Kazuyo Kuwabara

The Relationship between Very High Levels of Serum High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in a 20-Year Follow-Up Study of Japanese General Population

AIMS There is no community-based cohort study to examine the effect of very high level of high-density lipoprotein cholesterol (HDL-C) on coronary heart disease (CHD) and other cause-specific mortality. Therefore, we investigated the relationship between HDL-C including very high level and cause-specific mortality in a 20-year cohort study of the representative sample of Japanese. METHODS We followed 7,019 individuals from the Japanese general population (2,946 men and 4,073 women). We defined HDL-C levels as follow: low (HDL-C ＜1.04 mmol/L), reference (1.04-1.55 mmol/L), high (1.56-2.06 mmol/L), very high (≥2.07 mmol/L). The multivariate adjusted hazard ratio (HR) for all-cause or cause-specific mortality was calculated using a Cox proportional hazards model adjusted for other traditional risk factors. RESULTS During follow-up, we observed 1,598 deaths. No significant association was observed between HDL-C and all-cause mortality. Serum HDL-C also showed no association with stroke. In contrast, the risk for CHD among high HDL-C was lower than reference, HRs were 0.51 [95% confidence interval (CI): 0.21-1.23] in men, 0.33 (95% CI: 0.11-0.95) in women, and 0.41 (95% CI: 0.21-0.81) when men and women were combined. However, very high HDL-C did not show significant association with CHD and other cause-specific mortality. CONCLUSIONS HDL-C was not associated with all-cause and stroke mortality. In contrast, high serum HDL-C levels, at least up to 2.06 mmol/L, were protective against CHD, although further high levels were not. However, sample size of cause-specific death in very high HDL-C group was not enough even in this 20-year follow-up of 7,019 Japanese; larger cohort studies should be warranted.

Profiling of plasma metabolites in postmenopausal women with metabolic syndrome

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/m2, 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.

Relationship between non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in the general population: The KOBE study and Tsuruoka Metabolomic cohort study

AIM The Japan Atherosclerosis Society (JAS) Guidelines for Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases for Japanese 2012 version have set a non-high-density lipoprotein cholesterol (non-HDL-C)-management target of low-density lipoprotein cholesterol (LDL-C) ＋30 mg/dL. However, the actual difference between non-HDL-C and LDL-C is not clear. Therefore, we evaluated its joint distribution and assessed the validity of this criterion in the general Japanese population. METHODS We used baseline cross-sectional data of 4,110 participants from two studies; the KOBE Study (n=1,108) and the Tsuruoka Metabolomic Cohort Study (n=3,002). To evaluate whether the difference between LDL-C and non-HDL-C in the general population match that of the current guidelines, we classified LDL-C levels into four groups according to the JAS Guideline and evaluated its agreement with the corresponding non-HDL-C group. Analysis was also done using six groups (the previous four groups plus the upper and lower cut-off values). RESULTS The mean difference (mg/dL) between the non-HDL-C and LDL-C (for the KOBE Study and Tsuruoka Metabolomic Cohort Study, respectively) was 19.6 and 24.1 (p<0.001) for men and 15.9 and 18.3 (p<0.001) for women. In both the cohort studies, the difference was lower than 30 mg/dL. It was especially small among individuals with normal triglyceride levels. CONCLUSIONS In the general Japanese population, the difference between non-HDL-C and LDL-C was lower than the expected difference of 30 mg/dL. Changes to the criteria for non-HDL-C target levels may be considered in the future.

Metabolic Profiling of Total Physical Activity and Sedentary Behavior in Community-Dwelling Men

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.

Effects of a school-based stroke education program on stroke-related knowledge and behaviour modification-school class based intervention study for elementary school students and parental guardians in a Japanese rural area

Objectives This study aimed to determine the effect of a stroke education programme on elementary school students and their parental guardians in a rural area in Japan that has high stroke mortality. Design School class based intervention study. Setting Eleven public elementary schools in Tochigi Prefecture, Japan. Participants 268 students aged 11–12 years and 267 parental guardians. Interventions Students received lessons about stroke featuring animated cartoons and were instructed to communicate their knowledge about stroke to their parental guardians using material (comic books) distributed in the lessons. Stroke knowledge (symptoms, risk factors and attitude towards stroke) and behavioural change for risk factors were assessed at baseline, immediately after the programme and at 3 months. We also evaluated behavioural change for risk factors among parental guardians. Results The percentage of students with all correct answers for stroke symptoms, risk factors and the recommended response to stroke was significantly increased at 3 months P<0.001). We observed a significant increase in the percentage of guardians who chose all correct symptoms (P<0.001: 61.0% vs 85.4%) and risk factors (P<0.001: 41.2% vs 59.9%) at 3 months compared with baseline. The percentage of parental guardians with a high behavioural response to improving risk factors was significantly increased at 3 months compared with baseline (P<0.001). Conclusions In a rural population with high stroke mortality, stroke education can improve knowledge about stroke in elementary school students and their parental guardians. Ethics and dissemination We conducted the intervention as a part of compulsory education; this study was not a clinical trial. This study was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (M27-026).

Reliability of plasma polar metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry

Background Cohort studies with metabolomics data are becoming more widespread, however, large-scale studies involving 10,000s of participants are still limited, especially in Asian populations. Therefore, we started the Tsuruoka Metabolomics Cohort Study enrolling 11,002 community-dwelling adults in Japan, and using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography–mass spectrometry. The CE-MS method is highly amenable to absolute quantification of polar metabolites, however, its reliability for large-scale measurement is unclear. The aim of this study is to examine reproducibility and validity of large-scale CE-MS measurements. In addition, the study presents absolute concentrations of polar metabolites in human plasma, which can be used in future as reference ranges in a Japanese population. Methods Metabolomic profiling of 8,413 fasting plasma samples were completed using CE-MS, and 94 polar metabolites were structurally identified and quantified. Quality control (QC) samples were injected every ten samples and assessed throughout the analysis. Inter- and intra-batch coefficients of variation of QC and participant samples, and technical intraclass correlation coefficients were estimated. Passing-Bablok regression of plasma concentrations by CE-MS on serum concentrations by standard clinical chemistry assays was conducted for creatinine and uric acid. Results and conclusions In QC samples, coefficient of variation was less than 20% for 64 metabolites, and less than 30% for 80 metabolites out of the 94 metabolites. Inter-batch coefficient of variation was less than 20% for 81 metabolites. Estimated technical intraclass correlation coefficient was above 0.75 for 67 metabolites. The slope of Passing-Bablok regression was estimated as 0.97 (95% confidence interval: 0.95, 0.98) for creatinine and 0.95 (0.92, 0.96) for uric acid. Compared to published data from other large cohort measurement platforms, reproducibility of metabolites common to the platforms was similar to or better than in the other studies. These results show that our CE-MS platform is suitable for conducting large-scale epidemiological studies.

Spreading Awareness of Stroke through School-Based Education: A Pooled Analysis of Three Community-Based Studies

BACKGROUND Advancing school-based education is a promising means to spread knowledge pertaining to stroke. The aim of the current study was to clarify whether stroke lessons provided by schoolteachers could deliver stroke knowledge to children (aged 9-11 years) and their parents, at a similar level to when taught by medical staff. METHODS Schoolteachers conducted lessons on stroke for school children using the educational materials we prepared (i.e., the teacher group; 1051 children and 719 parents). This was compared with our previous data from Akashi city and Tochigi prefecture, in which the stroke lessons were conducted by medical staff (i.e., the medical group; 1031 children and 756 parents). Three campaigns were conducted between September 2014 and May 2016. Each child was given education materials to take home to discuss stroke with their parents. The children and their parents answered questionnaires on stroke knowledge, at baseline, immediately after the lesson, and at 3 months after the lesson. RESULTS Compared with the time point before the lesson, both children and parents instructed by the teacher group showed significant increases in the scores about stroke symptoms and risk factors, immediately and at 3 months after the lesson (P < .001). The combined analysis for the group instructed by medical personnel showed no significant differences in the stroke knowledge scores between the 2 groups at 3 months. CONCLUSIONS Teacher-led lessons, using our educational material, adequately delivered knowledge of stroke to children and parents, in a manner that was similar to when medical staff delivered this information.

Impacts of chronic kidney disease and diabetes on cardiovascular mortality in a general Japanese population: A 20-year follow-up of the NIPPON DATA90 study:

Background Studies have shown significant associations of chronic kidney disease (CKD) and diabetes mellitus (DM) with cardiovascular disease (CVD) mortality. The impact on the general population is an important public health issue. However, the population attributable fraction (PAF) of CVD because of CKD and/or DM in a general population is uncertain. Methods We followed 7229 participants (age: ≥30 years) with no history of CVD in a Japanese community. We divided participants into four categories according to CKD and/or DM and calculated hazard ratios (HRs) of CVD mortality for each category using a Cox proportional hazards model adjusted for age, dyslipidemia, smoking and alcohol consumption. In addition, PAFs of CVD were estimated among populations with CKD and/or DM. Results During 20-year follow-up, 488 participants died. HRs for CVD were 1.63 [95% confidence interval (CI): 1.16–2.30] with DM only, 1.42 (95% CI: 1.08–1.86) with CKD only and 2.37 (95% CI: 1.40–4.01) with CKD + DM. In men, the corresponding HRs for CVD were 1.88 (95% CI: 1.19–2.97), 1.71 (95% CI: 1.15–2.56) and 3.26 (95% CI: 1.69–6.30), respectively; the corresponding PAFs of CVD were 4.1%, 5.1% and 2.9%, respectively. PAFs for CVD among women were lower than those in men, 1.6% for DM only, 2.0% for CKD only and 0.7% for CKD + DM. Conclusions PAFs of CVD mortality due to CKD and/or DM were not so high in past 20 years; however, they might increase in the future because of recent increase in prevalence of these in Japanese population.

Positive Association of Plasma Homocysteine Levels with Cardio-Ankle Vascular Index in a Prospective Study of Japanese Men from the General Population

AIM Observational studies have reported that elevated homocysteine (Hcy) levels are associated with the risk of cardiovascular disease (CVD). However, interventions that lower Hcy do not provide a corresponding risk reduction. Therefore, the causal role of Hcy in CVD remains unclear. This 5-year prospective study investigated the associations of Hcy levels, folate intake, and host factors with arterial stiffness among the general Japanese population. METHODS We prospectively recruited 658 participants (40-69 years old) from the general population during regular health checkup examinations. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) at baseline and the 5-year follow-up. Folate intake was estimated using a structured questionnaire. Genotyping was used to evaluate the MTHFR C677T and MS A2756G gene polymorphisms. Ultrafast liquid chromatography was used to measure total plasma Hcy levels. Association between these variables and CAVI values was evaluated using general linear regression and logistic regression models that were adjusted for atherosclerosis-related factors. RESULTS Men had higher Hcy levels and CAVI values and lower folate intake than women (all, p＜0.001). At baseline, Hcy, folate intake, and the two genotypes were not associated with CAVI values for both sexes. Among men, Hcy levels were positively associated with CAVI values at the 5-year follow-up (p=0.033). Folate intake and the two genotypes were not associated with the 5-year CAVI values. CONCLUSION Plasma Hcy may be involved in arterial stiffness progression, as monitored using CAVI, among men.

Fatty liver index predicts incident diabetes in a Japanese general population with and without impaired fasting glucose

Fatty liver is associated with the development of diabetes. However, to our knowledge, no study has examined the relationship between the fatty liver index (FLI), calculated scores of hepatic steatosis, and the development of diabetes among individuals without impaired fasting glucose (IFG). We aimed to examine whether FLI predicts the development of diabetes in individuals with and without IFG in a Japanese general population.