Japan’s health checkup system has developed over the last four decades as a principal national strategy for preventing cerebrovascular and cardiovascular diseases (CVD). Early community-based health checkups, implemented under the Health Services for the Elderly Act of 1982, contributed to reductions in CVD mortality and the demand for inpatient care through the improved detection and management of hypertension. As lifestyle-related diseases became increasingly prominent, the government introduced Health Japan 21 and subsequently launched the Specific Health Checkups and Specific Health Guidance (SHC/SHG) program in 2008 to strengthen evidence-based population-wide prevention targeting of visceral obesity and the associated cardiometabolic risks. The SHC program provides standardized assessments, including anthropometric measurements, laboratory testing, medical history, and lifestyle questionnaires. Risk stratification is primarily based on abdominal obesity and the accumulation of metabolic risk factors, which determine individualized health guidance through motivational or intensive support. The SHG program offers structured behavioral interventions delivered by trained health professionals to promote sustainable lifestyle modifications. Growing evidence supports the effectiveness of the SHC/SHG program. Health checkup participation has been associated with lower mortality, and health guidance has demonstrated favorable improvements in obesity indicators, metabolic parameters, and pharmacotherapy initiation. Economic evaluations further suggest that the program is cost effective. However, some limitations remain, including modest long-term effects and insufficient risk identification among non-obese individuals with elevated cardiometabolic risk. Improving the participation rates and refining risk stratification beyond obesity-based criteria are ongoing priorities. Continued research and periodic revision of checkup items are essential for enhancing the program’s impact as a nationwide strategy for ASCVD prevention.

Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Although small dense low-density lipoprotein cholesterol (sdLDL-C) is a highly atherogenic lipid fraction, the association of the sdLDL-C level with MASLD and other steatotic liver disease (SLD) subcategories remain unclear. We investigated the association between various SLDs and the sdLDL-C level calculated by Sampson’s equation.

Methods: A total of 15,734 Japanese participants (men/women: 10,228/5,506, mean age: 49±9 years) who underwent annual health examinations including abdominal ultrasonography were recruited after the exclusion of subjects with triglycerides ≥ 800 mg/dL.

Results: Among SLD subcategories including MASLD, MASLD with increased alcohol consumption (MetALD) and alcohol-associated liver disease (ALD), the mean levels of sdLDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) were the highest in participants with MASLD. Triglyceride levels were significantly lower in participants with MASLD than in those with MetALD and those with ALD. After adjustment for age, sex, body mass index, current smoking and alcohol drinking habits, treatment of hypertension, diabetes and dyslipidemia, and triglyceride level, MASLD and MetALD were independently associated with sdLDL-C level, and the association was stronger in MASLD than in other SLD subcategories. The sdLDL-C level was also independently associated with each SLD subcategory after adjustment for the same covariates. The addition of sdLDL-C to traditional risk factors significantly improved the discriminatory capacity for the presence of MASLD in comparison to the addition of non-HDL-C.

Conclusion: MASLD is independently associated with elevated estimated sdLDL-C levels in Japanese individuals, leading to an increased risk of ASCVD.

Aims: Visceral fat accumulation is the central feature of metabolic syndrome and subsequent atherosclerotic cardiovascular disease. Soluble T-cadherin (sT-cad) has been identified in circulation, but its clinical significance in the general population remains unclear. We investigated the associations of circulating sT-cad levels with metabolic syndrome and its components in a population undergoing health checkups.

Methods: A total of 1321 Japanese participants (825 males and 496 females) undergoing health checkups were enrolled. Serum levels of sT-cad (130-kDa, 100-kDa, and 30-kDa), adiponectin (APN), and other clinical parameters were measured. Associations between sT-cad and metabolic risk factors were analyzed.

Results: Among the three sT-cad isoforms, serum 130-kDa sT-cad levels were significantly negatively correlated with waist circumference, blood pressure, Homeostatic Model Assessment for Insulin Resistance (HOMA-R), triglycerides, Alanine aminotransferase (ALT), uric acid, and high-sensitivity C-reactive protein (hsCRP), and positively correlated with high-density lipoprotein (HDL) cholesterol and APN. In multivariate analysis, high TG levels and/or HDL-C levels and hsCRP were independent negative determinants of 130-kDa sT-cad levels in both sexes. Furthermore, 130-kDa sT-cad levels decreased progressively with an increasing number of metabolic risk factors (P for trend ＜0.001).

Conclusion: Low serum 130-kDa sT-cad levels are associated with the presence and accumulation of metabolic syndrome-related abnormalities in a Japanese population undergoing health checkups. Inflammation and lipid abnormalities of metabolic syndrome (high TG and/or low HDL-C) may influence the serum 130-kDa sT-cad levels.

Aim: Tendon xanthomas are part of the clinical triad of diagnostic criteria for familial hypercholesterolemia (FH) in Japan. The Achilles tendon generally has a twisted structure, and we investigated the impact of torsion on Achilles tendon thickness (ATT) assessment.

Methods: In this single-center retrospective study, 61 acute coronary syndrome (ACS) patients who underwent ATT assessment using radiography (ATT-Xp) and ultrasonography (ATT-US) were analyzed. Ultrasonographic ATT assessment used two axes - antero-posterior axis (ATT-US (AP)) and corrected axis according to Achilles tendon torsion (ATT-US (correct)) - and the torsion angle was measured. The association of torsion with each ATT assessment was investigated.

Results: The torsion angle of the Achilles tendon varied widely. Both ATT-US (AP) and ATT-US (correct) were significantly correlated with ATT-Xp, although the correlation between ATT-Xp and ATT-US (correct) was modest compared to the correlation with ATT-US (AP) (ATT-US (AP)-Right: r= 0.91, p＜0.001, Left: r= 0.91, p＜0.001; ATT-US (correct)-Right: r = 0.82, p＜0.001, Left: r = 0.76, p＜0.001, respectively). Torsion angle was well correlated with the differences in ATT between ATT-Xp and ATT-US (correct) (Right: r= 0.62, p＜0.001, Left: r= 0.66, p＜0.001). There were no independent factors associated with Achilles tendon torsion.

Conclusion: This is the first study to quantitatively evaluate the three-dimensional twisted structure of the Achilles tendon and demonstrate that Achilles tendon torsion is associated with the difference between ATT-Xp and ATT-US (correct). Torsion of the Achilles tendon should be considered in Achilles tendon assessment, particularly radiographical assessment.

Aims: Persistent Chlamydia pneumoniae (C. pneumoniae) infection has been suggested to be a risk factor for cardiovascular events; however, only findings from studies on small populations are available so far. This study investigated this hypothesis in a large general population through a longitudinal analysis.

Methods: We included 9,064 community residents who participated in the Nagahama study (mean age: 52.8 years). C. pneumoniae infection (seropositivity) was determined by serum levels of immunoglobulin A and immunoglobulin G assessed by enzyme-linked immunoassay. The incidence rates of cardiovascular diseases (CVDs), including stroke and coronary artery diseases, were determined by reviewing participants’ hospital records and death certificates. Basic clinical parameters were obtained using the baseline survey of the Nagahama study.

Results: During a mean follow-up duration of 4,390 days, we observed 323 cases of CVDs. The incidence rates of CVDs were 45.0 and 24.5 per 10,000 person-years in the seropositive and seronegative groups, respectively (log-rank test: p＜0.001). The results of the Cox proportional hazard model analysis indicated that C. pneumoniae seropositivity was remarkably associated with CVDs (1.30, 95% confidence interval: 1.04−1.64) after adjusting for established risk factors, including arterial stiffness (p = 0.023). The hazard ratio was higher in the subpopulation aged ≤ 55 years (2.62, 95% confidence interval: 1.45−4.75, p = 0.001) and reached 3.66 (95% confidence interval: 1.39–9.65, p = 0.009) in the subpopulation aged ≤ 45 years.

Conclusion: C. pneumoniae seropositivity was significantly associated with CVDs incidence, especially in adolescents and middle-aged individuals.

Aim: Cilostazol, a phosphodiesterase III inhibitor, reduces the risk of stroke recurrence among patients with noncardioembolic ischemic stroke through inhibition of the platelet function and its pleiotropic effects. Its potential mechanisms include inhibiting angiotensin II-induced endothelial cell apoptosis and promoting vasodilation, which may lower systolic blood pressure (SBP). We hypothesized that the decreased risk of stroke recurrence could be attributed to a reduction in SBP.

Methods: In a post hoc analysis of CSPS.com, we defined change in SBP as its change at the last visit compared with baseline and treated it as a time-dependent mediator. We performed causal mediation analyses to separate the overall effects of cilostazol on the first recurrence of ischemic stroke into indirect effects (mediated by change in SBP on cilostazol) and direct effects (mediated through pathways other than a change in SBP on cilostazol). The effects were summarized by cumulative hazard rate difference.

Results: Ischemic stroke recurred in 27 (3%) of 889 patients on dual therapy with cilostazol and aspirin or clopidogrel and 62 (6.8%) of 906 patients on monotherapy with aspirin or clopidogrel alone during a median follow-up period of 1.4 years. The mediation analysis showed that the positive effect of dual therapy was not mediated by the association between SBP change and stroke recurrence. The estimated direct and indirect effects of cilostazol on stroke recurrence during the same follow-up period were cumulative hazard rate differences of -0.043 (95% CI, -0.070 to -0.015) and -0.0008 (-0.0024 to 0.00035), respectively.

Conclusions: Our results indicate that cilostazol reduced stroke recurrence without lowering SBP, likely through other pleiotropic pathways.

Aims: Bempedoic acid is an ATP citrate lyase (ACLY) inhibitor acting in the cholesterol biosynthesis pathway. This study evaluated long-term safety and efficacy of bempedoic acid 180 mg/day for 52 weeks in Japanese patients with hypercholesterolemia.

Methods: A multicenter, open-label, single-arm Phase 3 long-term study was conducted at 26 hospitals and clinics across Japan in patients aged 18 to 85 years. Newly enrolled patients had previously failed to achieve their lipid management targets because of inadequate response to statins or statin intolerance; rollover patients had completed the 12-week treatment period of a domestic Phase 3 confirmatory study (the CLEAR-J trial) and had not met the discontinuation criteria at Week 12.

Results: Bempedoic acid was administered to 130 patients. Treatment-emergent adverse events (TEAEs) occurred in 83.8%, treatment-related TEAEs in 14.6%, serious TEAEs in 6.2%, and AEs leading to discontinuation in 4.6%. None were severe. Between baseline and Week 52, low-density lipoprotein-cholesterol (LDL-C) decreased by 21.6% (overall population) and 25.3% (newly enrolled group), as observed in both statin response subgroups. LDL-C target levels based on risk category were achieved by 65.6% at Week 52 (overall population). Long-term efficacy was also demonstrated for non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein.

Conclusions: Bempedoic acid 180 mg/day for 52 weeks was well tolerated in patients with hypercholesterolemia, with no major safety concerns. Serious AEs were infrequent, and no new safety signals specific to the Japanese population were observed. More than 60% of patients achieved and sustained their LDL-C target levels.

Aim: Small dense low-density lipoprotein cholesterol (sdLDL-C) is recognized as an atherogenic risk factor. This study investigated the prognostic significance of sdLDL-C levels in patients with premature acute coronary syndrome (PACS) and multivessel disease (MVD).

Methods: This retrospective study enrolled 847 hospitalized patients diagnosed with PACS and MVD between May 2022 and November 2023. Patients were stratified based on clinical outcomes and tertiles of sdLDL-C levels. Multivariate Cox proportional hazard models were applied to determine whether or not sdLDL-C was a prognostic risk factor for major adverse cardiovascular events (MACEs). Cumulative event curves were estimated using the Kaplan–Meier method. The predictive efficacy of sdLDL-C for MACEs was assessed through a time-dependent receiver operating characteristic (ROC) analysis. In addition, a restricted cubic spline (RCS) analysis was conducted to explore the relationship between sdLDL-C levels and the risk of MACEs.

Results: During a median follow-up of 12 months (interquartile range: 9–15 months), 124 MACEs (14.64%) were observed. The sdLDL-C levels in the MACEs group were significantly higher compared to the non-MACEs group (P＜0.001). A multivariate Cox hazards regression analysis revealed that the risk of MACEs in the highest sdLDL-C tertile group was 2.38 times greater than in the lowest tertile group (hazard ratio [HR]: 2.38, 95% confidence interval [CI]: 1.42–4.00; P = 0.001). Furthermore, each 1-mg/dL increase in sdLDL-C levels corresponded to a 12.2% increase in the risk of MACEs (HR: 1.12, 95% CI: 1.08–1.16; P＜0.001). A Kaplan–Meier survival analysis identified significant differences in event-free survival among sdLDL-C tertiles (log-rank test, P＜0.001). The time-dependent ROC analysis demonstrated a progressive increase in the area under the curve during the follow-up period, particularly within the first 12 months. The RCS analysis revealed a nonlinear dose-response relationship between higher sdLDL-C levels and increased cumulative risk of MACEs (P_nonlinear = 0.001).

Conclusion: sdLDL-C is a predominant predictor of a poor prognosis in patients with PACS and MVD, underscoring its clinical relevance for risk stratification and the early identification of high-risk individuals who may benefit from targeted intervention.

Aim: The relationship between multiple modifiable risk factors (RFs) and coronary plaque development remains unclear. This study investigated the relationship between the cumulative RF burden and coronary inflammation, a key driver of atherosclerosis, and whether this relationship varies according to the status of coronary artery stenosis.

Methods: We analyzed 958 patients who underwent coronary computed tomography angiography. Modifiable RFs included hypertension, diabetes, a body mass index ≥ 30 kg/m ², and current smoking status. Risk factor burden was categorized by the number of risk factors, ranging from none to ≥ 2. Coronary inflammation was quantified by the perivascular fat attenuation index (FAI), defining a high FAI as a value above the 75th percentile (＞-70.2 HU).

Results: Among the patients, 142 had no RFs, 467 had 1 RF, and 349 had ≥ 2 RFs. The median FAI was -76.2HU, and a high FAI was observed in 239 patients. Compared to those with no RFs, the multivariable Poisson regression with robust error variance demonstrated a significant increase in the prevalence of a high FAI among patients with higher RF burdens: 1 RF (relative risk [RR] 1.56; 95% confidence interval [CI], 1.06–2.30) and ≥ 2 RFs (RR 1.71; 95% CI, 1.16–2.52). Similar associations were observed in patients with no or minimal atheroma (＜25%): one RF (RR, 1.65; 95% CI, 1.01–2.68) and ≥ 2 RFs (RR 2.25; 95% CI, 1.38–3.66).

Conclusions: A greater RF burden was associated with increased coronary inflammation in a dose-dependent manner. These findings indicate that RF clustering is associated with higher coronary inflammation even in the absence of significant coronary plaque.

Aims: While glomerular hyperfiltration (GHF) emerged as a risk factor for cardiovascular disease (CVD), little is known about the association between GHF and blood lipid profile. We aimed to examine the association between GHF and blood lipid parameters in adults with few comorbidities.

Methods: A cross-sectional study was performed on adults undergoing health screening in Osaka, Japan. Adults with a history of heart disease or stroke, those with diabetes mellitus, chronic kidney disease (estimated glomerular filtration rate (eGFR) ＜60 mL/min/1.73m²), or those using lipid-lowering medication were excluded. The outcome was GHF, defined as ＞95^th percentile of eGFR after stratification by age and sex. The exposure was blood lipid parameters, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), non-HDL-C, TG/HDL-C ratio, small dense LDL-C (sdLDL-C), and sdLDL-C/LDL-C ratio. Associations between blood lipid parameters and GHF were examined by multiple logistic regression under a Bayesian framework, adjusted for established risk factors of GHF, including body mass index, blood pressure, and lifestyle factors.

Results: Of 17,288 eligible individuals (mean age 50.1±9.9 years; 45.5% women), 853 individuals (4.9%) had GHF. Multiple logistic regression analyses demonstrated an association between a higher sdLDL-C/LDL-C ratio and GHF (odds ratio (OR) = 1.51, 95% credible interval (CrI) 1.21–1.88). LDL-C showed an inverse association with GHF (OR = 0.94, 95% CrI 0.92–0.97).

Conclusion: Our findings demonstrated an independent association between a higher sdLDL-C/LDL-C ratio and GHF. The role of an sdLDL-C/LDL-C ratio in GHF development and CVD risk merits further investigation.