Published papers

Objective: The individual components of metabolic syndrome are defined as levels ranging from moderate to high level as to require medication. We investigated the impact of moderate metabolic risk factor clustering on cardiovascular disease (CVD) mortality. Methods: We followed up 6758 non-lean Japanese in randomly selected areas from all over the country who had no history of CVD for 15 years. The multivariate-adjusted hazards ratio (HR) and 95% confidence interval (CI) for CVD mortality according to the number of moderate metabolic risk factors (BMI≥25kg/m2, 130/85mmHg≤systolic/diastolic BP<140/90mmHg, 140mg/dl≤casual blood glucose<200mg/dl, triglycerides≥150mg/dl and/or HDL cholesterol<40mg/dl [men], 50mg/dl [women]) were estimated using the Cox proportional hazards model. The population-attributable risk fraction of moderate metabolic risk factor clustering was also estimated. Results: During the follow-up, 282 participants died of CVD. CVD mortality tended to increase with the number of moderate metabolic risk factors. However, they were not statistically significant. The multivariate-adjusted HRs were 1.82 (95%CI: 0.89-3.73) for having any moderate metabolic risk factors and 2.87 (95%CI: 1.46-5.64) for having any medication-required metabolic risk factors, compared with participants without any moderate metabolic risk factors. The population-attributable risk fractions were 7.3% and 52.4% for any moderate and medication-required metabolic risk factors, respectively. Conclusions: We did not find the statistically significant increase of CVD mortality for moderate metabolic risk factor clustering. Its attribution was relatively small in this Japanese population. More efforts would be required to detect and control medication-required risk factors. © 2010 Elsevier Ireland Ltd.

Background: It has been considered that reducing protein intake is one of important measures to delay the progression of chronic kidney disease (CKD). However, the relationship between protein intake and renal function is still uncertain, especially in relatively healthy general population. Methods: 7404 individuals (3099 men and 4305 women) who participated in both National Survey on Circulatory Disorders and National Nutrition Survey in 1990 and were free from past history of renal diseases were included in the present study. We estimated sex-specific age- and multivariate-adjusted glomerular filtration rate (GFR) and odds ratios for the presence of CKD according to the quartiles of protein (total, animal, vegetable) intake per body weight (kg). Results: There were significant differences in each protein intake among the age groups in both men and women. Both participants with and without CKD took more protein intake than that of each recommended level. There were positive relationships between GFR and the quartiles of each protein intake in both sexes. The odds ratios for the presence of CKD were significantly decreased in the higher quartile of protein intake in women. Conclusions: The higher protein intake was associated with higher GFR in both sexes and low prevalence of CKD in women. However, further studies are needed to conclude the relationships between protein intake and renal function. © 2010 by the Japan Epidemiological Association.

Aim: To examine the relation between lifestyle and the number of metabolic syndrome (MetS) diagnostic components in a general population, and to find a means of preventing the development of MetS components. Methods: We examined baseline data from 3,365 participants (2,714 men and 651 women) aged 19 to 69 years who underwent a physical examination, lifestyle survey, and blood chemical examination. The physical activity of each participant was classified according to the International Physical Activity Questionnaire (IPAQ). We defined four components for MetS in this study as follows: 1) high BP: systolic BP ≥ 130 mmHg or diastolic BP ≥85 mmHg, or the use of antihypertensive drugs; 2) dyslipidemia: high-density lipoprotein-cholesterol concentration <40 mg/dL, triglycerides concentration ≥150 mg/dL, or on medication for dyslipidemia; 3) Impaired glucose tolerance: fasting blood sugar level ≥110 mg/d, or if less than 8 hours after meals ≥140 mg/dL), or on medication for diabetes mellitus; 4) obesity: body mass index ≥25 kg/m2. Results: Those who had 0 to 4 MetS diagnostic components accounted for 1,726, 949, 484, 190, and 16 participants, respectively, in the Poisson distribution. Poisson regression analysis revealed that independent factors contributing to the number of MetS diagnostic components were being male (regression coefficient b = 0.600, p<0.01), age (b = 0.027, p<0.01), IPAQ class (b = -0.272, p = 0.03), and alcohol consumption (b = 0.020, p = 0.01). The contribution of current smoking was not statistically significant (b = -0.067, p = 0.76). Conclusion: Moderate physical activity was inversely associated with the number of MetS diagnostic components, whereas smoking was not associated.

The purpose of this study was to investigate the relationship between the frequency of outpatient visits and hypertension control as determined from health insurance records. This 9-year cohort study in Japan was based on 518 participants with hypertension who underwent health checkups in 2004. Participants were aged 35-56 years and none had a history of cardiovascular or cerebrovascular disease. All were covered by the same employee health insurer. Mean annual outpatient visit days at a hospital/clinic during the 9-year period were classified within four quartiles (Q1, Q2, Q3, Q4). Uncontrolled hypertension was defined as a systolic blood pressure (BP) ≥140 mm Hg and a diastolic BP ≥90 mm Hg. Logistic regression analysis was used to estimate the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of uncontrolled hypertension in groups Q1, Q2 and Q3 vs. Q4. The median (25th-75th percentile) annual outpatient visit days was 9.4 (4.0-15.5). Uncontrolled hypertension was observed in 62.4% of the participants in 2013. The multivariable-adjusted ORs and 95% CIs for uncontrolled hypertension in Q1, Q2 and Q3 vs. Q4 were 4.03 (2.28-7.12), 1.67 (0.99-2.81) and 1.44 (0.86-2.41), respectively. Uncontrolled hypertension increased significantly as the number of outpatient visits decreased (P for trend

Purpose: Low-carbohydrate diets (LCD) are a popular dietary strategy for weight reduction. The effects of LCD on long-term outcome vary depending on type of LCD, possibly due to the fact that effects on cardiometabolic risk factors may vary with different types of LCD. Accordingly, we studied these relations. Methods: We assessed serum concentrations of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), high-sensitivity C-reactive protein (CRP), total cholesterol, glycated hemoglobin, and uric acid, and nutrient intakes by standardized methods in men and women ages 40–59 years from four population samples of Japanese in Japan (553 men and 544 women, combined). For people consuming usual, animal-based, and plant-based LCDs, we calculated LCD scores, based on relative level of fat, protein, and carbohydrate, by modifying the methods of Halton et al. Instead of calculating scores based on animal or vegetable fat, we used saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA) + polyunsaturated fatty acids (PUFA). Results: In multivariate regression analyses with adjustment for site, age, sex, BMI, smoking, alcohol intake, physical activity, and years of education, all three LCD scores were significantly positively related to HDLc (all P < 0.001), but not to LDLc. The plant-based LCD score was significantly inversely related to log CRP (coefficient = −0.010, P = 0.018). Conclusions: All three LCD scores were significantly positively related to HDLc. The plant-based LCD score was significantly inversely related to CRP. Carbohydrate intake below 50 % of total energy with higher intakes of vegetable protein and MUFA + PUFA, and lower intakes of SFA may be favorable for reducing cardiometabolic risk factors.

© 2020, Japan Atherosclerosis Society. All rights reserved. Aims: The present study was conducted to establish a practical method for measuring non-cholesterol sterols and reference intervals of serum levels. Methods: Healthy subjects (109 men and 151 women), four patients with sitosterolemia, and 10 heterozygous mutation carriers of ABCG5/ABCG8 genes were investigated. Then, three non-cholesterol sterols (sitosterol, campesterol, and lathosterol) of fasting serum samples were measured via a practical and highly sensitive gas chromatography (GC) method with 0.2 µg/mL as the lower limit of quantification. The coefficient of variation (CV) values for within-run reproducibility were 3.06%, 1.89%, and 1.77% for lathosterol, campesterol, and sitosterol, respectively. The CV values for between-run reproducibility were 2.81%, 2.06%, and 2.10% for lathosterol, campesterol, and sitosterol, respectively. Results: The serum levels of sitosterol and campesterol were significantly higher in women than in men, whereas the serum levels of lathosterol were significantly higher in men than in women. Because of these gender difference, the determination of reference intervals of the three sterol values was performed by considering gen-der. The reference intervals of sitosterol, campesterol, and lathosterol were 0.99–3.88, 2.14–7.43, and 0.77–3.60 µg/mL in men and 1.03–4.45, 2.19–8.34, and 0.64–2.78 µg/mL in women, respectively. The serum levels of sitosterol and campesterol were higher in patients with sitosterolemia (94.3±47.3 and 66.3±36.6 µg/mL, respectively) than in healthy subjects. Conclusion: These results demonstrate a practical and highly sensitive GC method to measure non-cholesterol sterol levels and gender-segregated reference intervals of sitosterol, campesterol, and lathosterol in Japanese healthy subjects.

Aim: The Framingham risk score (FRS) is one of the standard tools used to predict the incidence of coronary heart disease (CHD). No previous study has investigated its efficacy for a Japanese population cohort. The purpose of this study was to develop new coronary prediction algorithms for the Japanese population in the manner of the FRS, and to compare them with the original FRS.Methods: Our coronary prediction algorithms for Japanese were based on a large population-based cohort study (Suita study). The study population comprised 5,521 healthy Japanese. They were followed-up for 11.8 years on average, and 213 cases of CHD were observed. Multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model.Results: Our coronary prediction algorithms for Japanese patients were based on a large population-based cohort study (the Suita study). A multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model. The C-statistics showed that the new model had better accuracy than the original and recalibrated Framingham scores. The net reclassification improvement (NRI) by the Suita score with the inclusion of CKD was 41.2% (P＜0.001) compared with the original FRS. The recalibration of the FRS slightly improved the efficiency of the prediction, but it was still worse than the Suita score with the CKD model. The calibration analysis suggested that the original FRS and the recalibrated FRS overestimated the risk of CHD in the Japanese population. The Suita score with CKD more accurately predicted the risk of CHD.Conclusion: The FRS and recalibrated FRS overestimated the 10-year risk of CHD for the Japanese population. A predictive score including CKD as a coronary risk factor for the Japanese population was more accurate for predicting CHD than the original Framingham risk scores in terms of the C-statics and NRI.

Aims Left bundle branch block (LBBB) is generally considered to be associated with a poorer prognosis in comparison with normal controls. However, there are some studies that showed no difference in prognosis of LBBB in comparison with normal controls. Methods and Results We studied prognostic values of BBBs on cardiovascular disease (CVD) and total mortality using the NIPPON DATA80 database with a 24-year follow-up. At the baseline in 1980, data were collected on study participants, ages 30 years and over, from randomly selected areas in Japan. We followed 9,090 participants (44% men, mean age 51). During the 24 year follow-up, there were 886 CVD, and 2,597 total mortality cases. Among participants, 0.2% of them were in LBBB, 1.3% in RBBB, 4.3% in other ventricular conduction defect (VCD) groups. The multivariate-adjusted hazard ratio (HR) using the Cox model including biochemical and other ECG variables revealed that LBBB was significantly positively associated with CVD (HR = 2.71, 95% confidence intervals [CI]: 1.35-5.45, P = 0.005), and total (HR = 2.07, 95%CI: 1.26-3.39, P = 0.004) mortality in men and women combined compared to participants without VCD. RBBB and other VCDs did not carry any significant risk for CVD or total mortality. Conclusions We found significant positive associations of LBBB with CVD and total mortality independent of confounding factors including other ECG changes. © 2013 Elsevier Inc.

There are limited studies addressing whether proteinuria and estimated glomerular filtration rate (eGFR) are independently associated with cardiovascular disease in Asia. Using data from 7 prospective cohorts recruited between 1980 and 1994 in Japan, we assessed the influence of proteinuria (≥1+ on dipstick) and reduced eGFR on the risk of cardiovascular disease mortality in 39,405 participants (40-89 years) without kidney failure. During a 10.1-year follow-up, 1,927 subjects died from cardiovascular disease. Proteinuria was associated with a 1.75-fold (95% confidence interval (CI): 1.44, 2.11) increased risk of cardiovascular disease mortality after adjustment for potential confounding factors. Additionally, the multivariate-adjusted hazard ratio of cardiovascular disease mortality increased linearly with lower eGFR levels (Ptrend < 0.001): Subjects with eGFR of <45 mL/minute/1.73 m2 had a 2.22-fold (95% CI: 1.60, 3.07) greater risk of cardiovascular disease mortality than those with eGFR of ≥90 mL/minute/1.73 m2. Subjects with both proteinuria and eGFR of <45 mL/minute/1.73 m2 had a 4.05-fold (95% CI: 2.55, 6.43) higher risk of cardiovascular disease mortality compared with those with neither of these risk factors. There was no evidence of interaction in the relationship between proteinuria and lower eGFR (Pinteraction = 0.77). The present results suggest that proteinuria and lower eGFR are independent risk factors for cardiovascular disease mortality in the Japanese population. © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

Aim: Heterozygous patients of familial hypercholesterolemia (FH) are known to have a high risk of coronary artery disease (CAD). Early diagnosis and prompt treatment are necessary to prevent their CAD. In this study we tried to amend the Japanese diagnostic criteria of FH for general practitioners by examining each component of the current criteria. Methods: A multicenter study was performed, which included 1356 dyslipidemic patients at 6 centers. Pretreatment demographic information including LDL-cholesterol (LDL-C), Achilles tendon thickness (ATT), family history of FH and premature CAD and the result of genetic analysis were analyzed. Results: Of 1356 patients, 419 were diagnosed with FH by criteria in 1988, which were used as a golden standard. We tried to define FH according to 3 conventional major items, i.e., 1) LDL-C, 2) ATT and/or cutaneous nodular xanthomas (CX), 3) family history of FH and/or family history of premature CAD. We then determined the cutoff of LDL-C using the new criteria. When we used 180 mg/dL as the cutoff of LDL-C, 94.3% of FH patients and 0.85% of non-FH satisfied 2 or more criteria. When we used 190 mg/dL, 92.1% of FH and 0.85% of non-FH satisfied 2 or more criteria; therefore, we chose 180 mg/dL for the cutoff of LDL-C in the new criteria and proposed that the diagnosis of definite FH can be made if 2 or more criteria are satisfied. Conclusions: We examined each component for the diagnosis of heterozygous FH in a multicenter study in Japan.

Background: Although clockwise rotation and counterclockwise rotation are distinct findings of the ECG, their prognostic significance is rarely studied. Methods and Results: We studied prognostic values of clockwise and counterclockwise rotation on total, cardiovascular disease (CVD), and subtype mortality using the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980-2004 (NIPPON DATA80) database with a 24-year follow-up. At baseline in 1980, data were collected on study participants aged ≥30 years from randomly selected areas in Japan. We followed 9067 participants (44% men; mean age, 51 years). During the 24-year follow-up, mortality was as follows: 2581 total, 887 CVD, 179 coronary heart disease, 173 heart failure, and 411 stroke. The multivariate-adjusted hazard ratio (HR) with the use of the Cox model including biochemical and other ECG variables revealed that clockwise rotation was significantly positively associated with heart failure in men and women combined (HR=1.79; 95% confidence interval [CI], 1.13-2.83; P=0.013), CVD in men and in men and women combined (HR=1.49; 95% CI, 1.12-1.98; P=0.007 in men; HR=1.28; 95% CI, 1.02-1.59; P=0.030 in combined), and total mortality in men and in men and women combined (HR=1.19; 95% CI, 1.00-1.49; P=0.0496inmen; HR=1.15; 95% CI, 1.00-1.32; P=0.045 in combined). Counterclockwise rotation was significantly inversely associated stroke in men and women combined (HR=0.77; 95% CI, 0.62-0.96; P=0.017), CVD in men and in men and women combined (HR=0.74; 95% CI, 0.59-0.94; P=0.011 in men; HR=0.81; 95% CI, 0.70-0.94; P=0.006 in combined), and total mortality in women (HR=0.87; 95% CI, 0.77-0.98; P=0.023). Conclusions: We found a significant positive association of clockwise rotation and a significant inverse association of counterclockwise rotation with CVD mortality in men and in men and women combined, independent of confounding factors including other ECG changes. © 2012 American Heart Association, Inc.

Little is known about the prognostic value of ST-segment depression and/or T wave (ST-T abnormalities) with or without left high R waves on electrocardiogram recorded at rest for death from cardiovascular disease (CVD) in Asian populations. Japanese participants without a history of CVD and free of major electrocardiographic (ECG) abnormalities were followed for 24 years. Subjects were divided into 4 groups based on baseline ECG findings: isolated left high R waves, isolated ST-T abnormalities, ST-T abnormalities with left high R waves, and normal electrocardiogram. Cox proportional hazard model was used to estimate risk of CVD mortality in groups with ECG abnormalities compared to the normal group. Of 8,572 participants (44.4% men, mean age 49.5 years; 55.6% women, mean age 49.4 years), 1,142 had isolated left high R waves, 292 had isolated ST-T abnormalities, and 128 had ST-T abnormalities with left high R waves at baseline. Multivariable-adjusted hazard ratios of ST-T abnormalities with left high R waves for CVD mortality were 1.95 (95% confidence interval 1.25 to 3.04) in men and 2.68 (95% confidence interval 1.81 to 3.97) in women. Isolated ST-T abnormalities increased the risk for CVD death by 1.66 times (95% confidence interval 1.01 to 2.71) in men and 1.62 times (95% confidence interval 1.18 to 2.24) in women. Association of ECG abnormalities with CVD mortality was independent of age, body mass index, systolic blood pressure, serum cholesterol, blood glucose, smoking and drinking, and antihypertensive medication. In conclusion, ST-T abnormalities with or without left high R waves on electrocardiogram recorded at rest constitute an independent predictor of CVD mortality in Japanese men and women. © 2011 Elsevier Inc. All rights reserved.