Population Attributable Fraction of Smoking and Metabolic Syndrome on Cardiovascular Disease Mortality in Japan: a 15-Year Follow Up of NIPPON DATA90

  • Naoyuki Takashima1Email author,

    Affiliated with

    • Katsuyuki Miura1,

      Affiliated with

      • Atsushi Hozawa1, 2,

        Affiliated with

        • Aya Kadota1,

          Affiliated with

          • Tomonori Okamura3,

            Affiliated with

            • Yasuyuki Nakamura4,

              Affiliated with

              • Takehito Hayakawa5,

                Affiliated with

                • Nagako Okuda1,

                  Affiliated with

                  • Akira Fujiyoshi1,

                    Affiliated with

                    • Shin-ya Nagasawa1,

                      Affiliated with

                      • Takashi Kadowaki1,

                        Affiliated with

                        • Yoshitaka Murakami1,

                          Affiliated with

                          • Yoshikuni Kita1,

                            Affiliated with

                            • Akira Okayama6,

                              Affiliated with

                              • Hirotsugu Ueshima1 and

                                Affiliated with

                                • for the NIPPON DATA 90 Research group1

                                  Affiliated with

                                  BMC Public Health201010:306

                                  DOI: 10.1186/1471-2458-10-306

                                  Received: 29 September 2009

                                  Accepted: 3 June 2010

                                  Published: 3 June 2010

                                  Abstract

                                  Background

                                  Smoking and metabolic syndrome are known to be related to cardiovascular diseases (CVD) risk. In Asian countries, prevalence of obesity has increased and smoking rate in men is still high. We investigated the attribution of the combination of smoking and metabolic syndrome (or obesity) to excess CVD deaths in Japan.

                                  Methods

                                  A cohort of nationwide representative Japanese samples, a total of 6650 men and women aged 30-70 at baseline without history of CVD was followed for 15 years. Multivariate-adjusted hazard ratio for CVD death according to the combination of smoking status and metabolic syndrome (or obesity) was calculated using Cox proportional hazard model. Population attributable fraction (PAF) of CVD deaths was calculated using the hazard ratios.

                                  Results

                                  During the follow-up period, 87 men and 61 women died due to CVD. The PAF component of CVD deaths in non-obese smokers was 36.8% in men and 11.3% in women, which were higher than those in obese smokers (9.1% in men and 5.2% in women). The PAF component of CVD deaths in smokers without metabolic syndrome was 40.9% in men and 11.9% in women, which were also higher than those in smokers with metabolic syndrome (7.1% in men and 3.9% in women).

                                  Conclusion

                                  Our results indicated that a large proportion of excess CVD deaths was observed in smokers without metabolic syndrome or obesity, especially in men. These findings suggest that intervention targeting on smokers, irrespective of the presence of metabolic syndrome, is still important for the prevention of CVD in Asian countries.

                                  Background

                                  Obesity and clustering of its related factors, now called as metabolic syndrome, have been widely reported as important risk factors for cardiovascular diseases (CVD) [16], and, also in Asian countries including Japan, obesity has emerged as a new health problem [5]. The National Health and Nutrition Survey in Japan in 2005 showed that 22.4% of adult men and 10.8% of adult women were diagnosed as having metabolic syndrome [7]. Therefore, it is expected that metabolic syndrome or obesity would contribute to a large part of excess CVD events in Japan.

                                  On the other hand, cigarette smoking is an established risk factor for CVD [812] and one of the biggest health problems in Asian countries including Japan [9, 12, 13]. In Asian countries, smoking rate in men is still high at 40 to 50% [14]. In Japan, smoking rate in 2005 was also high at 39.3% in men [15]. Therefore, smoking has largely contributed to increase CVD events in Asia, and it was reported that up to 30% of cardiovascular deaths was attributed by smoking in Asia Pacific region [16].

                                  However, there have been few reports on the attribution of the combination of smoking status and metabolic syndrome (or obesity) to CVD deaths in Asian countries. Several previous studies also reported that CVD risk was high in both smokers and non-smokers with clustering of metabolic risk factors [17]. Therefore, it is important to elucidate the attribution of obesity, metabolic syndrome, and smoking to CVD mortality in Asia, where obesity is still less common compared with Western countries.

                                  The purpose of this report is to examine excess CVD deaths and population attributable fractions on CVD deaths by the combination of smoking and metabolic syndrome (or obesity) in a 15-year cohort study of randomly selected representative Japanese samples from the National Survey on Circulatory Disorders of Japan.

                                  Methods

                                  Participants and follow-up

                                  Cohort studies of the National Survey on Circulatory Disorders of Japan comprise the National Integrated Project for Prospective Observation of Non-communicable Disease and Its Trends in the Aged (NIPPON DATA). Baseline surveys for the cohort of this report were performed in 1990 (NIPPON DATA90) [18, 19]. We analyzed the 15-year follow-up data of NIPPON DATA90 in this report.

                                  A total of 8383 men and women aged ≥ 30 years from 300 randomly selected districts were participated in the survey in 1990. The baseline surveys were carried out at local public health centers. The participation rate in the baseline survey was 76.5%. The present study was for 7329 participants aged 30 to 70 years at baseline. From these participants, we excluded 379 participants who had a history of coronary heart disease or stroke (n = 249) or who had missing information in the baseline survey (n = 130). Thus, 6650 participants (2752 men and 3898 women) were eligible for the analyses.

                                  NIPPON DATA90 has completed follow-up surveys until 2005. We used the National Vital Statistics data to indentify the cause of death. The underlying causes of death in the National Vital Statistics were coded according to the 9th International Classification of Disease (ICD-9) until the end of 1994 and according to the 10th International Classification of Disease (ICD-10) from 1995. Deaths from any CVD were identified by ICD-9 codes (393-459) and ICD-10 codes (I00-I99). The details of the classification are described elsewhere [18, 19]. The Institutional Review Board of Shiga University of Medical Science (NO.12-18, 2000) approved the study.

                                  Biochemical and physical examinations

                                  Public health nurses obtained data including smoking habit, as well as current health status and medical history. Public health nurses asked all participants about current smoking status (current smoking, past smoking and never-smoking), the number of cigarettes per day and the duration of smoking. Smoking habit was categorized into non-smoker, past smoker and current smoker. Drinking habit was categorized into non-drinker, past drinker, occasional drinker and daily drinker. Body mass index was calculated as weight divided by height squared (kg/m2).

                                  Non-fasting blood samples were obtained at the baseline survey. The serum was separated and centrifuged soon after blood coagulation. Plasma samples were collected in siliconized tubes containing sodium fluoride and shipped to one laboratory (SRL, Tokyo, Japan) for blood measurements. Plasma glucose was measured enzymatically. Serum triglycerides and total cholesterol were also measured enzymatically, and high density lipoprotein (HDL) cholesterol was measured after heparin-calcium precipitation [20].

                                  We defined metabolic risk factors using the Japanese criteria of the metabolic syndrome [21, 22] as follow: obesity as body mass index ≥ 25 kg/m2; high blood pressure: BP ≥ 130/85 mm Hg or on treatment for hypertension; high blood glucose: serum glucose ≥ 110 mg/dl or on treatment for diabetes; dyslipidemia: serum triglyceride ≥ 150 mg/dl, HDL cholesterol < 40 mg/dl or on treatment for dyslipidemia. We defined the metabolic syndrome as having obesity (defined as body mass index ≥ 25 kg/m2) and two or more other metabolic risk factors; the definition was modified from the Japanese criteria [22] where the presence of obesity is essential. We defined metabolic risk factors clustering as having two or more metabolic risk factors.

                                  Statistical analysis

                                  Multivariate-adjusted hazard ratios (HR) of all CVD deaths for each component of metabolic risk factors including BMI, systolic BP (SBP), triglyceride, glucose, HDL cholesterol were calculated using Cox proportional hazards models. Multivariate-adjusted HR for all CVD deaths according to metabolic risk factors and smoking categories were calculated using Cox proportional hazards models adjusted for age and drinking. Non-smokers without metabolic syndrome or obesity were set as the reference group.

                                  Population attributable fractions (PAF) for CVD deaths due to the combination of smoking and metabolic syndrome (or obesity) were calculated based on hazard ratios assessed by proportional hazards models [23, 24]. PAF was estimated as pd × (HR-1)/HR where pd is the proportion of death cases arising from the each categories. All analyses were performed by SAS 9.1 (Statistical Analysis System, Cary, NC).

                                  Results

                                  Baseline characteristics are shown in Table 1. Mean age at baseline was 49.9 years in men and 49.0 years in women. Mean body mass index was 23.1 kg/m2 in men and 22.9 kg/m2 in women. Smoking rate was 58.0% in men and 9.6% in women. The prevalence of hypertension and obesity were 66.9% and 25.1% in men and 54.4% and 23.4% in women.
                                  Table 1

                                  Baseline characteristics of study population. NIPPON DATA90, men and women aged 30 to 70 years in 1990.

                                   

                                  Men

                                  Women

                                  Number (N)

                                  2752

                                  3898

                                  Age (year)

                                  49.9

                                  ±11.2

                                  49.0

                                  ±11.3

                                  BMI (kg/m2)

                                  23.1

                                  ±3.0

                                  22.9

                                  ±3.3

                                  SBP (mmHg)

                                  136.2

                                  ±19.5

                                  131.3

                                  ±19.9

                                  DBP (mmHg)

                                  83.8

                                  ±11.7

                                  79.4

                                  ±11.8

                                  Total cholesterol (mg/dl)

                                  199.6

                                  ±36.6

                                  205.5

                                  ±38.0

                                  HDL cholesterol (mg/dl)

                                  50.4

                                  ±15.0

                                  57.5

                                  ±14.9

                                  Triglyceride (mg/dl)

                                  151.8

                                  ±108.8

                                  119.1

                                  ±79.8

                                  Blood glucose (mg/dl)

                                  102.0

                                  ±33.4

                                  101.1

                                  ±28.9

                                  Drinking

                                      

                                     Non drinker

                                  921

                                  33.5%

                                  3572

                                  91.6%

                                     Ex-drinker

                                  141

                                  5.1%

                                  39

                                  1.0%

                                     Current drinker

                                  1690

                                  61.4%

                                  287

                                  7.4%

                                  Smoking

                                      

                                     Never smoker

                                  556

                                  20.2%

                                  3431

                                  88.0%

                                     Ex-smoker

                                  601

                                  21.8%

                                  94

                                  2.4%

                                     Current smoker

                                  1595

                                  58.0%

                                  373

                                  9.6%

                                  Obesity

                                  689

                                  25.1%

                                  912

                                  23.4%

                                  High blood pressure

                                  1840

                                  66.9%

                                  2119

                                  54.4%

                                  High blood glucose

                                  578

                                  21.0%

                                  829

                                  21.3%

                                  Dyslipidemia

                                  1280

                                  46.5%

                                  1094

                                  28.1%

                                  Values are number, %, or mean ± SD.

                                  High blood pressure, BP ≥ 130/85 mmHg or on treatment of hypertension; high blood glucose, blood glucose≥ 110 mg/dl or on treatment of diabetes; dyslipidemia as triglyceride≥ 150 mg/dl or high density lipoprotein < 40 mg/dl or on treatment of dyslipidemia.

                                  BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL, high density lipoprotein.

                                  During 15 years of follow-up, 87 men and 61 women died due to CVD (37 men and 22 women died due to stroke and 30 men and 8 women died due to coronary heart disease). Table 2 shows HRs of CVD death for each component of metabolic risk factors including all factors in a model, simultaneously. It showed that current smoking, past-smoking, SBP and glucose were significant risk factors of CVD mortality. Table 3 shows adjusted HRs and PAFs for CVD deaths according to the combination of obesity and smoking status. Irrespective of obesity, smoking and CVD mortality in both men and women were positively related. HRs (95% confidence interval [CI]) for non-obese smokers was 3.13 (1.33 to 7.36) in men and 4.32 (1.99 to 9.37) in women compared with non-obese, non-smokers. Estimated numbers of excess CVD deaths (and PAF component) in the non-obese smokers and obese smokers were 32.0 (36.8%), and 7.9 (9.1%) in men and 6.9 (11.3%) and 3.2 (5.2%) in women. The sum of the estimated number of excess CVD deaths (PAF) due to smoking and/or obesity was 49.3 (56.9%) in men and 15.3 (25.1%) in women.
                                  Table 2

                                  Adjusted HR for 1 standard deviation increasing in the continuous variables and sex, smoking and drinking habits for mortality from cardiovascular diseases.

                                   

                                  Adjusted hazard ration (95%CI)

                                  Current -smoker

                                  3.45

                                  (2.12

                                  -5.60)

                                  Past-smoker

                                  2.04

                                  (1.11

                                  -3.75)

                                  Body mass index (1 SD increasing)

                                  0.99

                                  (0.83

                                  -1.18)

                                  Systolic blood pressure (1 SD increasing)

                                  1.32

                                  (1.13

                                  -1.54)

                                  Triglyceride (1 SD increasing)*

                                  0.85

                                  (0.69

                                  -1.04)

                                  High density lipoprotein cholesterol (1 SD increasing)

                                  0.93

                                  (0.76

                                  -1.11)

                                  Glucose (1 SD increasing)

                                  1.10

                                  (1.00

                                  -1.24)

                                  Female

                                  1.00

                                  (0.61

                                  -1.64)

                                  This Cox model also includes age, and drinking habit.

                                  * The variable was tested after log-transferred.

                                  Table 3

                                  Hazard ratio and population attributable fraction for cardiovascular disease deaths according to the combination of smoking status and obesity*: NIPPON DATA90

                                    

                                  Number of participants

                                  Person-years of follow-up

                                  CVD deaths (n)

                                  CVD mortality rate (per 1,000 person-years)

                                  Adjusted hazard ratio (95% CI)†

                                  Estimated excess CVD deaths (n)

                                  PAF component for CVD deaths (%)

                                  Men

                                           

                                  Non smoker

                                  Non-obese

                                  420

                                  5938

                                  6

                                  1.01

                                  1.00

                                      
                                   

                                  Obese

                                  136

                                  1988

                                  1

                                  0.50

                                  0.67

                                  (0.08

                                  -5.53)

                                  --

                                  --

                                  Past smoker

                                  Non-obese

                                  431

                                  6116

                                  16

                                  2.62

                                  1.93

                                  (0.75

                                  -4.96)

                                  7.7

                                  8.8

                                   

                                  Obese

                                  170

                                  2414

                                  5

                                  2.07

                                  1.52

                                  (0.46

                                  -4.99)

                                  1.7

                                  2.0

                                  Smoker

                                  Non-obese

                                  1212

                                  16780

                                  47

                                  2.80

                                  3.13

                                  (1.33

                                  -7.36)

                                  32.0

                                  36.8

                                   

                                  Obese

                                  383

                                  5277

                                  12

                                  2.27

                                  2.92

                                  (1.09

                                  -7.82)

                                  7.9

                                  9.1

                                  Women

                                           

                                  Non smoker

                                  Non-obese

                                  2,638

                                  37960

                                  29

                                  0.76

                                  1.00

                                      
                                   

                                  Obese

                                  793

                                  11256

                                  17

                                  1.51

                                  1.34

                                  (0.74

                                  -2.45)

                                  4.3

                                  7.1

                                  Past smoker

                                  Non-obese

                                  66

                                  843

                                  1

                                  1.19

                                  1.43

                                  (0.19

                                  -10.61)

                                  0.3

                                  0.5

                                   

                                  Obese

                                  28

                                  383

                                  1

                                  2.61

                                  2.46

                                  (0.33

                                  -18.09)

                                  0.6

                                  1.0

                                  Smoker

                                  Non-obese

                                  282

                                  3889

                                  9

                                  2.31

                                  4.32

                                  (1.99

                                  -9.37)

                                  6.9

                                  11.3

                                   

                                  Obese

                                  91

                                  1224

                                  4

                                  3.27

                                  4.74

                                  (1.66

                                  -13.58)

                                  3.2

                                  5.2

                                  *Obesity was defined as body mass index ≥ 25 kg/m2.

                                  †Hazard ratios were adjusted for age and drinking.

                                  CVD, cardiovascular diseases; PAF, population attributable fraction; CI, confidence interval.

                                  Table 4 shows adjusted HRs and PAF components due to combination of smoking status and metabolic syndrome. Compared to non-smokers without metabolic syndrome, adjusted HRs (95% CI) for CVD deaths was higher in smokers with and without metabolic syndrome (HR 3.19 [1.13 to 9.03] and 3.47 [1.48 to 8.12] in men; 4.94 [1.52 to 16.09] and 3.63 [1.75 to 7.50] in women, respectively). PAFs for CVD mortality in smokers with and without metabolic syndrome were 7.1% and 40.9% in men and 3.9% and 11.9% in women, respectively. The sum of PAF components due to smoking and/or metabolic syndrome was 60.4% in men and 17.0% in women.
                                  Table 4

                                  Hazard ratio and population attributable fraction for cardiovascular disease deaths according to the combination of smoking status and metabolic syndrome: NIPPON DATA90.

                                   

                                  Metabolic syndrome*

                                  Number of participants

                                  Person-years of follow-up

                                  CVD deaths (n)

                                  CVD mortality rate (per 1,000 person-years)

                                  Adjusted hazard ratio( 95% CI) †

                                  Estimated excess CVD deaths (n)

                                  PAF component for CVD deaths (%)

                                  Men

                                            

                                  Non smoker

                                  -

                                  480

                                  6817

                                  6

                                  0.88

                                  1.00

                                      
                                   

                                  +

                                  76

                                  1109

                                  1

                                  0.90

                                  1.32

                                  (0.16

                                  -10.97)

                                  0.2

                                  0.3

                                  Past smoker

                                  -

                                  494

                                  7036

                                  18

                                  2.56

                                  2.13

                                  (0.84

                                  - 5.39)

                                  9.5

                                  11.0

                                   

                                  +

                                  107

                                  1494

                                  3

                                  2.01

                                  1.49

                                  (0.37

                                  - 6.01)

                                  1.0

                                  1.1

                                  Smoker

                                  -

                                  1343

                                  18620

                                  50

                                  2.69

                                  3.47

                                  (1.48

                                  - 8.12)

                                  35.6

                                  40.9

                                   

                                  +

                                  252

                                  3437

                                  9

                                  2.62

                                  3.19

                                  (1.13

                                  - 9.03)

                                  6.2

                                  7.1

                                  Women

                                            

                                  Non smoker

                                  -

                                  3,034

                                  43585

                                  38

                                  0.87

                                  1.00

                                      
                                   

                                  +

                                  397

                                  5631

                                  8

                                  1.42

                                  0.83

                                  (0.38

                                  - 1.78)

                                  --

                                  --

                                  Past smoker

                                  -

                                  81

                                  1042

                                  1

                                  0.96

                                  1.06

                                  (0.15

                                  - 7.81)

                                  0.05

                                  0.1

                                   

                                  +

                                  13

                                  184

                                  1

                                  5.45

                                  2.98

                                  (0.41

                                  -21.79)

                                  0.6

                                  1.1

                                  Smoker

                                  -

                                  336

                                  4627

                                  10

                                  2.16

                                  3.63

                                  (1.75

                                  - 7.50)

                                  7.2

                                  11.9

                                   

                                  +

                                  37

                                  486

                                  3

                                  6.17

                                  4.94

                                  (1.52

                                  -16.09)

                                  2.4

                                  3.9

                                  *Metabolic syndrome were defined as follows: obesity (body mass index ≥ 25 kg/m2) plus any two of the following three factors: high blood pressure as blood pressure ≥ 130/85 mmHg or on treatment of hypertension, high blood glucose as blood glucose ≥ 110 mg/dl or on treatment of diabetes, dyslipidemia as triglyceride ≥ 150 mg/dl or high density lipoprotein cholesterol <40 mg/dl or on treatment of dyslipidemia.

                                  †Hazard ratios were adjusted for age and drinking.

                                  CVD, cardiovascular diseases; PAF, population attributable fraction; CI, confidence interval.

                                  Table 5 shows adjusted HRs and PAF components due to the combination of smoking status and clustering of metabolic risk factors. Compared to non-smokers without metabolic risk factor clustering, adjusted HRs (95% CI) for CVD death in smokers with and without metabolic risk factor clustering were 5.85 (1.40 to 24.38) and 4.17 (0.98 to 17.71) for men, and 5.86 (2.41 to 14.23) and 4.56 (1.62 to 12.87) for women, respectively. PAF components for CVD mortality in non-smokers with metabolic risk factors clustering, smokers without metabolic risk factors clustering and smokers with metabolic risk factors clustering were 2.8%, 20.1% and 34.3% for men, and 18.7%, 6.4% and 10.9% for women, respectively.
                                  Table 5

                                  Hazard ratio and population attributable fraction for cardiovascular disease deaths according to the combination of smoking status and clustering of metabolic risk factors: NIPPON DATA90.

                                   

                                  Clustering of metabolic risk factors*

                                  Number of participants

                                  Person-years of follow-up

                                  CVD deaths (n)

                                  CVD mortality rate (per 1,000 person-years)

                                  Adjusted hazard ratio (95% CI) †

                                  Estimated excess CVD deaths (n)

                                  PAF component for CVD deaths (%)

                                  Men

                                            

                                  Non smoker

                                  0 or 1

                                  281

                                  4002

                                  2

                                  0.50

                                  1.00

                                      
                                   

                                  2 ≤

                                  275

                                  3924

                                  5

                                  1.27

                                  1.94

                                  (0.38

                                  -10.00)

                                  2.4

                                  2.8

                                  Past smoker

                                  0 or 1

                                  282

                                  4084

                                  7

                                  1.71

                                  2.41

                                  (0.50

                                  -11.65)

                                  4.1

                                  4.7

                                   

                                  2 ≤

                                  319

                                  4446

                                  14

                                  3.15

                                  3.37

                                  (0.76

                                  -14.96)

                                  9.8

                                  11.3

                                  Smoker

                                  0 or 1

                                  819

                                  11465

                                  23

                                  2.01

                                  4.17

                                  (0.98

                                  -17.71)

                                  17.5

                                  20.1

                                   

                                  2 ≤

                                  776

                                  10592

                                  36

                                  3.40

                                  5.85

                                  (1.40

                                  -24.38)

                                  29.8

                                  34.3

                                  Women

                                            

                                  Non smoker

                                  0 or 1

                                  2,117

                                  30554

                                  14

                                  0.46

                                  1.00

                                      
                                   

                                  2 ≤

                                  1314

                                  18661

                                  32

                                  1.71

                                  1.55

                                  (0.82

                                  -2.95)

                                  11.4

                                  18.7

                                  Past smoker

                                  0 or 1

                                  54

                                  698

                                  0

                                  --

                                    

                                  --

                                  --

                                  --

                                   

                                  2 ≤

                                  40

                                  527

                                  2

                                  3.79

                                  3.08

                                  (0.69

                                  -13.81)

                                  1.4

                                  2.2

                                  Smoker

                                  0 or 1

                                  222

                                  3098

                                  5

                                  1.61

                                  4.56

                                  (1.62

                                  -12.87)

                                  3.9

                                  6.4

                                   

                                  2 ≤

                                  151

                                  2016

                                  8

                                  3.97

                                  5.86

                                  (2.41

                                  -14.23)

                                  6.6

                                  10.9

                                  *Metabolic risk factors were any of the following four factors: obesity (body mass index ≥ 25 kg/m2), high blood pressure as blood pressure ≥ 130/85 mmHg or on treatment of hypertension, high blood glucose as blood glucose ≥ 110 mg/dl or on treatment of diabetes, dyslipidemia as triglyceride ≥ 150 mg/dl or high density lipoprotein cholesterol < 40 mg/dl or on treatment of dyslipidemia.

                                  †Hazard ratios were adjusted for age and drinking.

                                  CVD, cardiovascular diseases; PAF, population attributable fraction; CI, confidence interval.

                                  Discussion

                                  The present report of a representative Japanese cohort showed that the majority of excess CVD deaths were observed in smokers without metabolic syndrome. The PAF component of CVD deaths in smokers without metabolic syndrome were 5 times higher than those in participants with metabolic syndrome in men (40.9% vs. 8.5%). The HR of CVD deaths in smokers without metabolic syndrome were also higher than non-smokers without metabolic syndrome, and it was similar to the HR in smokers with metabolic syndrome (3.47 vs. 3.19).

                                  In Asian countries including Japan, there has been a rise in metabolic syndrome [7, 25]. In these areas, prevalence of smoking has been higher than that in Western countries and smoking rates has been still increasing in younger women [14]. Previous studies have reported that obesity and smoking are risk factors for CVD [5, 6, 10, 11]. The association of clustering of metabolic risk factors, including hyperglycemia, dyslipidemia, and hypertension, with CVD risk has also been widely reported [1, 4, 17, 18]. Furthermore, a previous study from Japan reported that the effect of risk factor accumulation on CVD incidence was more evident among smokers than non smokers [17]. However, these previous reports did not show the attribution of the combination of smoking and metabolic syndrome (or obesity) to CVD events. To our knowledge, this is the first report showing that the majority of excess CVD deaths occurred in smokers without metabolic syndrome in a Asian population. A strength of our report is that the study was conducted in a 15-year cohort of nationwide representative Japanese samples.

                                  In Japan, new health checkups and healthcare advice focusing on the metabolic syndrome to prevent CVD began in April 2008 through health insurance providers [7]. Our results support the necessity of intervention for people with metabolic syndrome because these people appear to be at higher CVD risk; however, PAF component in men and in women with metabolic syndrome were only 8.5% and 5.0%, respectively. On the other hand, the present study indicated that PAFs among smokers without metabolic syndrome were 40.9% in men and 11.9% in women; who are not the target population of the new health educational program in Japan. Moreover, not only PAF but also HR of smokers without metabolic syndrome was substantially higher. Thus the program might overlook a large population at an increased risk of CVD. Activities of smoking cessation for non-obese people would be still important for the prevention of CVD in Japan.

                                  In the present study, we examined the association between each component of metabolic risk factors and CVD death. We conformed that current and past smoking, SBP and glucose were significant risk factors of CVD mortality in our study participants. Several previous reports revealed that clustering of metabolic risk factors increases CVD risk, irrespective of the presence of obesity [17, 18]. When obesity was dealt with one of metabolic risk factors (not an essential factor) in the present study (Table 5), the PAF in smokers with metabolic risk factor clustering got larger in men (34.3%). However, even for smokers without metabolic risk factors clustering in the present study, PAF was 20.1% in men. This finding indicated that even if obesity is not essential for the diagnostic criteria of metabolic syndrome like the National Cholesterol Education Program (NCEP) [26], an intervention for smokers without clustering of metabolic risk factors would be also important for the prevention of CVD.

                                  This study has several limitations. First, we used non-fasting blood samples and thus we might have misclassified several individuals with diabetes and dyslipidemia. Second, we used body mass index ≥ 25 kg/m2 to define obesity and thus we might have misclassified individuals with abdominal obesity with higher waist circumference. However, this limitation would be ignorable because the correlation between BMI and waist circumstance is usually high enough. The cut-off point of body mass index for Japanese [21] is different from that for Asia-Pacific Region in the WHO definition (body mass index ≥ 23 kg/m2) [27], which may underestimate the PAF in Asian people. Third, we did not adjust for socioeconomic status in this study. However, all Japanese are covered by the national health insurance program and socioeconomic status would not limit access to treatment in Japan. Fourth, in this study, we used information on smoking habit from self-reported smoking history; this may cause recall and information biases. Fifth, the numbers of participants or CVD events were not enough to analyze according to the number of cigarettes per day; therefore, we did not consider the intensity of smoking in this paper.

                                  Conclusions

                                  In conclusion, this long-term cohort study of representative Japanese samples indicated that CVD mortality in smokers without metabolic syndrome or without obesity was substantially high and a large proportion of excess deaths were observed in these groups. These findings suggest that intervention targeting on smokers, irrespective of the presence of metabolic syndrome (or obesity), is still important for the prevention of CVD death in relatively lean Japanese population with high smoking rate. This could apply to other Asian populations with high smoking rate but with lower prevalence of obesity compared with Western populations.

                                  Declarations

                                  Acknowledgements

                                  The authors thank all public health centers that cooperated with our study.

                                  List of the NIPPON DATA90 Research Group

                                  Chairperson: Hirotsugu Ueshima (Department of Health Science, Shiga University of Medical Science, Otsu, Shiga).

                                  Research members: Akira Okayama (The First Institute for Health Promotion and Health Care, Japan Anti-Tuberculosis Association, Tokyo), Kazunori Kodama and Fumiyoshi Kasagi (Radiation Effects Research Foundation, Hiroshima), Shigeyuki Saitoh (Department of 2nd Internal Medicine, Sapporo Medical University, Sapporo, Hokkaido), Kiyomi Sakata (Department of Hygiene and Preventive Medicine, Iwate Medical University, Morioka, Iwate), Yoshikazu Nakamura (Department of Public Health, Jichi Medical University, Shimotsuke, Tochigi), Yoshikuni Kita (Department of Health Science, Shiga University of Medical Science, Otsu, Shiga), Tomonori Okamura (Department of Preventive Cardiology, National Cardiovascular Center, Suita, Osaka), Koji Tamakoshi (Department of Public Health and Health Information Dynamics, Nagoya University Graduate School of Medicine, Nagoya, Aichi), Yasuyuki Nakamura (Cardiovascular Epidemiology, Kyoto Women's University, Kyoto), Yutaka Kiyohara (Department of Environmental Medicine, Kyushu University, Fukuoka), Yasuhiro Matsumura (Faculty of Healthcare, Kiryu University, Midori City, Gunma), Katsushi Yoshita (Project for the Naitonal Health and Nutrition Survey, National Institute of Health and Nutrition, Tokyo), Hideaki Nakagawa (Department of Epidemiology and Public Health, Kanazawa Medical University, Ishikawa), Takehito Hayakawa (Department of Hygiene and Preventive Medicine, Fukushima Medical University, Fukushima), Katsuyuki Miura (Department of Health Science, Shiga University of Medical Science, Otsu, Shiga), Toshiyuki Ojima (Department of Community Health and Preventive Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka), Nagako Okuda (Department of Health Science, Shiga University of Medical Science, Otsu, Shiga), Atsushi Hozawa (Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University School of Medicine, Sendai, Miyagi).

                                  Role of Sponsor: The sponsors did not participate in the design or conduct of the study; the collection; management, analysis, and interpretation of the study; or the preparation, review, or approval of the manuscript.

                                  Funding: This study was supported by the grant-in-aid of the Ministry of Health and Welfare under the auspices of Japanese Association for Cerebro-cardiovascular Disease Control, the Research Grant for Cardiovascular Diseases (7A-2) from the Ministry of Health, Labour and Welfare and a Health and Labour Sciences Research Grant, Japan (Comprehensive Research on Aging and Health: H11-chouju-046, H14-chouju-003, H17-chouju-012 and H19-chouju-014).

                                  Authors’ Affiliations

                                  (1)
                                  Department of Health Science, Shiga University of Medical Science
                                  (2)
                                  Department of Public Health, Yamagata University School of Medicine
                                  (3)
                                  Department of Preventive Cardiology, National Cardiovascular Center
                                  (4)
                                  The Cardiovascular Epidemiology, Kyoto Women's University
                                  (5)
                                  Department of Hygiene and Preventive Medicine, Fukushima Medical University
                                  (6)
                                  The First Institute for Health Promotion and Health Care, Japanese Anti-Tuberculosis Association

                                  References

                                  1. Criqui MH, Barrett-Connor E, Holdbrook MJ, Austin M, Turner JD: Clustering of cardiovascular disease risk factors. Prev Med 1980, 9:525–33.PubMedView Article
                                  2. Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988, 37:1595–607.PubMedView Article
                                  3. Kaplan NM: The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989, 149:1514–20.PubMedView Article
                                  4. DeFronzo RA, Ferrannini E: Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991, 14:173–94.PubMedView Article
                                  5. World Health Organization: Obesity: preventing and managing the global epidemic. Report of a WHO consultation. Geneva, Switzerland: World Health Organization; 2004.
                                  6. Melanson KJ, McInnis KJ, Rippe JM, Blackburn G, Wilson PF: Obesity and cardiovascular disease risk: research update. Cardiol Rev 2001, 9:202–7.PubMedView Article
                                  7. Annual Report on Health Labour Welfare Tokyo Japan Ministry of Health Labour and Welfare; 2007.
                                  8. Lakier JB: Smoking and cardiovascular disease. Am J Med 1992, 93:8S-12S.PubMedView Article
                                  9. Ueshima H, Choudhury SR, Okayama A, Hayakawa T, Kita Y, Kadowaki T, Okamura T, Minowa M, Iimura O: Cigarette smoking as a risk factor for stroke death in Japan: NIPPON DATA80. Stroke 2004, 35:1836–41.PubMedView Article
                                  10. Higa M, Davanipour Z: Smoking and stroke. Neuroepidemiology 1991, 10:211–22.PubMedView Article
                                  11. Seltzer CC: Framingham study data and "established wisdom" about cigarette smoking and coronary heart disease. J Clin Epidemiol 1989, 42:743–50.PubMedView Article
                                  12. Murakami Y, Ueshima H, Okamura T, Kadowaki T, Hozawa A, Kita Y, Hayakawa T, Okayama A: Life expectancy among Japanese of different smoking status in Japan: NIPPON DATA80. J Epidemiol 2007, 17:31–7.PubMedView Article
                                  13. Ueshima H, Sekikawa A, Miura K, Turin TC, Takashima N, Kita Y, Watanabe M, Kadota A, Okuda N, Kadowaki T, Nakamura Y, Okamura T: Cardiovascular Disease and Risk Factors in Asian: A Selected Review. Circulation 2008, 118:2702–2709.PubMedView Article
                                  14. Brundtland GH: The Tobacco Atlas. Geneva Switzerland the World Health Organization; 2002.
                                  15. Health and Welfare Statistics Association: Journal of Health and Welfare Statistics. Tokyo Japan Health and Welfare Statistics Association. 2007.
                                  16. Martiniuk AL, Lee CM, Lam TH, Huxley R, Suh I, Jamrozik K, Gu DF, Woodward M, Asia Pacific Cohort Studies Collaboration: The fraction of ischaemic heart disease and stroke attributable to smoking in the WHO Western Pacific and South-East Asian regions. Tob Control 2006, 15:181–8.PubMedView Article
                                  17. Iso H, Sato S, Kitamura A, Imano H, Kiyama M, Yamagishi K, Cui R, Tanigawa T, Shimamoto T: Metabolic syndrome and the risk of ischemic heart disease and stroke among Japanese men and women. Stroke 2007, 38:1744–51.PubMedView Article
                                  18. Kadota A, Hozawa A, Okamura T, Kadowaki T, Nakmaura K, Murakami Y, Hayakawa T, Kita Y, Okayama A, Nakamura Y, Kashiwagi A, Ueshima H: Relationship between metabolic risk factor clustering and cardiovascular mortality stratified by high blood glucose and obesity: NIPPON DATA90, 1990–2000. Diabetes Care 2007, 30:1533–8.PubMedView Article
                                  19. Okamura T, Hayakawa T, Kadowaki T, Kita Y, Okayama A, Ueshima H, NIPPON DATA90 Research Group: The inverse relationship between serum high-density lipoprotein cholesterol level and all-cause mortality in a 9.6-year follow-up study in the Japanese general population. Atherosclerosis 2006, 184:143–50.PubMedView Article
                                  20. Nakamura M, Sato S, Shimamoto T: Improvement in Japanese clinical laboratory measurements of total cholesterol and HDL-cholesterol by the US Cholesterol Reference Method Laboratory Network. J Atheroscler Thromb 2003, 10:145–153.PubMed
                                  21. Examination Committee of Criteria for 'Obesity Disease' in Japan; Japan Society for the Study of Obesity: New criteria for 'obesity disease' in Japan. Circ J 2002, 66:987–92.View Article
                                  22. Committee to Evaluate Diagnostic Standards for Metabolic Syndrome: Definition and the diagnostic standard for metabolic syndrome--Committee to Evaluate Diagnostic Standards for Metabolic Syndrome. Nippon Naika Gakkai Zasshi 2005, 94:794–809. (in Japanese)
                                  23. Rockhill B, Newman B, Weinberg C: Use and misuse of population attributable fractions. Am J Public Health 1998, 88:15–9.PubMedView Article
                                  24. Hozawa A, Okamura T, Murakami Y, Kadowaki T, Nakamura K, Hayakawa T, Kita Y, Nakamura Y, Abbott RD, Okayama A, Ueshima H: Joint impact of smoking and hypertension on cardiovascular disease and all-cause mortality in Japan: NIPPON DATA80, a 19-year follow-up. Hypertens Res 2007, 30:1169–75.PubMedView Article
                                  25. World Health Organization: World Health Statistics 2007. Geneva, Switzerland: World Health Organization; 2007.
                                  26. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP): Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001, 285:2486–2497.View Article
                                  27. Choo V: WHO reassesses appropriate body-mass index for Asian populations. Lancet 2002, 360:235.PubMedView Article
                                  28. Pre-publication history

                                    1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2458/​10/​306/​prepub

                                  Copyright

                                  © Takashima et al. 2010

                                  This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.