Journal of atherosclerosis and thrombosis最新文献

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: 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.

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: 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.

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.

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.

Aims: Bempedoic acid is an ATP citrate lyase (ACLY) inhibitor acting in the cholesterol biosynthesis pathway. This study evaluated long-term safety and efficacy of bempedoic acid 180 mg/day for 52 weeks in Japanese patients with hypercholesterolemia.

Methods: A multicenter, open-label, single-arm Phase 3 long-term study was conducted at 26 hospitals and clinics across Japan in patients aged 18 to 85 years. Newly enrolled patients had previously failed to achieve their lipid management targets because of inadequate response to statins or statin intolerance; rollover patients had completed the 12-week treatment period of a domestic Phase 3 confirmatory study (the CLEAR-J trial) and had not met the discontinuation criteria at Week 12.

Results: Bempedoic acid was administered to 130 patients. Treatment-emergent adverse events (TEAEs) occurred in 83.8%, treatment-related TEAEs in 14.6%, serious TEAEs in 6.2%, and AEs leading to discontinuation in 4.6%. None were severe. Between baseline and Week 52, low-density lipoprotein-cholesterol (LDL-C) decreased by 21.6% (overall population) and 25.3% (newly enrolled group), as observed in both statin response subgroups. LDL-C target levels based on risk category were achieved by 65.6% at Week 52 (overall population). Long-term efficacy was also demonstrated for non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein.

Conclusions: Bempedoic acid 180 mg/day for 52 weeks was well tolerated in patients with hypercholesterolemia, with no major safety concerns. Serious AEs were infrequent, and no new safety signals specific to the Japanese population were observed. More than 60% of patients achieved and sustained their LDL-C target levels.

Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Although small dense low-density lipoprotein cholesterol (sdLDL-C) is a highly atherogenic lipid fraction, the association of the sdLDL-C level with MASLD and other steatotic liver disease (SLD) subcategories remain unclear. We investigated the association between various SLDs and the sdLDL-C level calculated by Sampson's equation.

Methods: A total of 15,734 Japanese participants (men/women: 10,228/5,506, mean age: 49±9 years) who underwent annual health examinations including abdominal ultrasonography were recruited after the exclusion of subjects with triglycerides ≥ 800 mg/dL.

Results: Among SLD subcategories including MASLD, MASLD with increased alcohol consumption (MetALD) and alcohol-associated liver disease (ALD), the mean levels of sdLDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) were the highest in participants with MASLD. Triglyceride levels were significantly lower in participants with MASLD than in those with MetALD and those with ALD. After adjustment for age, sex, body mass index, current smoking and alcohol drinking habits, treatment of hypertension, diabetes and dyslipidemia, and triglyceride level, MASLD and MetALD were independently associated with sdLDL-C level, and the association was stronger in MASLD than in other SLD subcategories. The sdLDL-C level was also independently associated with each SLD subcategory after adjustment for the same covariates. The addition of sdLDL-C to traditional risk factors significantly improved the discriminatory capacity for the presence of MASLD in comparison to the addition of non-HDL-C.

Conclusion: MASLD is independently associated with elevated estimated sdLDL-C levels in Japanese individuals, leading to an increased risk of ASCVD.

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.