Aims: Although administrative claims databases have recently been used for clinical research in Japan, no detailed description of their utilization in stroke research is available. We reviewed stroke studies using the Diagnosis Procedure Combination (DPC), the National Database of Health Insurance Claims and Specific Health Checkups (NDB), and several commercial databases sourced from social health insurance associations, focusing on their applications and limitations.

Methods: Original articles on stroke published by April 2024 using the DPC, NDB, and commercial databases were identified in Ovid MEDLINE. The characteristics of each database were compared in terms of comprehensiveness, traceability, baseline information, and outcome assessment in stroke research.

Results: A total of 114 studies were included (83 for DPC, 6 for NDB, and 25 for commercial databases). The number of stroke studies using administrative databases in Japan is still approximately 10 per year, although there is a slowly increasing trend. The DPC database was utilized for short-term outcome studies because of its detailed baseline and outcome information, although the inability to track patients once they changed facilities limits their use in long-term studies. The NDB database is potentially useful for long-term studies because of its comprehensiveness and traceability, but difficulties in data access restrict its usage. The most commonly used commercial database utilizes baseline information on lifestyle and blood test data, although the lack of coverage for those over 75 years old may limit its generalizability.

Conclusions: Administrative claims databases are beginning to be used in stroke research in Japan but are not yet fully utilized. Researchers need to understand their applications and limitations.

Intervention for severe aortic stenosis (AS) has dramatically progressed since the introduction of transcatheter aortic valve replacement (TAVR). Decades ago, controversies existed regarding comparing clinical outcomes between TAVR and surgical aortic valve replacement (SAVR) in various risk profiles. Recently, we discussed the durability of transcatheter heart valves and their lifetime management after aortic valve replacement (AVR). Regarding the management of AS, we discuss the appropriate timing of intervention for severe aortic stenosis, especially in asymptomatic patients. In spite of dramatic progression of intervention for AS, there are no established medications available to prevent or slow the progression of AS at present. Basic research and genome studies have suggested several targets associated with the progression of aortic valve calcification. Randomized controlled trials evaluating the efficacy of medications to prevent AS progression are ongoing, which might lead to new strategies for AS management. In this review, we summarize the current management of AS and the drugs expected to prevent the progression of AS.

Aim: Peripheral artery disease (PAD) severely impairs patient prognosis and quality of life (QOL). Although lipoprotein apheresis (LA) has been applied to patients with PAD and elevated serum atherogenic lipoproteins, we hypothesized that LA can be effective for treating PAD even in patients with controlled serum lipoproteins through pleiotropic anti-atherosclerotic effects beyond lipoprotein removal. This study aimed to evaluate the efficacy of LA in patients with treatment-resistant PAD and controlled serum lipoproteins focusing on QOL.

Methods: In a single-arm prospective study, 30 patients with refractory PAD who had controlled serum lipoproteins underwent sequential LA sessions using dextran sulfate adsorption columns, aiming to complete 10 sessions. The ankle-brachial pressure index (ABI) and vascular QOL (VascuQOL) score were evaluated as the primary outcomes. Secondary outcomes included reactive hyperemia index (RHI) and biological antioxidant potential (BAP) as an endothelial function test and serum antioxidative-capacity evaluation, respectively.

Results: ABI significantly increased after LA sessions (pre-treatment 0.60±0.09 vs. post-treatment 0.65±0.13, p=0.023). Total VascuQOL score (3.7±1.1 vs 4.6±1.1, p＜0.001) and RHI (1.70±0.74 vs 2.34±1.76, p=0.023) significantly improved after the LA sessions. BAP tended to increase after the LA sessions, and the change reached statistical significance 3 months after treatment.

Conclusion: ABI and QOL improved after a series of LA sessions in conventional treatment-resistant PAD patients with controlled serum lipoprotein levels. Increased antioxidative capacity and ameliorated endothelial function were observed after the LA treatment.

Aims: Obicetrapib is a highly selective cholesteryl ester transfer protein (CETP) inhibitor shown to reduce low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), when taken as monotherapy and in combination with ezetimibe on a background of statins, in clinical trials predominantly conducted in Northern European/Caucasian participants. We characterized the efficacy, safety, and tolerability of obicetrapib within an Asian-Pacific region population.

Methods: This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL. Endpoints included LDL-C, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol, apolipoproteins, TG, steady state pharmacokinetics (PK) in obicetrapib arms, safety, and tolerability.

Results: In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all p＜0.0001 vs. placebo). The PK profile demonstrated near complete elimination of drug by 4 weeks. Obicetrapib was well tolerated and there were no adverse safety signals.

Conclusions: All doses of obicetrapib taken as an adjunct to stable statin therapy significantly lowered atherogenic lipoprotein lipid parameters, showed near complete elimination of drug by 4 weeks, and were safe and well tolerated in a Japanese population, similar to previous studies of obicetrapib conducted in predominantly Caucasian participants.

Aims: Evidence regarding the modification effects of age, sex, ethnicity, socioeconomic status, or weight status on the associations of sedentary behavior (SB) with cardiovascular diseases (CVDs) is limited. Moreover, the mechanisms for the associations also remain unclear. We aimed to investigate the possible influence of these factors on the associations of SB with CVD events and whether the associations are mediated by metabolic phenotypes.

Methods: This study included 42,619 participants aged 20-74 years, recruited from the Shanghai Suburban Adult Cohort and Biobank study. SB was assessed at baseline and integrated with health information systems to predict future CVD events. Cox proportional hazards models, interaction analyses, restricted cubic splines and causal mediation analyses were used for assessments.

Results: Compared to those with ＜3 h/d sedentary time, participants having SB ≥ 5 h/d had significantly higher risks of CVD (HR[95%CI]: 1.27[1.12-1.44]), coronary heart disease (CHD, 1.35[1.14-1.60]), and ischemic stroke (IS, 1.30[1.06-1.60]). The association of CHD was more pronounced in the retired individuals than their counterparts (1.45[1.20-1.76] versus 1.06[0.74-1.52], p_interaction=0.046). When SB was expressed as a continuous variable, a 1 h/d increment in SB was positively associated with risks of CVD (1.03[1.01-1.05]), CHD (1.04[1.01-1.07]), and IS (1.05[1.01-1.08]). High-density lipoprotein cholesterol (HDL-C, proportion mediated: 12.54%, 12.23%, and 11.36%, all p＜0.001), followed by triglyceride (TG, 5.28%, 4.77%, and 4.86%, all p＜0.01) and serum uric acid (SUA, 3.64%, 4.24%, and 2.29%, all p＜0.05) were major mediators through metabolic phenotypes.

Conclusions: Higher SB was associated with elevated risks of CVD events. The detrimental effect of SB on CHD risk was more pronounced among retired individuals. Moreover, HDL-C, TG and SUA partially mediated the relationships between SB and CVD events. Our findings may have implications for preventing and controlling CVD associated with SB.

Aim: Atrial cardiomyopathy (ACM) is characterized by atrial dysfunction. This study aims to assess the prognostic significance of ACM in patients with noncardioembolic stroke (NCS).

Methods: Patients with NCS within seven days of onset were prospectively enrolled between January 2019 and December 2020. ACM was defined as either an N-terminal pro-brain natriuretic peptide (NT-pro BNP) ＞250 pg/ml or a P-terminal force in precordial lead V1 (PTFV1) ≥ 5000µV·ms. A poor functional outcome was determined as a score of 3-6 on the modified Rankin Scale (mRS) within a 2-year follow-up period. Logistic regression and Cox regression analyses were employed to examine the relationship between ACM and the long-term prognosis of patients with NCS.

Results: A total of 1,346 patients were enrolled, of whom 299 (22.2%) patients were diagnosed with ACM. A total of 207(15.4%) patients experienced a poor functional outcome, and 58 (4.3%) patients died. A multivariate logistic regression analysis indicated that ACM was significantly associated with a poor functional outcome in NCS patients [adjusted odds ratio (aOR): 2.01; 95% confidence interval (CI): 1.42-2.87; p＜0.001]. Additionally, a multivariate Cox regression analysis showed that an NT-pro BNP ＞250 pg/ml was significantly associated with an increased risk of all-cause mortality [adjusted hazard ratio (aHR), 2.51; 95% CI: 1.42-4.43; p=0.001].

Conclusions: ACM may serve as a novel predictor of a poor long-term functional outcome in patients with NCS. Elevated NT-pro BNP levels (＞250 pg/ml) were found to be associated with a higher risk of all-cause mortality. These findings warrant further validation in multicenter studies.

Aim: Older patients with chronic kidney disease (CKD) are more likely to be excluded from clinical trials. This exclusion affects the quality of cardiovascular disease (CVD) prevention in this population.

Methods: Baseline data from the Fukuoka Kidney Disease Registry (FKR) cohort, which included 4476 adult patients with CKD stages G1–G5, were cross-sectionally analyzed to compare the use of recommended drugs for preventing CVD in each age group.

Results: Different prescribing patterns were observed according to age for the cardiovascular drug classes. Older patients with CKD were less likely to receive renin–angiotensin system (RAS) inhibitors and were more likely to receive calcium channel blockers. The proportion of anticoagulation prescriptions for patients with CKD and atrial fibrillation decreased in the older age group (≥ 75 years). However, the proportion of antiplatelet therapy in patients with ischemic CVD increased linearly with age, even in the very old group aged ≥ 85 years. These findings suggest a severe cardiovascular burden in patients with CKD. Notably, RAS inhibitor use was avoided in the older group despite a severe cardiovascular burden, such as a high prevalence of CVD history and massive albuminuria ＞300 mg/g creatinine. This finding indicates that an older age independently contributed to the non-use of RAS inhibitors, even after adjusting for other covariates.

Conclusions: This study suggests that age is a potential barrier to the treatment of patients with CKD and highlights the need to establish individualized treatment strategies for cardiovascular protection in this population.

Aims: Several diet quality indicators have been developed primarily for cardiovascular disease (CVD) prevention in Western countries. However, those previous indicators are complicated and less feasible in clinical and health-promoting settings. Therefore, we aimed to develop a concise dietary risk score for CVD prevention in Japanese.

Methods: Using the self-administered food frequency questionnaire with 35 food items, we developed a concise healthy diet score (cHDS) ranging from 0 to 5 points. We examined the association of cHDS with risks of all-cause and cause-specific mortality among 23,115 men and 35,557 women who were free of CVD and cancer.

Results: During 19.2 years of median follow-up, 6,291 men and 5,365 women died. In men, the multivariable hazard ratios (95% confidence intervals) for the highest cHDS (5 points) compared to the lowest (0-1 points) were 0.74 (0.60–0.91, P-trend=0.008) for CVD and 0.86 (0.77-0.95, P-trend=0.05) for all causes. No significant associations were found for stroke, coronary heart disease, and other causes in men. The corresponding hazard ratio in women was 0.65 (0.52–0.81, P-trend＜0.001) for CVD, 0.63 (0.45–0.88, P-trend＜0.001) for stroke, 0.48 (0.30–0.78, P-trend=0.008) for coronary heart disease, 0.67 (0.54-0.84, P-trend＜0.001) for other causes, and 0.75 (0.66–0.85, P-trend＜0.001) for all causes.

Conclusion: We developed a concise diet quality score named cHDS in the Japanese population and found the inverse association of cHDS with mortality from CVD and all causes for both men and women.

Aim: JNK pathway-associated phosphatase (JKAP) regulates T cell-mediated immunity and inflammation, which are involved in atherosclerosis pathogenesis. This study investigated the effects of JKAP on T-helper (Th) cell polarization, inflammation, and atherosclerotic progression.

Methods: Serum JKAP levels were measured in 30 patients with coronary heart disease (CHD) and 30 controls. CHD blood naïve CD4^＋ T cells were acquired, followed by JKAP overexpression and knockdown with or without treatment with PD98059 (ERK inhibitor) or BAY-11-7082 (NF-κB inhibitor) in vitro. CD4^＋ T-cell conditional JKAP ablation mice were established in vivo, followed by the construction of an atherosclerosis model.

Results: JKAP was reduced and negatively correlated with the Gensini score, CRP, Th1 cells, Th17 cells, and proinflammatory cytokines in patients with CHD. In vitro, JKAP overexpression suppressed Th1 and Th17 cell differentiation and proinflammatory cytokines, whereas JKAP knockdown exerted the opposite effect; however, JKAP modification did not affect Th2 cell differentiation. Interestingly, JKAP negatively regulated the ERK and NF-κB pathways; meanwhile, the PD98059 and BAY-11-7082 treatments repressed Th1 and Th17 cell differentiation, and attenuated the effect of JKAP knockdown on these indices. In vivo, conditional CD4^＋ T-cell JKAP ablation increased Th1 and Th17 cell polarization in the spleen, lymph node, blood, and/or aortic root. Furthermore, CD4^＋ T-cell conditional JKAP ablation exaggerated atherosclerotic lesions in the aorta, elevated CD4⁺ cell infiltration and proinflammatory cytokines in the aortic root, and activated the ERK and NF-κB pathways in the aortic root.

Conclusion: JKAP ablation facilitates atherosclerosis progression by promoting Th1 and 17 polarization and inflammation through regulation of the ERK and NF-κB pathways.