Journal of atherosclerosis and thrombosis最新文献

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: 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: The aim of this study is to evaluate the impact of each level atherosclerotic lesion subset on clinical outcomes following EVT in CLTI patients.

Methods: We identified 705 consecutive CLTI patients undergone successful EVT between January 2010 and December 2019 at our hospital in Japan. The technical success was defined as the acquisition of one straight line flow to the ulcerated or gangrenous region. We excluded 15 patients with follow up ＜30days. The primary endpoint was major adverse limb event (MALE) at 2 years after EVT. MALE was defined as composite of all cause death and major amputation (MA). MA was defined as an above-the-ankle amputation.

Results: The median follow-up duration was 24.4 months. MALE rate was significantly higher in BK group (adjusted HR 1.48, 95% CI, 1.04-2.10 p = 0.028). Cardiovascular mortality was significantly higher in BK group (adjusted HR 1.94, 95% CI, 1.06-3.56 p = 0.031). Isolated BK lesions were identified an independent predictor of MA (adjusted HR 2.12, 95% CI, 1.01-4.48 p = 0.048).

Conclusion: In CLTI patients who received EVT, those with BK lesions were associated with poorer clinical outcomes after EVT than those without BK lesion, mainly due to increased cardiovascular death. Additionally, isolated BK lesion was associated with higher MA rate after EVT than both FP and BK lesions or isolated FP lesions in our study population.

Aims: This study aimed to develop a model to simultaneously assess the genetic and epigenetic contributions to plasma lipids.

Methods: The study used two cardiovascular risk groups: individuals with high low-density lipoprotein cholesterol (LDL-C) levels (N = 296) and coronary artery disease (CAD) (N = 315), in contrast to the reference (max N = 3,801) and non-CAD individuals (N = 164). For genetic predisposition, rare pathological variants in five target genes related to familial hypercholesterolemia (FH) were screened, while common variants were characterized to calculate a polygenic risk score (PRS). The methylation risk score (MRS) was also calculated for the epigenetic profile based on the DNA methylation levels at the 17 CpG sites. The relationship between each lipid level and these variables was analyzed using regression and quantile models.

Results: Functionally significant rare variants were identified more frequently in patients with high LDL-C or CAD than in the general Japanese population (3.8% vs. 2.3%). For LDL-C, the model incorporating both PRS_LDL-C (plus rare variants) and MRS_LDL-C showed a higher correlation between the predicted and measured values (r = 0.272, P = 3.7×10^-12) than those using PRS_LDL-C alone (r = 0.106, P = 0.008) and PRS_LDL-C plus rare variants (r = 0.263, P = 1.9×10^-11). PRS and MRS had the most significant impact on high-density lipoprotein cholesterol and triglycerides, respectively; the two risk scores had additive effects on these lipid traits, as well as LDL-C.

Conclusion: Our results provide a proof-of-concept that assesses the relative contribution of genetic predisposition and DNA methylation levels, which may help individuals refine their dyslipidemia treatment.

Aim: Since comprehensive data on the pathogenic variants of ABCG5 and ABCG8 and clinical features in sitosterolemia remain limited, we aimed to compile a catalog through an extensive literature search of case reports from 2002 to 2024, as well as an evaluation of variants reported in review articles.

Methods: We compiled 155 cases of sitosterolemia from 133 families with nonsynonymous variants in ABCG5 and ABCG8, along with data on clinical information from case reports. Pathogenic variants were defined either as 1) protein-truncating variants, 2) classified as pathogenic or likely pathogenic variants according to the ACMG guidelines, or 3) serum sitosterol level of the case was measured at ≥ 1 mg/dL.

Results: Xanthoma was observed in 69.2% of patients, ischemic heart disease in 14.2%, and hematologic abnormalities in 57.9%. Fifty-three variants in ABCG5 and 52 in ABCG8 were evaluated for their pathogenicity, in which 33 in ABCG5 and 29 in ABCG8 were protein-truncating variants. Additionally, based on the ACMG criteria and serum sitosterol levels, 50 variants in ABCG5 and 51 variants in ABCG8 were finally classified as pathogenic. Among them, the frequently observed R446X and R389H in ABCG5 were highly prevalent in East Asians, while W361X and S107X in ABCG8 were predominantly found in Europeans.

Conclusion: We provided the largest catalog of clinical features and pathogenic variants of ABCG5 and ABCG8 in the world. This study may help clarify the pathogenicity of variants in ABCG5 and ABCG8 and provide a valuable reference for the genetic diagnosis of sitosterolemia.

Aims: Pemafibrate effectively reduces the triglyceride levels in patients with coronary artery disease (CAD). However, its effect on the fibrinogen levels in these patients remains unclear. This study aimed to investigate the effects of pemafibrate on thrombogenicity and the plasma fibrinogen levels in patients complicated by hypertriglyceridemia.

Methods: This multicenter, randomized, controlled trial enrolled 101 patients with hypertriglyceridemia (fasting triglycerides ≥ 150 mg/dL) and CAD who received antiplatelet monotherapy and statin therapy. After exclusion, 98 participants were randomly assigned to receive either pemafibrate 0.1 mg twice daily (intervention group) or standard care without any additional lipid-lowering therapy (control group), and 96 patients were analyzed. The fibrinogen levels were assessed at the baseline and after 12 weeks of treatment. The primary endpoint was the change in the fibrinogen level from baseline to week 12. The secondary endpoints included thrombogenicity measured using the Total Thrombus-formation Analysis System (T-TAS).

Results: Among the 96 patients, the median baseline fasting triglyceride, HDL cholesterol, LDL cholesterol, and fibrinogen levels were 175 mg/dL, 45 mg/dL, 72 mg/dL, and 299 mg/dL, respectively. The median decrease in triglycerides from baseline to 12 weeks was greater in the pemafibrate group than in the control group (-62 mg/dL vs. -5 mg/dL, p＜0.001), as was the median decrease in fibrinogen (-58 mg/dL vs. 9 mg/dL, p＜0.001).

Conclusions: Pemafibrate significantly reduced fibrinogen levels in patients with CAD and hypertriglyceridemia, thus highlighting its primary benefit in lowering thrombotic risk.

Aim: Chronic kidney disease (CKD) is linked to accelerated vascular remodeling, characterized by medial thickening and fibrosis; however, the molecular mechanisms driving this process remain unclear.

Methods: We investigated the role of toll-like receptor 4 (TLR4) in CKD-associated vascular remodeling using a 5/6 nephrectomy mouse model. TLR4 signaling was selectively inhibited by the long-term administration of TAK-242, a small-molecule-specific inhibitor of TLR4.

Results: TLR4 blockade decreased aortic medial thickening and perivascular fibrosis independent of blood pressure. Immunostaining revealed that blockade of TLR4 decreased Mac-3-positive macrophage accumulation and Ki-67-positive proliferating cells in the aorta. The mRNA expression of IL-6 was suppressed in aortas treated with TAK-242. Disulfide HMGB1 induced the expression of IL-6 in macrophages. Serum from CKD mice induced the expression of IL-6 in RAW264.7 cells and promoted in vitro vascular smooth muscle cell growth, both of which were attenuated with serum from TAK-242-treated CKD mice.

Conclusion: These findings suggest that TLR4-mediated sterile inflammation may contribute to vascular remodeling in CKD and that modulation of TLR4 signaling could be explored as a potential therapeutic strategy to mitigate cardiovascular complications in CKD patients.