Aim: This study attempted to clarify the prevalence and clinical characteristics of Janus kinase 2 V617F (JAK2) gene mutations in patients with cerebrovascular diseases.

Methods: We prospectively enrolled patients who were admitted to or referred to our department with cerebrovascular disease due to suspected major cerebral artery disease or small-vessel occlusion within 30 days of onset between January 1, 2021, and April 30, 2024, and who consented to undergo a JAK2 mutation analysis. We investigated the prevalence of JAK2 mutations based on the clinical subtype of stroke and the presence or absence of major cerebral artery disease. We also examined the clinical characteristics of patients with positive JAK2 mutation.

Results: Among 316 consecutive inpatients (216 males; median age, 74 years old), JAK2 mutations were detected in 4 of 102 (3.9%) patients with large artery atherosclerosis, 2 of 101 patients (2.0%) with small-vessel occlusion, and 2 of 113 (1.8%) with other stroke subtypes. A multiple logistic regression analysis showed that patients with the positive JAK2 mutation had significantly higher hematocrit values (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.07–1.62; p = 0.010), platelet counts (OR, 1.19; 95% CI, 1.07–1.31; p = 0.001), and thrombomodulin levels (OR, 1.08; 95% CI 1.01–1.15; p = 0.025) at admission than patients with the negative JAK2 mutation.

Conclusions: The frequency of JAK2 mutations is very low among patients with major cerebral artery diseases and small-vessel occlusion. The mechanisms underlying stroke onset in patients with the positive JAK2 mutation may involve factors beyond hematopoietic cells, such as endothelial dysfunction.

MicroRNAs (miRNAs) serve as fundamental post-transcriptional regulators of gene expression, among which the miR-33 family, consisting of miR-33a and miR-33b, has emerged as a critical modulator in the pathogenesis of cardiovascular and metabolic diseases. These miRNAs are embedded within the intronic regions of SREBF genes and play pivotal roles in cholesterol homeostasis, fatty acid metabolism, and inflammatory regulation. Notably, miR-33a is highly conserved across various species, whereas miR-33b is found primarily in primates and some other mammals, complicating the development of relevant animal models. These miRNAs inhibit their target genes involved in cholesterol metabolism, fatty acid oxidation, and insulin signaling, consequently influencing the development and progression of cardiovascular and metabolic diseases. Inhibition or genetic ablation of miR-33 has shown therapeutic potential, improving dyslipidemia, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease, through altered cholesterol metabolism, attenuation of inflammation, and increased fatty acid utilization. In addition, miR-33 suppression has been shown to promote skeletal muscle regeneration. However, systemic inhibition of miR-33 requires caution due to the role of miR-33 in hunger signaling and sympathetic nerve activity in the central nervous system, which may lead to obesity. Therefore, the development of tissue-specific strategies is essential for the safe and effective therapeutic targeting of miR-33.

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

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

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

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

Aims: Chronic limb-threatening ischemia (CLTI) is a serious complication in patients with kidney failure. We aimed to investigate the frequency and clinical burden of CLTI in patients undergoing hemodialysis.

Methods: We analyzed a historical cohort of 2,292 maintenance hemodialysis patients to examine the prevalence, risk factors, and clinical outcomes of CLTI, defined as prior surgical or endovascular arterial revascularization and/or lower limb amputation. We also evaluated the incidence of new-onset CLTI during follow-up and its association with the subsequent risk of mortality.

Results: At baseline, 198 patients (8.6%) had prevalent CLTI. These individuals had longer dialysis duration, poorer nutritional status, and higher serum calcium and phosphorus levels, in addition to traditional risk factors. During a median follow-up of 5.8 years, 436 patients experienced cardiovascular events, 77 underwent interventions for CLTI, and 712 died. Prevalent CLTI at baseline was associated with 2.2-, 3.2-, and 9.3-fold higher risks of all-cause mortality, cardiovascular events, and CLTI-related interventions, respectively. These associations were attenuated but remained significant after comprehensive adjustment for potential confounders. Among the 2,094 patients without CLTI at baseline, 49 developed new-onset CLTI. New-onset CLTI was also associated with an increased risk of subsequent mortality, particularly in the early phase following its onset.

Conclusions: CLTI is common and associated with poor clinical outcomes in patients undergoing hemodialysis. Our findings highlight the substantial and persistent burden of CLTI in this population and underscore the urgent need for effective strategies to prevent or delay the progression of lower extremity arterial disease.

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

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

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

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

Aim: A decline in the estimated glomerular filtration rate (eGFR) is associated with vascular dysfunction, a cardiovascular disease (CVD) risk. However, since the eGFR is based on the standard body surface area (BSA) of 1.73 m², its reliability may be affected by body size. We aimed to clarify whether the individual’s BSA adjustment of eGFR enhances the relationship with kidney and vascular functions in the general healthy Japanese population.

Methods: This cross-sectional analysis was conducted in a total of 58,837 Japanese individuals. The BSA-adjusted eGFR (mL/min) was defined as the product of the conventional eGFR and the individual’s BSA divided by 1.73 m². Arterial stiffness was assessed by the cardio-ankle vascular index (CAVI), and a high CAVI was defined as CAVI ≥ 9.0.

Results: Compared with the eGFR, the BSA-adjusted eGFR showed higher values in males in their 20s to 50s and lower values in females of all ages. The BSA-adjusted eGFR showed a stronger negative correlation with the CAVI than the eGFR (R: –0.444 vs. –0.388 in males, –0.449 vs. –0.416 in females). In a receiver-operating characteristic curve analysis, the discriminative power for a high CAVI was stronger for the BSA-adjusted eGFR than for the eGFR (area under the curve: 0.776 vs. 0.723 in males, 0.757 vs. 0.716 in females). The upper tertile of the BSA-adjusted eGFR showed higher odds ratios for a high CAVI than that of the eGFR in both sexes, after adjusting for covariates.

Conclusions: The BSA-adjusted eGFR appropriately assesses the kidney function according to differences in sex, age and body size. Furthermore, a CAVI analysis suggested that the BSA-adjusted eGFR might facilitate the achievement of more precise preventive care for CVD.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of early onset atherosclerosis. Evinacumab, an angiopoietin-like protein 3 (ANGPTL3)-inhibiting monoclonal antibody, lowers LDL-C independently of LDL receptor activity. However, its effects on other lipid-related markers remain poorly investigated in real-world clinical practice. We herein report a 54-year-old Japanese woman with genetically confirmed compound heterozygous familial hypercholesterolemia (FH) treated with evinacumab in combination with other lipid-lowering agents. Lipoprotein apheresis was continued every two weeks throughout the treatment. Serum sampling before and after evinacumab administration found that, following evinacumab initiation, LDL-C decreased from 324 to 205 mg/dL (reduction of 119 mg/dL, −36.7%) and triglycerides from 155 to 51 mg/dL (reduction of 103 mg/dL, −66.8%). Notably, atherosclerosis-related markers showed substantial reductions, with remnant-like particle cholesterol (RLP-C) decreasing from 10.5 to ＜2.0 mg/dL, small dense LDL-C (sdLDL-C) from 80.2 to 22.1 mg/dL, and malondialdehyde-modified LDL (MDA-LDL) from 105 to 87 mg/dL. Apolipoproteins (ApoB, ApoC2, ApoC3, ApoE, and ApoA5) decreased as well. No significant changes were observed in lipoprotein (a), free fatty acids, interleukin-6, or high-sensitivity C-reactive protein levels. This is the first clinical report to comprehensively evaluate the lipid-modifying effects of evinacumab in a Japanese HoFH patient. In this case, evinacumab was highly efficacious against atherosclerosis-related markers and apolipoproteins, beyond simple LDL-C reduction, suggesting additional cardiovascular benefits. These findings provide mechanistic insights that may inform therapeutic strategies for the management of HoFH.

Aims: Angiopoietin-like proteins (ANGPTLs) are key regulators of lipid metabolism; however, their response to lipid-lowering therapies remains incompletely understood. The PRESTIGE study compared the effects of pemafibrate add-on versus statin dose doubling on small dense low-density lipoprotein-cholesterol (sdLDL-C) in patients with type 2 diabetes and hypertriglyceridemia receiving statins. This post-hoc analysis investigated changes in circulating ANGPTL levels.

Methods: Participants were randomized to receive either pemafibrate (0.2 mg/day; n = 48) or double-dose statin therapy (n = 49). Plasma ANGPTL levels and lipid parameters were assessed at baseline and after 12 weeks. ANGPTLs were quantified using specific human ELISA kits. sdLDL-C, LDL-triglycerides (TG), and HDL3-C were measured using the homogeneous assays.

Results: Pemafibrate treatment significantly increased circulating ANGPTL3 (+71%) and ANGPTL4 (+143%) levels, with no change in ANGPTL8, whereas statin dose doubling had no effect on ANGPTL levels. Pemafibrate markedly reduced TGs and sdLDL-C, while increasing large buoyant LDL-C, LDL-TG, HDL2,3-C, apolipoprotein AI, and apolipoprotein AII. The increase in ANGPTL3 was not correlated with changes in LDL subspecies but was positively associated with changes in HDL2,3-C. When participants were stratified by baseline ANGPTL3 levels, those in the low ANGPTL3 group showed an increase in LDL-C and LDL-TG in response to pemafibrate. The substantial elevation in ANGPTL4 induced by pemafibrate did not show associations with lipid changes.

Conclusions: Pemafibrate markedly elevated circulating ANGPTL3 and ANGPTL4 levels, but these increases were not associated with pro-atherogenic changes in lipoprotein profiles. Notably, baseline ANGPTL3 concentrations may influence the effect of fibrates on LDL-C levels.

Aims: The HELT-E₂S₂ score is a newly developed risk stratification tool for stroke in patients with atrial fibrillation. We investigated the prognostic value of the HELT-E₂S₂ score in patients with lower extremity artery disease (LEAD) and compared it with other risk scores for atrial fibrillation (AF) and LEAD.

Methods: Patients undergoing endovascular therapy (EVT) for symptomatic LEAD between August 2015 and August 2016 were enrolled in the I-PAD NAGANO registry, a prospective, multicenter, observational registry. The primary endpoint was major adverse cardiovascular events (MACEs), defined as a composite of all-cause death, nonfatal myocardial infarction, and stroke at 5 years.

Results: A total of 366 patients were divided into low-risk (HELT-E₂S₂ score ＜2, n = 146) and high-risk (HELT-E₂S₂ score ≥ 2, n = 218) groups. The major criteria of the HELT-E₂S₂ score were hypertension (81.9%) and elderly age (75-84 years old) (34.1%). The incidence of MACEs at 5 years was significantly higher in the high-risk group than in the low-risk group (43.7% vs. 22.8%, P＜0.001). In the COX multivariate analysis, the high-risk group emerged as a significant predictor of MACEs at 5 years (hazard ratio 1.87, 95% confidence interval 1.22-2.89, P = 0.004). The C-statistics for MACEs were comparable among the HELT-E₂S₂ and other AF and LEAD risk scores.

Conclusions: The HELT-E₂S₂ score was associated with an increased risk of cardiovascular events in patients with LEAD undergoing EVT.

Aims: Despite strong recommendations for medical consultation, the treatment status and low-density lipoprotein cholesterol (LDL-C) levels at 1-year follow-up of individuals with referral-level LDL-C identified in health checkups remain unclear. We evaluated the treatment status and 1-year LDL-C control among individuals identified in health checkups as requiring early medical consultation due to LDL-C levels of ≥ 180 mg/dL.

Methods: We conducted a nationwide cohort study including health checkup data for individuals aged 20–74 years. We identified 102,049 individuals (median age: 48 years; male: 66.8%) with uncontrolled LDL-C (≥ 180 mg/dL) at baseline, who had no prior lipid-lowering therapy. Poisson regression with robust error variance was used to assess factors associated with uncontrolled LDL-C at 1 year.

Results: Among individuals with LDL-C ≥ 180 mg/dL at baseline, 56,147 (55.0%) visited a medical institution within 3 months of the checkup, and 13,124 (12.9%) were prescribed lipid-lowering medications at 1 year. At 1 year follow-up, 49,260 (48.3%) still had LDL-C ≥ 180 mg/dL. Factors associated with persistent LDL-C ≥ 180 mg/dL at 1 year included obesity (RR: 1.07, [95% CI: 1.06–1.09]), 10 mg/dL increase in LDL-C at baseline (1.11 [1.10–1.11]), smoking (1.05 [1.04–1.07]), alcohol consumption (0.95 [0.94–0.97]), poor sleep quality (1.02 [1.01–1.03]), and skipping breakfast ≥ 3 times per week (1.07 [1.05–1.08]).

Conclusions: Despite being classified as requiring early medical intervention, only half of individuals with LDL-C ≥ 180 mg/dL visited a physician within 3 months, and nearly half continued to have uncontrolled LDL-C at 1 year. Strategies to facilitate timely medical visits and appropriate lipid management in health checkup-identified cases are warranted.

Aim: Frailty, particularly chronic limb-threatening ischemia (CLTI), is a major health concern in patients with peripheral artery disease. CLTI onset can lead to increased frailty and impaired ability to perform daily activities. However, its in-hospital frailty progression in these patients remain poorly defined. This study aims to address this knowledge gap.

Methods: We analyzed 841 CLTI patients (mean age, 75.8 years; 60.2% male) who underwent endovascular therapy (EVT) and were discharged alive from a multicenter registry. Frailty was assessed at admission and discharge using the Clinical Frailty Scale (CFS), categorized as non-frail (1–3), mildly frail (4–5), or advanced frail (6–9). Frailty progression was defined as a transition to a higher frailty category during hospitalization. The predictors of frailty progression during hospitalization were assessed using logistic regression analyses.

Results: Overall, 103 patients (12.2%) experienced frailty progression. Compared to those without progression, these patients had lower left ventricular ejection fraction (LVEF), lower hemoglobin and albumin levels, and more severe wounds. Independent predictors of frailty progression included LVEF ＜40% (odds ratio [OR], 2.02), hemoglobin ＜11 g/dL (OR 1.67), and Wound Grade 3 (OR 2.04). Within 2 years after discharge, the amputation-free survival rate was significantly lower in the progression group than in the non-progression group (42.6% vs. 56.0%; log-rank p = 0.008). The wound healing rate within 2 years after EVT was also significantly lower in the progression group than in the non-progression group (78.2% vs. 88.8%; log-rank p = 0.001).

Conclusions: In-hospital frailty progression was observed in one of the eight patients with CLTI undergoing EVT. Frailty progression was linked to more severe clinical status and worse life and limb outcomes than cases without progression.

Aim: Overproduction of large very low-density lipoprotein1 (VLDL1) is a central abnormality in metabolic dyslipidemia. Excess-triglycerides (Ex-TG), based on the Friedewald equation, is considered to be a marker for TG-rich VLDL, but it remains uncertain whether Ex-TG reflects large VLDL particles.

Methods: We conducted a retrospective sub-analysis of the PROUD48 study, which compared the effects of pemafibrate and omega-3 fatty acids (FAs) on apolipoprotein B48, with data available on VLDL subfractions. Hyperlipidemic patients on statins were treated with pemafibrate (n = 56) or omega-3FAs (n = 56) for 16 weeks. VLDL subfractions: large (L), middle (M), and small (S) were separated using high-performance liquid chromatography. Ex-TG was calculated as plasma TG minus 5 x calculated VLDL-cholesterol (C).Calculated VLDL=total-C minus directly measured LDL-C minus HDL-C.

Results: Pemafibrate and omega-3FAs reduced plasma TG levels by 42% and 27%, respectively; however, a marked reduction in Ex-TG was observed only with omega-3 FAs. Ex-TG was positively correlated with L-VLDL-TG, %L-VLDL-TG, (L–M+S)-VLDL-TG, and L-VLDL-TG/C, while it showed no positive correlation with smaller VLDLs and apoB48. TG exhibited stronger correlations with L-VLDL-related parameters than Ex-TG, but was also positively associated with smaller VLDLs and apoB48. These correlation patterns remained consistent even when examining the relationship between changes in Ex-TG, TG, or apoB48 and corresponding changes in VLDL subfractions using lipid-lowering agents.

Conclusions: The behavior of Ex-TG appears consistent with previous kinetic studies showing that omega-3FAs primarily suppress VLDL1 production, whereas fibrates promote TG removal, suggesting that Ex-TG serves as a surrogate marker for VLDL1 overproduction.

Inflammation plays a crucial role in the initiation, progression, and destabilization of atherosclerotic plaques and it contributes to recurrent cardiovascular events in patients with coronary artery disease (CAD). High-sensitivity C-reactive protein (hsCRP) is a well-established biomarker of systemic inflammation and it is a predictor of adverse outcomes, independent of low-density lipoprotein cholesterol (LDL-C) levels. Elevated hsCRP levels are consistently associated with higher event rates in both chronic and acute coronary syndromes, thus reflecting the residual inflammatory risk not addressed by lipid-lowering therapy or revascularization. Imaging studies have revealed that higher hsCRP levels correlate with a greater plaque burden and vulnerability. Recent trials have shown that anti-inflammatory therapies, including low-dose colchicine and interleukin-6 inhibition, can reduce this residual risk, while agents such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter 2 inhibitors, and bempedoic acid offer additional anti-inflammatory effects. The integration of anti-inflammatory strategies with intensive lipid management may thus provide additional cardiovascular benefits.

A 79-year-old Chinese man was referred for nephrotic syndrome (proteinuria 4.4 g/day). In blood tests, serum high-density lipoprotein (HDL) cholesterol was undetectable, and the esterified cholesterol to total cholesterol ratio was very low. Lecithin: cholesterol acyltransferase (LCAT) activity was also undetectable. Since he had neither corneal opacity nor pathological mutations in the LCAT gene and anti-LCAT antibodies were detected in serum, a diagnosis of acquired LCAT deficiency was made. Renal biopsy revealed glomerulopathy associated with LCAT deficiency and membranous nephropathy (MN). Since the patient’s proteinuria did not improve despite prescribing an angiotensin II receptor blocker (ARB), we suggested the prescription of prednisolone, but he returned to China due to the expiration of his residence visa for Japan. One year after the initial visit, his proteinuria had improved to 0.9 g/day without immunosuppressive therapy. However, his HDL cholesterol level was still low at around 3 mg/dL, indicating a discrepancy between remission of nephrotic syndrome and lack of improvement in lipid levels.

Of the 11 patients with acquired LCAT deficiency reported to date, 4 with undetectable LCAT activity and MN on renal biopsy required immunosuppressive therapy to alleviate proteinuria. The present patient was prescribed only an ARB according to his preference, which happened to be consistent with the MN treatment guideline that states, “Wait 6 months for spontaneous remission while using maximal antiproteinuric therapy.” The clinical course of acquired LCAT deficiency varies, and further case reports are needed to determine the necessity of immunosuppressive therapy.

Aims: In-stent restenosis (ISR) is a significant limitation of coronary stent implantation, but the exact mechanism of ISR remains unclear. Patients after percutaneous coronary intervention (PCI) are in a hypercoagulable state; however, there is less information on its association with chronic coronary artery disease (CAD) in patients with ISR after PCI. We aimed to clarify whether or not CAD patients with ISR after PCI are in a hypercoagulable state and whether or not PS exposure on extracellular vesicles (EVs), blood cells (BCs), and endothelial cells (ECs) is involved in the hypercoagulable state.

Methods: Phosphatidylserine (PS) exposure to EVs, BCs, and ECs was analyzed using flow cytometry. Procoagulant activity (PCA) was analyzed by clotting time (CT), purified clotting complex assays, and fibrin production assays.

Results: Compared with pre-PCI or controls, levels of exposed PS on EVs, BCs, and ECs were significantly increased from 1 day, peaked at 3 months, and gradually decreased within 1 year in CAD patients after PCI, especially in CAD patients with ISR after PCI. Furthermore, their increased levels significantly decrease CT and enhance intrinsic/extrinsic FXa, thrombin, and fibrin generation. PCA was weakened by approximately 80% when lactadherin was used.

Conclusions: Our results revealed that CAD patients after PCI, especially those patients with ISR after PCI, are associated with a hypercoagulable state in which PS exposure on EVs, BCs, and ECs plays a more important role than tissue factors. Therefore, blocking PS exposure to EVs, BCs, and ECs may provide a new target for preventing ISR in these patients.

Aims: The phase angle (PhA) derived from a bioelectrical impedance analysis (BIA) is a risk factor for cardiovascular disease (CVD). The present study explored the relationship between PhA and the progression of subclinical atherosclerosis in asymptomatic adults.

Methods: Two cross-sectional studies were performed on 15579 participants who underwent carotid ultrasound testing and a BIA as well as 8228 participants who underwent brachial ankle pulse wave velocity (baPWV) testing and a BIA. We also conducted a longitudinal study in participants without CVD and carotid atherosclerosis (CAS) at baseline who underwent carotid ultrasound ≥ 2 times (n = 2680) or baPWV testing [≥ 2 times] (n = 1775). CAS and the brachial ankle pulse wave velocity (baPWV) were selected as the subclinical atherosclerosis markers.

Results: In the cross-sectional studies, participants with CAS (5.43±0.60° vs. 5.73±0.61°, P＜0.001) or elevated baPWV (5.38±0.62° vs. 5.74±0.59°, P＜0.001) had lower PhA values than controls. Furthermore, the PhA value was independently and inversely correlated with CAS (adjusted odds ratio [OR] = 0.41, 95% confidence interval [CI] 0.37-0.46, P＜0.001) and elevated baPWV (adjusted OR = 0.45, 95% CI 0.39-0.52, P＜0.001). Restricted cubic spline curve analyses indicated dose-response associations of PhA values with subclinical atherosclerosis. In the longitudinal study, high PhA values at baseline decreased the risk of incident CAS (adjusted hazard ratio = 0.44, 95% CI 0.36-0.54, P＜0.001). Multivariate linear regression analyses showed that the PhA was negatively associated with absolute or relative annual changes in baPWV.

Conclusion: The PhA value is significantly associated with the progression of subclinical atherosclerosis, indicating that PhA may serve as a noninvasive marker for monitoring subclinical atherosclerosis in a primary prevention setting.

High-density lipoprotein (HDL) levels have long been inversely associated with cardiovascular disease (CVD) and are traditionally evaluated by serum HDL-cholesterol (HDL-C) levels. However, recent studies have raised doubts regarding the causal role of HDL quantity (HDL-C), drawing attention to HDL functionality. Reverse cholesterol transport (RCT) is a major anti-atherosclerotic mechanism involving ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1), scavenger receptor class B type I (SRB1), and regulatory factors, such as liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ). Notably, HDL-C levels do not necessarily reflect RCT efficiency, and novel regulatory factors, such as microRNAs, endothelial lipase, and ANGPTL3, have been implicated. HDL also exhibits vasoprotective functions by enhancing nitric oxide (NO) production and modulating sphingosine-1-phosphate (S1P) signaling. Furthermore, it exerts anti-inflammatory effects by suppressing adhesion molecules, proinflammatory cytokines, and innate immune activation while modulating adaptive immune responses and attenuating tissue fibrosis. In addition, HDL influences megakaryopoiesis and platelet activation, thereby contributing to its antithrombotic properties. Despite these broad functional spectra, clinical assessments remain largely limited to cholesterol efflux capacity, and other key functional aspects have not been adequately explored. A more comprehensive understanding of HDL’s pleiotropic roles, spanning lipid metabolism, vascular biology, inflammation, and hemostasis, is necessary from both the basic and clinical perspectives. Recent studies have further suggested potential roles of HDL in the central nervous system, expanding its relevance beyond cardiovascular prevention and toward broader therapeutic applications.

Aim: This study addressed the alteration and related factors of cholesterol efflux capacity (CEC) and anti-oxidative activity in patients with chronic kidney disease (CKD).

Methods: This retrospective cross-sectional observational study included 333 patients (median age: 50 [20, 81] years old, male: 46.5%) who underwent a kidney biopsy at Kitano Hospital. CEC and oxygen radical adsorption capacity (ORAC) were measured using serum obtained at the time of the kidney biopsy. Changes in CEC and ORAC in relation to the clinical and kidney injury parameters were evaluated.

Results: Mean CEC and ORAC were 0.83±0.15 and 0.86±0.14, respectively. High-density lipoprotein-cholesterol (HDL-C) levels were significantly associated with CEC (r = 0.673, p＜0.001) and ORAC (r = 0.164, p = 0.003). CEC showed a weak association with ORAC (r = 0.333, p＜0.001). Both HDL-C and CEC were negatively associated with the body mass index (r = −0.407, p＜0.001 and r = −0.248, p＜0.001, respectively) and were significantly higher in women than in men (p＜0.001). The ORAC was positively associated with the serum albumin level (r = 0.330, p＜0.001) and negatively associated with the urinary protein creatinine ratio (UPCR) (r = −0.236, p＜0.001). A multiple regression analysis showed that CEC was associated with the estimated glomerular filtration rate (eGFR), serum albumin, and ORAC. There was no significant correlation between global sclerosis and either CEC or ORAC.

Conclusions: The HDL-C level did not represent HDL functionalities in CKD patients. The decreased eGFR and reduced serum albumin levels induced by an increased UPCR might therefore be associated with impaired HDL functionalities.

Aims: Interleukin-6 (IL-6) is a cytokine involved in the development of atherosclerosis and ischemic stroke. Herein, we investigated the association between serum IL-6 levels at stroke onset and long-term outcomes in patients with ischemic stroke.

Methods: This prospective observational study enrolled 655 consecutive patients (mean age, 70 years; male, 62.1%) with ischemic stroke within one week of onset followed-up for one year. Patients were divided into 3 groups according to baseline serum IL-6 tertiles: tertile 1, ＜2.6 pg/mL (n = 216); tertile 2, 2.6-6.1 pg/mL (n = 217); and tertile 3, ＞= 6.2 pg/mL (n = 222). We evaluated the association of serum IL-6 levels with a composite of major adverse cardiovascular events (MACE; nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death) and the poor functional outcome defined as modified Rankin Scale score of ≥ 3 at one year.

Results: Higher serum IL-6 levels were associated with increased prevalence of chronic kidney disease, atrial fibrillation, chronic heart disease, active cancer, and post-stroke pneumonia. The three groups showed significant differences in the one-year MACE risk (annual rate, 11.2%, 10.8%, and 19.1% in the tertiles 1, tertile 2, and tertile 3 groups, respectively). Higher serum IL-6 levels were significantly associated with poor functional outcomes at one year after stroke (14.4%, 29.5%, and 56.8% in the tertile 1, tertile 2, and tertile 3 groups, respectively; P＜0.001), even when adjusting for baseline covariates and MACE during follow-up.

Conclusions: Higher serum IL-6 level at ischemic stroke onset was an independent predictor of poor functional prognosis at one year.

Aims: This study examined whether or not the coexistence of smoking and metabolic syndrome synergistically increases the risk of cardiovascular disease (CVD) beyond their individual effects.

Methods: This prospective cohort study included 68,743 workers from the Japan Epidemiology Collaboration on Occupational Health Study. The participants were categorized into four groups based on their smoking status and metabolic syndrome. Biological interactions were evaluated using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S).

Results: During a mean follow-up of 7.2 (range: 0.1–10.9) years, 346 participants developed CVD. Current smokers with metabolic syndrome had the highest CVD risk (hazard ratio: 6.45, 95% confidence interval [CI]: 4.73–8.80). Approximately 35% of CVD cases among individuals exposed to both factors were attributed to their biological interactions (RERI: 2.27, 95% CI: 0.56–3.98; AP: 0.35, 95% CI: 0.15–0.55; S: 1.71, 95% CI: 1.16–2.52). An analysis of CVD subtypes revealed a significant biological interaction for myocardial infarction (RERI: 5.14, 95% CI: 0.65–9.62; AP: 0.52, 95% CI: 0.26–0.78; S: 2.38, 95% CI: 1.22–4.62) but not for stroke (RERI: 1.34, 95% CI: -0.46–3.13; AP: 0.25, 95% CI: -0.03–0.53; S: 1.44, 95% CI: 0.89–2.34).

Conclusion: Smoking and metabolic syndrome interact synergistically to elevate CVD risk, particularly for myocardial infarction. Targeting both factors is essential for CVD prevention.

Hyperuricemia, the biochemical precursor to gout, is usually defined as the theoretical limit of solubility of serum uric acid (UA) of ＞7.0 mg/dL. Hyperuricemia is closely associated with hypertension, diabetes mellitus, and dyslipidemia, which are well known to be related to risk factors for coronary artery disease (CAD). Furthermore, hyperuricemia has been associated with increased mortality in both the general population and individuals with cardiovascular diseases. Elevated UA in patients with CAD is accompanied by surrogate markers of atherosclerosis, including C-reactive protein, platelet activation, and endothelial dysfunction, which can contribute to possible pathogenic links between hyperuricemia and subsequent adverse cardiovascular events. Similarly, patients with gout have higher rates of cardiovascular diseases than those without it, independent of traditional cardiovascular risk factors. Gout is a disease with variable levels of inflammation, driven by deposition of monosodium urate (MSU) crystals. Recent imaging technology has revealed that deposition of MSU crystals can occur in the coronary arteries as well as the joints. However, current evidence does not support the efficacy of urate-lowering therapy on reducing cardiovascular events in patients with hyperuricemia; therefore, identifying individuals who may benefit from a sustained decrease in UA is crucial. We herein review the current understanding and future perspectives for management of hyperuricemia as a residual risk in patients with CAD.

Aim: Intracranial artery calcification (IAC) in patients with acute ischemic stroke may cause cerebral hemodynamic injury and aggravate ischemia-reperfusion injury. However, its relationship with brain damage and clinical outcomes has not yet been fully explored.

Methods: Patients with acute anterior circulation ischemic stroke who underwent intravenous thrombolysis (IVT) were enrolled. Intracranial artery calcification (IAC) was assessed using the IAC volume and number of calcified vessels (NCV) on pre-IVT computed tomography. Outcomes included the degree of brain injury at 24 h post-IVT, measured by serum glial fibrillary acidic protein (GFAP) levels, final infarct volumes, intracranial hemorrhaging within 24 h of IVT, and a poor prognosis at 90 days (modified Rankin Scale ＞2). A multivariate regression analysis was conducted to evaluate the associations between IAC parameters and clinical outcomes.

Results: A total of 348 patients were enrolled in the study, of whom 273 (78.4%) had IAC. Patients were divided into four quartile groups (Q1, Q2, Q3, and Q4) based on the total IAC volume. The fourth quartile (Q4), which included patients with the highest IAC volume, was independently associated with elevated GFAP levels (odds ratio [OR] = 2.449, 95% confidence interval [CI], 1.057–5.673; P = 0.037). The second quartile (Q2) was independently associated with final infarct volume (β:0.483, 95% CI:0.014–0.952, P = 0.044). In addition, NCV was independently correlated with increased GFAP levels (OR = 1.265, 95% CI:1.010–1.584, P = 0.040) and a poor prognosis (OR = 1.270, 95% CI: 1.008-1.600, P = 0.043).

Conclusion: IAC was independently associated with the degree of brain injury, final infarct volume, and prognosis in patients after IVT.

Aims: MN-001 (tipelukast), a compound with lipid-modulating and anti-inflammatory properties, and its active metabolite MN-002, have been suggested to influence cholesterol metabolism. This study aimed to investigate whether MN-001 and MN-002 enhance cholesterol efflux via ABCA1 and ABCG1, thereby reducing foam cell formation. We also evaluated cholesterol efflux capacity in patients with diabetes before and after MN-001 administration.

Methods: Cholesterol efflux was assessed in THP-1 macrophages treated with MN-001 and MN-002 in the presence of ApoA-I or HDL. ABCA1 and ABCG1 expression were evaluated using western blot and qPCR analyses. A 12-week observational study in patients with diabetes evaluated the cholesterol efflux capacity using ApoB-depleted serum and radiolabeled J774.1 macrophages. Molecular docking simulations were conducted to explore MN-002 binding affinities, aiming to identify potential target proteins and elucidate the molecular mechanisms underlying their effects on cholesterol metabolism.

Results: MN-002 enhanced ABCA1-mediated cholesterol efflux and upregulated ABCA1 expression independently of PKA. It also increased ABCG1 expression; however, neither MN-001 nor MN-002 influenced HDL-mediated efflux. MN-001 showed no significant improvement in cholesterol efflux capacity (p = 0.6507) in patients with diabetes. Molecular docking simulations indicated that MN-002 may bind to PPAR-alpha, suggesting a potential mechanism for its effects.

Conclusion: MN-002 offers a novel therapeutic approach for atherosclerosis by upregulating ABCA1 and ABCG1 expression and enhancing ApoA-I-mediated cholesterol efflux. Further studies are required to clarify the underlying mechanisms and assess their clinical potential in atherosclerosis and metabolic disorders.

Familial lecithin–cholesterol acyltransferase (LCAT) deficiency with a primary LCAT gene mutation results in various conditions, including corneal opacity, anemia, kidney disease, and low high-density lipoprotein (HDL) levels. In recent years, secondary LCAT deficiency with nearly identical symptoms has been identified as a rare case of immune-mediated acquired LCAT deficiency caused by LCAT autoantibodies. In limited cases, prednisolone treatment is required for severe conditions and has been shown to favorably modulate LCAT autoantibodies and restore LCAT activity, resulting in improved HDL-cholesterol (HDL-C) levels, renal dysfunction, and other complications. However, there is little detailed information regarding LCAT activity, lipid changes, and renal dysfunction after the initiation of prednisorone treatment. In the present study, in addition to the effects on LCAT activity, lipids, and proteinuria, we for the first time monitored the HDL cholesterol efflux capacity (CEC), an important anti-atherosclerotic HDL function, during the first month of treatment in a patient with this disease. We found that the LCAT activity, HDL-C concentration, and HDL CEC increased from undetectable or low values to normal ranges during this period, as did proteinuria. Specifically, the HDL CEC and LCAT activity recovered faster than the HDL-C levels. Based on these findings, the effects of prednisolone treatment on LCAT and HDL CEC activities prior to HDL-C levels suggest that normal HDL-C levels may not be essential as a treatment target in immune-mediated acquired LCAT deficiency patients who require treatment.

Aim: Mounting evidence suggests apolipoprotein E-containing high-density lipoprotein cholesterol (APOE-HDLC) as an indicator of the anti-atherogenic function of HDLC, but data are lacking on whether or not APOE-HDLC is involved in the development of atherosclerosis in humans. This study was performed to explore whether or not APOE-HDLC is associated with atherosclerotic plaque progression in humans.

Methods: Among 823 participants 45 to 74 years old who were free of cardiovascular disease, we assessed nuclear magnetic resonance spectroscopy-measured HDL particle concentrations, APOE-HDLC levels and HDLC levels at baseline, and performed carotid ultrasound measurements in surveys conducted in 2002 and again in 2007 after a 5-year interval. The ratio of APOE-HDLC to total HDLC (APOE-HDLC/HDLC ratio) was calculated to assess the relative proportion of APOE-HDLC in total HDLC, given the strong correlation between them.

Results: The baseline APOE-HDLC/HDLC ratio was significantly associated with the risk of 5-year plaque progression (relative risk [RR] = 0.71; 95% confidence interval [CI] = 0.53-0.95), which is independent of the ratio of HDLC to the HDL particle number (HDLC/P ratio). In particular, participants with an HDLC/P ratio ≥ 44.8 (denoted very high level of cholesterol content per HDLP, a marker of dysfunctional HDL) had a 36% reduced 5-year plaque progression risk (RR = 0.64; 95% CI = 0.43-0.97) if combined with the highest APOE-HDLC/HDLC ratio, as compared with the lowest APOE-HDLC/HDLC ratio.

Conclusions: These results highlight the potential utility of APOE-containing HDL as a candidate emerging biomarker for the anti-atherosclerotic function of HDL particles.

Familial hypercholesterolemia (FH) is an inherited disorder characterized by elevated LDL cholesterol levels and an increased risk of early-onset atherosclerotic cardiovascular disease. In pregnant female with FH, apheresis is the preferred treatment because standard therapeutic agents such as statins are contraindicated during pregnancy. LDL adsorption therapy is commonly used; however, after 27 weeks of gestation, it is often switched to dual filtration plasma exchange (DFPP) due to the significant drop in blood pressure caused by bradykinin production. However, DFPP has limited ability to adapt to the increase in circulating plasma volume associated with pregnancy. Here we discuss the case of a 32-year-old female with homozygous FH who underwent different apheresis strategies during her pregnancies. In her first pregnancy, she continued LDL adsorption therapy using DFPP but ultimately delivered a small-for-gestational-age infant via cesarean section. For her second pregnancy, double-filtration plasmapheresis thermo mode, DF-thermo, was introduced to mitigate the limitations of DFPP and LDL adsorption therapies, such as hypotension during apheresis and albumin loss. By minimizing these complications, DF-thermo allowed for a successful delivery without compromising fetal growth.

Although the risk of acute coronary syndrome increases during pregnancy and the postpartum period compared to the non-pregnant state, dyslipidemia–one of the key risk factors for atherosclerotic cardiovascular disease–is often undertreated in this population. Several lipid-lowering medications, including statin, have not been used due to concerns about their impact on the fetus. Herein, we report a pregnant woman with possible familial hypercholesterolemia (FH) and coronary artery stenosis, whose low-density lipoprotein cholesterol (LDL-C) level was managed by a combination of statin and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the secondary prevention of coronary artery disease.

A 37-year-old pregnant woman with dyslipidemia was found to have severe coronary artery stenosis. She was suspected of having FH, and her lipid control was initiated with the goal of lowering LDL-C levels to ＜100 mg/dL. Although ezetimibe and colestimide were administered at 14 weeks, the target LDL-C level was not achieved. Thus, treatment with pravastatin was started at 23 weeks and evolocumab at 32 weeks of gestation. With the combination of pravastatin and evolocumab, her LDL-C levels decreased to 67 mg/dL after 35 weeks of gestation. The patient delivered vaginally at 37 weeks of gestation without any cardiac events, and her baby did not present with any abnormalities. In conclusion, the combined use of statin and PCSK9 inhibitor could effectively manage LDL-C levels, and it might be a safe option during pregnancy. Nevertheless, further research is required to assess the safety and efficacy of this combination therapy during pregnancy.

Aim: The preoperative to early remote postoperative von Willebrand factor (VWF) large multimer index (LMI) in patients with aortic stenosis (AS) remains unclear. Assessment of LMI changes may be better understood if other valvular diseases are integrated. However, this association requires further investigation.

Methods: A quantitative time-course assessment of the VWF, including LMI, was performed in 23 patients with AS who underwent aortic valve replacement. The proposed total valve score was used to study the correlation between the LMI and valvular diseases, including diseases other than AS.

Results: The postoperative VWF LMI was significantly higher; this increase was sustained across nine measurements up to one year postoperatively. The total valve score showed a moderate negative correlation with the VWF LMI (Spearman correlation coefficient r_s = -0.5483, p = 0.0068), demonstrating a stronger negative correlation and a lower p-value than the peak flow velocity and mean pressure gradient.

Conclusions: Improved VWF LMI was maintained one year after AS surgery and correlated better with echocardiographic severity when considering other valvular diseases than AS severity alone. VWF LMI may indicate overall cardiac shear stress and treatment effectiveness in early remote stages.

Aims: We aimed to evaluate the effect of serum lipoprotein(a) (Lp(a)) levels on carotid artery ulceration using digital subtraction angiography (DSA), which is the gold standard for assessing atherosclerotic plaque surface morphology.

Methods: Of the consecutive cerebrovascular patients prospectively collected serum Lp(a) levels from June 2021 to October 2024 admitted to our institution, patients with carotid artery stenosis were enrolled in this study. Blood samples were collected within three months of admission. Based on common carotid angiography and 3D rotational angiography to confirm the morphology of stenotic lesions, patients were dichotomized according to the presence or absence of carotid artery ulceration.

Results: Of the 439 cerebrovascular patients, 94 with carotid artery stenosis were analyzed (18 females, median 75 [interquartile range, 71–81] years) and carotid artery ulceration was confirmed in 38 (40.0 %) patients. Patients with carotid artery ulceration showed a higher proportion of dyslipidemia (94.7% versus 75.0%; p = 0.013), and higher L(a) levels (28 [11–56] vs 10 [5–25] mg/dL, p = 0.007) than those without. Multivariable logistic analysis adjusted for other atherosclerotic risk factors showed a significant association between higher Lp(a) levels and carotid artery ulceration (odds ratio per 10 mg/dL increase, 1.21; 95%CI, 1.02–1.43; p = 0.026). Receiver operating characteristic curve analysis showed that Lp(a) ≥ 26 mg/dL was the threshold to predict the presence of carotid artery ulceration (area under the curve = 0.67; sensitivity, 52.6%; specificity, 78.6%).

Conclusions: In patients with carotid artery stenosis who may be considered candidates for surgical treatment, elevated Lp(a) levels were associated with carotid artery ulceration.

Aims: Although previous studies have shown that epicardial adipose tissue (EAT) volume is increased in patients with acute coronary syndrome (ACS), its correlation with left ventricular (LV) remodeling and LV ejection fraction (LVEF) after ACS remains unknown. This study evaluated the association between the EAT volume and temporal LVEF changes in patients with ACS.

Methods: This prospective cohort study included 197 patients hospitalized for ACS. Among them, 143 (86 males, 67±12 years) underwent follow-up. Echocardiography was performed for three years. The patients were divided into three groups according to their LVEF: heart failure with reduced EF (HFrEF), heart failure with mildly reduced EF (HFmrEF), and heart failure with preserved EF (HFpEF).

Results: There was no association between the EAT volume at the onset of ACS and the difference in LVEF during follow-up (β = −0.08, p = 0.42). Peak creatine phosphokinase levels during ACS were most strongly correlated with the chronic-phase LVEF (r = −0.51, p＜0.01). Patients with HFrEF had the highest EAT volume (HFrEF: 134±38 mL; HFmrEF: 102±35 mL; HFpEF: 120±51mL; p = 0.04). Among patients with chronic HFmrEF and HFpEF, but not HFrEF, EAT volume was positively correlated with body mass index (r = 0.37, p = 0.03, and r = 0.45, p＜0.01, respectively).

Conclusions: EAT volume was not associated with LVEF changes at 3 years after ACS. However, patients with chronic HFrEF had a significantly higher EAT volume despite not being obese.

Aim: The long-term clinical outcomes of endovascular therapy (EVT) for aortoiliac (AI) artery lesions remain unclear. This study aimed to investigate 10-year patency and mortality after AI stent implantation.

Methods: This multicenter retrospective study included 1919 patients (2375 limbs) who underwent AI stent implantation to treat symptomatic peripheral artery disease (PAD) between January 2005 and December 2010. The study outcome was primary patency, which was defined as a treated vessel without restenosis, mortality, and associated factors.

Results: The mean age of the study cohort was 71±9 years. Chronic limb-threatening ischemia (CLTI) accounted for 17.2% of cases, and chronic total occlusion (CTO) was found in 24.6% of cases. During a median follow-up period of 2.9 years (interquartile range: 1.0–6.0 years), 412 patients lost patency, whereas 467 patients died without experiencing loss of patency. At 1, 6, and 10 years post-EVT, respectively, the primary patency rates were estimated to be 92.8%, 79.3%, and 77.2%, and the survival rates were 94.9%, 77.0%, and 63.1%. Female sex, CTO, and the presence of outflow lesions were significantly associated with an increased risk of patency loss after stent implantation (all P＜0.05), whereas age, dialysis-dependent renal failure, heart failure, and CLTI were significantly associated with an increased risk of mortality.

Conclusion: Stent implantation for AI lesions achieved favorable 10-year patency, with patency loss plateauing after six years. No AI lesion characteristic was associated with mortality. These results support the long-term efficacy of EVT in the clinical practice.

Aim: Serum syndecan-1 (SDC-1) concentration is a biomarker for endothelial glycocalyx (EG) degradation, which is elevated in type 2 diabetes (T2D). EG degradation is an early step in vascular endothelial dysfunction. This study investigated the association between serum SDC-1 concentration and visceral fat accumulation, which is closely related to vascular endothelial dysfunction, in people with and without T2D.

Methods: This was a cross-sectional study with two independent groups, one including 219 individuals without diabetes (ND) and the other including 203 individuals with T2D. Visceral fat accumulation was assessed as the visceral fat area (VFA) using computed tomography (CT) in ND or dual bioelectrical impedance analysis (BIA) in T2D. Multivariate analyses were performed for ND and T2D to assess the association between VFA and serum SDC-1 concentrations.

Results: The medians of serum SDC-1 concentration were 16.0 ng/mL and 26.5 ng/mL in ND and T2D, respectively. In the univariate analysis, both CT-VFA in the ND group and BIA-VFA in the T2D group were positively correlated with serum SDC-1 concentration. Moreover, the association between VFAs and serum SDC-1 concentration was independent of other covariates in multivariate analysis for each group. However, neither the body mass index nor subcutaneous fat area were associated with serum SDC-1 concentrations in either group.

Conclusions: CT-VFA and BIA-VFA were independently associated with serum SDC-1 concentrations. Our findings suggest that visceral fat accumulation is involved in the degradation of EG irrespective of the presence of T2D.

Aim: To investigate the association between a prolonged heart rate-corrected QT (QTc) interval on a 12-lead electrocardiogram and the risk of developing dementia and its subtypes using long-term prospective longitudinal data from a Japanese community.

Methods: A total of 1,082 residents ≥ 60 years old without dementia were followed up for 24 years. The QT interval was corrected for the heart rate using Bazett’s equation. QTc prolongation was defined as QTc ≥ 440 ms, and participants with QTc ＜440 ms were divided into tertiles. Therefore, QTc interval levels at baseline were divided into 4 ranges: ≤ 401, 402–417, 418–439, and ≥ 440 ms. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) of QTc interval levels on the risk of dementia.

Results: During the follow-up period, 475 participants developed all-cause dementia, 146 had vascular dementia (VaD), and 295 had Alzheimer’s disease (AD). Compared with the lowest QTc level (≤ 401 ms), the multivariable-adjusted HRs for VaD increased significantly with longer QTc intervals (HR [95% confidence interval] 1.80 [1.05 to 3.08] for 402–417 ms, 1.93 [1.12 to 3.34] for 418–439 ms, and 2.64 [1.49 to 4.68] for ≥ 440 ms; p for trend = 0.01). No significant association was found between QTc interval and the risk of both all-cause dementia and AD.

Conclusion: The present findings suggest that QTc prolongation serves as a potential indicator for identifying individuals at a high risk of developing VaD. QTc measurement may assist in the primary prevention of VaD.

Aims: Stroke severity may affect the benefits and safety of antiplatelet therapies. We aimed to investigate whether the efficacy and safety of indobufen versus aspirin were affected by stroke severity.

Methods: We compared the efficacy and safety of indobufen versus aspirin in patients with NIHSS scores of 4–6, 7–9, and 10–18. The primary efficacy outcome was new stroke (ischemic or hemorrhagic) within 90 days, and the primary safety outcome was moderate or severe bleeding within 90 days. The non-inferiority criteria were set at 1.25 for the upper bounds of the 95% CI of the HR for indobufen versus aspirin based on the statistical analysis of the primary clinical trial.

Results: In total, 3921 patients presented with NIHSS scores of 4–6, 998 patients presented with NIHSS scores of 7–9, and 515 patients presented with NIHSS scores of 10–18. The risk of the primary outcome among patients with NIHSS scores of 4–6 was higher in indobufen group than that in aspirin group (HR, 1.62; 95% CI, 1.26 to 2.08). However, indobufen was non-inferior to aspirin in patients with NIHSS scores of 7–9 (HR, 0.66; 95% CI, 0.38 to 1.15; non-inferiority P = 0.01) and NIHSS scores of 10–18 (HR, 0.49; 95% CI, 0.23 to 1.05; non-inferiority P = 0.008), with a significant statistical interaction (P = 0.001). Moderate or severe bleeding risk differences between treatments did not vary with stroke severity.

Conclusions: This exploratory analysis indicates that the benefit of indobufen in reducing new strokes within 3 months may vary across stroke severity. The potential non-inferiority of indobufen relative to aspirin in patients with NIHSS scores of ≥ 7, with no significant difference in safety, requires further study.

Aim: Women with familial hypercholesterolemia (FH) face specific challenges during pregnancy and childbirth, such as treatment restrictions and the absence of guidelines. This study therefore assessed the status of perinatal management and the needs of women with FH.

Methods: We contacted 240 board-certified FH specialists, and these physicians screened eligible patients for the survey. Two internet-based surveys were conducted between August 2023 and March 2024: one for physicians and one for women with FH.

Results: A total of 72 physicians completed the questionnaires. Fifty-seven percent had managed pregnant women with FH, and 64% reported difficulties, including “selecting and adjusting treatment options” and “the absence of guidelines on pregnancy and childbirth for women with FH.” Few physicians referred their patients to obstetricians prior to pregnancy. Eighty-three women with FH completed a questionnaire. Among those who had given birth after being diagnosed with FH, the most common problems reported were “could not be treated,” “obstetricians’ insufficient knowledge of FH,” and “insufficient information about pregnancy and delivery for women with FH.” Half of these women discontinued treatment for over one year. In addition, 78% of women indicated a need for counseling on pregnancy-related matters.

Conclusion: Many physicians have reported challenges in managing pregnant women with FH, and some women have lost years of treatment during pregnancy-related periods. Women with FH should receive advice on planned pregnancy and breastfeeding to balance FH treatment with childbearing and parenting, and obstetricians should actively collaborate with physicians.

Aim: Desmosterol, a cholesterol precursor, is converted by Δ24-dehydrocholesterol reductase. Hence, desmosterol levels are considered to reflect cholesterol metabolism. This study aimed to evaluate sterols as novel biomarkers of liver condition in Asian moderate obese patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods: In total, 218 patients with MASLD who underwent liver biopsy were prospectively enrolled. Liver biopsy samples were evaluated by a well-versed pathologist according to the criteria. The serum sterols of biopsy-proven patients’, such as desmosterol, sitosterol, and campesterol, of the patients with biopsy-proven MASLD were analyzed using liquid chromatography-mass spectrometry.

Results: Inflammation grade 0/1/2/3 was observed in 8/107/90/12 patients, and fibrosis stage 0/1/2/3/4 was observed in 25/48/64/63/17 patients, respectively. Serum desmosterol levels were significantly different by inflammation grade 0-3 (one-way analysis of variance [ANOVA], p = 0.004), with a beta coefficient of 0.219 (95% confidence interval [CI]: 0.088-0.350, p＜0.01). Ordinal logistic regression analysis data on inflammation grade, adjusted for other parameters, showed that desmosterol had an odds ratio of 3.727 (95% CI 1.422-9.901, p＜0.005). Although desmosterol levels are influenced by statin treatment, in non-statin-treated patients, serum desmosterol levels remained significantly different by inflammation grade (one-way ANOVA, p = 0.041), and the beta coefficient was 0.233 (95% CI: 0.066-0.400, p＜0.01).

Conclusions: Serum desmosterol levels indicated the degree of hepatic inflammatory activity in patients with MASLD. Since desmosterol, a ligand of nuclear receptor LXR, reflects hepatic cholesterol metabolism, we hope that our findings will contribute to establishing a novel biomarker to screen the high-risk patients for cardiovascular diseases in MASLD.

Aim: This study investigated regional disparities in the incidence, management, and in-hospital outcomes of critical limb ischemia (CLI) in Japan to inform standardized care practices.

Methods: We conducted a retrospective cohort study using the nationwide Diagnosis Procedure Combination database, including patients ≥ 18 years old who were discharged from acute-care hospitals between April 2018 and March 2020. Patients with CLI were identified using ICD-10 codes and restricted to those undergoing invasive treatments including endovascular therapy (EVT), bypass surgery, or amputation. Regional differences in patient demographics, in-hospital management, and outcomes were analyzed across seven regions in Japan.

Results: In total, 19,699 records were identified. CLI admissions per million population were highest in the Kyushu region (112.1) and lowest in the Kanto region (59.9). The proportion of patients with a body mass index (BMI) ＜18.5 kg/m² ranged from 17.8% (Kanto) to 23.9% (Kansai), while the proportion with a BMI ≥ 30.0 kg/m² ranged from 3.3% (Kyushu) to 8.2% (Okinawa). The proportion of patients requiring dialysis ranged from 33.8% in the Chugoku-Shikoku region to 38.2% in the Okinawa region (P = 0.005). Anti-platelet agents were prescribed to 82.1% of patients with CLI, whereas statins were prescribed to 36.1% of patients. The EVT rates varied from 67.6% (Hokkaido-Tohoku) to 84.8% (Kansai) (P＜0.001), while the amputation rates varied from 22.2% (Kansai) to 33.4% (Chugoku-Shikoku) (P＜0.001). The in-hospital mortality rates varied from 5.7% (Chugoku-Shikoku) to 10.9% (Okinawa) (P = 0.001).

Conclusions: This study revealed significant regional disparities in CLI incidence, management, and outcomes across Japan. These findings highlight the need for standardized, evidence-based care strategies that address regional disparities to improve outcomes for patients with CLI.

Aim: Per- and polyfluoroalkyl substances (PFASs) are widespread environmental pollutants that were previously associated with dyslipidemia and type 2 diabetes mellitus (T2DM). We therefore investigated the association between PFAS exposure and clinical outcomes after percutaneous coronary intervention (PCI) in patients with T2DM and assessed the extent to which lipidomic alterations mediate this association.

Methods: This case-control study was nested within a prospective cohort of patients with type 2 diabetes who underwent primary PCI for obstructive coronary artery disease between September 2017 and September 2019. During the 2-year follow-up after PCI, 150 matched pairs of patients with T2DM who did not experience major adverse cardiovascular and cerebrovascular events (MACCEs) were included. Serum PFASs and lipidomes were measured at baseline using liquid chromatography–mass spectrometry and analyzed using multipollutant models and integrative approaches.

Results: Overall, a higher exposure to a mixture of nine PFASs was associated with an increased odds of two-year MACCEs after PCI, with perfluoroundecanoic acid and perfluorodecanoic acid contributing the most to the association. Integration with the serum lipidome generated a network of 110 PFAS-associated lipids with differential contributions to discriminating MACCEs, half of which were identified as significant mediators explaining 9.6%–56.4% of the PFAS-MACCE association. Furthermore, we estimated a cluster of patients with high probabilities of developing MACCEs after PCI, characterized by high PFAS levels; increased abundance of phosphatidylcholine, triacylglycerol, diacylglycerol, and acylcarnitine lipids; and decreased abundance of phosphatidylethanolamine and phosphatidylethanol lipids.

Conclusion: With mediation by serum lipidomic perturbations, PFAS exposure contributes to poor outcomes after PCI in patients with T2DM.

Aim: Arteriosclerosis is a condition that leads to coronary artery disease (CAD) and stroke. Basic and clinical studies have suggested a link between the gut microbiota and various diseases, including atherosclerosis. Therefore, we focused on gut microbiota and aimed to develop a probiotic-based treatment for atherosclerosis.

Method: From 6 to 14 weeks of age, apoE-deficient mice, a mouse model of atherosclerosis, were orally administered with Phocaeicola dorei and Phocaeicola vulgatus or saline five times/week. The diet was changed to a western diet at eight weeks of age. Finally, the mice were sacrificed at 14 weeks of age, and the atherosclerotic lesion area was evaluated.

Result: Previous studies have shown that atherosclerosis is suppressed by the administration of live type strains (TS) of P. dorei and P. vulgatus in apoE-deficient mice. In this study, we isolated P. vulgatus AF299, which highly expresses commensal colonization factors. Oral administration of P. dorei TS and AF299 to model mice further suppressed atherosclerosis compared to the administration of P. dorei TS and P. vulgatus TS. Genetic analysis of lesion tissues showed that the expression levels of genes associated with inflammatory responses were significantly reduced in mice treated with P. dorei TS and AF299. Moreover, gene expression related to immune response and IgA secretion was increased in the ileum.

Conclusion: Our results suggest that the bacteria-induced immune response in the gut leads to the suppression of the inflammatory response in atherosclerotic lesions. These results indicate the potential for the development of prophylactic drugs for atherosclerosis.

Aims: To present an update on undiagnosed coronary artery disease (CAD) in patients starting hemodialysis at a Japanese hospital, with a focus on CAD prevalence, risk factors, and coronary lesions’ distribution in this population.

Methods: A cross-sectional, retrospective study of patients who began hemodialysis due to end-stage renal disease (ESRD) in a Japanese hospital between January 2009 and December 2023 and underwent coronary computed tomography (CCT) was carried out. Coronary artery disease was screened using CCT immediately after the initiation of hemodialysis and then confirmed by CCT/coronary angiography (CAG). Based on these evaluations, patients were divided into CAD and non-CAD groups, and their demographic and clinical characteristics were compared. Logistic regression analysis was performed to detect factors associated with CAD. Additionally, variations in CAD prevalence and coronary artery calcification scores (CACS) over time were assessed considering 3-year intervals.

Results: Data from 272 patients were included. CAD was observed in nearly half (47%) of them. Lesions were mainly observed in the left anterior descending artery (73%). The prevalence of a coronary artery calcification score of ＞65 notoriously increased from 2012–2014 to 2015–2017 and thereafter stabilized, while the proportion of patients diagnosed with CAD tended to decrease overall. Multiple regression analysis indicated that only a history of smoking, statin use, low albumin levels, and low HDL-C levels were independently and significantly associated with CAD occurrence in these ESRD patients.

Conclusions: Many well-known CAD risk factors in the general population were not predictors of undiagnosed CAD in our target population.

Aims: The blood inflammatory marker interleukin 6 (IL-6) has been shown to predict future stroke, major adverse cardiovascular events (MACEs), and dementia. However, no study has yet examined this relationship in the same population. The present study compared the predictive utility of IL-6 levels in stroke, MACEs, and Alzheimer’s disease (AD) dementia.

Methods: In this post-hoc analysis, we derived data from a Japanese observational registry in which 1011 patients with evidence of cerebral vessel disease were enrolled. After excluding patients who required assistance with daily tasks, were suspected of having dementia, and lacked IL-6 measurement, 471 patients were included. The patients were followed up until March 2023. The outcomes were incident stroke, MACEs, and AD dementia.

Results: During a median follow-up period of 4.6 years, stroke, MACEs, and AD dementia occurred in 24, 36, and 21 patients, respectively. Serum IL-6 levels are associated with age, sex, and vascular factors. A Cox proportional hazard analysis revealed that the highest IL-6 tertile (≥ 2.5 pg/mL) was associated with a significantly higher risk of stroke and MACEs than the lowest IL-6 tertile after adjusting for confounding factors (stroke, adjusted hazard ratio 4.84 [95% confidence interval, 1.02-23.05], P = 0.048; MACEs, adjusted hazard ratio 3.68 [95% confidence interval, 1.01-13.51], P = 0.049). However, no association was found between IL-6 tertile groups and AD dementia.

Conclusion: Serum IL-6 levels predicted stroke and cardiovascular events but not AD dementia in patients with vascular risk factors. The involvement of low-grade systemic inflammation appears to be significantly greater in atherothrombotic events than that in AD dementia.

Aim: Recently, we reported that a pemafibrate extended-release (XR) formulation lowered low-density lipoprotein cholesterol (LDL-C) and cholesterol synthesis and absorption markers in a phase 2 clinical pharmacology study. Here we describe our post-hoc analysis of that study, discuss the mechanism by which pemafibrate lowers LDL-C, and suggest which patients may respond favorably to pemafibrate treatment.

Methods: In the phase 2 study, patients with hypertriglyceridemia received treatment with pemafibrate immediate-release (IR) 0.2 mg/day or XR 0.4 mg/day or 0.8 mg/day. This post-hoc subgroup analysis examined the percentage change in LDL-C, apolipoprotein B (ApoB), non-HDL-C, and cholesterol synthesis and absorption markers, in subgroups by baseline LDL-C, and then determined the correlation between the percentage change in LDL-C and the percentage change in cholesterol synthesis and absorption markers.

Results: Our analysis included 60 patients who received two of three formulations of the drug. A total of 78.3% (47/60) were male, 16.7% (10/60) had type 2 diabetes mellitus, and 10% (6/60) received concomitant statins. The percentage of LDL-C lowering was greater in the population with high baseline LDL-C, and similar trends were noted for the ApoB, non-HDL-C, and cholesterol synthesis and absorption markers. The percentage change in LDL-C was positively correlated with the percentage change in lathosterol, β-sitosterol, and campesterol.

Conclusions: In patients with hypertriglyceridemia, results suggested that pemafibrate lowered LDL-C by inhibiting cholesterol synthesis in the liver and cholesterol absorption from the intestinal tract. This lowering effect was greater in populations with higher baseline LDL-C.

Aim: The aim of this study was to clarify the association between serum total cholesterol and fatal subarachnoid hemorrhage in Japanese men and women.

Methods: The study involved a pooled analysis of individual data from 12 well-qualified cohort studies conducted in Japan. The participants were classified according to their serum total cholesterol levels: ＜4.14 mmol/L (＜160 mg/dL), 4.14–4.64 mmol/L (160–180 mg/dL), 4.65–5.16 mmol/L (180–199 mg/dL), 5.17–5.68 mmol/L (200–219 mg/dL), 5.69–6.20 mmol/L (220–239 mg/dL), and ≥ 6.21 mmol/L (≥ 240 mg/dL). The outcome of the analysis was death from subarachnoid hemorrhage.

Results: A total of 120,973 participants (70,947 women and 50,026 men) aged 18–96 years at baseline underwent follow-up for a median of 12.7 years, and 261 participants died from subarachnoid hemorrhage during this period. In women, both low (＜5.69 mmol/L [＜220 mg/dL]) and high (≥ 6.21 mmol/L [≥ 240 mg/dL]) serum total cholesterol levels were significantly associated with a higher risk of fatal subarachnoid hemorrhage compared with the reference group (5.69–6.20 mmol/L [220–239 mg/dL]). These associations remained significant after adjustment for confounding factors. In contrast, no associations were observed in men.

Conclusion: Both low and high serum total cholesterol levels were associated with a higher risk of fatal subarachnoid hemorrhage in 70,947 female participants from 12 cohort studies throughout Japan.

Aims: Intensive lipid-lowering therapy is recommended for secondary prevention of cardiovascular events after acute myocardial infarction (AMI). However, the prescription rate of PCSK9 inhibitors (PCSK9is) remains low among patients not achieving low-density lipoprotein (LDL) cholesterol target levels.

Methods: A retrospective analysis was conducted on 194 patients with AMI who were discharged alive and followed up as outpatients at our institution between October 2022 and October 2024. In October 2023, we implemented the Physician-led Strike Early–Strike Strong Lipid-Lowering Protocol (Physician-led Protocol) to enhance lipid management. Patients were divided into two groups: pre-protocol (October 2022–September 2023) and post-protocol (October 2023–October 2024). Patient background characteristics, lipid-lowering therapies, and LDL cholesterol levels in the chronic phase were compared between the two groups. The outcomes included post-discharge PCSK9i initiation rates and chronic-phase LDL levels.

Results: While the prescription rates of strong statins and ezetimibe were similar between the groups, PCSK9i use was significantly higher in the post-protocol group than in the pre-protocol group (15.3% vs. 2.8%, p = 0.002). Furthermore, the chronic LDL levels were significantly lower in the post-protocol group than in the pre-protocol group (51.0 vs. 58.0 mg/dL, p = 0.007). Multivariate logistic regression showed that initial LDL levels and PCSK9i use were associated with achieving chronic LDL levels ＜55 mg/dL. Among eligible patients in the post-protocol group, 36.4% received PCSK9is.

Conclusions: The physician-led protocol increased PCSK9i prescriptions, achieving a median chronic LDL level of 51 mg/dL.