Title: Impact of Metabolic Syndrome on the Risk of Cardiovascular Disease Mortality in the United States and in Japan
Abstract: 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. 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.1Lakka H.M. Laaksonen D.E. Lakka T.A. Niskanen L.K. Kumpusalo E. Tuomilehto J. Salonen J.T. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men.JAMA. 2002; 288: 2709-2716Crossref PubMed Scopus (4081) Google Scholar, 2Beckman J.A. Creager M.A. Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.JAMA. 2002; 287: 2570-2581Crossref PubMed Scopus (2267) Google Scholar, 3Kadota A. Hozawa A. Okamura T. Kadowak T. Nakmaura K. Murakami Y. Hayakawa T. Kita Y. Okayama A. Nakamura Y. Kashiwagi A. Ueshima H. 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Bundle branch block and other cardiovascular disease risk factors: US-Japan comparison.Int J Cardiol. 2010; 143: 432-440Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar 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.8National Center for Health Statistics. National Health and Nutrition Examination Survey Data. Available at: http://www.cdc.gov/nchs/surveys.htm. Accessed April 16, 2010.Google Scholar 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.8National Center for Health Statistics. National Health and Nutrition Examination Survey Data. Available at: http://www.cdc.gov/nchs/surveys.htm. Accessed April 16, 2010.Google Scholar The NHANES III mortality follow-up study was conducted and linked with the National Death Index.13Data Linkage Team. Comparative analysis of the NHANES III public-use and restricted-use linked mortality files: 2010 public-use data release—National Center for Health Statistics. Available at: http://www.cdc.gov/nchs/data/datalinkage/nhanes3_mort_compare_2010_final.pdf. Accessed July 18, 2010.Google Scholar This linked study provides mortality follow-up from the date of baseline NHANES III participants (1988 to 1994) through December 31, 2006.13Data Linkage Team. Comparative analysis of the NHANES III public-use and restricted-use linked mortality files: 2010 public-use data release—National Center for Health Statistics. Available at: http://www.cdc.gov/nchs/data/datalinkage/nhanes3_mort_compare_2010_final.pdf. Accessed July 18, 2010.Google Scholar 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). 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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.8National Center for Health Statistics. National Health and Nutrition Examination Survey Data. Available at: http://www.cdc.gov/nchs/surveys.htm. Accessed April 16, 2010.Google Scholar, 13Data Linkage Team. Comparative analysis of the NHANES III public-use and restricted-use linked mortality files: 2010 public-use data release—National Center for Health Statistics. Available at: http://www.cdc.gov/nchs/data/datalinkage/nhanes3_mort_compare_2010_final.pdf. Accessed July 18, 2010.Google Scholar Several criteria for the definition of metabolic syndrome (MS) have been proposed.12Liu L. Okamura T. Kadowaki T. Murakami Y. Hozawa A. Kita Y. Takashima N. Okuda N. Okayama A. Ueshima H. Bundle branch block and other cardiovascular disease risk factors: US-Japan comparison.Int J Cardiol. 2010; 143: 432-440Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 18Grundy S.M. Cleeman J.I. Daniels S.R. Donato K.A. Eckel R.H. Franklin B.A. Gordon D.J. Krauss R.M. Savage P.J. Smith Jr., S.C. Spertus J.A. Costa F. American Heart Association National Heart, Lung, and Blood Institute Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.Circulation. 2005; 112: 2735-2752Crossref PubMed Scopus (9386) Google Scholar, 19Batsis J.A. Nieto-Martinez R.E. Lopez-Jimenez F. Metabolic syndrome: from global epidemiology to individualized medicine.Clin Pharmacol Ther. 2007; 82: 509-524Crossref PubMed Scopus (128) Google Scholar, 20Liu L. Nunez A.E. Cardiometabolic syndrome and its association with education, smoking, diet, physical activity, and social support: findings from the Pennsylvania 2007 BRFSS survey.J Clin Hypertens (Greenwich). 2010; 12: 556-564PubMed Google Scholar 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/m2. When doing data analysis for Japanese patients only, we also defined obesity using a cut-off point of BMI ≥25 kg/m2, according to the criteria of the Japan Society for the Study of Obesity.21Kanazawa M. Yoshiike N. Osaka T. Numba Y. Zimmet P. Inoue S. Criteria and classification of obesity in Japan and Asia-Oceania.World Rev Nutr Diet. 2005; 94: 1-12Crossref PubMed Scopus (175) Google Scholar (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 (HbA1c) ≥5.7%. We used HbA1c because it does not require a fasting blood sample. HbA1c level has been shown to be a highly reliable and correlated marker of fasting glucose in several studies when fasting sample is not available.22American Diabetes Association Executive summary: standards of medical care in diabetes—2010.Diabetes Care. 2010; 33: S4-S10PubMed Google Scholar, 23Selvin E. Steffes M.W. Gregg E. Brancati F.L. Coresh J. Performance of A1c for the classification and prediction of diabetes.Diabetes Care. 2011; 34: 84-89Crossref PubMed Scopus (118) Google Scholar, 24Grundy S.M. Brewer Jr., H.B. Cleeman J.I. Smith Jr., S.C. Lenfant C. American Heart Association, National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition.Circulation. 2004; 109: 433-438Crossref PubMed Scopus (4404) Google Scholar, 25Ferreira I. Beijers H.J. Schouten F. Smulders Y.M. Twisk J.W. Stehouwer C.D. Clustering of metabolic syndrome traits is associated with maladaptive carotid remodeling and stiffening: a 6-year longitudinal study.Hypertension. 2012; 60: 542-549Crossref PubMed Scopus (30) Google Scholar Participants with previous diagnoses of diabetes or those using antidiabetic medications (insulin or oral agents) were classified as having elevated glucose.22American Diabetes Association Executive summary: standards of medical care in diabetes—2010.Diabetes Care. 2010; 33: S4-S10PubMed Google Scholar (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.3Kadota A. Hozawa A. Okamura T. Kadowak T. Nakmaura K. Murakami Y. Hayakawa T. Kita Y. Okayama A. Nakamura Y. Kashiwagi A. Ueshima H. NIPPON DATA Research GroupRelationship between metabolic risk factor clustering and cardiovascular mortality stratified by high blood glucose and obesity: NIPPON DATA90 1990-2000.Diabetes Care. 2007; 30: 1533-1538Crossref PubMed Scopus (112) Google Scholar Subjects with ≥3 of 5 MS components were classified having MS.6Liu L. Liu Z. Ma M. Xue F. Sorel E. The cardiometabolic syndrome and risk of mortality from cardiovascular diseases and all causes among African Americans and white Americans.JCMD. 2012; 3: 1-9Google Scholar, 24Grundy S.M. Brewer Jr., H.B. Cleeman J.I. Smith Jr., S.C. Lenfant C. American Heart Association, National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition.Circulation. 2004; 109: 433-438Crossref PubMed Scopus (4404) Google Scholar 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.26SAS Institute Inc SAS/STAT User's Guide, Version 9.1. SAS Institute Inc., Cary, North Carolina2005Google Scholar, 27Szklo M. Nieto F.J. Epidemiology: Beyond the Basics. Jones & Bartlett, Sudbury, Massachusetts2007Google Scholar 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 (HR1 − HR2)/(HR1 − 1.0) × 100%, where HR1 represents then HR derived from model 1, HR2 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.28Liao Y. Greenlund K.J. Croft J.B. Keenan N.L. Giles W.H. Factors explaining excess stroke prevalence in the US stroke belt.Stroke. 2009; 40: 3336-3341Crossref PubMed Scopus (111) Google Scholar, 29Cheng C.Y. Reich D. Haiman C.A. Tandon A. Patterson N. Selvin E. Akylbekova E.L. Brancati F.L. Coresh J. Boerwinkle E. Altshuler D. Taylor H.A. Henderson B.E. Wilson J.G. Kao W.H. African ancestry and its correlation to type 2 diabetes in African Americans: a genetic admixture analysis in three u.s. population cohorts.PLoS One. 2012; 7: e32840Crossref PubMed Scopus (65) Google Scholar 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."26SAS Institute Inc SAS/STAT User's Guide, Version 9.1. SAS Institute Inc., Cary, North Carolina2005Google Scholar, 27Szklo M. Nieto F.J. Epidemiology: Beyond the Basics. Jones & Bartlett, Sudbury, Massachusetts2007Google Scholar Two-sided p values ≤0.05 were considered as having statistical significance. Table 1 shows that the United States participants had significantly higher means of BMI, total cholesterol, TG and HbA1c 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.Table 1Baseline characteristics of participants aged ≥30 years in the Third National Health and Nutrition Examination Survey (1988 to 1994) and in the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in Aged (1990)VariableMenWomenUnited States (n = 5,896)Japan (n = 3,129)p Value∗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.United States (n = 6,665)Japan (n = 4,324)p Value∗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.Continuous variables Age (yrs)49.48 ± 0.3653.36 ± 0.24<0.00151.32 ± 0.5252.48 ± 0.210.03 BMI (kg/m2)27.00 ± 0.1122.96 ± 0.05<0.00126.98 ± 0.1722.86 ± 0.05<0.001 Systolic BP (mm Hg)126.83 ± 0.43138.01 ± 0.36<0.001123.86 ± 0.54133.72 ± 0.32<0.001 Diastolic BP (mm Hg)78.01 ± 0.2283.78 ± 0.21<0.00173.27 ± 0.2279.62 ± 0.18<0.001 Total cholesterol (mg/dl)208.83 ± 1.03198.58 ± 0.66<0.001212.64 ± 0.94206.82 ± 0.59<0.001 HDL cholesterol (mg/dl)45.32 ± 0.3850.37 ± 0.27<0.00155.34 ± 0.4256.73 ± 0.230.002 TG (mg/dl)†Nonfasting in Japanese data.165.73 ± 3.10147.62 ± 1.88<0.001139.33 ± 3.09121.12 ± 1.20<0.001 HbA1c (%)5.49 ± 0.025.37 ± 0.01<0.0015.45 ± 0.035.25 ± 0.01<0.001Categorical variables Smoking status<0.001<0.001Never53.77%20.29%71.63%88.32%Former8.76%24.32%4.77%2.52%Current37.47%55.39%23.60%9.16% Current alcohol use‡Defined by self-report, if a subject had consumed ≥1 drink of any type (beer, wine, or liquor) per month.62.00%65.10%<0.00139.16%7.54%<0.001 Hypertension§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.37.47%53.563%<0.00137.15%46.21%<0.001 HypercholesterolemiaDefined as self-report of physician diagnosis of hyperlipidemia or total cholesterol ≥240 mg/dl (6.2 mmol/L).35.31%17.034%<0.00136.92%22.94%<0.001 Diabetes mellitus¶Defined as self-report of physician diagnosis of diabetes mellitus or serum HbA1c ≥6.5% or use of medication to treat diabetes.9.14%8.69%0.359.57%5.20%<0.001 Coronary heart disease#Defined as self-report of physician diagnosis of each disease.6.13%3.10%<0.0013.27%2.61%0.10 Stroke#Defined as self-report of physician diagnosis of each disease.2.49%2.52%0.132.49%1.36%<0.001Data are expressed as mean ± SEM or percentages. To convert total and HDL cholesterol from milligrams per deciliter to millimoles per liter, divide by 38.61. To convert TG from milligrams per deciliter to millimoles per liter, divide by 89.∗ 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 HbA1c ≥6.5% or use of medication to treat diabetes.# Defined as self-report of physician diagnosis of each disease. Open table in a new tab Data are expressed as mean ± SEM or percentages. To convert total and HDL cholesterol from milligrams per deciliter to millimoles per liter, divide by 38.61. To convert TG from milligrams per deciliter to millimoles per liter, divide by 89. 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/m2 and BMI ≥25 kg/m2 for the United States and Japanese samples, respectively. Obesity, high BP, elevated TG, and elevated HbA1c significantly predicted CVD mortality in the United States population, and high BP and elevated HbA1c 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/m2 for the United States and BMI ≥25 kg/m2 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/m2 for the 2 populations. Similar associations were observed for participants without baseline CVD conditions.Table 2Multivariate-adjusted hazard ratios of individual metabolic syndrome factors and metabolic syndrome for cardiovascular mortality in the United States and JapanMS Relation to CVD MortalityUnited StatesJapanRate∗Age-adjusted rate using the world population as a standard across the 2 countries.HR (95% CI)p ValueRate∗Age-adjusted rate using the world population as a standard across the 2 countries.HR (95% CI)p ValueIn total participants 1aBMI ≥30 kg/m2 (U.S.), BMI ≥25 kg/m2 (Japan)†Obesity was defined per the American Heart Association definition (BMI ≥30 kg/m2) for the United States population and per the Japan Society for the Study of Obesity (BMI ≥25 kg/m2) for the Japanese population.25.3%1.27 (1.05–1.55)0.01723.7%0.80 (0.62–1.04)0.09 1bBMI ≥30 kg/m2 (both countries)†Obesity was defined per the American Heart Association definition (BMI ≥30 kg/m2) for the United States population and per the Japan Society for the Study of Obesity (BMI ≥25 kg/m2) for the Japanese population.25.3%1.27 (1.05–1.55)0.0172.4%0.89 (0.39–2.06)0.79 2High BP‡Defined as self-report of physician diagnosis of hypertension, systolic BP ≥130 mm Hg or diastolic BP ≥85 mmHg, or medication use.43.9%1.51 (1.18–1.93)<0.00160.5%2.62 (1.74–3.96)<0.001 3Low HDL cholesterol§Defined as HDL cholesterol <40 mg/dl (<1.0 mmol/L) for male participants and <50 mg/dl (<1.3 mmol/L) for female participants.38.0%1.18 (1.00–1.40)0.0629.1%1.06 (0.85–1.33)0.59 4Elevated triglyceridesDefined as nonfasting TG ≥200 mg/dl (≥2.3 mmol/L) in Japan and as fasting TG ≥150 mg/dl (≥1.7 mmol/L) in the United States.35.8%1.17 (1.02–1.35)0.02819.1%1.21 (0.95–1.54)0.13 5Elevated HbA1c¶25.7%1.45 (1.25–1.68)<0.00112.4%1.64 (1.31–2.07)<0.001MS (Japan, ≥3 of 1a to 5 components)#Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c).26.7%1.43 (1.24–1.64)<0.00119.3%1.35 (1.08–1.69)0.027MS (U.S., ≥3 of 1b to 5 components)#Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c).26.7%1.43 (1.24–1.64)<0.00112.6%1.53 (1.20–1.94)0.001In participants without baseline CVD histories 1aBMI ≥30 kg/m2 (U.S.), BMI ≥25 kg/m2 (Japan)†Obesity was defined per the American Heart Association definition (BMI ≥30 kg/m2) for the United States population and per the Japan Society for the Study of Obesity (BMI ≥25 kg/m2) for the Japanese population.25.0%1.37 (1.10–1.69)0.0123.6%0.83 (0.62–1.10)0.18 1bBMI ≥30 kg/m2 (both countries)†Obesity was defined per the American Heart Association definition (BMI ≥30 kg/m2) for the United States population and per the Japan Society for the Study of Obesity (BMI ≥25 kg/m2) for the Japanese population.25.0%1.37 (1.10–1.69)0.012.4%1.04 (0.45–2.39)0.94 2High BP‡Defined as self-report of physician diagnosis of hypertension, systolic BP ≥130 mm Hg or diastolic BP ≥85 mmHg, or medication use.42.5%1.66 (1.27–2.16)<0.00160.0%2.58 (1.68–3.97)<0.001 3Low HDL cholesterol§Defined as HDL cholesterol <40 mg/dl (<1.0 mmol/L) for male participants and <50 mg/dl (<1.3 mmol/L) for female participants.37.2%1.06 (0.86–1.31)0.5829.0%0.93 (0.72–1.20)0.57 4Elevated triglyceridesDefined as nonfasting TG ≥200 mg/dl (≥2.3 mmol/L) in Japan and as fasting TG ≥150 mg/dl (≥1.7 mmol/L) in the United States.34.8%1.09 (0.92–1.28)0.3018.8%1.16 (0.88–1.52)0.29 5Elevated HbA1c¶Defined as HbA1c ≥5.7% or self-report of physician diagnosis of diabetes. We did not use glucose level, because fasting blood samples were not available for most participants in the Japanese data.24.9%1.38 (1.10–1.73)0.0112.0%1.62 (1.25–2.09)<0.001MS (Japan, ≥3 of 1a to 5 components)#Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c).25.7%1.39 (1.17–1.66)<0.00118.9%1.30 (1.01–1.67)0.039MS (U.S., ≥3 of 1b to 5 components)#Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c).25.7%1.39 (1.17–1.66)<0.00112.2%1.48 (1.13–1.93)<0.01Baseline CVD history includes coronary heart disease and stroke. HRs were adjusted for age, gender, smoking status, alcohol consumption, and total cholesterol.∗ Age-adjusted rate using the world population as a standard across the 2 countries.† Obesity was defined per the American Heart Association definition (BMI ≥30 kg/m2) for the United States population and per the Japan Society for the Study of Obesity (BMI ≥25 kg/m2) for the Japanese population.‡ Defined as self-report of physician diagnosis of hypertension, systolic BP ≥130 mm Hg or diastolic BP ≥85 mmHg, or medication use.§ Defined as HDL cholesterol <40 mg/dl (<1.0 mmol/L) for male participants and <50 mg/dl (<1.3 mmol/L) for female participants.|| Defined as nonfasting TG ≥200 mg/dl (≥2.3 mmol/L) in Japan and as fasting TG ≥150 mg/dl (≥1.7 mmol/L) in the United States.¶ Defined as HbA1c ≥5.7% or self-report of physician diagnosis of diabetes. We did not use glucose level, because fasting blood samples were not available for most participants in the Japanese data.# Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c). Open table in a new tab Baseline CVD history includes coronary heart disease and stroke. HRs were adjusted for age, gender, smoking status, alcohol consumption, and total cholesterol. Table 3 shows that the HR of the United States versus Japan for CVD mortality was 2.01 (95% CI 1.84 to 2.21; model 1). After additionally adjusting for obesity (model 2), the HR was reduced to 1.90 (955 CI 1.71 to 2.11). However, the HR increased to 2.12 (95% CI 1.93 to 2.32) when adjusting for high BP (model 3). The HR was largely reduced (15.81%) when adjusting for elevated HbA1c (model 6). An overall 13.34% reduction was observed when adjusting for MS (model 7). The HR was further reduced to 44.17% when adjusting for MS plus baseline CVD conditions (model 8). Similar findings were observed in a subsample excluding those who had CVD conditions at baseline. No significant interaction effects of MS and country on CVD mortality were observed in the total study sample (HR 0.99, 95% CI 0.94 to 1.05, p = 0.84) and in the subsample (HR 0.98, 95% CI 0.92 to 1.06, p = 0.66).Table 3Hazard ratios and 95% confidence intervals for the likelihood of cardiovascular disease mortality between the United States and JapanModelCovariates in the ModelUnited States vs Japan% of Excess Mortality Accounted For∗Percentage of the excess CVD and all-cause mortality in the United States that was accounted for by adding the covariates from model 2 to model 8 (in addition to covariates adjusted in model 1).HR (95% CI)p ValueIn total participants M1†Model 1, the basic model, was adjusted for age, gender, smoking, alcohol consumption, and total cholesterol level.Basic model2.01 (1.84–2.21)<0.001Base model M2Adjusted for M1 + obesity (BMI ≥30 kg/m2)1.90 (1.71–2.11)<0.00111.26% M3Adjusted for M1 + high BP2.12 (1.93–2.32)<0.001−10.28% M4Adjusted for M1 + low HDL cholesterol2.00 (1.82–2.19)<0.0011.48% M5Adjusted for M1 + elevated TG1.96 (1.79–2.15)<0.0015.04% M6Adjusted for M1 + elevated HbA1c1.85 (1.67–2.06)<0.00115.81% M7Adjusted for M1 + MS‡Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c). (≥3 of 5 factors)1.88 (1.71–2.06)<0.00113.34% M8Adjusted for M7 + baseline CVD history1.57 (1.22–2.01)<0.00144.17%In participants without baseline CVD histories M1†Model 1, the basic model, was adjusted for age, gender, smoking, alcohol consumption, and total cholesterol level.Basic model1.81 (1.62–2.03)<0.001Base model M2Adjusted for M1 + obesity (BMI ≥30 kg/m2)1.69 (1.49–1.92)<0.00115.04% M3Adjusted for M1 + high BP1.92 (1.72–2.15)<0.001−13.69% M4Adjusted for M1 + low HDL cholesterol1.81 (1.62–2.03)<0.001−0.25% M5Adjusted for M1 + elevated TG1.79 (1.60–2.00)<0.0012.71% M6Adjusted for M1 + elevated HbA1c1.69 (1.48–1.92)<0.00115.17% M7Adjusted for M1 + MS‡Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c). (≥3 of 5 factors)1.70 (1.52–1.91)<0.00113.19%Percentage of change = (HR1 − HR2)/(HR1 − 1) × 100 (keeping model 1 as HR1).∗ Percentage of the excess CVD and all-cause mortality in the United States that was accounted for by adding the covariates from model 2 to model 8 (in addition to covariates adjusted in model 1).† Model 1, the basic model, was adjusted for age, gender, smoking, alcohol consumption, and total cholesterol level.‡ Defined as having ≥3 of the 5 factors (obesity, high BP, low HDL cholesterol, elevated TG, and elevated HbA1c). Open table in a new tab Percentage of change = (HR1 − HR2)/(HR1 − 1) × 100 (keeping model 1 as HR1). The present study, using nationally comparable databases, is the first to document and compare the differences in MS and the impact of MS on CVD mortality between the United States and Japan. The main findings suggest that the United States had a significantly higher prevalence of MS than Japan. An estimated 13% of the excess CVD mortality could be explained by the differences in MS and 44% by MS plus baseline CVD conditions in the United States compared with Japan. Of the 5 MS components, obesity significantly predicted CVD mortality in the United States but not in Japan. The reason for the nonsignificant association in Japan is still unknown. Two conditions may partly explain this difference. First, increased BMI as a measure of obesity may be less sensitive than waist circumference. In the present study, we did not use waist circumference as the measure of obesity, because waist circumference was not measured in the Japanese survey. Second, because increased BMI has a stronger association with coronary heart disease than with stroke, the nonsignificant association between obesity and CVD might be due to a significantly different distribution of the subtypes of CVD, in which coronary heart disease is dominant in the United States, while stroke occurs more frequently in Japan.10Ueshima H. Sekikawa A. Miura K. Turin T.C. Takashima N. Kita Y. Watanabe M. Kadota A. Okuda N. Kadowaki T. Nakamura Y. Okamura T. Cardiovascular disease and risk factors in Asia: a selected review.Circulation. 2008; 118: 2702-2709Crossref PubMed Scopus (552) Google Scholar It should be noted that when obesity is defined as BMI ≥30 kg/m2 for the Japanese sample, the HR of MS for CVD mortality was higher in Japan than in the U.S. (1.53 vs 1.43; Table 2). We conducted further sensitivity analyses by comparing the prevalence of MS components in those with MS and with BMIs ≥30 kg/m2 between the United States and Japanese samples. The results showed that the prevalence rates of high BP, decreased HDL cholesterol, and elevated TG were significantly higher in the Japanese compared with Americans (97.5% vs 82.0% for high BP, 82.5% vs 71.7% for decreased HDL cholesterol, and 80.8% vs 74.7% for elevated TG). This difference may partly contribute to a higher HR of MS for CVD mortality in Japan when obesity is defined as BMI ≥30 kg/m2. However, it does not mean that Japanese have a higher risk for CVD, because the Japanese have a much lower prevalence of obesity (BMI ≥30 kg/m2) than Americas (2.4% vs 25.3%, p <0.001). Certainly the magnitudes of individual MS components using different cut-off points on the association between MS and CVD risk in different populations need to be further studied. In the study, we also observed that the HR of high BP for CVD mortality in the Japanese participants was higher than in the American participants. These findings may suggest a different impact of risk factors on CVD mortality across different countries and racial and ethnic populations. The present study had several strengths. First, its findings are derived from nationally representative population samples. The measurements of exposures and outcomes were conducted using standardized approaches. Therefore, it offers a unique opportunity for the study results to be generalized. Second, the association between MS and CVD mortality was analyzed prospectively, which makes it possible to interpret a potentially temporal association. Third, the findings of the study, by addressing the impacts of individual components of MS on the risk for CVD mortality between countries, are informative for health policy decisions and health practice in controlling CVD mortality. There were also limitations that should be kept in mind. First, individual MS components that are continuous measures (i.e., BMI, BP, TG, HDL, and HbA1c) were dichotomized on the basis of the current definition of MS. This dichotomization approach would lead a reduction in statistical power and an underestimation of the strengths of associations between these factors and CVD mortality. Second, all risk factors had single measurements at baseline. Therefore, we are unable to test any time-varying effects of these variables on CVD mortality. Third, because BMI may have less sensitivity for the measure of obesity, new biomarkers should be included in further studies. Despite these limitations, 2 clear and important conclusions follow from our present study. First, obesity, high BP, elevated TG, and elevated HbA1c in the United States and high BP and elevated HbA1c in Japan were the most significant individual predictors for CVD mortality. Second, MS and MS plus baseline CVD history are among the important risk factors that may significantly contribute to the explanation of excess CVD mortality in the United States versus Japan. We thank the members of the NIPPON DATA80 and NIPPON DATA90 Research Group for their important contributions. A list of the members is provided in Nakamura et al.4Nakamura Y. Okamura T. Higashiyama A. Watanabe M. Kadota A. Ohkubo T. Miura K. Kasagi F. Kodama K. Okayama A. Ueshima H. NIPPON DATA80 Research GroupPrognostic values of clockwise and counterclockwise rotation for cardiovascular mortality in Japanese subjects: a 24-year follow-up of the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged 1980-2004 (NIPPON DATA80).Circulation. 2012; 125: 1226-1233Crossref PubMed Scopus (23) Google Scholar The authors have no conflicts of interest to disclose.