Aim: The accumulation of metabolic risk factors, namely high blood pressure, hyperlipidemia, and hyperglycemia, has been associated with cardiovascular diseases. However, little evidence is available on the prognostic significance of metabolic risk factor accumulation in nonobese individuals. This study investigated this issue by analyzing prefecture-wide health checkup and health insurance data in Japan.

Methods: We analyzed data from 366,881 adults aged 40–74 years who were enrolled in the National Health Insurance, excluding those who experienced a stroke or coronary artery diseases or required long-term care. Baseline clinical information was obtained from annual health checkup data. Incidences of stroke and coronary artery diseases were obtained from insurance data.

Results: In the nonobese population, the hazard ratio for stroke increased linearly with the number of accumulated metabolic risk factors, particularly among those aged ＜65 years men (one factor: 2.21, two factors: 2.60; three factors: 3.93) and women (one factor: 1.49, two factors: 1.57; three factors: 2.27). Similar results were observed in the analysis for coronary artery diseases. After excluding participants receiving medications, the association of metabolic risk factor with stroke remained significant, although its association with coronary artery disease became less significant. In the analysis for each metabolic risk factors, high blood pressure (men: hazard ratio = 2.85; women: hazard ratio = 2.17; P＜0.001), but not hyperlipidemia and hyperglycemia, was associated with stroke in the nonobese population.

Conclusion: The accumulation of metabolic risk factors needs to be considered a risk factor for cardiovascular diseases even in individuals without obesity.

Aim: Screening for familial hypercholesterolemia (FH) is important for reducing the incidence of cardiovascular diseases (CVDs). Cost-effectiveness was evaluated using the Kagawa FH screening model, which is a combination of universal screening (US) in the universal health examination for children 9–10 years old conducted in Kagawa Prefecture, and reverse cascade screening (RCS) of the probands’ relatives.

Methods: A lifetime simulation was conducted using mathematical models (decision tree and Markov model) to determine the cost-effectiveness of introducing a series of FH screenings (US in children + RCS in adult relatives). Only screening-related costs and direct medical costs were included, using quality-adjusted life years (QALYs) as an outcome. The costs of statins were estimated using the public health insurance claims database DeSC Healthcare, Inc. The risk of each CVD event was estimated using the same claims data and adjusted for age. We hypothesized that standard statin treatment decreases CVD risk by reducing plasma low-density lipoprotein cholesterol levels.

Results: A series of FH screenings (US in children + RCS in adult relatives) was cost-effective compared to no screening, with an incremental cost-effectiveness ratio (ICER) of approximately JPY 150,000 (USD 1,042)/QALY, which was below the willingness-to-pay threshold of JPY 5,000,000 (USD 34,722)/QALY for medical technology in Japan (USD 1 = JPY 144). The ICER for the US without RCS was also acceptable at approximately JPY 2,720,000 (USD 18,889)/QALY.

Conclusion: The cost-effectiveness analysis revealed that a series of FH screenings (US in children + RCS in adult relatives) based on the Kagawa model was cost-effective.

Aims: Intermittent claudication is a major barrier to establishing an exercise routine in patients with peripheral artery disease (PAD). This study investigated the preconditioning effects of neuromuscular electrical stimulation (NMES) on walking capacity in patients with PAD and intermittent claudication. Additionally, it aimed to determine the optimal NMES settings and the underlying mechanisms of its effects.

Methods: A total of 15 patients with PAD (Fontaine II) participated in a crossover study. Each patient underwent 10-min sessions of NMES at two frequencies (4 and 20 Hz) and two intensities (moderate and high), plus a sham condition, before treadmill walking tests using the modified Gardner protocol.

Results: Pain-free walking distance significantly increased after a single session of 20 Hz high-intensity NMES (259.2±27.5 m; p＜0.05) relative to the sham group (201.9±23.6 m). The maximum walking distance also improved significantly after 4 and 20 Hz high-intensity NMES. The vascular endothelial function, assessed by flow-mediated dilation, was significantly enhanced following 20 Hz moderate- and high-intensity NMES, as well as 4 Hz high-intensity NMES, relative to the sham group. Additionally, lower extremity blood flow, as measured via transcutaneous partial pressure of oxygen, improved significantly in all NMES conditions. However, serum markers such as myeloperoxidase, hepatocyte growth factor, vascular endothelial growth factor, and CD34^＋/CD133^＋ progenitor cell counts did not differ significantly between the NMES and sham groups.

Conclusion: High-intensity 20 Hz NMES is an effective preconditioning strategy for instantaneously enhancing the walking capacity in patients with PAD, likely due to nitric oxide-mediated vasodilation. These findings suggest that NMES is a promising therapeutic approach for PAD rehabilitation.

Aims: Long-term safety and efficacy of pemafibrate once-daily extended-release (XR) tablets, taken in morning or evening, were evaluated in dyslipidemic patients with high triglycerides (TG).

Methods: In this multicenter, randomized, open-label, parallel-group, phase 3 long-term study, dyslipidemic patients with high TG were randomly assigned to morning or evening administration of XR for 52 weeks. The dose was started at 0.2 mg/day and increased to 0.4 mg/day for patients having fasting serum TG ≥ 150mg/dL during treatment. The primary efficacy endpoint was percent change in fasting serum TG.

Results: The study enrolled 121 patients, assigning 61 to morning and 60 to evening administration. The study population included 71.1% males. Mean age was 58.5±11.1 (mean±SD) years, body mass index 27.7±4.3 kg/m², and fasting TG 264.0±109.2 mg/dL. Fasting serum TG decreased significantly from baseline to 52 weeks among patients overall and in the morning and evening groups (−45.7%, −44.8%, and −46.6%, respectively, p＜0.001 vs. baseline). The difference in least-squares mean between the morning and evening groups was 3.0%, not statistically significant. The dose was increased in 82 patients (44 morning and 38 evening), with 57.3% (95%CI 45.9, 68.2) achieving fasting serum TG ＜150 mg/dL. Adverse events occurred in 83.5% and adverse drug reactions in 19.0% but with no notable safety problems.

Conclusions: Long-term, once-daily administration of XR was effective and safe in dyslipidemic patients with high TG. XR provided favorable TG-lowering effects regardless of morning or evening administration, and the XR dose increase proved effective in patients having initially inadequate response.

Aims: To investigate the association between metabolic health status, defined by the combination of metabolic syndrome (MetS) and obesity, and cardiovascular disease (CVD) in a Japanese community.

Methods: A total of 2,842 participants without prior CVD, aged 40 years or older, were followed up from 2007 until 2017. Participants were classified into 4 metabolic health statuses based on the presence of obesity (body mass index ≥ 25 kg/m²) and MetS: metabolically healthy normal weight (MHN) (obesity [-] and MetS [-]), metabolically unhealthy normal weight (MUN) (obesity [-] and MetS [+]), metabolically healthy obesity (MHO) (obesity [+] and MetS [-]), and metabolically unhealthy obesity (MUO) (obesity [+] and MetS [+]). The risk estimates were computed by using a Cox hazard regression analysis.

Results: During the follow-up period, 190 participants developed CVD. The MUO group had a 1.94-times greater risk of developing CVD than the MHN group after adjusting for confounders, but no excess risk was observed in the MHO group. Moreover, in 1,595 participants who had undergone a health checkup in 2002, 5 years before baseline, the risk of developing CVD was 2.18-times greater in the group that transitioned from MHO to MUO and 1.75-times higher in the stable MUO group than in the stable MHN group, but was not higher in the stable MHO group.

Conclusions: The present findings suggest that cardiovascular risk increases when metabolic abnormalities are present simultaneously with obesity. In individuals with obesity, it may be important to maintain metabolic health and/or lose weight to prevent CVD.

Aims: Previous studies have linked platelet-derived growth factors (PDGFs) and their receptor beta (PDGFRB) genetic variants to coronary artery disease (CAD), but their impact on major adverse cardiovascular events (MACEs) remains unclear.

Methods: A cohort study of 3139 patients with CAD followed up until December 1, 2022 (median 5.42 years), genotyped 13 tagSNPs in PDGFs/PDGFRB pathway genes to establish weighted genetic risk scores (wGRS). Multiple Cox regression models analyzed the association of SNPs and wGRS with MACE outcomes using hazard ratios (HRs) and 95% confidence intervals (CIs). The wGRS improvement on traditional risk factors (TRFs) and the Global Registry of Acute Coronary Events (GRACE) score for MACEs were assessed using the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

Results: Compared to low MACE-GRS (Q1 of quintile), high MACE-GRS (Q5 of quintile) had an increased risk of MACEs, with an adjusted HRs of 1.441 (P = 0.006). Compared to the TRF prediction model, the addition of MACE-GRS showed an improved discrimination with an NRI of 5.1% (95% CI, 0.7%-9.5%, P＜0.001) and IDI of 0.3% (95% CI, 0.0%-0.6%, P＜0.001). In addition, compared to the TRFs and GRACE score model, the addition of MACE-GRS showed an improved discrimination with an NRI of 5.1% (95% CI, 0.7%-9.6%, P＜0.001) and IDI of 0.3% (95% CI, 0.0%-0.5%, P＜0.001).

Conclusions: Variants in the PDGF-PDGFRB pathway genes contribute to the risk of MACEs after CAD, and the wGRS might be able to serve as a risk predictor of MACEs in addition to TRFs.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, including in Japan, where the aging population intensifies its impact. This review evaluated the potential impact of digital healthcare on the prevention and management of ASCVD, covering both primary and secondary prevention strategies. Digital health tools, such as risk assessment applications remote monitoring, lifestyle modification support, and remote rehabilitation, have shown promise in improving patient engagement, adherence, and outcomes. However, while digital health interventions demonstrate significant benefits, challenges persist, including interoperability issues, privacy concerns, low digital literacy among older adults, and limited health insurance coverage for digital interventions. Through an analysis of recent advancements and case studies, this review demonstrates the need for user-centered design, enhanced regulatory frameworks, and expanded insurance support to facilitate the effective integration of digital health in ASCVD care. Furthermore, emerging technologies such as personalized healthcare modules offer promising directions for tailored and impactful care. Addressing these barriers is critical to unleashing the full potential of digital healthcare to reduce the burden of ASCVD and enhance patient outcomes.

Aims: Long-term exposure to fine particulate matter (PM_2.5) is causally associated with mortality and cardiovascular disease. However, in terms of cardiovascular cause-specific outcomes, there are fewer studies about stroke than about coronary heart disease, particularly in Asia. Furthermore, there remains uncertainty regarding the PM_2.5-respiratory disease association. We examined whether long-term exposure to PM_2.5 is associated with all-cause, cardiovascular and respiratory disease mortality in Japan.

Methods: We used data of 46,974 participants (19,707 men; 27,267 women), who were enrolled in 2009 and followed up until 2019, in a community-based prospective cohort study (the second cohort of the Ibaraki Prefectural Health Study). We estimated PM_2.5 concentrations using the inverse distance weighing methods based on ambient air monitoring data, and assigned each participant to administrative area level concentrations. A Cox proportional hazard model was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality.

Results: During the average follow-up of 10 years, we confirmed 2,789 all-cause deaths. All outcomes including stroke mortality did not significantly increase as the PM_2.5 concentration increased. For non-malignant respiratory disease mortality, the multivariable adjusted HR per 1 µg/m³ increase in the PM_2.5 concentration was 1.09 (95% CI = 0.97–1.23).

Conclusions: In this population exposed to PM_2.5 at concentrations of 8.3–13.1 µg/m³, there was no evidence that long-term exposure to PM_2.5 had adverse effects on mortality. Weak evidence of positive association observed for non-malignant respiratory disease mortality needs further studies in other populations.

Aims: Evidence supporting the prescription of anticoagulant therapy for patients with atrial fibrillation (AF) with advanced chronic kidney disease (CKD) has been limited, and its clinical application in this context remains controversial.

Methods: We identified AF patients with advanced CKD (G4-G5) and a history of stroke who were admitted to the First Affiliated Hospital of Dalian Medical University between January 1, 2011, and June 30, 2023. Patients were classified into warfarin, non-vitamin K antagonist oral anticoagulant (NOAC), antiplatelet therapy, and control (no antithrombotic therapy) groups. We evaluated the benefits and safety of different antithrombotic therapies by comparing the long-term clinical outcome measures, including the incidence of subsequent ischemic stroke events, bleeding, and all-cause death.

Results: In total, 570 patients were included. In this cohort, 87 (15.3%) patients had no antithrombotic treatment, 252 (44.2%) received antiplatelet therapy, 105 (18.4%) received warfarin, and 126 (22.1%) received NOAC therapy. Compared with patients without treatment, we found that treatment with anticoagulant therapy significantly decreased the risk of ischemic stroke, but antiplatelet therapy did not. Treatment with anticoagulant therapy was associated with significantly lower mortality than no antithrombotic therapy or antiplatelet therapy , at least within the study period. Furthermore, compared with warfarin treatment, patients treated with NOAC therapy showed a significant decrease in the incidence of bleeding risks.

Conclusion: Among AF patients with advanced CKD and prior stroke, receiving anticoagulants resulted in a reduced risk of recurrent ischemic stroke events than no antithrombotic treatment, and lower mortality than no antithrombotic treatment or antiplatelet therapy.

Aim: Branch atheromatous disease (BAD), characterized by the occlusion of perforating branches near the orifice of a parent artery, often develops early neurological deterioration because the mechanisms underlying BAD remain unclear. Abnormal wall shear stress (WSS) is strongly associated with endothelial dysfunction and plaque growth or rupture. Therefore, we hypothesized that computational fluid dynamics (CFD) modeling could detect differences in WSS between BAD and small-vessel occlusion (SVO), both of which result from perforating artery occlusion/stenosis.

Methods: This cross-sectional observational study included consecutive patients admitted to our institution within 7 days after symptom onset who met the following criteria: absence of stenosis/occlusion in the intracranial major arteries on brain magnetic resonance angiography (MRA) or extracranial carotid arteries on carotid ultrasonography. The WSS and blood flow velocity in the M1 segment of the middle cerebral artery were analyzed using CFD based on MRA.

Results: The number of patients with a WSS ratio (ipsilesional/contralesional) of ＞1 was significantly higher in patients with BAD (n = 27) than in those with SVO (n = 27) [20 (74.1%) vs. 11 (40.7%), p = 0.013]. Higher WSS on ipsilesional M1 than on contralesional M1 was an independent risk factor for BAD (adjusted odds ratio 4.38, 95% confidence interval 1.29–14.82, p = 0.018). Blood flow velocity in the M1 segment was not associated with BAD.

Conclusions: In patients with BAD, higher M1 segment WSS on CFD can be a risk factor for the development of vulnerable plaques in branch orifices. Moreover, the use of CFD may contribute to the diagnosis of BAD.

The deposition of cholesterol containing cholesterol crystals and the infiltration of immune cells are features of atherosclerosis. Although the role of cholesterol crystals in the progression of atherosclerosis have long remained unclear, recent studies have clarified the involvement of cholesterol crystals in inflammatory responses. Cholesterol crystals activate the NLRP3 inflammasome, a molecular complex involved in the innate immune system. Activation of NLRP3 inflammasomes in macrophages cause pyroptosis, which is accompanied by the release of inflammatory cytokines such as IL-1β and IL-1α. Furthermore, NLRP3 inflammasome activation drives neutrophil infiltration into atherosclerotic plaques. Cholesterol crystals trigger NETosis against infiltrated neutrophils, a form of cell death characterized by the formation of neutrophil extracellular traps (NETs), which, in turn, prime macrophages to enhance inflammasome-mediated inflammatory responses. Colchicine, an anti-inflammatory drug effective in cardiovascular disease, is expected to inhibit cholesterol crystal-induced NLRP3 inflammasome activation and neutrophil infiltration. In this review, we illustrate the reinforcing cycle of inflammation that is amplified by inflammasome activation and NETosis.

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is a pervasive chronic disease that affects millions of people worldwide. It predisposes individuals to a range of severe microvascular and macrovascular complications, which drastically impact the patient’s quality of life and increase mortality rates owing to various comorbidities. This extensive review explores the intricate pathophysiology underlying diabetic complications, focusing on key mechanisms, such as atherosclerosis, insulin resistance, chronic inflammation, and endothelial dysfunction. It also highlights recent therapeutic advancements, including the introduction of SGLT2 inhibitors and GLP-1 receptor agonists, which provide benefits beyond glycemic control and offer cardiovascular and renal protection. Furthermore, the future position of SGLT2 inhibitors and GLP-1 receptor agonists in terms of the prevention of diabetes and macrovascular diseases will be discussed. Considering the differences in insulin secretion capacity between Western and Asian patients, including Japanese patients, we propose a treatment strategy for high-quality diabetes in Japan.

Apolipoprotein E (apoE) is a key apoprotein in lipid transport and is susceptible to genetic mutations. ApoE variants have been studied for four decades and more than a hundred of them have been reported. This paper presents an up-to-date review of the function and structure of apoE in lipid metabolism, the E2, E3, and E4 isoforms, the APOE gene, and various pathologies, such as familial type III hyperlipidemia and lipoprotein glomerulopathy, caused by apoE variants. Alzheimer’s disease was barely mentioned in this paper. But this review should help researchers obtain a comprehensive overview of human apoE in lipid metabolism.

Aim: Previous studies have shown that higher educational levels are associated with slower progression of arterial stiffness; however, evidence from Asian countries is lacking. We aimed to examine the association between educational level and arterial stiffness measured using the cardio-ankle vascular index (CAVI) over time in a sample of Japanese men and women.

Methods: A total of 1381 participants (453 men and 928 women) were included in the present study. Arterial stiffness was measured using the CAVI at baseline (2009–2012) and 5 years later (2014–2018). The educational level was divided into two groups (junior or senior high school vs. junior college, professional school, college, or higher) based on a self-administered questionnaire. A mixed-effects model was used to analyze the association between education and the CAVI at baseline and its change over 5 years. The participants were stratified by sex and age (＜65 vs. ≥ 65 years).

Results: The CAVI at baseline did not differ significantly according to education in any of the four subgroups accorded to age and sex. However, among women of ≥ 65 years of age, the change in the CAVI over 5 years was significantly smaller in the higher education group (p=0.04). No such association was found in women of ＜65 years of age or men.

Conclusions: Education is a factor that affects arterial stiffness in women of ≥ 65 years of age. These results suggest that educational level affects arterial stiffness, depending on sex and age.

Aim: We aimed to clarify the degree and factors associated with low-density lipoprotein (LDL)-cholesterol treatment target attainment among patients with heterozygous familial hypercholesterolemia (HeFH) using the Hokuriku-plus FH registry.

Methods: The Hokuriku-plus FH registry (UMIN000038210) was a prospective, observational, multicenter cohort study that enrolled consecutive patients with FH who fulfilled the clinical criteria for FH in Japan from 37 participating hospitals, mostly in the Hokuriku region, from April 2020 to March 2024. This registry collects data on clinical parameters, including lipid levels, physical findings, genetic background, and clinical events. In total, 431 patients were enrolled, and the median followup period was 3.1 years. We assessed the degree and factors associated with LDL-cholesterol treatment target attainment among patients with HeFH using the Hokuriku-plus FH registry.

Results: Among the 431 patients, sufficient data were collected from 386 patients. Logistic regression analysis revealed that male sex (odds ratio [OR] = 2.16, 95% confidence interval [CI]: 1.14–3.18, p＜0.001) and genetic testing (OR = 1.68, 95% CI: 1.10–2.26, p＜0.001) were significantly associated with LDL-cholesterol treatment target attainment. In fact, female patients were less likely to attain LDL-cholesterol treatment target than male patients (24.0% vs. 38.1%, p＜0.001), and patients who did not undergo genetic testing were less likely to attain LDL-cholesterol treatment target than those who underwent genetic testing (24.5% vs. 37.1%, p＜0.001).

Conclusion: Sex bias and masked genetic status are significant barriers to the clinical management of patients with HeFH.

Aim: This study assessed the predictive value of pericarotid fat density (PFD) on carotid computed tomography angiography (CTA) for recurrent ischemic stroke or transient ischemic attack (TIA).

Methods: In total, 739 patients who underwent CTA between January 2014 and December 2021 were retrospectively included in this study. The PFD was evaluated using carotid CTA. The clinical endpoint was recurrent ischemic stroke or transient ischemic attack (TIA). The association between PFD and the endpoint was examined using Kaplan-Meier and Cox analyses. The combination model was established using significant clinical imaging risk factors and PFD. The predictive performance of the model was assessed using the receiver operating characteristic curve (ROC).

Results: A total of 739 patients (mean age: 64.28±9.44 years old, 496 males) completed a median of 3.31 years of follow-up (interquartile range, 2.11-4.05). During the follow-up period, 166 patients reached the clinical end point. The event-free survival (EFS) rate was lower in the high-PFD group than in the low-PFD group (log-rank P＜0.001). Multivariate Cox analyses showed that the PFD was associated with recurrent stroke or TIA (all P＜0.05). The combination model demonstrated excellent performance in predicting the clinical endpoint (area under the curve = 0.89). In addition, the endpoint event prognostic value was significantly improved by adding the PFD to the baseline model (C-statistic improvement: 0.61–0.84).

Conclusion: CTA-assessed PFD is an independent predictor of recurrent stroke or TIA.

Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of mortality, and recent research has underscored the critical role of lipoproteins in modulating cardiovascular (CV) risk. Elevated low-density lipoprotein cholesterol (LDL-C) levels have been linked to increased CV events, and while numerous trials have confirmed the efficacy of lipid-lowering therapies (LLT), significant gaps remain between recommended LDL-C targets and real-world clinical practice. This review addresses care gaps in LLT, emphasizing the necessity for innovative approaches that extend beyond LDL-C management. It explores combination therapy approaches such as statins combined with ezetimibe or PCSK9 inhibitors, which have shown promise in enhancing LDL-C reduction and improving outcomes in high-risk patients. Additionally, this review discusses new approaches in lipid modification strategies, including bempedoic acid, inclisiran, and drugs that lower Lp(a), highlighting their potential for CV risk reduction. Furthermore, it emphasizes the potential of polygenic risk scores to guide LLT and lifestyle changes despite challenges in implementation and genetic testing ethics. This article discusses the current guidelines and proposes innovative approaches for optimizing lipoprotein management, ultimately contributing to improved patient outcomes in ASCVD prevention.

Aims: Several risk-scoring models, including the Fukuoka Stroke Risk Score, Essen Stroke Risk Score, and Stroke Prognosis Instrument II, have been developed to predict recurrent cerebrovascular events in patients with ischemic stroke. As myocardial infarction (MI) and ischemic stroke are both atherosclerotic diseases, these scoring models in the field of cerebrovascular disease may be applicable and useful for risk stratification in patients with acute MI. We therefore evaluated the diagnostic ability and clinical applicability of these stroke risk scores in predicting atherosclerotic events after acute MI.

Methods: This multicenter retrospective study included 2016 patients with acute MI who underwent percutaneous coronary intervention and survived to discharge. The three risk-scoring models were calculated, and their diagnostic ability for major adverse cardiovascular events (MACE) after discharge, a composite of cardiovascular death, recurrent MI, and ischemic stroke, was evaluated.

Results: During the median follow-up of 523 days, 218 (10.8%) patients experienced MACE after discharge. High values for Fukuoka Stroke Risk Score, Essen Stroke Risk Score, and Stroke Prognosis Instrument II were progressively associated with an increased risk of MACE after discharge. Overall, the diagnostic abilities of the three risk scores were similar.

Conclusions: Risk prediction models in the field of ischemic stroke, including the Fukuoka Stroke Risk Score, Essen Stroke Risk Score, and Stroke Prognosis Instrument II, were useful in stratifying MACE risk in patients with acute MI. Risk-scoring models for atherosclerotic cardiovascular disease may be applicable to patient populations with other cardiovascular diseases in different arterial territories.

Aims: Atherogenic dyslipidemia (AD) is regarded as a residual risk of cardiovascular diseases characterized by low high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) levels and related to the intracranial stenosis of atheromatous thrombotic brain infarction (ATBI). Further, atherosclerosis is possibly related to another stroke subtype, including cryptogenic stroke (CS). In particular, an aortic complicated lesion (ACL) is a notable embolic source of CS, since recurrence of aortogenic brain embolism is not rare. This study aimed to clarify the underlying association between AD and CS.

Methods: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) had extensive data from CS patients who underwent transesophageal echocardiography (TEE). AD was defined as HDL-C ≤ 40 mg/dl and TG ≥ 150 mg/dl. Based on these criteria, patients were divided into an AD group and a non-AD group to compare the clinical features.

Results: Of 664 CS patients (446 men, 68.7±12.8 years), 68 (10.2%) met the criteria of AD (AD group), and 596 (89.8%) were in the non-AD group. On multiple logistic regression analysis, body mass index (unit OR 1.11, 95%CI 1.04-1.19, p=0.002), diabetes mellitus (OR 2.23, 95%CI 1.28-3.87, p=0.004), ACL in the arch (OR 1.89, 95%CI 1.09-3.31, p=0.025), and deterioration during hospitalization (OR 3.96, 95%CI 1.32-10.68, p=0.009) were independently associated with AD.

Conclusion: AD was not rare in the present CS population. Moreover, AD was crucially related to ACL in CS. Therefore, intensive and pleiotropic lipid-modifying therapy would be efficacious for further treatment of aortogenic brain embolism.

Aim: Patients with type 2 diabetes mellitus (T2D) are prone to develop vascular calcification. Fetuin-A protects against vascular calcification but it increases insulin resistance. T50 calciprotein crystallization (also called serum calcification propensity) is a novel marker of calcification stress. This study examined whether T2D affects T50 and the potential role of fetuin-A in the relationship between T2D and T50.

Methods: This cross-sectional study included 101 individuals with T2D and 101 individuals without diabetes (controls). T50 and fetuin-A levels were measured using the established nephelometric method and an enzyme-linked immunosorbent assay, respectively.

Results: Although fetuin-A levels were higher in the T2D group, T50 was not significantly different between the T2D and control groups. In multivariable-adjusted analyses of the total population, T50 was not independently associated with the presence of T2D, fasting plasma glucose, or HbA1c, whereas T50 was significantly associated with fetuin-A, phosphate, and calcium levels. The association between T50 and fetuin-A was modified by the presence of T2D. A subgroup analysis revealed that the positive association between T50 and fetuin-A was significant but smaller in the T2D group, and that the associations of T50 with serum phosphate and calcium were more evident in the T2D group. Additional analyses showed that T50/fetuin-A ratio was lower in the T2D group and that T50/fetuin-A ratio was inversely correlated with fasting glucose and HbA1c levels.

Conclusions: T2D itself was not significantly associated with T50 but T2D modified the association between T50 and fetuin-A in favor of developing vascular calcification in T2D.

Aim: Few studies have evaluated the midterm prognosis of patients with intermittent claudication who underwent endovascular therapy (EVT) for femoropopliteal lesions. Therefore, we aimed to assess 2-year mortality and prognostic factors in these patients.

Methods: We retrospectively analyzed 947 patients who underwent EVT for intermittent claudication between January 2018 and December 2021 at eight Japanese cardiovascular centers. Kaplan–Meier survival analysis was performed for mortality, and prognostic factors were analyzed using the Cox proportional hazards regression model. Patient backgrounds and medications were included in the investigation of prognostic factors.

Results: Notably, 79 deaths occurred during the mean follow-up period of 20.9±6.2 months. The 2-year mortality rate was 9.1%. In multivariate analysis, body mass index (BMI) ＜18.5 kg/m² (p＜0.001), coronary artery disease (CAD) (p＜0.001), dialysis (p＜0.001), and ankle-brachial pressure index (ABI) ＜0.6 (p=0.012) were risk factors. Statins and cilostazol were protective factors (p=0.014 and p=0.036, respectively). When the study population was stratified based on the number of these risk factors, the mortality rate was highest (32.5% at 2 years) in patients with at least three risk factors. However, when stratified according to protective factors, the mortality rate was lowest in patients with two protective factors (2.1% at 2 years).

Conclusions: Dialysis, low BMI, CAD, and low ABI were risk factors for a worse 2-year prognosis in patients with intermittent claudication who underwent EVT for femoropopliteal lesions. Statins and cilostazol may improve the 2-year prognosis of patients with lower extremity artery disease.

Aim: In the PEMA-FL study in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), pemafibrate was shown to significantly decrease low-density lipoprotein cholesterol (LDL-C) levels. We aimed to investigate the mechanisms of pemafibrate-induced LDL-C reduction in patients with MASLD by conducting an additional sub-analysis of the PEMA-FL study.

Methods: The PEMA-FL study randomized 118 patients with MASLD to receive pemafibrate or placebo for 72 weeks. This sub-analysis examined the percentage change in LDL-C and related lipid markers by tertile of baseline LDL-C levels and the correlation between these changes in the pemafibrate group.

Results: Pemafibrate significantly decreased LDL-C levels approximately 25% (p＜0.001 at all timepoints) from baseline in the highest tertile of baseline LDL-C levels (≥ 137.5 mg/dL), with similar trends for non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) levels. Lipoprotein (a) [Lp(a)] levels decreased only in patients with the highest baseline LDL-C levels. Regardless of the baseline LDL-C levels, pemafibrate altered the LDL particle profile (increased LDL particle size and decreased the number); reduced lathosterol, β-sitosterol, and campesterol; and increased angiopoietin-like protein 3 (ANGPTL3). The percentage change in LDL-C positively correlated with that in ApoB, non-HDL-C, Lp(a), lathosterol, β-sitosterol, and campesterol but not HDL-C and ANGPTL3.

Conclusion: Pemafibrate reduced LDL-C, ApoB, and non-HDL-C levels in patients with MASLD, and the effect was greater in those with higher baseline LDL-C levels. Pemafibrate may clinically benefit patients with MASLD by improving LDL-C levels and the LDL particle profile.

Aims: To investigate the association between triglyceride levels and major adverse cardiovascular events (MACE) in primary and secondary prevention cohorts.

Methods: This retrospective study was conducted with a nationwide health insurance claims database, which included approximately 3.8 million participants with medical checkups between January 2005 and August 2020 in Japan. The participants were classified into primary prevention (n=3,415,522) and secondary prevention (n=29,806) cohorts based on cardiovascular or cerebrovascular disease history. Each participant was categorized as having very low (triglyceride ＜50 mg/dL), low normal (50–99), high normal (100–149), or hypertriglyceridemia (≥ 150). The primary prevention cohort was further stratified into low-, intermediate-, and high-risk groups according to atherosclerotic cardiovascular diseases risk. Outcome was MACE, including acute myocardial infarction (AMI), unstable angina, ischemic stroke, and cardiac death.

Results: Over a mean follow-up of 3.25 years, 0.3% and 2.6% MACE occurred in primary and secondary prevention, respectively. Hypertriglyceridemia was associated with high risk of MACE in the primary prevention, but not in the secondary prevention. A significant interaction was observed between prevention categories and the association of TG levels with MACE in those with TG ＜150 mg/dL and ischemic stroke in those with TG ≥ 150 mg/dL. The population-attributable fraction for hypertriglyceridemia in primary prevention was 4.1% for MACE. In primary prevention, lower risks of AMI were observed in the lower TG category compared to the current threshold.

Conclusions: This study suggests distinct triglyceride thresholds for MACE risk in primary and secondary prevention cohorts, requiring further prospective validation for clinical implementation.

Aims: Plasma S-adenosylhomocysteine (SAH) level is positively associated with cardiovascular risk. However, the relationship between plasma SAH levels and the risk of all-cause and cardiovascular mortality remains unknown. This study aimed to explore the relationship between plasma SAH levels and the risk of all-cause and cardiovascular mortality in patients with coronary artery disease (CAD).

Methods: Plasma SAH levels were measured in 1553 patients with CAD. The association between plasma SAH level and the risk of all-cause and cardiovascular mortality was estimated using Cox Proportional hazards regression models.

Results: Relative to participants in the lowest quartile of plasma SAH levels, those in the highest quartile of plasma SAH levels had a higher risk of all-cause death (adjusted Hazard Ratio [HR], 2.15; 95% CI, 1.54-3.01; P＜0.001) and cardiovascular death (adjusted HR, 2.20; 95% CI, 1.49-3.25; P=0.001) in the age- and sex-adjusted model. The results of the multivariable adjusted analysis were similar (all-cause death [adjusted HR, 1.81; 95% CI, 1.27-2.58; P=0.002] and cardiovascular death [adjusted HR, 1.84; 95% CI, 1.21-2.79; P=0.031]). The age- and sex-adjusted HRs for each 1 SD increase in plasma SAH level were 1.30 (95% CI, 1.22-1.38) for all-cause mortality, and 1.34 (95% CI, 1.25-1.43) for cardiovascular mortality, respectively. A 1 SD increase in the SAH level was associated with a 25% higher risk of total death (adjusted HR, 1.25; 95% CI, 1.17-1.34) and a 29% greater risk of cardiovascular death (adjusted HR, 1.29; 95% CI, 1.20-1.39) in multivariable adjusted analysis.

Conclusions: We found that the plasma SAH level is positively correlated with the risk of all-cause and cardiovascular mortality in patients with CAD in both age- and sex-adjusted and multivariable-adjusted models.

A 59-year-old Japanese woman was referred for an extremely low level of circulating high-density lipoprotein cholesterol (HDL-C). The serum HDL-C level had long been within the normal range but suddenly decreased asymptomatically to 7 mg/dL. She had no typical symptoms associated with familial lecithin, cholesterol acyltransferase deficiency (FLD), including proteinuria, anemia, and corneal opacity. The circulating level of ApoA-1 was also markedly decreased at 48 mg/dL, and the proportion of esterified cholesterol to free cholesterol was irregularly low at 26%. Whole-genome sequencing revealed no apparent pathological mutations in the LCAT gene. Notably, anti-LCAT antibodies were detected in the serum at 146±1.7 ng/mL, resulting in her being diagnosed with acquired LCAT insufficiency (ALCATI) caused by anti-LCAT antibodies. Five years after her HDL-C levels spontaneously decreased, they increased without any identifiable cause. To our knowledge, only six cases of ALCATI caused by anti-LCAT antibodies have been reported to date. In contrast to the present case, previously reported cases of ALCATI manifested proteinuria that improved with steroid therapy. The unique clinical course in the present case highlights the heterogeneity of ALCATI, warranting further research to clarify the molecular pathophysiology of FLD and ALCATI.

Aims: There is a lack of evidence regarding the sex-specific impact of arterial stiffness on the incidence of chronic kidney disease (CKD). This study assessed the relationship between arterial stiffness based on brachial-ankle pulse wave velocity (baPWV) and incident CKD in men and women.

Methods: Individuals who participated in health checkups and underwent concomitant baPWV measurement between 2006 and 2019 were included. They were free of CKD at baseline. The participants were categorized into 4 groups based on their baPWV values (cm/s) as follows: ＜1,200 cm/s for normal, ≥ 1,200 and ＜1,400 for high normal, ≥ 1,400 and ＜1,800 for borderline, and ≥ 1,800 cm/s. The primary outcome was CKD development (estimated glomerular filtration rate ＜60 mL/min/1.73 m²).

Results: A total of 130,100 participants were enrolled, with a mean age of 40.5±8.2 years old. During the mean of 5.6 years of follow-up, 906 (0.7%) participants developed incident CKD. The cumulative incidence of CKD was 0.3%, 0.5%, 1.4%, and 6.2% in the normal, high normal, borderline, and abnormal groups, respectively. In the multivariable-adjusted model including systolic blood pressure, compared with the normal baPWV group, abnormal baPWV group demonstrated a significantly increased risk of incident CKD in women. However, among men, any other baPWV groups were not associated with a significantly elevated risk of incident CKD.

Conclusions: Increased arterial stiffness, as measured by baPWV, was associated with an increased risk of incident CKD, with notable sex-specific differences. These findings underscore the utility of baPWV for identifying CKD risk in women and offer valuable insights into sex-specific differences in arterial stiffness and CKD development.

Aims: Direct oral anticoagulants (DOACs) are used to treat venous thromboembolism (VTE). However, their impact on thrombus regression and the clinical outcomes after 2-week post-therapy computed tomography (CT) monitoring remains unexplored. This study aimed to elucidate the characteristics of patients with VTE treated with individual DOACs, assess the incidence of clinical events, and evaluate their impact on pulmonary artery thrombus regression.

Methods: This prospective, multicenter study in Japan included 175 patients with VTE treated with rivaroxaban, apixaban, and edoxaban. We employed 2-week post-therapy CT monitoring to compare thrombus regression rates, patient backgrounds, and clinical outcomes.

Results: Rivaroxaban users had higher body weight, hemoglobin levels, pulmonary embolism prevalence, and larger thrombus volume, but a lower prevalence of active cancer than apixaban and edoxaban users. The median thrombus regression rate after approximately 2 weeks of treatment was 89.9%, with no significant differences between the DOACs. During the 13.5-month follow-up, the recurrence or aggravation of symptomatic VTE did not differ significantly among the groups; however, the apixaban group exhibited a slightly higher major bleeding rate. Among the 95 patients receiving rivaroxaban intensive therapy, 34 (35.8%) experienced early termination due to sufficient thrombus resolution within 2 weeks compared to the standard duration group. This did not increase VTE recurrence, aggravation, or mortality.

Conclusions: Substantial thrombus regression and a low incidence of VTE and bleeding support the effectiveness of DOACs. Terminating intensive therapy in one-third of the rivaroxaban group after 2-week CT monitoring did not increase the occurrence of VTE events, thereby suggesting suitability for patients at a high risk of bleeding.

Aims: The Pemafibrate for Prevention of Atherosclerotic Diseases in Stroke (PPAR Stroke) study aimed to assess the effects of pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, on the progression of cerebrovascular atherosclerosis in patients with stroke and hypertriglyceridemia.

Methods: Ninety-nine patients (mean age, 65.6 years; male, 74.7%) with hypertriglyceridemia and a history of stroke or transient ischemic attack of non-cardioembolic origin were included in this prospective single-arm study. Hypertriglyceridemia was defined as a fasting serum triglyceride (TG) level ≥ 150 mg/dL. All patients were treated with pemafibrate (0.2 mg or 0.1 mg/day) for 2 years. The primary outcome was change in carotid intima-media thickness (IMT) from baseline at 2 years, as assessed using carotid ultrasonography. The secondary outcomes were changes in blood biomarker levels and progression of intracranial artery stenosis on magnetic resonance angiography.

Results: The mean TG level significantly decreased from 269 mg/dL at baseline to 139 mg/dL at 2 years (P＜0.001) and high-density lipoprotein cholesterol level increased from 49 to 54 mg/dL (P＜0.001), whereas low-density lipoprotein cholesterol level remained unchanged. Significant reductions in high-sensitivity C-reactive protein and interleukin-6 levels were also observed (P=0.003 and P=0.002, respectively). With regard to mean IMT in the internal carotid arteries, the difference was significant for the left side (1.59 mm at baseline vs. 1.52 mm at 2 years; P=0.009) and borderline significant for the right side (1.32 mm at baseline vs. 1.28 mm at 2 years; P=0.053). Among the 48 stenotic lesions in the intracranial arteries, regression and progression was observed in 9 (18.8%) and 4 (8.3%) cases, respectively.

Conclusions: Pemafibrate was observed to have TG-lowering and anti-inflammatory effects and could attenuate atherosclerosis progression in the intra- and extracranial arteries of patients with stroke and hypertriglyceridemia.

Aims: To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease.

Methods: Summary statistics of CTRP1 from the available genome-wide association studies and atherosclerosis in classic vascular sites (including cerebral, coronary, and other arteries) from the FinnGen biobank were extracted for a primary MR analysis, and the analysis was replicated using Ischemic Stroke cohort (large artery atherosclerosis) for validation. The inverse variance-weighted method was used for primary assessment. Sensitivity analysis was performed by Cochrane’s Q test and leave-one-out analysis. Potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to investigate the independent effect of CTRP1 on atherosclerosis after removing confounding factors.

Results: Reliable causal evidence was found for CTRP1 involvement in three atherosclerosis endpoints: causal effects of CTRP1 on cerebral atherosclerosis (OR=1.31, CI:1.04–1.66; FDR_P=0.0222)], coronary atherosclerosis (OR=1.13, CI: 1.08–1.19; FDR_P=2.86e-07), and atherosclerosis at other sites (OR=1.06, CI:1.02–1.11; FDR_P=0.0125). The validation cohort further confirmed its causal effect on large-artery atherosclerosis (OR=1.10, CI:1.03–1.18; FDR_P=0.0115). The reverse MR analysis did not support the causal effect of atherosclerosis on CTRP1. Moreover, the MVMR analysis, adjusting for confounders (CTRP3, CTRP5, and CTRP9A), highlighted a significant independent causal effect of CTRP1 remaining on atherosclerosis.

Conclusion: CTRP1 may represent a promising target for preventing and treating systemic atherosclerosis.

Aims: The impact of a reduced renal function on the risk of venous thromboembolism (VTE) remains controversial. The association between VTE and the renal function, as well as genetic susceptibility, requires further clarification in a large population.

Methods: This study included 358,723 participants with non-renal failure from the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of VTE incidence associated with the renal function at baseline were estimated using the Cox proportional hazards model. In addition, the relationship between the renal function and cumulative risk of VTE was visualized using Kaplan-Meier curves and restricted cubic spline (RCS). Furthermore, this study investigated the combined effects and interactions between the renal function and genetic susceptibility on the risk of VTE onset.

Results: Renal function biomarkers in the highest quartile levels for urine creatinine, serum creatinine, urea, urate, cystatin C, and urine microalbumin and lowest quartile levels for the estimated glomerular filtration rate (eGFR) were associated with an elevated risk of VTE onset. For the joint analysis with genetic susceptibility, participants with both high levels of renal function biomarkers (a low eGFR) and high genetic risk had the highest risk of developing VTE, with an HR (95% CI) of 2.83 (2.46-3.26) for urine creatinine, 2.72 (2.37-3.13) for serum creatinine, 2.49 (2.18-2.84) for urea, and 2.63 (2.26-3.05) for urate, 3.52 (3.01-4.13) for cystatin C, 2.90 (2.33-3.60) for urine microalbumin, and 3.37 (2.86-3.98) for the eGFR.

Conclusions: A decreased renal function increases the risk of VTE and genetic susceptibility has a positive additive effect on VTE risk. This suggests that biomarkers of the renal function may be used as predictors of VTE, especially in populations with genetic susceptibility to VTE.

Aims: Clonal hematopoiesis of indeterminate potential (CHIP), which has recently been shown to be an age-related phenomenon, is associated with cardiovascular diseases, including atherosclerosis and stroke. This study focused on the association between CHIP and short- and long-term stroke recurrence in patients with acute ischemic stroke and intracranial atherosclerotic stenosis (ICAS).

Methods: This study included 4,699 patients with acute ischemic stroke based on data from the Third China National Stroke Registry (CNSR-III), a nationwide prospective hospital-based registry. The ICAS assessment followed the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease Study and Brain Imaging. Atherosclerosis Scores (AS) were used to assess the atherosclerosis burden, as determined by the number and severity of steno-occlusions in the intracranial arteries. The primary outcome was stroke recurrence three months and one year after the event.

Results: Among the 4,699 patients, 3,181 (67.7%) were female, and the median age was 63.0 (55.0–71.0) years. We found that CHIP significantly increased the risk of stroke recurrence at the 1-year follow-up in patients with ICAS (adjusted hazard ratio [HR] 2.71, 95% confidence interval [CI] (1.77–4.16), P for interaction, 0.008).

Conclusions: Our results revealed that CHIP might have a significant impact on the long-term risk of recurrent stroke, particularly in patients with a higher atherosclerotic burden.

Aim: Superficial erosion accounts for approximately one-third of all cases of acute coronary syndrome (ACS). Previously, we found that a nearby bifurcation is independently associated with superficial erosion; however, the effect of long-term oscillatory flow on superficial erosion remains unexplored. Endothelial-to-mesenchymal transition (EndMT) is a dynamic process in which endothelial cells acquire mesenchymal properties and, in turn, give rise to smooth muscle cell (SMC)-like cells and extracellular matrix (ECM) accumulation, similar to the autopsy pathology of superficial erosion. This finding prompted us to suspect that EndMT plays a role in the effect of chronic oscillatory flow on superficial erosion.

Methods: We established oscillatory flow in mouse carotid arteries and analyzed neointimal hyperplasia, endothelial continuity, ECM content, and EndMT markers 4 weeks later. Furthermore, bioinformatic data analyses and in vitro studies were performed to elucidate the underlying mechanisms.

Results: Carotid arteries exposed to long-term oscillatory flow exhibited hyperplastic neointima, reduced endothelial continuity, and increased SMC-like cells and ECM, indicating superficial erosion-prone lesions. In addition, oscillatory flow significantly induced EndMT, whereas inhibition of EndMT ameliorated the formation of superficial erosion-prone lesions. Bioinformatic data analyses and in vitro studies showed a remarkable reduction in anti-EndMT KLF2 and KLF4 in a DNA methyltransferase (DNMT)-dependent manner, and the suppression of DNMTs attenuated oscillatory flow-induced EndMT and superficial erosion-prone lesions.

Conclusions: Chronic oscillatory flow causes superficial erosion-prone lesions by activating EndMT in a DNMT-dependent manner. Our findings highlight a promising therapeutic strategy for the prevention of superficial erosions.

Aim: We examined the association between dairy intake and all-cause, cancer, and cardiovascular disease mortality in a cohort of the general population followed up for 12 years across Japan.

Methods: We conducted a longitudinal cohort study of 79,715 participants from the Japan Multi-Institutional Collaborative Cohort study (57.2% women, mean age 54.7 years old). The amount of dairy (milk and yogurt) intake was determined using a validated short-food frequency questionnaire. The hazard ratio for mortality according to sex-specific tertile of dairy intake was calculated using Cox proportional hazards regression models with adjustment for potential confounding factors and dietary factors by sex.

Results: During the follow-up period (932,738 person-years), 3,723 participants died, including 2,088 cancer and 530 cardiovascular disease deaths. The highest tertile of total dairy intake (versus the lowest tertile) was associated with a 19% lower all-cause mortality risk (hazard ratio=0.81, 95% confidence interval: 0.70-0.92; P for trend=0.001) in women. Similarly, we observed inverse associations between milk intake and all-cause and cancer mortality risk in women, yogurt intake and cardiovascular disease risk in women, and yogurt intake and all-cause mortality risk in both sexes.

Conclusion: A higher total dairy and milk intakes in women and yogurt intake in both sexes were associated with a reduced risk of all-cause mortality in the general population across Japan during the 12-year follow-up period.

Aim: Lipoprotein (a) [Lp(a)] is a well-established risk factor for cardiovascular disease independent of low-density lipoprotein-cholesterol (LDL-C). The Lp(a) concentrations were inconsistent between the immunoassays. This study aimed to investigate whether harmonization of Lp(a) measurements can be achieved using a serum panel value assigned with the IFCC-endorsed mass spectrometry-based reference measurement procedure (IFCC-MS-RMP).

Methods: We measured the Lp(a) concentrations using five Lp(a) immunoassays in 40 panel sera provided by the Centers for Disease Control and Prevention (CDC), and 500 Japanese subjects enrolled in the Bunkyo Health Study. Of the five immunoassays, only the Roche Lp(a) assay was traceable to the WHO-IFCC reference material SRM2B. Lp(a) concentrations in CDC samples were also determined by IFCC-MS-RMP, provisionally calibrated to SRM2B. Lp(a) concentrations were expressed in mass units (mg/dL) for most reagents, but in SI units (nmol/L) for Roche’s reagent and IFCC-MS-RMP.

Results: In the CDC panel sera, all immunoassays, including Roche’s reagent, showed good correlations with IFCC-MS-RMP. In the Bunkyo Health Study samples, all immunoassays showed good correlations with Roche’s reagent (r_s, 0.986-0.998) although the slopes of the regression lines ranged from 0.292 to 0.579. After recalibration with the CDC’s panel sera, Lp(a) results of Bunkyo Health Study samples were converted to the equivalent values determined by the IFCC-MS-RMP, thus resulting in a marked reduction in the intermethod CV among the assays.

Conclusion: We achieved harmonization of Lp(a) measurements with five immunoassays using a serum panel value assigned with the IFCC-MS-RMP.

Aim: Venous thromboembolism (VTE) risk significantly increases in patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), which is characterized by an enhanced inflammatory response. This study aimed to evaluate the predictive value of inflammatory biomarkers for VTE in AECOPD.

Methods: A prospective, multicenter study was conducted to include patients hospitalized for AECOPD. Inflammatory biomarkers on admission were compared between the patients who developed VTE during hospitalization and the patients without VTE. A logistic regression analysis was used to identify inflammatory biomarkers with an independently predictive value.

Results: Among the 13,531 AECOPD inpatients, 405 (2.99%) developed VTE during hospitalization. Patients who developed VTE had higher levels of inflammatory biomarkers, including the white blood cell count, neutrophil percentage, systemic immune/inflammatory index, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio, C-reactive protein (CRP), procalcitonin (PCT), and lactate dehydrogenase (LDH), and lower lymphocyte and eosinophil ratios (ESOR), platelet, and albumin (p all ＜0.05). NLR, LDH, CRP, PCT, and ESOR were identified as independent predictors of VTE (odds ratios (ORs) were 2.22, 1.95, 1.64, 1.59, and 1.37, respectively). The incidence of VTE increased with increasing NLR, LDH, CRP, and PCT quartiles, and a decreasing ESOR quartile. Among them, NLR and LDH had predictive capabilities for VTE that were comparable to the widely used Padua and IMPROVE scores.

Conclusion: Easily available inflammatory parameters, such as NLR and LDH, can identify AECOPD patients at increased risk for VTE who may therefore be candidates for thromboprophylaxis.

Aims: Artificial intelligence is increasingly used in the medical field. We assessed the accuracy and reproducibility of responses by ChatGPT to clinical questions (CQs) in the Japan Atherosclerosis Society Guidelines for Prevention Atherosclerotic Cardiovascular Diseases 2022 (JAS Guidelines 2022).

Methods: In June 2024, we assessed responses by ChatGPT (version 3.5) to CQs, including background questions (BQs) and foreground questions (FQs). Accuracy was assessed independently by three researchers using six-point Likert scales ranging from 1 (“completely incorrect”) to 6 (“completely correct”) by evaluating responses to CQs in Japanese or translated into English. For reproducibility assessment, responses to each CQ asked five times separately in a new chat were scored using six-point Likert scales, and Fleiss kappa coefficients were calculated.

Results: The median (25th–75th percentile) score for ChatGPT’s responses to BQs and FQs was 4 (3–5) and 5 (5–6) for Japanese CQs and 5 (3–6) and 6 (5–6) for English CQs, respectively. Response scores were higher for FQs than those for BQs (P values ＜0.001 for Japanese and English). Similar response accuracy levels were observed between Japanese and English CQs (P value 0.139 for BQs and 0.586 for FQs). Kappa coefficients for reproducibility were 0.76 for BQs and 0.90 for FQs.

Conclusions: ChatGPT showed high accuracy and reproducibility in responding to JAS Guidelines 2022 CQs, especially FQs. While ChatGPT primarily reflects existing guidelines, its strength could lie in rapidly organizing and presenting relevant information, thus supporting instant and more efficient guideline interpretation and aiding in medical decision-making.

Aim: D-dimer, lipoprotein (a) (Lp(a)), and high-sensitivity C-reactive protein (hs-CRP) are known predictors of vascular events; however, their impact on the stroke prognosis is unclear. This study used data from the Third China National Stroke Registry (CNSR-III) to assess their combined effect on functional disability and mortality after acute ischemic stroke (AIS).

Methods: In total, 9,450 adult patients with AIS were enrolled between August 2015 and March 2018. Patients were categorized based on a cutoff value for D-dimer, Lp(a), and hs-CRP in the plasma. Adverse outcomes included poor functional outcomes (modified Rankin Scale (mRS score ≥ 3)) and one- year all-cause mortality. Logistic and multivariate Cox regression analyses were performed to investigate the relationship between individual and combined biomarkers and adverse outcomes.

Results: Patients with elevated levels of all three biomarkers had the highest odds of functional disability (OR adjusted: 2.01; 95% CI (1.47-2.74); P＜0.001) and mortality (HR adjusted: 2.93; 95% CI (1.55-5.33); P＜0.001). The combined biomarkers improved the predictive accuracy for disability (C-statistic 0.80 vs.0.79, P＜0.001) and mortality (C-statistic 0.79 vs.0.78, P=0.01).

Conclusion: Elevated D-dimer, Lp(a), and hs-CRP levels together increase the risk of functional disability and mortality one-year post-AIS more than any single biomarker.

Aim: We aimed to elucidate the effect of a healthy diet containing adequate amounts of protein and vegetables on metabolic indices.

Methods: In this randomized crossover study, twenty-two healthy Japanese participants ingested two different test meals: fish diet (F) or fish diet with adequate vegetable content (FV). Each 5-day diet load test was separated by a washout period of at least seven days. Metabolic indices were measured in fasting blood and 24-h urine samples.

Results: The delta (Δ) plasma glucose and Δserum low-density lipoprotein (LDL) cholesterol concentrations were significantly larger in the participants in group FV than in group F (p=0.042, p=0.013, respectively). The urinary pH in participants in group F on day 6 was significantly lower than on day 1 (p=0.008), and the Δurinary pH and Δnet gastrointestinal absorption of alkali of participants in group FV tended to be smaller than in group F (p=0.070, p=0.075, respectively).

Conclusions: This study showed that a healthy diet containing adequate protein and vegetables reduced the dietary acid load and improved plasma glucose and serum LDL concentrations in healthy Japanese participants.

Aims: Few studies have investigated the impact of sleep duration at night and daytime napping on mortality from aortic disease. In this study, we examined the associations of sleep duration at night with daytime napping and mortality from aortic disease.

Methods: We followed 67,269 participants (26,826 men and 40,443 women, aged 40–79 years) who were not night shift workers and had no history of stroke, heart disease, or cancer. The baseline survey was conducted in 1988–1990, and follow-up continued until the end of 2009. Sleep duration at night was classified into three categories: ≤ 6, 7, and ≥ 8 hours/day. We also asked the presence or absence of daytime napping. Hazard ratios (HRs) for mortality from aortic disease with 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model.

Results: During an average 16.3-year follow-up period, we observed 87 deaths from aortic dissection and 82 from aortic aneurysms. There was no association between sleep duration at night and mortality from aortic disease, but daytime napping was associated with an increased risk of mortality from total aortic disease; the multivariable-adjusted HRs were 1.48 [95% CIs: 1.08–2.02]. Furthermore, the stratified analysis revealed a stronger association with medium sleep duration (7 hours at night) compared to the other shorter and longer sleep duration: the multivariable-adjusted HR for aortic disease, 2.02 [1.16–3.52].

Conclusion: Daytime napping but not sleep duration at night was associated with an increased risk of mortality from aortic disease.

Aim: We aimed to determine whether baseline high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) at the time of coronary angiography (CAG) could serve as a prognostic marker for future major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) through a systematic review and meta-analysis.

Methods: The MEDLINE, Cochrane, and Embase databases were used for data collection. As of April 2024, 2,871 studies have been identified. Clinical studies comparing MACEs over an observational interval exceeding 12 months in patients with angiographically defined CAD with estimated hazard ratios (HRs) of MACEs in the higher or top-quartile HDL-CEC (H-HDL-CEC) group compared with the lower or bottom-quartile HDL-CEC (L-HDL-CEC) group, after adjusting for six confounding variables, including HDL-C, were included. HRs of 1) overall cardiovascular outcomes, composite of cardiovascular mortality, myocardial infarction, any coronary revascularization, and all-cause mortality (Model-1), and 2) cardiovascular outcomes excluding all-cause mortality from Model-1 (Model-2), compared between the L-HDL-CEC and H-HDL-CEC groups, were estimated using a random-effects model, respectively.

Results: In five studies, 5,725 patients with CAD with a mean observational interval of 4.9 years were included. The H-HDL-CEC group had significantly lower risks for both estimates (Model-1: HR: 0.34, 95% confidence interval [CI]: 0.18–0.63 [p=0.0005], and I²=59.8% [p=0.04]; Model-2: HR: 0.28, 95% CI: 0.13–0.60 [p=0.0013], and I²=64% [p=0.04]).

Conclusion: This is the first systematic review and meta-analysis to demonstrate a significant inverse relationship between the baseline HDL-CECs on CAG and long-term MACEs in CAD patients.

Aims: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), and its level is genetically determined. Although guidelines and consensuses in various cardiovascular fields have emphasized the importance of Lp(a), screening for Lp(a) in China has not been well studied.

Methods: A cross-sectional study was conducted using a random sample of 30,000 medical examiners from each of the five health check-up centres. The distribution of Lp(a) was described for those who completed Lp(a) testing, and logistic regression modelling was used to evaluate the relationship between Lp(a) levels and vascular structure and function in the population who underwent carotid ultrasound and brachial‒ankle pulse wave velocity (baPWV) measurements.

Results: Lp(a) was measured in only 4400 (3.02%) of the 150,000 participants. Among those tested for Lp(a), the median concentration was 15.85 mg/dL. The proportion of participants with Lp(a) levels ≥ 30 mg/dL was 15.00%. Multiple logistic regression analysis revealed a significant correlation between Lp(a) and cIMT ≥ 1.0 mm (OR: 1.008, 95% CI: 1.001-1.014, P=0.020) and carotid artery plaques (OR: 1.010, 95% CI: 1.004-1.016, P=0.001) but no correlation with baPWV ≥ 1400 (OR: 0.999, 95% CI: 0.993-1.005, P=0.788) or baPWV ≥ 1800 (OR: 1.002, 95% CI: 0.993-1.011, P=0.634).

Conclusions: The detection rate of Lp(a) at health checkups is low, and Lp(a) is positively associated with cervical vascular sclerosis and plaque but not with baPWV. Therefore, the testing rate of Lp(a) and the awareness of the risk of vascular structural changes due to Lp(a) should be further improved.

Aims: To investigate the distribution of lipoprotein(a) (Lp(a)) and its association with atherosclerotic cardiovascular disease (ASCVD) in Japanese patients at high risk for ASCVD using a health insurance database.

Methods: Between July 2013 and June 2021, patients eligible for ASCVD prevention according to the 2017 Japan Atherosclerosis Society (JAS) guidelines with documented Lp(a) test results were extracted from the Medical Data Vision claims database and divided into three groups: primary prevention high-risk (Group I), secondary prevention (Group II) and secondary prevention high-risk (Group III). Data on lipid levels, cardiovascular morbidity risk factors and lipid-lowering treatments were extracted.

Results: Of 700,580 patients with documented low-density lipoprotein cholesterol (LDL-C), 2,967 (0.42%) were tested for Lp(a). In 2,170 eligible patients, the median [interquartile range] serum concentration of Lp(a) was 13.9 [7.5-24.6] mg/dL, with 151 patients (7.0%) above the recommended risk threshold of ≥ 50 mg/dL. Lp(a) levels increased with risk across all prevention groups. Being in the highest Lp(a) quintile (Q5) was associated with an increased frequency of ASCVD (28.9% versus 18.9% in the lowest quintile (Q1) for unstable angina; 18.7% versus 10.1% for myocardial infarction; 27.9% versus 17.0% for ischemic stroke). In the secondary prevention groups, the proportion of patients meeting an LDL-C target of ＜70 mg/dL decreased from 30.2% in Q1 to 19.0% in Q5 for Group II and from 32.9% to 16.3% for Group III.

Conclusions: Despite a high prevalence of Lp(a) ≥ 50mg/dL in Japanese patients at high risk for ASCVD, it found that the Lp(a) testing rate was very low.

Aims: It is uncertain if there is a connection between subclavian steal phenomenon (SSP) and atherosclerotic stenosis in the opposite vertebral artery (VA). We aimed to explore the association between SSP and the incidence of contralateral vertebral artery stenosis (VAS) in vivo.

Methods: In this prospective registry study, we included patients diagnosed with ＞50% stenosis of proximal subclavian artery (SA) or innominate artery (INA) by digital subtraction angiography (DSA) from our comprehensive stroke center between 2011 and 2022. VAS and SSP was diagnosed by DSA in the resting state. Propensity score matching (PSM) was conducted among all participants and subgroups with a 1:1 ratio according to the presence of SSP. We further conducted sensitivity analysis by dividing all participants into subgroups according to the degree of stenosis and type of SSP. Binomial logistic regression analysis was applied to investigate the association of SSP with contralateral VAS.

Results: A total of 774 patients were included in this study and 309 (39.9%) were found with SSP. After PSM, presence of SSP was associated with lower prevalence of contralateral VAS among all participants (OR 0.45; 95% CI 0.31−0.65; p＜0.001). In subgroup analysis, the association was respectively found within left subclavian (LSA) stenosis group (OR 0.43; 95% CI 0.29−0.65; P＜0.001) and right subclavian artery (RSA) / INA stenosis group (OR 0.36; 95% CI 0.19−0.69; P=0.002).

Conclusions: SSP is associated with lower prevalence of contralateral VAS.

Aims: The effect of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular disease requires further investigation. This study aimed to evaluate the long-term effects of febuxostat on arterial stiffness, focusing on liver function.

Methods: The PRIZE study involved random assignment of patients with asymptomatic hyperuricemia to receive either add-on febuxostat treatment (febuxostat group) or non-pharmacological treatment (control group). Of the 514 participants, 23 and 14 patients in the febuxostat and control groups, respectively, underwent assessment of arterial stiffness using the cardio-ankle vascular index (CAVI). The participants in each group were further grouped on the basis of their baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels (above or below the media value or 30 U/L). The primary endpoint was the change in the CAVI from baseline to 12 and 24 months.

Results: Overall, no significant differences were found between the control and febuxostat groups in the least-squares mean estimates of changes in CAVI at 24 months (mean between-group difference, −0.41 [95% CI, −1.05 to 0.23]; p=0.204). However, there were significant differences in participants with higher baseline ALT or AST levels above 30 U/L at 24 months (mean between-group difference, −1.12 [95% CI, −2.23 to −0.01]; p=0.048 for ALT ≥ 30 U/L and −1.08 [95% CI, −2.13 to −0.03]; p=0.044 for AST ≥ 30 U/L).

Conclusions: Two-year treatment with febuxostat demonstrated a beneficial effect on CAVI in patients with hyperuricemia and liver dysfunction.