Published papers

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.

Background: Chronic kidney disease (CKD) has been identified as a risk factor for cardiovascular disease (CVD). Methods and Results: The risk of cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. Participants (mean age, 52.4 years) free of previous CVD were followed up for 10 years. Glomerular filtration rate (GFR) was estimated using the abbreviated equation developed at the Cleveland Clinic laboratory for the Modification of Diet in Renal Disease study. Of the 7,316 participants, 6.7% had CKD with a GFR <60 at baseline. Even after adjustment for other risk factors, the presence of CKD conferred an increased risk of cardiovascular death with a hazard ratio of 1.20 (95% confidence interval, 0.82-1.76). Furthermore, a negative, graded correlation between GFR and risk of cardiovascular death was observed: 1.09 (0.72-1.64) for a 60≤ GFR <90, 1.15 (0.67-1.99) for a 45≤ GFR <60, 1.23 (0.49-3.09) for a 30≤ GFR <45, 5.52 (1.62-18.75) for a 15≤ GFR <30, 9.12 (2.12-39.29) for a GFR <15, as compared with normal kidney function (GFR ≥90). The proportion of excess cardiovascular death due to CKD was 1.3%. Conclusion: CKD was an independent risk factor for cardiovascular death in a community-dwelling Japanese population.

Background: To examine the prognostic significance of the high-risk group with combined cardiovascular risk factors in the Japanese, we analyzed the relationship between the high-risk group with combined risks and coronary heart disease (CHD) and stroke mortality using the NIPPON DATA80 database. Methods and Results: At baseline in 1980, those of age ≥30 years were randomly selected and 4,144 men and 5,318 women without CHD and/or stroke at baseline were followed for 14 years. The cutoff values for risk components obtained heuristically by Cox analysis were hypertension (systolic ≥130, or diastolic ≥85 mmHg, or on antihypertensive drugs), hypercholesterolemia (total cholesterol ≥200 mg/dl), hyperglycemia (≥130 mg/dl, or self-reported diabetes) and obesity (body mass index ≥27 kg/m2). Subjects were divided into 3 groups (0, 1-2 and 3-4 risks). Compared with those men in the risk 0 group, the hazard ratios in men in the risk 3-4 for CHD mortality was 8.04 (95% confidence interval: 1.03-62.6), and the stroke mortality was 5.06 (1.53-16.7). In women, no statistically significant difference was found due to a lesser number of events. Conclusion: The high-risk group with combined risk factors is important risk for Japanese men.

Background: The KCNQ1 single nucleotide polymorphism (SNP), G643S, is known to be associated with secondary long QT syndrome (LQTS) and to cause a mild reduction in KCNQ1 current. However, the precise incidence and its association with QT intervals remain unknown in the greater cohort of the population in Japan. Methods and Results: The genotype was screened at codon 643 of KCNQ1 in 992 residents of a farming community. Eighty-eight individuals (female/male=52/36, 8.9%) were found to have a heterozygous G643S SNP. Matching both gender and age, we randomly selected 243 control (G643G) cases and compared the electrocardiogram parameters in both groups; QT, QTf (QT corrected by Fridericia's formula) intervals, the peak and the end of the T wave (Tpe) interval, and the Tpe/QT ratio. The latter 2 reflect the transmural dispersion of ventricular repolarization (TDR). In G643S carriers, both Tpe and Tpe/QT were significantly longer than in noncarriers, without significant QT prolongation. Both genders showed a tendency for an increase in QTf with aging. In females, both Tpe and Tpe/QT showed a similar significant increase with age, which was not observed in males. Conclusions: In elderly females, G643S might be an independent risk factor for secondary LQTS by causing a greater TDR.

Levels of adiponectin are inversely associated with obesity levels. We examined the levels of adiponectin in American (n = 98) and Japanese (n = 92) men aged 40 to 49 years. Contrary to our expectations, the American men had higher levels of adiponectin than the Japanese men (13.3 ± 5.8 vs 7.3 ± 4.2 (μg/mL) despite higher levels of obesity. Smaller areas of visceral adipose tissue in American than in Japanese men may have resulted in the higher levels of adiponectin. © 2006 Elsevier Inc. All rights reserved.

It has been reported that the β3-adrenergic receptor gene (ADRB3) is associated with abnormal metabolic risk factors. Therefore, we examined whether the Trp64Arg polymorphism of ADRB3 affects the occurrence of metabolic syndrome (MS). The participants were 2,395 subjects who underwent a medical examination in Shigaraki in Shiga, Japan. Among them, 1,416 subjects who gave informed consent for genetic analysis and were not receiving treatment for hypertension, diabetes, or hyperlipidemia were enrolled in this study. MS was diagnosed in 86 (16.0%) of 537 men, and 8 (0.9%) of 879 women. There was no significant relationship between ADRB3 polymorphism and the frequency of MS. Multiple logistic regression analysis including smoking, sex, and age as confounding factors showed no interaction between MS and ADRB3 polymorphism (odds ratio: 0.94; 95% confidence interval: 0.59-1.49; p=0.78). Subjects were also analyzed according to differences in the number of abnormal metabolic risk factors. However, there was no significant relationship between ADRB3 polymorphism and the number of such factors. In conclusion, in a general sample, the frequency of MS as 16.0% in men, and 0.9% in women. There was no relationship between ADRB3 polymorphism and MS.

BACKGROUND AND METHODS: A cohort study investigating medical costs associated with the combination of hypertension and diabetes was conducted. The participants included 4535 community-dwelling Japanese individuals, aged 40-69 years, who were classified into the following four categories: 'Neither hypertension nor diabetes', 'Hypertension alone', 'Diabetes alone' or 'Both hypertension and diabetes'. Medical costs per person per month were compared among the four categories. RESULTS AND CONCLUSION: Of the study population, 1.3% had both hypertension and diabetes. During the 10-year follow-up period, participants with both hypertension and diabetes incurred higher medical costs, as compared with those without hypertension, diabetes or their combination, even after adjustment for other confounding factors. © 2006 Lippincott Williams & Wilkins, Inc.

Background: The relationship between body mass index (BMI) and stroke mortality remains unclear. The aim of the present study was to elucidate the relationship between BMI and stroke death in a representative cohort of Japanese men and women. Methods: We analyzed a database of 9,526 men and women aged 30 years and older who were randomly selected throughout Japan in 1980. These individuals had no history of stroke and were followed for 19 years. Hazard ratios (HR) and their 95% confidence intervals (CI) of deaths due to total stroke, cerebral infarction, and intracerebral hemorrhage were examined using Cox's proportional hazards regression models of BMI levels. Results: A U-shaped association between BMI and cerebral infarction mortality was observed. Participants with the highest BMI category (BMI ≥ 30.0) showed a significantly highest HR for cerebral infarction (HR 2.46, 95% CI 1.01-5.99). The excess risk at the lower extreme of the BMI was confined to men. These associations did not change after excluding deaths occurring in the first 2 years of follow-up. Conclusions: In the Japanese general population, a U-shaped association between BMI and cerebral infarction mortality was found and the excess risk at the lower extreme of the BMI was confined to men. Copyright © 2006 S. Karger AG.

Smoking prevalence among males is conspicuously high in Asian countries including Japan. There are few prospective intervention studies on the duration of smoking cessation within regions with a high prevalence of smokers, such as Asia. We investigated the extent to which subjects continued abstaining from smoking after receiving smoking cessation support provided for all smokers in an occupational setting, regardless of their willingness to quit smoking. The subjects were 251 male workers who were smokers and had received a smoking cessation intervention in 1997 in an occupational setting. Smoking cessation rates and body mass index (BMI) at 10, 18, 30, 42, 54, and 66 months after the initial intervention were confirmed during annual health check-ups. Those who quit smoking following the intervention and continuously abstained from smoking throughout the study period were separately examined for BMI. After five years, 10.6% of the smokers continued smoking cessation. Of the abstainers who quit following the intervention, the abstinence rate decreased in the first and second year, but it stabilized at approximately 45% after the third year. High nicotine dependence and a selfreported lack of willingness to quit smoking did not lower long-term abstinence rates. Abstainers initially gained 1.55 BMI on average, but decreased the weight gain to 0.96 BMI over six years. Introducing smoking cessation support without nicotine replacement therapy is an effective long-term strategy in a healthy population with a high smoking prevalence. Abstainers maintain their smoking cessation if they refrain from smoking for three years.

Epidemiologic studies have investigated the relation between alcohol intake and coronary calcification, with controversial results. Furthermore, the influence of heavy drinking has not been well elucidated. In the present study, a random sample of community-based Japanese men aged 40 to 49 years without a history of cardiovascular disease (n = 245) were examined for coronary artery calcium (CAC) determined by electron-beam computed tomography and drinking status. There was a J-shaped association between alcohol intake and CAC. There was an increase of CAC in heavy drinkers (≥46 g/day), and participants who were drinking ≥69 g/day showed a significant increase in CAC compared with never drinkers after adjusting for other cardiovascular risk factors. © 2006 Elsevier Inc. All rights reserved.

Visceral adipose tissue (VAT) is an independent risk factor for metabolic and cardiovascular disorders. There has been no study that demonstrated different abdominal fat distribution between Asian and Caucasian men. As the Japanese are less obese but more susceptible to metabolic disorders than Caucasians, they may have larger VAT than Caucasians at similar levels of obesity. We compared the abdominal fat distribution of the Japanese (n=239) and Caucasian-American (n=177) men aged 40-49 years in groups stratified by waist circumference in a population-based sample. We obtained computed tomography images and determined areas of VAT and subcutaneous adipose tissue (SAT). We calculated VAT to SAT ratio (VSR). The Japanese men had a larger VAT and VSR in each stratum, despite substantially less obesity overall. In multiethnic studies, difference in abdominal fat distribution should be considered in exploring factors related to obesity. © 2006 Nature Publishing Group All rights reserved.

Japanese serial television dramas are becoming very popular overseas, particularly in other Asian countries. Exposure to smoking scenes in movies and television dramas has been known to trigger initiation of habitual smoking in young people. Smoking scenes in Japanese dramas may affect the smoking behavior of many young Asians. We examined smoking scenes and smoking-related items in serial television dramas targeting young audiences in Japan during the same season in two consecutive years. Fourteen television dramas targeting the young audience broadcast between July and September in 2001 and 2002 were analyzed. A total of 136 h 42 min of television programs were divided into unit scenes of 3 min (a total of 2734 unit scenes). All the unit scenes were reviewed for smoking scenes and smoking-related items. Of the 2734 3-min unit scenes, 205 (7.5%) were actual smoking scenes and 387 (14.2%) depicted smoking environments with the presence of smoking-related items, such as ashtrays. In 185 unit scenes (90.2% of total smoking scenes), actors were shown smoking. Actresses were less frequently shown smoking (9.8% of total smoking scenes). Smoking characters in dramas were in the 20-49 age group in 193 unit scenes (94.1% of total smoking scenes). In 96 unit scenes (46.8% of total smoking scenes), at least one non-smoker was present in the smoking scenes. The smoking locations were mainly indoors, including offices, restaurants and homes (122 unit scenes, 59.6%). The most common smoking-related items shown were ashtrays (in 45.5% of smoking-item-related scenes) and cigarettes (in 30.2% of smoking-item-related scenes). Only 3 unit scenes (0.1 % of all scenes) promoted smoking prohibition. This was a descriptive study to examine the nature of smoking scenes observed in Japanese television dramas from a public health perspective. © The Author (2006). Published by Oxford University Press. All rights reserved.

To test the effectiveness of a low-intensity intervention program for smoking cessation targeting the worksite environment in employees who had a low readiness to quit, we conducted an intervention trial at six intervention and six control worksites in Japan. A total of 2,307 smokers at baseline who remained at their worksite throughout the three-year study period were analyzed (1,017 in intervention and 1,290 in control groups). The multi-component program at the worksites consisted of (1) presenting information on the harms of tobacco smoking and the benefits of cessation by posters, websites, and newsletters; (2) smoking cessation campaigns for smokers; (3) advice on designation of smoking areas; and (4) periodic site-visits of the designated smoking areas by an expert researcher. At baseline, the intervention and control groups each had high prevalence of immotive or precontemplation, that reflected low readiness to quit (71.5% and 73.2%, respectively). The smoking cessation rate, as not having smoked for the preceding six months or longer, assessed at 36 months after the baseline survey by a self-administered questionnaire was significantly higher in the intervention group than the control group (12.1%, vs. 9.4%, p=0.021). The intervention program still had a significant effect on the smoking cessation rate after multiple logistic regression analysis adjusted for sex, age, type of occupation, age of starting smoking, quit attempts in the past, number of cigarettes per day, and readiness to quit (odds ratio: 1.38, 95% confidence interval: 1.05-1.81, p=0.02). The cost per additional quitter due to the intervention was calculated to be ¥ 70,080. These findings indicate that this program is effective and can be implemented in similar workplaces where the prevalence of smoking is high and smokers' readiness to cease smoking is low.

Little is known about the efficacy of left ventricular hypertrophy diagnosed by electrocardiography for predicting cardiovascular disease in a general Japanese population. In a large cohort of participants selected randomly from the overall Japanese population, we attempted to evaluate the usefulness of a high amplitude R-wave (left high R-wave) on the electrocardiogram for predicting cardiovascular death. A total of 6,688 Japanese (mean age, 50.7 years old; 57% women) free of previous cardiovascular disease and use of antihypertensive agents at baseline were followed for 10 years, from 1990 to 2000. Left high R-wave on the electrocardiogram (the Minnesota Code, 3-1 or 3-3) was found in 9.4% of the 6,688 participants, in 14.6% of the 2,413 hypertensives and in 4.1% of the 4,275 normotensives. During the follow-up period, 128 participants died due to cardiovascular disease. After adjustment for systolic blood pressure and other risk factors, left high R-wave conferred an increased risk of cardiovascular death; the hazard ratio among all the participants was 1.88 (95% confidence interval, 1.22-2.89; p<0.01), that among hypertensives was 1.97 (1.20-3.24; p=0.01), and that among normotensives was 1.66 (0.69-3.98; p=0.26). The population attributable risk percent of left high R-wave for cardiovascular death was 7.6% among all participants, 12.4% among hypertensives and 4.1% among normotensives. Left high R-wave on electrocardiogram, irrespective of the level of systolic blood pressure, was a predictive marker for cardiovascular death among community-dwelling Japanese.

Background: Elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels were associated with higher incidence of type II diabetes. Elucidating the determinants of PAI-1 in various ethnicities may help to understand the susceptibility to developing diabetes. The aim of our study was to compare PAI-1 levels between Americans and the Japanese in the post-war generation and to elucidate the determinants of the PAI-1 levels. Methods: We conducted a cross-sectional study on a total of 198 men aged 40-49 in the US (Body mass index (BMI): 27.0 ± 3.3 kg/m2) and Japan (BMI: 23.3 ± 3.1 kg/m2). Examination included physique measurement (BMI and waist girth), blood analysis (lipid profiles, glucose, insulin, C-reactive protein, and PAI-1), and life-style assessment by self-administered questionnaires. Results: PAI-1 levels were significantly lower in American than in Japanese men, even after adjustment for age, waist girth, cigarette smoking, habitual alcohol drinking, and other factors. In the Americans, waist girth, insulin, and cigarette smoking were significantly associated with PAI-1 levels, while waist girth and triglycerides were significantly associated with PAI-1 levels in the Japanese. Conclusions: PAI-1 levels were significantly lower in American than in Japanese men and the determinants of PAI-1 levels differ for American and Japanese men aged 40-49. © 2005 Elsevier Ireland Ltd. All rights reserved.

Objective: To clarify the relationship between mortality due to cardiovascular diseases (CVD) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in young and elderly Japanese men in the absence of antihypertensive treatments. Design: A 19-year cohort study using the 1980 National Survey of Cardiovascular Diseases and the identification of the underlying causes of death using national vital statistics data. Methods: In 1999, a 19-year follow-up study was conducted among participants randomly selected from the Japanese population for the 1980 National Survey of Cardiovascular Diseases. Among the male participants that were not receiving antihypertensive treatment, information was obtained for about 91.3% of the subjects (n = 3779). Age-adjusted mortality rates using the person-year method were calculated to compare the relationships of SBP and DBP levels with CVD mortality for different age groups (aged 30-64, 65-74, and 75 years or more). Results: The total number of observed person-years was 64 598 and the number of CVD-related deaths after 19 years was 253. Both SBP and DBP levels were significantly and linearly related to CVD mortality in the age groups 30-64 years (P < 0.001 and P = 0.01, respectively) and 65-74 years (P < 0.001 and P = 0.03, respectively). In the group of participants that were at least 75 years old, however, no significant increase in the relative risk of CVD was observed with increasing DBP levels (P = 0.156), whereas the relative risk of CVD increased significantly with increasing SBP levels (P = 0.038). Multivariate analysis adjusting for major risk factors confirmed these relationships. Standardized hazard ratios (95% confidence intervals) of SBP were 1.53 (1.19-1.96) for 30-64 year olds, 1.70 (1.31-2.20) for 64-74 year olds, and 1.23 (1.03-1.47) for participants 75 years old or more, whereas those of DBP were 1.52 (1.12-2.06), 1.60 (1.21-2.10), and 1.10 (0.94-1.28), respectively. Conclusions: These data show that elevated SBP is an independent risk factor for CVD mortality for Japanese men of all ages, whereas elevated DBP is not an independent risk factor for CVD mortality for elderly men. © 2006 Lippincott Williams & Wilkins.

Objectives: To compare the effectiveness of health education on smoking cessation for all smokers regardless of their willingness to quit smoking and cumulative environmental changes including designation of smoking places, legislation, and price rise. Design: Comparison of smoking cessation rates over two time periods: the period of health education on smoking cessation (1997-1999), and the period of cumulative environmental changes (2002-2004). Setting: An occupational setting in a radiator manufacturing factory in Japan. Subjects: All habitual male smokers who remained in the worksite through the pertinent time period (n = 202 in the period of health education and n = 170 in the period of environmental changes). Main outcome measurements: Smoking cessation rates at the end of each time period. Results: The smoking cessation rates over the periods of health education and environmental changes were 8.9% and 7.1%, respectively. There was no difference between these two proportions in χ2 test (p = 0.513). The age adjustment did not significantly alter the cessation rate. Conclusions: Cumulative environmental changes are fairly effective in promoting smoking cessation, and may yield similar smoking cessation rates as a health education intervention reaching all smokers regardless of their willingness to quit smoking.

In populations with higher high-density lipoprotein cholesterol (HDL-C) levels and lower coronary mortality than Western populations, such as in Japan, the beneficial effect of HDL-C on all-cause mortality may be different. Furthermore, prior studies have not focused on very high level of HDL-C. A total of 7175 community Japanese residents without a past history of cardiovascular disease in 300 randomly selected districts were followed for 9.6 years. During follow-up, there were 636 deaths. The multivariate adjusted hazard ratio (HR) of HDL-C for all-cause or cause-specific mortality was calculated using a Cox proportional hazard model adjusted for other cardiovascular risk factors. The all-cause mortality suggested an inverse, graded relation with HDL-C categories; HR for the very high HDL-C category (≥1.82 mmol/L), compared with the reference group (1.04-1.55 mmol/L), was 0.73 (95% confidence interval, C.I., 0.50-1.06) for men, 0.63 (95% C.I., 0.41-0.94) for women and 0.70 (95% C.I., 0.53-0.93) when men and women were combined. Serum HDL-C as a continuous variable showed a significant inverse association with all-cause mortality. The cardiovascular mortality indicated a non-significant but inverse graded relation with HDL-C categories. As in the many Western populations, serum HDL-C levels were inversely associated with all-cause mortality in the Japanese general population. © 2005 Elsevier Ireland Ltd. All rights reserved.