) | 0.13 |
| 5 | Elevated HbA 1c ¶ | 25.7% | 1.45 (1.25–1.68) | <0.001 | 12.4% | 1.64 (1.31–2.07) | <0.001 |
| MS (Japan, ≥3 of 1a to 5 components) # | 26.7% | 1.43 (1.24–1.64) | <0.001 | 19.3% | 1.35 (1.08–1.69) | 0.027 | |
| MS (U.S., ≥3 of 1b to 5 components) # | 26.7% | 1.43 (1.24–1.64) | <0.001 | 12.6% | 1.53 (1.20–1.94) | 0.001 | |
| In participants without baseline CVD histories | |||||||
| 1a | BMI ≥30 kg/m 2 (U.S.), BMI ≥25 kg/m 2 (Japan) † | 25.0% | 1.37 (1.10–1.69) | 0.01 | 23.6% | 0.83 (0.62–1.10) | 0.18 |
| 1b | BMI ≥30 kg/m 2 (both countries) † | 25.0% | 1.37 (1.10–1.69) | 0.01 | 2.4% | 1.04 (0.45–2.39) | 0.94 |
| 2 | High BP ‡ | 42.5% | 1.66 (1.27–2.16) | <0.001 | 60.0% | 2.58 (1.68–3.97) | <0.001 |
| 3 | Low HDL cholesterol § | 37.2% | 1.06 (0.86–1.31) | 0.58 | 29.0% | 0.93 (0.72–1.20) | 0.57 |
| 4 | Elevated triglycerides || | 34.8% | 1.09 (0.92–1.28) | 0.30 | 18.8% | 1.16 (0.88–1.52) | 0.29 |
| 5 | Elevated HbA 1c ¶ | 24.9% | 1.38 (1.10–1.73) | 0.01 | 12.0% | 1.62 (1.25–2.09) | <0.001 |
| MS (Japan, ≥3 of 1a to 5 components) # | 25.7% | 1.39 (1.17–1.66) | <0.001 | 18.9% | 1.30 (1.01–1.67) | 0.039 | |
| MS (U.S., ≥3 of 1b to 5 components) # | 25.7% | 1.39 (1.17–1.66) | <0.001 | 12.2% | 1.48 (1.13–1.93) | <0.01 | |
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