Journal of atherosclerosis and thrombosis最新文献

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.

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.

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

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

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

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

Aim: 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.

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.