Aim: The triglyceride-glucose (TyG) index, a biomarker commonly used to evaluate metabolic health status, can predict unfavorable outcomes. Thus, we aimed to explore evidence regarding the prognostic value of the TyG index in patients with ischemic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF).

Methods: We enrolled 277 consecutive participants with new-onset ischemic cardiomyopathy and HFpEF who underwent coronary artery bypass grafting (CABG). The primary study endpoint was major adverse cardiovascular events (MACEs), defined as cardiac death, acute myocardial infarction, graft failure, and stroke.

Results: During a median follow-up of 43.34 months, 70 patients (25.1%) experienced MACEs. A multivariable Cox regression analysis identified the TyG index as an independent risk factor for MACEs, with a higher baseline TyG index associated with greater risk after adjusting for confounding factors. A restricted cubic spline showed that the TyG index had a linear relationship across the range. The optimal cut-off value of 9.167 for the TyG index demonstrated a sensitivity of 70% and specificity of 84.1%, with an AUC of 0.820 (p＜0.001, 95% CI: 0.762-0.878), thus effectively stratifying participants into lower TyG index (TyG ＜9.167, n = 182) and higher TyG index groups (TyG ≥ 9.167, n = 95), while subgroup analyses confirmed a robust association with MACEs across various populations. Furthermore, the time-dependent area under the curve, calibration curve, and decision curve analyses demonstrated that incorporating the TyG index into the traditional cardiovascular risk factor model significantly enhanced the prediction of MACE risk. Additionally, significant net reclassification improvement (0.335, 95% confidence interval [CI]: 0.136-0.518, p＜0.05) and integrated discrimination improvement (0.178, 95%CI: 0.089-0.270, p＜0.001) were also observed.

Conclusion: The TyG index is a reliable prognostic indicator for MACEs after CABG in patients with ischemic cardiomyopathy and HFpEF and it serves as a valuable complement to traditional cardiovascular risk factors by providing metabolic-related insights.

Aim: We investigated the association of obesity and metabolic health status with cerebral small-vessel disease (SVD), a predictor of stroke, in stroke-free participants during brain health checkups.

Methods: An observational cross-sectional study was conducted on 6,088 stroke-free participants who underwent brain magnetic resonance imaging (MRI). Abdominal obesity was defined as a waist circumference ≥ 90 cm for men and ≥ 80 cm for women. A metabolically healthy status was defined as having none of the three components of metabolic syndrome, except abdominal obesity. The total SVD scores were derived from four MRI markers: silent lacunar infarcts, cerebral microbleeds, moderate-to-severe white-matter hyperintensity, and enlarged perivascular spaces.

Results: The mean age of participants was 55±12 years old. Obesity was prevalent in 50% of the patients. The prevalence of a total SVD score ≥ 2 (moderate-to-severe SVD) was 348 (6%), which was elevated in metabolically unhealthy individuals regardless of obesity status. Compared with the metabolically healthy non-obese group, the metabolically unhealthy non-obese (odds ratio [OR] 2.08, [95% confidence interval {CI}, 1.33–3.27]) and metabolically unhealthy obese (OR 2.62, [95% CI, 1.70–4.04]) groups had a higher multivariable-adjusted risk for a total SVD score ≥ 2. Similar results were obtained for obesity defined as a body mass index ≥ 25 kg/m² instead of abdominal obesity.

Conclusions: Abdominal and general obesity alone were not associated with high total SVD scores in stroke-free individuals. Metabolically unhealthy status, especially high blood pressure and hyperglycemia, are significant risk factors for moderate-to-severe SVD.

Aims: To investigate the predictors associated with inadequate adherence in patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) in China and to assess the mean LDL-C levels and the percentage reduction of LDL-C.

Methods: Patients with at least one PCSK9-mAbs prescription filled between January 2021 and December 2022 were included in this study. The LDL-C levels before and after treatment initiation were assessed using medical records. Adherence to PCSK9-mAbs was assessed for up to 12 months after treatment initiation using the proportion of days covered.

Results: A total of 415 patients were enrolled. The medication adherence to PCSK9-mAbs after 12 months was 31.8%. A multivariate analysis revealed that better education (junior or high school adjusted OR 2.7 and college or higher adjusted OR 5.2) and LDL-C ＜1.4 mmol/L at 3 months after starting PCSK9-mAbs (adjusted OR 3.0) were consistent predictors of adherence. At 12 months, LDL-C was 1.5mmol/L in the adherence group (mean [SD] decrease, 44.5% [26.5%]) and 1.9 mmol/L in the poor adherence group (mean [SD] decrease, 31.0% [32.7%]), with a group difference of 0.42 mmol/L (group difference in decrease, 13.48%).

Conclusions: A better education and LDL-C ＜1.4 mmol/L at 3 months after starting treatment with PCSK9-mAbs were consistent predictors of adherence. In addition, the treatment effect declined more significantly in the poor adherence group over time.

Aims: Sex differences in the risk of venous thromboembolism (VTE) among patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) have so far only been sparsely described. This study aimed to investigate the differences in the risk of VTE events between male and female AECOPD patients and to determine whether any specific risk factors for VTE vary between the sexes.

Methods: We prospectively enrolled patients hospitalized for AECOPD from ten medical centers in China. The primary outcome was the occurrence of VTE. Univariate and multivariate logistic regression analyses were conducted to determine whether sex was an independent risk factor for VTE and also to identify any sex-specific risk factors.

Results: In total, 13,664 patients were included. VTE occurred in 5.5% of females and 3.3% of males (P＜0.001). A multivariate logistic regression analysis identified female sex as an independent risk factor for VTE in patients with AECOPD (odds ratio [OR] = 1.439, 95% confidence interval [CI] = 1.177–1.759, P＜0.001) after adjusting for confounding factors. Common risk factors for both sexes included age, chronic heart failure, severe lung disease, stroke, a recent surgical history, a history of VTE, and respiratory failure. Additional risk factors unique to males were sepsis (OR = 9.514, 95% CI = 4.513–20.056, P＜0.001), varicose veins (OR = 6.170, 95% CI = 3.237–11.763, P＜0.001), and rheumatological disorders (OR = 2.677, 95% CI = 1.184–6.052, P = 0.018). No sex-specific risk factors were identified for females.

Conclusion: Female sex was found to be an independent risk factor for VTE and some sex-specific risk factors exist among inpatients with AECOPD. These findings highlight the importance of considering sex and sex-related factors when assessing the VTE risk in AECOPD patients.

Aims: Lipoprotein(a) (Lp[a]) exhibits atherogenic and thrombogenic properties. We investigated the association between Lp(a) levels and the risk of coronary heart disease (CHD) and stroke.

Methods: We used data from 5138 people ≥ 30 years old registered in the Suita Study, a Japanese population-based prospective cohort study. All participants were initially free from CHD or stroke. Cox proportional hazard models were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CHD and stroke among participants with elevated Lp(a) levels.

Results: At baseline, only 17.0% of participants had Lp(a) levels ≥ 30 mg/dL. Within the median follow-up period of 11.7 years, 164 CHD and 234 stroke events were detected. In the multivariable-adjusted regression model, Lp(a) ≥ 30 mg/dL was associated with an increased risk of CHD (HR, 1.52 [95% CI, 1.05-2.21]). Every 10-ml/dL increment in Lp(a) level was associated with a 7.9% increase in CHD risk. The association with CHD did not change significantly after adjusting for total cholesterol level or lipid-lowering drugs. In contrast, increased Lp(a) levels were not associated with stroke risk or any subtype.

Conclusions: Lp(a) ≥ 30 mg/dL was associated with an increased risk of CHD in the Japanese population.

Aim: Cholesterol uptake capacity (CUC) is a functional assessment of high-density lipoprotein (HDL) and has drawn attention for the risk stratification of atherosclerotic cardiovascular disease (ASCVD). This study evaluated the usefulness of HDL-CUC as a predictive marker for long-term ASCVD events in patients with coronary artery disease (CAD).

Methods: This retrospective observational study included 503 patients with CAD who underwent coronary revascularization. Blood was sampled from the participants within three months before or after index revascularization. The CUC was assayed using a previously reported automated system. The study population was divided into three groups according to the tertiles of CUC levels. The primary outcome was ASCVD events, which were defined as a composite of all-cause death, acute myocardial infarction, stroke, and peripheral artery disease.

Results: A total of 29 events were observed during the follow-up (median 2.8 years). The risk of the primary outcome in the low-CUC group was significantly higher than that in the high-CUC group (3-year incidence: low CUC 8.8% vs. high CUC 4.0%; log-rank p = 0.046). After adjusting for age and sex, the risk in the low-CUC group relative to that in the high-CUC group remained significantly high (hazard ratio 3.17, 95% confidence interval 1.05–9.54, p = 0.040).

Conclusion: Low CUC in patients with CAD were associated with a higher risk of ASCVD events after coronary revascularization than high CUC levels. The assessment of HDL functionality measured by CUC would be useful for the risk prediction of ASCVD after coronary revascularization.

Aim: To evaluate the risk factors, location, treatment, and outcomes of stroke due to arterial dissection, we examined these characteristics in a substantial, long-standing, nationwide stroke cohort.

Methods: The study participants were patients with acute stroke who were registered in the Japan Stroke Data Bank between January 1999 and December 2020. We focused on patients with stroke caused by extracranial or intracranial artery dissection and examined their clinical characteristics, treatments, and outcomes. In addition, we compared the results between clinical subtypes with and without dissection.

Results: Among the 218,799 registered patients with acute stroke, 1,353 (0.62%) were attributed to artery dissection. Of these, 880 patients had ischemic stroke, 16 had intracerebral hemorrhage, and 457 had subarachnoid hemorrhage (SAH). Dissection cases were most prevalent among individuals in their 40s and 50s, with intracranial vertebral artery dissection being the primary cause of ischemic stroke and SAH. Male sex, dyslipidemia, diabetes mellitus, and a history of smoking were associated with a higher likelihood of ischemic stroke than SAH. Unfavorable outcomes, defined as a modified Rankin score ≥ 4 at discharge, were observed in 18.9% of ischemic stroke cases and 42.6% of SAH cases with dissection. Neurological severity and older age at admission are associated with unfavorable outcomes in patients with ischemic stroke and SAH.

Conclusions: Ischemic stroke was the most frequent subtype of stroke in patients with arterial dissection, followed by SAH. Patients with stroke due to dissection were younger than those without. Neurological severity and older age at admission are substantial risk factors for unfavorable stroke outcomes due to artery dissection.

Aims: Oxidative stress is a central factor in the pathogenesis of atherosclerosis and potentially exhibits sexual dimorphism. The induction of heme oxygenase-1 (HO-1) serves as a crucial mechanism against reactive oxygen species toxicity in the vascular wall, and this induction is regulated by the promoter (GT)n repeat length. We aim to investigate whether or not HO-1 gene (GT)n polymorphism is associated with the occurrence of large-artery atherosclerotic (LAA) stroke.

Methods: We consecutively recruited stroke patients, with a control group comprising age- and sex-matched non-stroke individuals. HO-1 (GT)n genotypes were determined using DNA extracted from the peripheral leukocytes. HO-1 (GT)n polymorphism was classified as short [S, ≤ 24 (GT)n], medium [M, 25 ≤ (GT)n ＜31], or long [L, 31 ≤ (GT)n]. Clinical data were collected, and stroke patients were categorized into LAA and non-LAA groups according to the TOAST classification. A multivariable logistic regression analysis was conducted to evaluate the association between HO-1 (GT)n variants and LAA occurrence stratified by sex.

Results: There was no significant difference in the distribution of HO-1 (GT)n genotypes between the stroke and non-stroke populations. However, the proportion of S/S genotype was significantly lower in the LAA stroke patients than in the non-LAA stroke patients (7.08% vs. 21.78%, p＜0.001). A multivariable logistic regression analysis indicated that non-SS genotypes were associated with a significantly increased risk of LAA compared to the S/S genotype patients (odds ratio [OR] 3.35, 95% confidence interval [CI] 1.98-5.67, p＜0.001). After stratification by sex, the protective effect of the HO-1 (GT)n S/S genotype was highly significant in men (OR 5.50, 95% CI 2.67-11.34, p＜0.001), whereas the association was not significant in women (OR 1.60, 95% CI 0.75-3.34, p = 0.228).

Conclusion: Short (GT)n variants in HO-1 may confer significant protection against LAA stroke in men but not in women.

Recombinant tissue plasminogen activator (rt-PA), specifically alteplase, remains the standard treatment for acute cerebral infarction across all stroke subtypes. However, per recent randomized controlled trials (RCTs), individuals with mild cerebral infarction, medical management alone without rt-PA can yield functional outcomes comparable to those achieved with thrombolytic therapy. This has sparked ongoing debate regarding the necessity of rt-PA administration in cases of mild stroke. Nonetheless, certain individuals with mild cerebral infarction derive clear benefits from rt-PA therapy. Therefore, an individualized treatment approach should be prioritized over a uniform thrombolytic strategy in these cases. This review examines the therapeutic efficacy and limitations of rt-PA therapy for mild cerebral infarction, integrating evidence from prior clinical studies with the authors’ perspectives.

Aim: The American Heart Association (AHA) proposed Life’s Essential 8 score (LE8) in 2022 as a new metric for cardiovascular health (CVH). This study investigated the association between the LE8 score and the development of carotid artery plaque.

Methods: Data were drawn from the Asymptomatic Polyvascular Abnormalities Community (APAC) cohort study. In 2010, 1,938 participants without carotid plaques were recruited and followed-up until 2012. LE8 scores ranging from 0 to 100 were categorized as low (0–49), moderate (50–79), and high (80–100), whereas carotid plaques were measured using color Doppler ultrasound. A logistic analysis was used to analyze the association between the LE8 score and carotid plaque.

Results: During the 2-year follow up period, 350 (18.1%) patients developed new carotid plaques. The incidence of newly developed carotid plaques decreased from 27.0% in the low-LE8 group to 13.7% in the high-LE8 group (p＜0.001). Adjusted odds ratios (ORs) for plaque development were 0.65 (95% confidence interval [CI], 0.45–0.93) in the moderate-LE8 group and 0.55 (95% CI, 0.34–0.90) in the high-LE8 group compared to the low-LE8 group. Higher LE8 scores were associated with a lower risk of stable and multiple carotid plaques.

Conclusions: An elevated LE8 score was associated with a lower risk of carotid plaque formation as well as plaque stability and quantity. Promoting adherence to optimal CVH levels may be beneficial in reducing the burden of carotid plaques and the risk of cardiovascular disease.

Aim: This study investigated the efficacy and safety of endovascular revascularization for symptomatic non-acute atherosclerotic intracranial LVO.

Methods: For non-acute atherosclerotic intracranial large vessel occlusion (LVO), despite aggressive medical treatment, recurrent ischemic stroke or transient ischemic attack related to the occluded artery still occurs repeatedly. This retrospective cohort study included stroke patients with intracranial LVO who received endovascular treatment (EVT), categorized by successful recanalization and the time interval from symptom onset to revascularization (＜30 days vs. ≥ 30 days). The primary efficacy outcome was stroke recurrence or mortality at the 6-month follow-up.

Results: Of the 264 patients in the study, 229 (87%) had successful recanalization, while 35 (13%) did not. In addition, 139 patients had recanalization times ≤ 30 days, and 125 had recanalization times ＞30 days. The successful recanalization group had a significantly lower rate of stroke recurrence or death during follow-up than the unsuccessful group (9.6% vs. 31.4%, adjusted odds ratio [OR]: 4.98, 95% confidence interval [CI]: 1.86 -13.37; P = 0.001). The group with a recanalization time ≤ 30 days also demonstrated a significantly lower rate of stroke recurrence or death during follow-up than the group with a recanalization time ＞30 days (7.9% vs.17.6%, P = 0.015). In addition, the rate of a favorable prognosis (modified Rankin Scale [mRS] 0-2) during the follow-up period was significantly higher in the successful recanalization group than in the successful recanalization group (71.1% vs. 51.4%, P = 0.021).

Conclusion: These findings suggest that successful recanalization may have therapeutic potential for patients with non-acute intracranial large-vessel occlusion, particularly for those with LVO recanalization lasting ＜30 days, who show more significant benefits than those with longer-lasting recanalization [please check this carefully].

Aims: This post-hoc analysis from the Behavioural Intervention by allied health professionals to promote Physical activity (BIP) trial examined the relationship between depression and step count and walking capacity over two years in people with peripheral artery disease (PAD).

Methods: BIP included participants with walking impairment due to PAD followed up at 4, 12 and 24 months to measure step count over 7 days using an accelerometer and six-minute walking distance. The relationships between depression at entry with step count and walking distance during follow-up were assessed using linear mixed effects models.

Results: At entry, 29 (14.5%) of the 200 participants had depression being treated with anti-depressant medication. Participants diagnosed with depression were more likely to be female (13 of 29, 44.8%) than those not diagnosed with depression (43 of 171, 25.1%). Over 24 months follow-up, daily step count progressively decreased in participants with depression (mean [SD] 4406 (2266) at entry to 3888 (2555) at 24 months) as compared to no change in participants without depression (mean (SD) 5271 (2526) at entry compared to 5120 (2446) at 24 months), inter-group difference p = 0.010. No significant difference in change in six-minute walking distance over 2 years was found between participants with and those without depression.

Conclusion: Depression is associated with greater decline in self-regulated walking in patients with PAD. Effective treatments for depression are needed which help promote physical activity in people with PAD.

Aim: We evaluated the efficacy and safety of bempedoic acid, an ATP-citrate lyase inhibitor, at doses of 60, 120, and 180 mg, administered for 12 weeks in conjunction with ongoing treatments (e.g., statin and/or other lipid-modifying therapy) and determined the phase 3 trial dosage in Japanese patients.

Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b trial included patients with hypercholesterolemia at risk for cardiovascular events and an inadequate response to statins/statin intolerance. The percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 12 was calculated.

Results: The bempedoic acid 60 mg, 120 mg, 180 mg, and placebo groups included 47, 46, 48, and 47 patients, respectively; 79% of patients had an inadequate response to statins and 21% had statin intolerance. Relative to placebo (–1.9%), LDL-C reduction from baseline to week 12 was significantly greater in the bempedoic acid treatment groups (least squares mean: 60 mg, −10.6%; 120 mg, −21.9%; 180 mg, −21.3%; p＜0.01 vs. placebo). Patients with an inadequate response and statin intolerance who were treated with bempedoic acid showed improved LDL-C levels by week 12. The incidence of treatment-emergent adverse events was higher in the bempedoic acid-treated groups (60 mg, 57.4%; 120 mg, 54.3%; and 180 mg, 58.3%) than in the placebo group (38.3%). There was no increasing trend with increasing doses. Adverse events related to muscular and hepatic disorders were infrequent, and no new or worsening cases of diabetes were reported.

Conclusions: The efficacy and safety of bempedoic acid in Japanese patients with elevated LDL-C levels were confirmed. The 180 mg dosage of bempedoic acid was found to be appropriate for a Japanese phase 3 trial.

Aim: Adiponectin is an anti-diabetic and anti-atherogenic protein secreted primarily from adipose tissue. Adiponectin and modified LDL (mLDL) form a complex to modulate their biological activity. To elucidate the significance of the complex formation, we analyzed its effects on vascular tissue and developed and verified novel quantifying methods for adiponectin.

Methods: To study the significance of the mLDL-adiponectin complex (MAC) formation, we used the wire-myography method on rat mesenteric artery. We developed a method to measure MAC by using LOX-1 as the capture protein and anti-adiponectin antibody for detection. We compared serum MAC levels between hemodialysis patients and control subjects.

Results: Administering mLDL alone to rat mesenteric artery impaired endothelium-dependent vasorelaxation, whereas simultaneously administering adiponectin with mLDL protected rat mesenteric artery from the mLDL-induced impairment of vasorelaxation. This finding indicates MAC formation prevents endothelium from mLDL-induced dysfunction in tissue. Using our novel ELISA for MAC, we found that MAC was increasingly detectable depending on the doses of mLDL and adiponectin in vitro. In serum, hemodialysis patients showed a significantly higher ratio of MAC-high patients (higher than the median level of MAC) than did healthy controls. Furthermore, the MAC-high hemodialysis group had lower mLDL activity measured as LOX-1 ligand containing apoB.

Conclusion: Using our ELISA, we detected MAC in human serum that protected blood vessels from the deleterious effects of oxidized LDL.

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.

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.

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.

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.

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.