Published papers

Objective: Age- and sex-specific population attributable fraction (PAF) and premature deaths attributable to smoking were estimated from a pooled analysis of cohort studies in Japan. Methods: A pooled analysis of individual participant data from 13 well-qualified cohort studies throughout Japan (a total of 183,251 Japanese aged 40-89, 69,502 men and 113,749 women; the baseline years between 1987 and 1995 with average 10 years of follow-up) was performed. Poison regression model was used to estimate age- and sex-specific hazard ratios, and their PAFs of all-cause deaths and number of annual premature deaths attributable to smoking were estimated. Results: Overall PAF attributable to smoking was 24.6% in men and 6.0% in women. The estimated number of annual premature deaths due to smoking was 121,854 (men: 109,998; women: 11,856) in Japan. The age-specific PAF was largest in men aged 60-69 (47.7%) and in women aged 50-59 (12.2%). In the older group aged 70-79 and 80-89, PAF was 15.4% and 8.0% in men and 3.5% and 1.5% in women, respectively. Conclusions: Age-specific PAFs attributable to smoking in Japanese men are much larger than that reported from other Asian countries. © 2010 Elsevier Inc.

Background: It is well-known that albumin is synthesized in the liver; serum albumin is a major component of serum proteins. However, it has not been well elucidated how dietary protein intakes are associated with serum albumin levels in general populations without extreme malnutrition. We cross-sectionally investigated in the representative Japanese the association between dietary protein intake and serum albumin levels. Methods: A total of 7715 subjects (3220 men and 4495 women, aged 30 years or more) with measurement of serum albumin who participated in both the National Survey on Circulatory Disorders in 1990 and the National Nutrition Survey in 1990 were analyzed in the present analysis. Multiple-adjustments were performed with linear regression models to estimate the association between serum albumin levels and animal or vegetable protein intake adjusting for age and body mass index. Results: The very weak positive association between animal protein and serum albumin levels was observed. On the other hand, there was no clear association observed between vegetable protein and serum albumin levels. Regardless of sex and models, age was inversely associated with serum albumin levels with statistically significance, and standardized coefficients of age were considerably larger in both sexes than other variables. Adjustment for body mass index hardly altered the coefficients of animal or vegetable protein intake, but adjustment for total cholesterol clearly attenuated the relationship between animal protein intake and serum albumin levels. Conclusions: Present analysis indicated the possibility that animal protein intake was related with serum albumin levels, while vegetable protein intake was not related. © 2010 by the Japan Epidemiological Association.

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. © 2010 Takashima et al; licensee BioMed Central Ltd.

Hypertension and smoking are major causes of disability and death, especially in the Asia-Pacific region, where there is a high prevalence of a combination of these two risk factors. We attempted to measure the medical expenditures of a Japanese male population with hypertension and/or a smoking habit over a 10-year period of follow-up. A cohort study was conducted that investigated the medical expenditures due to a smoking habit and/or hypertension during the decade of the 1990s using existing data on physical status and medical expenditures. The participants included 1708 community-dwelling Japanese men, aged 40-69 years, who were classified into the following four categories: neither smoking habit nor hypertension, smoking habit alone, hypertension alone or both smoking habit and hypertension. Hypertension was defined as a systolic blood pressure of 140 mm Hg, a diastolic blood pressure of 90 mm Hg or taking antihypertensive medications. In the study cohort, 24.9% had both a smoking habit and hypertension. During the 10-year follow-up period, participants with a smoking habit alone (18 444 Japanese yen per month), those with hypertension alone (21 252 yen per month) and those with both a smoking habit and hypertension (31 037 yen per month) had increased personal medical expenditures compared with those without a smoking habit and hypertension (17 418 yen per month). Similar differences were observed even after adjustment for other confounding factors (P<0.01). Japanese men with both a smoking habit and hypertension incurred higher medical expenditures compared with those without a smoking habit, hypertension or their combination. © 2010 The Japanese Society of Hypertension All rights reserved.

The association of the new diagnosis criteria for diabetes adopting hemoglobin A1c, recently proposed by the international expert committee, with macro-vascular complications was tested in a 12-year population-based cohort. The present analysis suggested that this new criteria were applicable to macro-vascular complications in the Japanese. © 2010 Elsevier Ireland Ltd.

BACKGROUND: Lectin-like oxidized LDL receptor 1 (LOX-1) is implicated in atherothrombotic diseases. Activation of LOX-1 in humans can be evaluated by use of the LOX index, obtained by multiplying the circulating concentration of LOX-1 ligands containing apolipoprotein B (LAB) times that of the soluble form of LOX-1 (sLOX-1) [LOX index = LAB X sLOX-1]. This study aimed to establish the prognostic value of the LOX index for coronary heart disease (CHD) and stroke in a community-based cohort. METHODS: An 11-year cohort study of 2437 residents age 30-79 years was performed in an urban area located in Japan. Of these, we included in the analysis 1094 men and 1201 women without history of stroke and CHD. We measured LAB and sLOX-1 using ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody and with 2 monoclonal antibodies against LOX-1, respectively. RESULTS: During the follow-up period, there were 68 incident cases of CHD and 91 cases of stroke (with 60 ischemic strokes). Compared with the bottom quartile, the hazard ratio (HR) of the top quartile of LOX index was 1.74 (95% CI 0.92-3.30) for stroke and 2.09 (1.00-4.35) for CHD after adjusting for sex, age, body mass index, drinking, smoking, hypertension, diabetes, non-HDL cholesterol, and use of lipid-lowering agents. Compared with the bottom quartile of LOX index, the fully adjusted HRs for ischemic stroke were consistently high from the second to the top quartile: 3.39 (95% CI 1.34-8.53), 3.15 (1.22-8.13) and 3.23 (1.24-8.37), respectively. CONCLUSIONS: Higher LOX index values were associated with an increased risk of CHD. Low LOX index values may be protective against ischemic stroke. © 2009 American Association for Clinical Chemistry.

Objective: Physical activity is known to be preventive against various non-communicable diseases. We investigated the relationship between daily physical activity level and plasma metabolites using a targeted metabolomics approach in a population-based study. Methods: A total of 1,193 participants (male, aged 35 to 74 years) with fasting blood samples were selected from the baseline survey of a cohort study. Information on daily total physical activity, classified into four levels by quartile of metabolic equivalent scores, and sedentary behavior, defined as hours of sitting per day, was collected through a self-administered questionnaire. Plasma metabolite concentrations were quantified by capillary electrophoresis mass spectrometry method. We performed linear regression analysis models with multivariable adjustment and corrected p-values for multiple testing in the original population (n = 808). The robustness of the results was confirmed by replication analysis in a separate population (n = 385) created by random allocation. Results: Higher levels of total physical activity were associated with various metabolite concentrations, including lower concentrations of amino acids and their derivatives, and higher concentrations of pipecolate (FDR p <0.05 in original population). The findings persisted after adjustment for age, body mass index, smoking, alcohol intake, and energy intake. Isoleucine, leucine, valine, 4-methyl-2-oxoisopentanoate, 2-oxoisopentanoate, alanine, and proline concentrations were lower with a shorter sitting time. Conclusions: Physical activity is related to various plasma metabolites, including known biomarkers for future insulin resistance or type 2 diabetes. These metabolites might potentially play a key role in the protective effects of higher physical activity and/or less sedentary behavior on non-communicable diseases.

OBJECTIVE:: The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population. METHODS:: The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation. RESULTS:: Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0?kg/m, 72.1?mg/dL, and 126.1?mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased. CONCLUSIONS:: Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

Background: The geographic distribution of cardiovascular (CV) health-care services has not been assessed systematically. Methods and Results: Data of the Japanese Circulation Society (JCS) annual survey were provided to the JCS working group with the permission of the JCS Scientific Committee. The status of CV practice in 2010 was then assessed in 47 prefectures retrospectively, along with national census and gross domestic product (GDP) data. The surveyed indices included resources (hospitals, beds and cardiologists), burden (number of inpatients), and outcome (CV mortality and autopsy) in each prefecture, which correlated well with respective populations or GDP. Inequality of geographic distribution was evident for pediatrics among the 47 prefectures, according to Lorenz curve, Gini coefficient or the maximum/minimum ratio for each index. According to the Gini coefficients, only the number of inpatients (medical or acute myocardial infarction) and beds for the total number of general hospitals or the hospitals surveyed in the present JCS study were lower than expected with regard to GDP. Conclusions: Geographic disparity of CV resources or burden was larger in pediatrics than in CV medicine or surgery. Improvement of equality in CV practice with regard to appropriateness and quality are the coming challenges for the JCS.

Oxidized low-density lipoprotein (LDL) exhibits various biological activities and accumulates in atheromas. LOX-1 (lectin-like oxidized LDL receptor) is the receptor that mediates oxidized LDL activity in vascular endothelial cells. Activation of LOX-1 results in oxidized LDL-induced endothelial dysfunction and hyperlipidemia-induced vascular lipid deposition. We hypothesized that LOX-1 is a candidate risk factor beyond LDL cholesterol (LDLC) and developed a novel assay to quantify LOX-1 ligand containing apoB (LAB). In men from the United States, serum LAB showed a significant positive association with carotid intima-media thickness, independent of LDLC. LAB and the LOX index (obtained by multiplying LAB by sLOX-1) were significantly associated with the incidence of coronary artery disease and ischemic stroke after adjusting for confounding factors, including non-HDL cholesterol. sLOX-1 is thought to be a better biomarker for early diagnosis of acute coronary syndrome than traditional biomarkers, including troponin T. LAB was associated with various atherosclerotic risk factors such as smoking, obesity, diabetes, diastolic hypertension, hypertriglyceridemia, and metabolic syndrome. Measurement of the soluble form of LOX-1 (sLOX-1) and LAB seems to be useful for evaluating the state and risk of atherosclerosis and atherosclerosis-related diseases. Further prospective studies using large populations and randomized clinical trials on sLOX-1, LAB, and the LOX index are needed.

Objective: To determine whether serum concentrations of long chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in the incidence rate of coronary artery calcification (CAC) between Japanese men in Japan and white men in the USA. Methods: In a population based, prospective cohort study, 214 Japanese men and 152 white men aged 40.49 years at baseline (2002.2006) with coronary calcium score (CCS)=0 were re-examined for CAC in 2007.2010. Among these, 175 Japanese men and 113 white men participated in the follow-up exam. Incident cases were defined as participants with CCS≥10 at follow-up. A relative risk regression analysis was used to model the incidence rate ratio between the Japanese and white men. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline. Results: Mean (SD) serum percentage of LCn3PUFA was >100% higher in Japanese men than in white men (9.08 (2.49) vs 3.84 (1.79), respectively, p<0.01). Japanese men had a significantly lower incidence rate of CAC compared to white men (0.9 vs 2.9/100 personyears, respectively, p<0.01). The incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% CI 0.150 to 0.690; p<0.01). After adjusting for age, systolic blood pressure, low density lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant (0.262, 95% CI 0.094 to 0.731; p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376, 95% CI 0.090 to 1.572; p=0.18). Conclusions: LCn3PUFAs significantly contributed to the difference in the incidence of CAC between Japanese and white men.

Objective: Higher marine-derived n-3 fatty acids (MDn3FAs) intake reduces the risk of sudden cardiac death via antiarrhythmic effects. The article evaluates whether MDn3FAs intake attenuates the increased risk of cardiac death associated with J-point elevation (JPE), characterised by an elevation of QRS-ST junction (J-point) ≥0.1 mV on electrocardiography. Design: A prospective population-based cohort study. Setting: The National Survey on Circulatory Disorders and the National Nutrition Survey of Japan. Participants: A total of 4348 community-dwelling men (mean age 49.3 years), without cardiovascular diseases at baseline, from randomly selected areas across Japan. Main outcome measures: Cardiac death (200 men) during the 24-year follow-up. Results: Dietary MDn3FAs intake was assessed using a dietary method to estimate individual intake of household-based weighed food records for 3 days. Cox models were used to calculate HRs and 95% CIs adjusted for possible confounding factors. JPE was present in 340 participants (7.8%). The median daily intake of MDn3FAs was 0.35%kcal (0.92 g/day). The risk of cardiac death was significantly higher in participants with JPE than in those without JPE in the low intake group (<0.35%kcal; adjusted HR 3.51; 95% CI 1.84 to 6.73; p<0.001), but not in the high intake group (≥0.35%kcal; adjusted HR 1.09; 95% CI 0.56 to 2.16; p=0.795). The interaction between dietary MDn3FAs intake and JPE on the risk of cardiac death was statistically significant (p=0.006). Conclusions: The increased risk of cardiac death associated with JPE may be attenuated by higher dietary MDn3FAs intake.

Lippincott Williams & Wilkins.Objective: In Western populations, blood pressure (BP) measured at baseline has been reported to predict long-term (over 20 years) risk of mortality from cardiovascular diseases (CVDs). However, corresponding evidence is scarce in Asia where stroke is dominant. We investigated the association between baseline BP and 24-year mortality risk due to CVD, in a representative Japanese general population. Methods: We followed up a nationwide sample of 8592 Japanese, aged 30 years or above without a history of CVD and antihypertensive medication at baseline, for 24 years. Hazard ratios for CVD mortality in BP categories defined according to JCN7 criteria were estimated using Cox model adjusted for potential confounding factors with normal BP treated as the reference category. Results: We observed 689 CVD deaths. Hazard ratios for CVD mortality were progressively and significantly increased from the category of prehypertension. Population-attributable fraction (PAF) demonstrated that 43 and 48% of CVD and stroke deaths were explained by non-normal BP at baseline. Hazard ratios and PAF were remarkably higher in younger participants (aged 30-59 years) than those in the elderly (aged 60 years or above). Particularly, in younger men, 81% of CVD deaths were explained by non-normal BP. In sensitivity analysis, participants with antihypertensive medication showed the highest hazard ratio for CVD morality compared with the other categories. Conclusions: BP levels above normal at baseline retained significant relative and absolute risks of CVD and stroke mortality during 24 years. Long-lasting burden of non-normal BP particularly in younger individuals suggests the importance of primary prevention of high BP from younger generation. © 2012 Wolters Kluwer Health

Background: In spite of the importance of a multifactorial approach to preventing cardiovascular disease in smokers, most information on the combined adverse effects of smoking and hypertension or high serum cholesterol on cardiovascular disease has been derived from Western populations, and coronary heart disease was often used as the only endpoint. Therefore, the present large-scale pooled analysis attempted to provide reliable information on the adverse effects of the coexistence of smoking and hypertension or high serum cholesterol on the risk of mortality from coronary heart disease and stroke in both, individuals and the entire population in Japan. Methods: A total of 27,385 male and 39,207 female participants aged 40-89 years were enrolled from 10 well-qualified Japanese cohort studies with a mean follow-up of 10.1 years. Hazard ratios and their corresponding 95% confidence intervals in smokers who had hypertension or high serum cholesterol were estimated for men and women separately using a Cox proportional hazards regression model that included age, body mass index, cohort and either serum total cholesterol or systolic blood pressure as covariates. Fractions of deaths attributable to the coexistence of these risk factors were also calculated. Results: The multivariate-adjusted hazard ratios in male and female current smokers with hypertension, compared with those with neither factor were 2.57 (95% confidence intervals, 1.51-4.38) and 6.14 (3.49-10.79) for coronary heart disease, and 3.28 (1.89-5.71) and 1.61 (0.81-3.18) for cerebral infarction, respectively. The fractions of deaths attributable to the coexistence of current smoking and hypertension in men and women were 24.6 and 9.6% for coronary heart disease and 28.1 and 2.0% for cerebral infarction, respectively. Smokers with high serum cholesterol were broadly comparable to hypertensive smokers only with respect to coronary mortality risk; the hazard ratios, compared with those with neither factor were 4.19 (2.33-7.53) for men and 3.90 (1.57-9.67) for women. The fraction of coronary deaths attributable to the coexistence of current smoking and high serum cholesterol was 6.3% in men and 2.2% in women. There was no interaction between smoking habit and blood pressure or serum total cholesterol for these two subtypes in both men and women. Conclusions: Particular attention should be given to smokers who have concomitant hypertension or high serum cholesterol for preventing deaths due to cardiovascular disease. From a public health perspective in Japan, priority should be given to hypertensive smokers, since this group makes a large contribution to the burden of both coronary and cerebral infarction deaths. Copyright © 2012 S. Karger AG, Basel.

Introduction. Hypertension and cigarette smoking are dominant risk factors for cardiovascular disease in Japan while in westernized countries, broader effects encompass obesity, diabetes, and hypercholesterolemia. This paper examines whether different associations also appear important in the manifestation of activities of daily living (ADL) in older Japanese men in Hawaii and Japan. Methods. Measures of ADL (feeding, toileting, dressing, bathing, and walking around the house) were assessed from 1995 to 1999 in 1,893 men in Hawaii and 543 men in Japan. Concomitant risk factors were measured from 1990 to 1993. Results. In Hawaii, diabetes increased the odds of ≥1 ADL impairment nearly 1.5-fold (P=.020). A similar association was absent in Japan. In contrast, the odds of an ADL impairment in Japan was increased more than 5-fold in the presence of stroke (P<.001). The association in Hawaii was significantly weaker (P=.007). In both cohorts, past alcohol use was associated with a greater likelihood of ADL impairment. Conclusion. In this comparison of genetically similar samples, findings suggest that different strengths in risk factor associations with cardiovascular disease in Japan and westernized countries may also include different strengths in associations with impaired ADL. © 2011 Robert D. Abbott et al.

Background: Diet is one of the most important lifestyle factors that a affect healthy life expectancy through onset of various lifestyle-related diseases. Large-scale cohort studies with sufficient baseline nutritional information are scarce. NIPPON DATA80/90 is cohort study of representative Japanese population, and the cohorts also participated in the National Nutrition Survey in Japan (NNSJ) at the baseline. The corresponding datasets could be combined. Methods: Individual records of NIPPON DATA and NNSJ were compared and integrated. Intakes of nutrients and food groups for individual participants were calculated by distributing intakes in the each household in NNSJ, considering age and sex of the individuals. The results from an international cooperative epidemiological study (INTERMAP) were utilized to estimate intakes of 75 nutrients for NNSJ80 and 70 nutrients for NNSJ90. Nutrient intakes calculated utilizing INTERMAP data were compared with those in the NNSJ datasets. Results: NIPPON DATA80/90 datasets were enhanced with detailed baseline nutrient intake data (the numbers of participants combined were 10 422 and 8342 for NIPPON DATA80 and 90, respectively). The mean nutrient intakes calculated through utilizing INTEMRAP data and those calculated from the NNSJ datasets were similar, and the calculated values were strongly correlated with those calculated from NNSJ datasets (Pearson's correlation coefficients greater than 0.8 [P < 0.001]). Detailed nutrient intakes (eg, cholesterol, fatty acids, amino acids, and dietary fiber) were complemented. Conclusions: The nutrient intakes calculated from NNSJ datasets for the participants of NIPPON DATA are appropriate as the baseline nutrient intake data. The enhanced cohort datasets are suitable for investigations of baseline dietary habits and the consequent health status. © 2010 by the Japan Epidemiological Association.

Background and purpose: Lifetime risk (LTR) is an epidemiologic measure that expresses the probability of disease in the remaining lifetime for an index age. The LTR for stroke has not been reported for the Japanese population. Methods: We included all participants from the Suita Study who were cardiovascular disease-free at baseline. Age (in years) was used as the time scale. Age-specific stroke incidence and all-cause mortality were calculated with the person-year method, and we estimated the sex-and index age-specific LTRs of first-ever stroke and its subtypes, taking into account the competing risk of death. Results: We followed up 5498 participants from 1989 to 2005 for a total of 67 475 person-years. At age 55 years, the LTR for stroke, after accounting for competing risks of death, was 18.3% for men and 19.6% for women. The LTR for cerebral infarction was 14.6% for men and 15.5% for women, and the LTR for intracerebral hemorrhage was 2.4% for men and 1.4% for women at the index age of 55 years. The LTR for stroke remained similar across other index ages of 45, 55, and 65 years. Conclusions: The observed probabilities illustrate that 1 in 5 men and women of middle age will experience stroke in their remaining lifetime. This easy understandable information can be used as an important index to assist in public health education and planning. Copyright © 2010 American Heart Association. All rights reserved.