Published papers

Background: Real-world utilization data for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be introduced in Japan in 2016, to date are limited. This study aimed to clarify the current real-world patient user profiles of evolocumab based on large-scale health claims data. Methods and Results: This retrospective database study examined patients from a health administrative database (MDV database) who initiated evolocumab between April 2016 (baseline) and November 2021. Characteristics and clinical profiles of this patient population are described. In all, 4,022 patients were included in the final analysis. Most evolocumab prescriptions occurred in the outpatient setting (3,170; 78.82%), and 940 patients (23.37%) had a recent diagnosis of familial hypercholesterolemia. Common recent atherosclerotic cardiovascular disease events at baseline included myocardial infarction (1,633; 40.60%), unstable angina (561; 13.95%), and ischemic stroke (408; 10.14%). Comorbidity diseases included hypertension (2,504; 62.26%), heart failure (1,750; 43.51%), diabetes (1,199; 29.81%), and chronic kidney disease (297; 7.38%). Among the lipid-lowering regimens concomitant with evolocumab, ezetimibe+statin was used most frequently (1,281; 31.85%), followed by no concomitant lipid-lowering regimen (1,190; 29.59%), statin (950; 23.62%), and ezetimibe (601; 14.94%). The median evolocumab treatment duration for all patients was 260 days (interquartile range 57-575 days). Conclusions: This study provides real-world insights into evolocumab utilization in Japan for optimizing patient care and adherence to guideline-based therapies to better address hypercholesterolemia in Japan.

Background: Prevention of heart failure (HF) is a public health issue. Using the National Vital Statistics, we explored risk factors for HF and coronary artery disease (CAD) mortality. Methods and Results: Altogether, 7,556 Japanese individuals aged ≥30 years in 1990 were followed over 25 years; of these, 139 and 154 died from HF and CAD, respectively. In multivariable Cox proportional hazard analysis, common risk factors for CAD and HF mortality were hypertension (hazard ratio [HR] 1.48 [95% confidence interval {CI} 1.00–2.20] and 2.31 [95% CI 1.48–3.61], respectively), diabetes (HR 2.52 [95% CI 1.63–3.90] and 2.07 [95% CI 1.23–3.50], respectively), and current smoking (HR 2.05 [95% CI 1.27–3.31) and 1.86 [95% CI 1.10–3.15], respectively). Specific risk factors for CAD were male sex, chronic kidney disease, history of cardiovascular disease, and both abnormal T and Q waves, with HRs (95% CIs) of 1.75 (1.05–2.92), 1.78 (1.19–2.66), 2.50 (1.62–3.88), and 11.4 (3.64–36.0), respectively. Specific factors for HF were current drinking (HR 0.43; 95% CI 0.24–0.78) and non-high-density lipoprotein cholesterol (non-HDL-C; HR 0.81; 95% CI 0.67–0.98). There was an inverse association between non-HDL-C and HF in those aged ≥65 years (HR 0.71; 95% CI 0.56–0.90), but not in those aged <65 years. Conclusions: We identified common risk factors for HF and CAD deaths; a history of cardiovascular disease was a specific risk for CAD.

No large-scale, longitudinal studies have examined the combined effects of blood pressure (BP) and total cholesterol levels on long-term risks for subtypes of cardiovascular death in an Asian population. To investigate these relationships, a meta-analysis of individual participant data, which included 73 916 Japanese subjects (age, 57.7 years; men, 41.1%) from 11 cohorts, was conducted. During a mean follow-up of 15.0 years, deaths from coronary heart disease, ischemic stroke, and intraparenchymal hemorrhage occurred in 770, 724, and 345 cases, respectively. Cohort-stratified Cox proportional hazard models were used. After stratifying the participants by 4 systolic BP ×4 total cholesterol categories, the group with systolic BP ≥160 mm Hg with total cholesterol ≥5.7 mmol/L had the greatest risk for coronary heart disease death (adjusted hazard ratio, 4.39; P<0.0001 versus group with systolic BP <120 mm Hg and total cholesterol <4.7 mmol/L). The adjusted hazard ratios of systolic BP (per 20 mm Hg) increased with increases in total cholesterol categories (hazard ratio, 1.52; P<0.0001 in group with total cholesterol ≥5.7 mmol/L). Similarly, the adjusted hazard ratios of total cholesterol increased with increases in systolic BP categories (P for interaction ≤0.04). Systolic BP was positively associated with ischemic stroke and intraparenchymal hemorrhage death, and total cholesterol was inversely associated with intraparenchymal hemorrhage, but no significant interactions between BP and total cholesterol were observed for stroke. High BP and high total cholesterol can synergistically increase the risk for coronary heart disease death but not for stroke in the Asian population.

This study examined the association between the latest blood pressure (BP) classification and cardiovascular disease (CVD) mortality risk, using data from 70,570 individuals across 10 Japanese cohorts. Participants were stratified by age (40–64 and 65–89 years) and antihypertensive treatment use. BP was classified according to the 2019 Japanese Society of Hypertension Guidelines. During a follow-up period of approximately 10 years, 2304 CVD deaths occurred. Cox models demonstrated that CVD mortality risk increased stepwise with the BP category, with this association being especially pronounced in patients aged 40–64 years, where the Grade I hypertension group showed the highest population-attributable fraction (PAF). When the treated participants were included in the hypertension group, the overall PAF for CVD mortality was 41.1%. Similar patterns were observed for CVD subtype mortality risk, with hypertension showing particularly high PAFs for intracerebral hemorrhage. These findings highlight the importance of early-stage prevention and management of hypertension. (Figure presented.)

© 2019, Japanese Circulation Society. All rights reserved. Background: In recent years, individuals with high serum total cholesterol (TC) have been more likely to modify their diet by reducing their intake of dietary lipids. The aim of this study was to investigate time-related changes in the relationships between the Keys score, dietary lipids, and TC between 1980 and 2010 in representative Japanese populations. Methods and Results: We used 3 cross-sectional cohort studies conducted among Japanese representative populations in 1980, 1990, and 2010 (NIPPON DATA80/90/2010) for the analyses. We analyzed data for 10,365, 7,714, and 2,657 participants, respectively, in each dataset. The relationships between TC and the Keys score (calculated by dietary lipids, cholesterol, and energy intake)/ dietary lipids were examined. In men, a 1-unit higher Keys score correlated with 0.92 mg/dL and 0.64 mg/dL TC in 1980 and 1990, respectively, but not in 2010. In women, a 1-unit higher Keys score correlated with 0.70 mg/dL and 0.74 mg/dL TC in 1980 and 1990, respectively, but with 0.33 mg/dL in 2010. In men and women, dietary cholesterol, saturated fatty acid (SFA), and trans fatty acid (TFA) levels were positively associated with TC concentrations in 1980 and 1990, but not in 2010. Conclusions: In these representative Japanese populations, a higher Keys score as well as dietary cholesterol, SFA, and TFA levels correlated with higher TC concentrations in 1980/1990, but the relationships were weaker or not observed in 2010.

BACKGROUND: Deterioration in lifestyle associated with poor mental health could be an important concern during the coronavirus disease 2019 (COVID-19) pandemic. However, few studies have investigated the association between mental health status and lifestyle changes during the pandemic in nationwide Japanese general population. METHODS: This cross-sectional study was conducted using the data among 1,546 participants of the follow-up study of NIPPON DATA2010 in 2021. Recent mental status, as assessed using the Kessler 6 (K6) scale, and lifestyle changes compared to before the pandemic were determined using self-reported questionnaires. Some lifestyle changes such as decreased physical activity were defined as undesirable, whereas others such as decreased alcohol drinking were defined as desirable. The participants were divided into three groups based on the K6 scores: the K6<5, 5≤K6<9, and K6≥9 groups. The odds ratios (ORs) and 95% confidence intervals (CIs) of the K6 groups for each lifestyle change compared with that in the K6<5 group were estimated after adjusting for possible confounders. RESULTS: The ORs of the K6≥9 group for all undesirable lifestyle changes were significantly high, especially increased alcohol drinking (OR 4.64; 95% CI, 2.71-7.93), and decreased physical activity (OR 4.63; 95% CI, 3.29-6.52). Among the desirable changes, the OR of the 5≤K6<9 group was significantly high for increased eating home cooking. CONCLUSIONS: Poor mental health showed a significant association with undesirable lifestyle changes, especially increased alcohol drinking and decreased physical activity, in a nationwide general Japanese population during the COVID-19 pandemic.

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = − 0.040, SE = 0.011), diastolic BP (β = − 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.

Aim: Sedentary behavior and physical inactivity increase the risk of cardiometabolic diseases. It is important to evaluate physical activity in daily life and understand the influence of these factors on cardiometabolic diseases in the Japanese population, which tends to have a prolonged sitting time. We examined the association between sedentary behavior and physical inactivity, characterized by extended television (TV) viewing and low step counts, which are easily monitored and modifiable, and cardiometabolic risk factors in the Japanese population. Methods: This cross-sectional study included 2,531 Japanese adults (1,087 men and 1,444 women) 20–91 years old, randomly selected throughout Japan. TV viewing was assessed using a self-reported questionnaire, and step counts were measured using pedometers. Cardiometabolic risk factors were determined using physical examinations or blood samples. The association between sedentary behavior and physical inactivity with each risk factor was examined using a cross-sectional analysis with multivariate-adjusted logistic regression models. Results: In both sexes, longer TV viewing positively correlated with low high-density lipoprotein (HDL) cholesterol and high triglycerides (TG). In women, TV viewing time is associated with obesity and increased abdominal circumference (AC). Conversely, in men, lower step counts were positively associated with obesity and increased AC, low HDL cholesterol, and high TG levels. Conclusions: The association between prolonged TV viewing and cardiometabolic risk factors was more pronounced in women than in men, whereas the influence of lower step counts was stronger in men than in women. These findings contribute to the improvement of cardiovascular health by monitoring and managing individual screen times and step counts in daily life.

Aim: Although social participation, defined as involvement in social activities, may be beneficial for cardiovascular health, evidence about the association remains limited. This systematic review summarized the relationship between social participation and cardiovascular risk factors. Methods: Original articles of longitudinal observational studies published in English before January 1, 2024, were searched via PubMed, Scopus, and Cochrane Library. Two investigators selected eligible literature for four health outcomes: hypertension, diabetes, dyslipidemia, and obesity. Results: Eight articles (including duplicates) covering cohort studies were included. The results indicated that social participation is associated with lower hypertension risk, but gender differences may exist in the association between social participation and hypertension. Two articles from a Japanese cohort study were found on diabetes, both of which reported significant preventive association with social participation. The only study on dyslipidemia showed a higher hyperlipidemia risk among women, but not men, with social participation. Two studies on the risk of obesity showed inconsistent results, with one reporting the association between social participation and maintenance of smaller waist circumference only among men, while the other found no association with body mass index. Conclusions: There is some evidence of the association between social participation and better cardiovascular health outcomes. However, evidence on gender differences and validation of the methodology for measuring social participation was still lacking.

Aim: The aim of this study was to clarify the association between serum total cholesterol and fatal subarachnoid hemorrhage in Japanese men and women. Methods: The study involved a pooled analysis of individual data from 12 well-qualified cohort studies conducted in Japan. The participants were classified according to their serum total cholesterol levels: ＜4.14 mmol/L (＜160 mg/dL), 4.14–4.64 mmol/L (160–180 mg/dL), 4.65–5.16 mmol/L (180–199 mg/dL), 5.17–5.68 mmol/L (200–219 mg/dL), 5.69–6.20 mmol/L (220–239 mg/dL), and ≥ 6.21 mmol/L (≥ 240 mg/dL). The outcome of the analysis was death from subarachnoid hemorrhage. Results: A total of 120,973 participants (70,947 women and 50,026 men) aged 18–96 years at baseline underwent follow-up for a median of 12.7 years, and 261 participants died from subarachnoid hemorrhage during this period. In women, both low (＜5.69 mmol/L [＜220 mg/dL]) and high (≥ 6.21 mmol/L [≥ 240 mg/ dL]) serum total cholesterol levels were significantly associated with a higher risk of fatal subarachnoid hemorrhage compared with the reference group (5.69–6.20 mmol/L [220–239 mg/dL]). These associations remained significant after adjustment for confounding factors. In contrast, no associations were observed in men. Conclusion: Both low and high serum total cholesterol levels were associated with a higher risk of fatal subarachnoid hemorrhage in 70,947 female participants from 12 cohort studies throughout Japan.

Objectives: Use of commercially available mobile health (mHealth) applications in supporting lifestyle improvements has become popular in recent years. However, the effectiveness of advice promoting the use of such applications based on individual behavioral goals in a health guidance setting remains unclear. This study explored how guiding participants of the Specific Health Guidance (SHG) program, a Japanese public health initiative to prevent cardiovascular disease, to use commercially available mHealth applications impacted their application usage, lifestyle habits, and cardiovascular risk factors. Methods: In this multicenter, randomized, open-label, parallel-group comparison study, 156 individuals with a history of SHG participation and who were engaged in the Motivational Health Guidance program (a type of SHG) in 2021 were assigned to intervention (n = 76) or control (n = 80) groups. Whereas both groups received standard guidance, the intervention group also received recommendations for mHealth applications based on their individual behavioral goals. The participants' application usage, behavioral changes, and body weight were assessed after 3 months, with health checkup data evaluated after 1 year. Results: The proportion of mHealth application users after 3 months was significantly higher in the intervention group (68.4%) than in the control group (40.0%). The intervention group also reported a significantly greater weekly frequency of mHealth application usage. Moreover, the intervention group reported a significantly decreased change in triglyceride levels after 1 year compared with the control group. Conclusions: Recommending commercially available mHealth applications in a health guidance setting significantly increased the number of mHealth application users and their frequency of use.

Aims: Despite strong recommendations for medical consultation, the treatment status and low-density lipoprotein cholesterol (LDL-C) levels at 1-year follow-up of individuals with referral-level LDL-C identified in health checkups remain unclear. We evaluated the treatment status and 1-year LDL-C control among individuals identified in health checkups as requiring early medical consultation due to LDL-C levels of ≥ 180 mg/dL. Methods: We conducted a nationwide cohort study including health checkup data for individuals aged 20–74 years. We identified 102,049 individuals (median age: 48 years; male: 66.8%) with uncontrolled LDL-C (≥ 180 mg/dL) at baseline, who had no prior lipid-lowering therapy. Poisson regression with robust error variance was used to assess factors associated with uncontrolled LDL-C at 1 year. Results: Among individuals with LDL-C ≥ 180 mg/dL at baseline, 56,147 (55.0%) visited a medical institution within 3 months of the checkup, and 13,124 (12.9%) were prescribed lipid-lowering medications at 1 year. At 1 year follow-up, 49,260 (48.3%) still had LDL-C ≥ 180 mg/dL. Factors associated with persistent LDL-C ≥ 180 mg/dL at 1 year included obesity (RR: 1.07, [95% CI: 1.06–1.09]), 10 mg/dL increase in LDL-C at baseline (1.11 [1.10–1.11]), smoking (1.05 [1.04–1.07]), alcohol consumption (0.95 [0.94–0.97]), poor sleep quality (1.02 [1.01–1.03]), and skipping breakfast ≥ 3 times per week (1.07 [1.05–1.08]). Conclusions: Despite being classified as requiring early medical intervention, only half of individuals with LDL-C ≥ 180 mg/dL visited a physician within 3 months, and nearly half continued to have uncontrolled LDL-C at 1 year. Strategies to facilitate timely medical visits and appropriate lipid management in health checkup-identified cases are warranted.

Background: Obesity has been linked to progressive loss of kidney function, but the independent and combined associations of body mass index (BMI) and visceral fat accumulation remain uncertain in healthy individuals. This study aimed to clarify the longitudinal relationship between BMI, visceral fat area (VFA), and chronic kidney disease (CKD), defined as an estimated glomerular filtration rate based on serum cystatin C (eGFRcys) < 60 mL/min/1.73 m² among the Kobe Study participants targeting healthy urban residents in Japan. Methods: A total of 897 participants (267 men, 630 women) without CKD and with a mean age of 61.4 years were analyzed. VFA was measured using the impedance method, and participants were followed for a median of 8.3 years. Participants were classified into four groups based on baseline BMI (kg/m²) and VFA (cm²): G1 (VFA < 100 and BMI < 25), G2 (VFA < 100 and BMI ≥ 25), G3 (VFA ≥ 100 and BMI < 25), G4 (VFA ≥ 100 and BMI ≥ 25). Multivariable linear regression models were used to estimate adjusted mean annual changes in eGFRcys, and Cox proportional hazards models were applied to calculate hazard ratios (HRs) for incident CKD, adjusting for potential confounders (age, sex, smoking status, alcohol consumption, dyslipidemia, diabetes, hypertension and eGFRcys at baseline). Results: During follow-up, 85 participants (9.5%) developed CKD. The adjusted mean annual decline in eGFRcys was − 2.17% in G1, − 3.29% in G2, − 2.81% in G3, and − 3.81% in G4. Compared with G1, both G3 and G4 showed an elevated risks of CKD incidence (G3: HR 2.40, 95% CI 1.14–5.05; G4: HR 3.89, 95% CI 2.17–6.98), whereas the confidence interval crossed 1 for G2 (HR 0.88, 95% CI 0.12–6.47). Participants in G4 exhibited the steepest decline in kidney function and the highest CKD incidence rate (49.2 per 1,000 person-years). Conclusions: In healthy adults, the combination of elevated BMI and VFA was associated with accelerated kidney function decline. These findings underscore the importance of evaluating visceral fat in addition to BMI for early identification of individuals at increased risk of CKD and enable preventive strategies. Clinical trial number: Not applicable.

Objectives: There is a growing interest in understanding the long-term impact of employment status on psychological stress. We aimed to explore the association between socioeconomic status and psychological stress over a long-term follow-up period across the COVID-19 pandemic, employing the Kessler 6-Item Psychological Distress Scale (K6). Methods: We evaluated K6 scores from the 2021 follow-up survey of NIPPON DATA2010 using a self-administered questionnaire. The association between employment status and changes in K6 scores over 11 years was examined. Multiple regression analyses were used to estimate both crude and adjusted differences in K6 score changes across various socioeconomic factors including employment category, annual household income, marital status, and household size. Analyses were stratified by age, gender, and prefectural population size. Results: This study included 1532 participants with an average age of 54.9 years. Over 11 years (2010–2021), participants in both gender and age groups showed increases in mean K6 scores (men: 2.79 to 3.06; women: 3.15 to 3.56; <65 years: 3.27 to 3.47; ≥65 years: 2.37 to 3.08). Nonemployed participants, particularly homemakers, showed significantly greater increases in K6 scores, compared with full-time employees, especially among women, younger individuals, and those in densely populated areas, with a significant interaction with age. Conclusions: Nonemployed individuals, especially homemakers, experienced greater psychological stress over the past 11 years than did their fully employed counterparts. Public interventions, including strengthened social connections and telemental health services, may help mitigate these disparities, enhance mental well-being, and foster a sense of belonging.