Published papers

Coronary heart disease incidence and mortality remain very low in Japan despite major dietary changes and increases in risk factors that should have resulted in a substantial increase in coronary heart disease rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in coronary heart disease in Japanese migrating to the United States. For men aged 40-49 years, levels of total cholesterol and blood pressure have been similar in Japan and the United States throughout their lifetimes. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification, and intima-media thickness of the carotid artery in men aged 40-49 years are similar in Japan and the United States. They conducted a population-based study of 493 randomly selected men: 250 in Kusatsu City, Shiga, Japan, and 243 White men in Allegheny County, Pennsylvania, in 2002-2005. Compared with the Whites, the Japanese had a less favorable profile regarding many risk factors. The prevalence ratio for the presence of a coronary calcium score of ≥10 for the Japanese compared with the Whites was 0.52 (95% confidence interval: 0.35, 0.76). Mean intima-media thickness was significantly lower in the Japanese (0.616 mm (standard error, 0.005) vs. 0.672 (standard error, 0.005) mm, p < 0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations. Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved.

Cholesteryl ester transfer protein (CETP) is a key enzyme in high-density lipoprotein (HDL) cholesterol metabolism. We studied the association between CETP TaqIB polymorphism and the HDL cholesterol levels considering environmental factors in a population-based sample consisting of 1729 participants who did not use lipid-lowering agents (659 men and 1070 women). The CETP TaqIB genotypes were determined by PCR-RFLP analysis. The serum HDL cholesterol levels of female participants with the B2B2 genotype were significantly higher than those with other genotypes (p < 0.001). Multiple regression analysis with covariates such as age, waist to hip (W/H) ratio, alcohol drinking, current smoking, non-HDL cholesterol, and logarithm of triglyceride revealed that the CETP TaqIB genotype was an independent determinant of HDL cholesterol levels in men (p = 0.049) and women (p < 0.001). Subgroup analysis revealed that an interaction was observed between the CETP TaqIB polymorphism and alcohol consumption in the regulation of HDL cholesterol levels in men (p = 0.049) and women (p = 0.022). No interactions were observed between the CETP TaqIB polymorphism and current smoking status, body mass index, or W/H ratio in the regulation of HDL cholesterol levels. The association between the CETP TaqIB polymorphism and HDL cholesterol levels was more evident in alcohol consumers than in non-drinkers. © 2006 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND AND PURPOSE - The age-adjusted stroke mortality rate in Japan was the highest in the world from 1950 to the 1970s, but it started to dramatically decrease after 1965. In addition to improved management of high blood pressure, the increase in average height might also contribute to this reduction. The present study investigates whether height is an independent risk for stroke mortality in Japan. METHODS - Among participants of the National Survey on Cardiovascular Diseases in 1980 who were randomly selected from the Japanese population, we followed up 3969 and 4955 Japanese men and women without prior cardiovascular disease for a maximum of 19 years and observed 158 and 132 stroke deaths. RESULTS - Height was inversely correlated with age and with crude stroke mortality. The relationship was attenuated in men when we adjusted for age or other possible confounders (multivariate adjusted relative hazards of a 5-cm increase of height for stroke mortality: 0.92, 95% CI: 0.79 to 1.08). For women, the inverse relationship (relative hazard: 0.77: 95% CI: 0.64 to 0.91) remained after multivariate adjustment. These relationships persisted when we stratified participants by age. CONCLUSIONS - Height is inversely related to stroke mortality and the relationship is statistically significant among Japanese women. © 2007 American Heart Association, Inc.

No study has shown a positive relationship between hypercholesterolemia and all-cause mortality in the Japanese population. Therefore, a cohort study of 17.3 years' duration was conducted on 9216 participants aged 30 years or older, selected randomly from throughout Japan. In both the lowest (<4.14 mmol/L, 160 mg/dl) and highest (≥6.71 mmol/L, 260 mg/dl) total cholesterol (TC) groups, there was a positive association between TC and risk of all-cause mortality (hazard ratio (HR) 1.19; 95% confidence interval (CI), 1.03-1.37 and 1.36 (95% CI, 1.05-1.77), respectively). The lowest TC group had an increased risk of liver disease (HR 3.03; 95% CI, 1.70-5.43), whereas the highest TC group had an increased risk of coronary heart disease (HR 3.81; 95% CI, 1.70-5.43). After exclusion of deaths due to liver disease during the entire follow-up period and all-cause deaths within the first 5 years of follow-up, the increased HR in the lowest TC group disappeared (HR 1.05; 95% CI, 0.89-1.24). Although the cut-off point seemed to be higher than that for Western populations, hypercholesterolemia was shown to be positively associated with all-cause mortality in Japan. © 2006 Elsevier Ireland Ltd. All rights reserved.

Background: Studies have shown that baseline serum γ- glutamyltransferase (GGT) is independently associated with cardiovascular disease (CVD) risk in men and women. However, less is known whether GGT is similarly associated with both stroke and heart disease (HD) risk in Asia. We examined an association between serum GGT and deaths from stroke and HD in Japanese men and women. Methods: From 1990 to 2005, we followed 7488 adults (3089 men) randomly selected from 300 districts throughout Japan, aged 30-95 with no history of coronary disease nor stroke at baseline. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) according to sex-specific GGT strata. Results: During the study period, observed deaths from HD and stroke were 165 (83 men), and 135 (66 men), respectively. After adjustment for confounding factors, HRs of HD death for 25th, 50th, 75th, and 90th GGT percentiles in reference to the lowest GGT stratum were 1.61, 2.28, 2.48, and 4.59 in women (P for trend = 0.001), and 0.90, 0.74, 1.42, and 1.56 in men (P for trend = 0.250). The corresponding HRs of total stroke death were 1.52, 0.95, 1.22, and 1.34 in women (P for trend = 0.785), and 0.75, 0.91, 1.26, and 1.02 in men (P for trend = 0.642). Results were similar when analysis was limited to never-drinkers. Conclusion: This cohort study of representative Japanese men and women suggested that baseline GGT independently predicts future HD mortality risk, especially in women, but not stroke mortality risk in Asian. © 2010 World Heart Federation. Published by Elsevier Ltd. All rights reserved.

Background: Risk factor clustering, the so-called metabolic syndrome (MetS), is an important risk factor for cardiovascular disease (CVD). Smoking is also an important CVD risk factor with still a high prevalence. However, few previous studies have compared the risk for CVD or the population-attributable fraction (PAF) of smoking, MetS, and both. Methods and Results: The present study was an 11.9-year cohort study of 1,822 men and 2,089 women, aged 40-74 years, selected randomly from an urban general population in Japan. MetS was defined according to the National Cholesterol Education Program on Adult Treatment Panel III (NCEP-ATPIII) guideline modified by the Asian criteria for waist circumference. The prevalence of smoking was 49.5% in men and 11.1% in women, and that of MetS was 19.8% and 23.5%, respectively. In men, the multivariate-adjusted hazard ratio for CVD incidence, compared with non-smoking participants without MetS, was 2.07 (1.26-3.40) in those who smoked, 2.09 (1.08-4.04) in those with MetS, and 3.56 (1.89-6.72) in those with both. In men the PAF for CVD incidence was 21.8% because of smoking, 7.5% because of MetS, and 11.9% because of both. Conclusions: Although countermeasures for MetS are important, smoking should continue to be considered an important public health problem and antismoking campaigns should be promoted, especially for men, to prevent CVD.

Background. Several epidemiological studies have shown that self-reported vision and hearing impairments are associated with adverse health outcomes (AHOs) in older populations; however, few studies have used objective sensory measurements or investigated the role of gender in this association. Therefore, we examined the association of vision and hearing impairments (as measured by objective methods) with AHOs (dependence in activities of daily living or death), and whether this association differed by gender. Methods. From 2005 to 2006, a total of 801 residents (337 men and 464 women) aged 65 years or older of Kurabuchi Town, Gunma, Japan, participated in a baseline examination that included vision and hearing assessments; they were followed up through September 2008. Vision impairment was defined as a corrected visual acuity of worse than 0.5 (logMAR = 0.3) in the better eye, and hearing impairment was defined as a failure to hear a 30 dB hearing level signal at 1 kHz in the better ear. Information on outcomes was obtained from the town hall and through face-to-face home visit interviews. We calculated the risk ratios (RRs) of AHOs for vision and hearing impairments according to gender. Results. During a mean follow-up period of 3 years, 34 men (10.1%) and 52 women (11.3%) had AHOs. In both genders, vision impairment was related to an elevated risk of AHOs (multi-adjusted RR for men and women together = 1.60, 95% CI = 1.05-2.44), with no statistically significant interaction between the genders. In contrast, a significant association between hearing impairment and AHOs (multi-adjusted RR = 3.10, 95% CI = 1.43-6.72) was found only in the men. Conclusion. In this older Japanese population, sensory impairments were clearly associated with AHOs, and the association appeared to vary according to gender. Gender-specific associations between sensory impairments and AHOs warrant further investigation. © 2009 Michikawa et al; licensee BioMed Central Ltd.

Salt intake is an important risk factor for hypertension. Because it has been reported that increased salt intake dulls the taste of salt, measuring the sense of taste might be a good way of identifying individuals who consume excessive salt. Using a recently developed simple salt taste test, we investigated the relationship between the taste of salt and blood pressure. The subjects in this cross-sectional study were 823 Japanese adults (479 women and 344 men) 40 years old or older. Following a taste test with salt-impregnated taste strips, the subjects were divided into two groups: normal (recognition threshold of salt at <1.0% concentration) and taste impaired (≥1.0%). We determined hypertension from the measured blood pressure. In women, the multi-adjusted odds ratio (95% CI) of hypertension in the impaired group was 2.47 (1.53-3.99) compared with the normal group, whereas no significant difference was observed between the two male groups. When we excluded subjects with moderate and severe hypertension, similar findings were observed. A sub-analysis of couples living alone showed a higher prevalence of hypertension among men whose wives were in the impairment group (58.8%) than in the normal group (36.7%, P=0.10). In conclusion, the taste of salt is associated with blood pressure in Japanese women, but not in men. Because most family meals in Japan are prepared by women, educating women about salt reduction may contribute to the prevention of hypertension, not only among women but also among their husbands and family members.

Chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease (CVD), and may also lead to an increase in medical expenditures. The effect of CKD on individual and population medical expenditures was examined in a Japanese cohort study. The participants included 4026 Japanese National Health Insurance beneficiaries aged 40-74 years living in one city, who had no history of major CVD. They were classified into three categories according to their glomerular filtration rate (GFR) at the baseline survey, and their total medical expenditures were followed-up for 3 years. The arithmetic and geometric means of the cumulative medical expenditures were calculated for each category. The geometric mean was also expressed after adjusting for several confounding factors using analysis of covariance. The CKD-related medical expenditures attributable to the participants with mild (60 ≤ GFR<90) or moderate (30 ≤ GFR<60) kidney dysfunction were compared with those of participants with normal (GFR < 90) kidney function. There was a negative correlation between the GFR category and the arithmetic and geometric means of personal medical expenditures (adjusted geometric mean: GFR < 90, 167879 yen; 60 ≤GFR <90, 210660 yen; and 30 ≤ GFR<60, 330050 yen). The CKD-related medical expenditures accounted for 11.5 and 6.5% of the total medical expenditures for the participants with mild and moderate kidney dysfunction, respectively. The prevention of mild CKD is very important for containing medical expenditures. Appropriate strategies, such as regular creatinine measurement, are needed for early detection of CKD.

Few studies have examined the association between Japanese diet and mortality outcomes. We analysed the relationship between a healthy Japanese diet and all-cause and cause-specific mortality using the database from the National Integrated Project for Prospective Observation of Non-Communicable Diseases and its Trends in the Aged, 1980. At baseline in 1980, data were collected on study participants aged ≧30 years from randomly selected areas in Japan. We defined a measure of a healthy reduced-salt Japanese diet based on seven components from FFQ. The total score ranged from 0 to 7, with 0 being least healthy and 7 being most healthy. Participants were divided into approximate tertiles of dietary scores (0-2, 3 and 4-7 scores). After excluding participants with co-morbidities, we followed 9086 participants (44% men) for 19 years. There were 1823 all-cause and 654 cardiovascular deaths during the follow-up. With the dietary score group 0-2 serving as a reference, the Cox multivariate-adjusted hazard ratios for groups with scores 3 and 4-7 were 0.92 (95% CI 0.83, 1.04) and 0.78 (95% CI 0.70, 0.88) for all-cause mortality (trend P<0.0001), and 0.91 (95% CI 0.75, 1.10) and 0.80 (95% CI 0.66, 0.97) for cardiovascular mortality (trend P = 0.022). Adherence to a healthy reduced-salt Japanese diet was associated with an approximate 20% lower rate of all-cause and cardiovascular mortality.

Aim: Little is known about the prognostic value of q wave abnormality for cardiovascular disease (CVD) on a resting electrocardiogram (ECG) of the Japanese general population with an extremely low incidence of myocardial infarction. Methods: We followed 8,339 participants without a past and present history of CVD for 19 years. The multivariate-adjusted hazard ratio (HR) of q wave abnormality for CVD mortality was estimated by the Cox proportional hazards model. Results: The multivariate-adjusted HR of composite findings of moderate or severe q wave abnormality was 1.75 (95% confidence interval (CI): 0.97-3.17) for mortality due to CVD and 2.97 (95%CI: 1.43-6.16) due to heart diseases. The multivariate-adjusted HR of mild abnormality for mortality from heart diseases was 1.95 (95%CI: 1.00-3.81). The relationship between moderate or severe abnormalities and mortality from CVD was unchanged when participants with ST-T changes and high amplitude R waves were excluded and when participants were divided by the presence of major CVD risk factors such as hypertension. Q wave abnormality was not associated with the risk of stroke. Conclusion: Moderate or severe q wave abnormalities are prominent and important predictors of mortality due to CVD and heart disease in the Japanese general population without CVD history.

Although several studies have reported on the relation between high blood pressure (BP) and impaired activities of daily living (ADL), only a few studies have reported on the relation of high BP in middle-aged subjects with future impaired ADL. Furthermore, no studies reported an excess impaired ADL due to non-normal BP. Using ADL 1999 data, we compared data from NIPPON DATA80 survivors without impaired ADL (N = 1816) with those with impaired ADL (N = 75) using baseline BP information collected in 1980. We analysed participants who were aged 47-59 years at baseline. Multiple adjusted logistic regression analyses were used to estimate the risk of impaired ADL, according to baseline BP categories using Joint National Committee 7 guidelines (normal BP, prehypertension, stage 1 hypertension (HT) and stage 2 HT). Subjects who used antihypertensive medications were classified as having stage 2 HT. We calculated excess impaired ADL due to non-normal BP. Compared with normal BP categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) of having impaired ADL was higher in subjects with prehypertension (OR = 1.50, 95% CI: 0.55-4.09), stage 1 HT (OR = 1.56, 95% CI: 0.56-4.32) and stage 2 HT (OR = 2.96, 95% CI: 1.09-8.05). Non-normal BP explained 45% (33.7/75) of impaired ADL. A positive relation of BP categories with the composite end point of mortality and impaired ADL was also observed. In conclusion, controlling BP in middle age may prevent deaths and future ADL decline.

Although moderate alcohol intake in diabetic Caucasians is associated with a reduction in coronary heart disease mortality, no study in Japanese with diabetes has examined the association between alcohol intake and mortality outcomes. We analyzed the relationship between alcohol intake and all-cause and cause-specific mortality using the database from NIPPON DATA80. At the baseline in 1980, data on history, lifestyle, and physical examinations were collected on study participants aged 30 years and older from randomly selected areas in Japan. After excluding participants with comorbidities, we followed 4,018 male participants (3,614 nondiabetics, 195 with impaired glucose tolerance and 209 diabetic) for 19 years. During the 19 years of follow-up, there were 990 deaths; 328 were from cardiovascular disease and 157 from all-heart diseases. With the never-drinking category serving as a reference, the Cox multivariate-adjusted hazard ratios for non-daily and daily drinkers for cardiovascular mortality were 0.43 (95% confidence intervals: 0.19-0.95) and 0.45 (0.25-0.80), respectively, and 0.33 (0.12-0.91) and 0.31 (0.15-0.67) for all-heart disease mortality in the combined impaired glucose tolerance and diabetic Japanese men. Alcohol drinking in men with glucose intolerance was associated with a significant reduction in cardiovascular and all-heart disease mortality as seen in the general population in Japan. © 2009 Elsevier Inc. All rights reserved.

Data from animal studies clearly indicate an association between leptin and hypertension; results of human studies are less concordant. We investigated the role of leptin in obesity-related higher blood pressure (BP) in Japanese Americans living in Hawaii and Japanese in Japan. Serum leptin and BP were examined by standardized methods in men and women ages 40 to 59 years from 2 population samples, one Japanese American in Hawaii (88 men and 94 women) and the other Japanese in central Japan (123 men and 111 women). Multiple linear regression models were used to assess role of leptin in obesity-related higher BP. Across quartiles of leptin, there were significantly higher mean body mass index levels, systolic BP, and diastolic BP for both sexes and sites (P<0.01 to 0.02). In multivariate regression analyses using all of the data combined, relations of body mass index and leptin to systolic BP and diastolic BP remained significant with the interaction term (body mass index×log-leptin) in the models (P<0.01 to <0.05). These findings are consistent with the inference that leptin may be an independent mediator for obesity-related elevations in BP. © 2009 American Heart Association. All rights reserved.

Background: Almost no studies have investigated the relationship between food intake measured at middle age and future disability. Objective: To examine the association of meat, fish and egg intake with risk of subsequent mortality and/or future decline in activities of daily living (ADL) among the elderly. Methods: The cohort consisted of 2,316 Japanese individuals aged 47-60 at the baseline who were randomly selected throughout Japan and followed up for 19 years from 1980. Results: Those who ate meat at least once every 2 days were younger, there were more men, daily drinkers, professional workers and urban residents compared to those who ate meat less than once every 2 days. Over 19 years of follow-up, 75 participants became dependent due to impaired ADL. A higher intake of meat was associated with a statistically significant decrease in impaired ADL occurrence (odds ratio = 0.61, 95% confidence intervals 0.38-0.99, p = 0.04). Fish and egg intake were not associated with any difference in impaired ADL occurrence. None of the 3 foods were associated with any changes in mortality. Conclusion: A higher intake of meat may prevent impaired ADL occurrence, although this was not associated with a lower mortality. Copyright © 2009 S. Karger AG, Basel.

The relation between cholesteryl ester transfer protein (CETP) levels and atherosclerosis is controversial. We examined whether the serum CETP levels were associated with subclinical atherosclerosis, independent of its most common gene variant, in a sample of Japanese men. A population-based cross-sectional study of 250 Japanese men aged 40 to 49 years was conducted to assess the intima-media thickness of the carotid artery, coronary artery calcium, serum CETP levels, and the CETP D442G gene variant. Compared with the lowest CETP quartile, the multivariate adjusted odds ratio for coronary artery calcium was 0.77 (95% confidence interval 0.18 to 3.36), 0.96 (95% confidence interval 0.27 to 3.40), and 3.49 (95% confidence interval 1.05 to 11.6) with increasing CETP quartiles. The serum CETP quartiles were also positively associated with the intima-media thickness of the carotid artery (adjusted mean 602, 616, 615, and 646 μm for the lowest to top quartile, respectively). The findings remained unchanged after additional adjustment for the CETP D442G gene variant. No significant difference was found in the prevalence of coronary artery calcium or in the mean intima-media thickness of the carotid artery between participants with and without the CETP D442G gene variant. © 2009 Elsevier Inc. All rights reserved.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), one of the isoforms of the 11β-hydroxysteroid dehydrogenase enzymes, acts as an oxo-reductase to reactivate cortisone to cortisol, plays a critical role in tissue-specific corticosteroid reactions, and is therefore a key molecule associated with the development of metabolic syndrome. We investigated whether variations in the 11β-HSD1 gene correlated with metabolic syndrome. We performed case-control study using a population-based urban Japanese cohort. Among 3005 urban residents, we examined 431 subjects diagnosed with metabolic syndrome according to the Japanese definition and 777 subjects with none of metabolic syndrome criteria as control. We genotyped three single nucleotide polymorphisms (SNPs) (+9410T>A, +17925C>T, +27447G>C) across the 11β-HSD1 gene in them and analyzed the associations of SNPs and haplotypes with metabolic syndrome. The +9410A allele showed a tendency to metabolic syndrome (OR = 1.5, 95%C.I., 1.0-2.2; P = 0.041 and Bonferroni corrected P = 0.123) without statistical significance. However, we could not find any significant association between metabolic syndrome and SNPs in the 11β-HSD1 gene. Our findings indicate that polymorphisms and haplotypes in the 11β-HSD1 gene are not significantly associated with metabolic syndrome in the Japanese population. © 2009 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND AND PURPOSE-: Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for stroke and myocardial infarction (MI). Few studies, however, have examined the relationship between blood pressure (BP) category and these diseases in subjects with and without CKD. METHODS-: We studied 5494 Japanese individuals (ages 30 to 79, without stroke or MI at baseline) who completed a baseline survey and received follow-up through December 2005. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease study equation modified by the Japanese coefficient. CKD was defined as an estimated GFR <60 mL/min/1.73m. BP categories were defined by the European Society of Hypertension and European Society of Cardiology 2007 criteria. RESULTS-: In 64 395 person-years of follow-up, we documented 346 incidences of cardiovascular diseases (CVD; 213 strokes and 133 MI events). Compared with the GFR (≥90 mL/min/1.73m) group, the hazard ratios (95% confidential intervals) for stroke were 1.9 (1.3 to 3.0) in the GFR 50 to 59 mL/min/1.73m group and 2.2 (1.2 to 4.1) in the GFR <50 mL/min/1.73m group. Results for cerebral infarction were similar. Compared with the optimal BP subjects without CKD, the normal BP, high-normal BP, and hypertensive subjects without CKD showed increased risks of CVD and stroke; however the impact of each BP category on CVD (P for interaction: 0.04 in men, 0.49 in women) and stroke (0.03 in men, 0.90 in women) was more evident in men with CKD. CONCLUSIONS-: CKD may increase the association of BP and CVD in a Japanese urban population. © 2009 American Heart Association, Inc.