Journal of atherosclerosis and thrombosis最新文献

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.

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.

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: 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: Physical exercise exerts antiatherosclerotic effects through several mechanisms. One anti-inflammatory effect of exercise is directly exerted on vascular endothelial cells by β-aminoisobutyric acid (BAIBA), which is released from the skeletal muscles during physical activity. The increased expression of estrogen-related receptor α (ERRα) and peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1β also plays a role in these mechanisms. However, the underlying mechanisms remain unknown, and we aimed to explore the effects of PGC-1β on the endothelial function.

Methods: We generated human umbilical vein endothelial cells (HUVECs) with PGC-1β knockdown using siRNA or by inducing the overexpression of PGC-1β using an adenovirus. We then examined the expression of inflammation-related genes induced by tumor necrosis factor α (TNFα) using qRT-PCR and the expression of endothelial nitric oxide synthase (eNOS) and its activation-related proteins using a western blot analysis.

Results: BAIBA treatment suppressed the TNFα-induced expression of inflammation-related molecules in HUVECs. However, these protective effects were diminished following PGC-1β knockdown, which correlated with decreased levels of IκBα protein. Additionally, in PGC-1β knockdown-HUVECs, the total and phosphorylated levels of eNOS decreased along with the levels of active AMP-activated protein kinase (AMPK) and protein kinase B (Akt). Conversely, the overexpression of PGC-1β in HUVECs resulted in the opposite effect.

Conclusion: These results suggest that BAIBA exerts various protective effects on vascular endothelial cells through the PGC-1β-NFκB and PGC-1β-AMPK-Akt-eNOS axes.

Aim: T50 is the time required for primary calciprotein particles (CPPs) to transform into secondary CPPs in vitro, reflecting serum calcification propensity, and used as a biomarker for calcification stress. Since secondary CPPs induce inflammation and oxidative stress, they may promote atherosclerosis. We investigated whether or not T50 was associated with carotid artery intima-media thickness (IMT).

Methods: This was a cross-sectional study of 202 health examinees. T50 was measured by the established nephelometric method. Carotid artery IMT was measured by high-resolution ultrasonography. The association between T50 and IMT was evaluated by a multivariable-adjusted linear regression analysis.

Results: In a univariate analysis, IMT was not significantly correlated with T50. A multivariable-adjusted linear regression analysis showed that IMT was independently associated with age, sex, diabetes mellitus, dyslipidemia, and fetuin-A but not with T50 in the total subjects. However, when stratified by the estimated glomerular filtration rate (eGFR), T50 was independently and inversely associated with IMT in the subgroup with an eGFR ＜60 mL/min/1.73 m² (β = -0.418, P = 0.013), whereas it was not in the subgroup with an eGFR ≥ 60 mL/min/1.73 m².

Conclusion: T50 was independently and inversely associated with IMT in health examinees with a reduced kidney function, suggesting a novel link between calcification stress and atherosclerosis, particularly in those with chronic kidney disease.

Aim: Notch signaling is a fundamental signal that regulates morphogenesis and cell differentiation during the embryonic period, and it plays a crucial role in macrophage differentiation. Macrophage-mediated inflammation promotes atherosclerosis from the initial lesion formation to acute thrombotic complications in advanced plaques. However, their role in atherosclerosis remains unclear. We herein focused on the Notch ligand Delta-like ligand 1 (Dll1), and examined its role in the pathobiology of atherosclerosis.

Methods: In Apoe^-/- mice, a blocking antibody against Dll1 (Dll1 Ab) was administered for 12 weeks from 8 weeks (early phase) or 20 weeks (late phase) of age.

Results: Dll1 blockade suppressed both initial lesion development and plaque vulnerability compared with lesions in mice treated with non-immune IgG. Dll1 Ab decreased lipid accumulation in advanced lesions and increased the collagen content. In ex vivo cultured macrophages, the blockade of Dll1-Notch signaling by Dll1 blocking antibodies suppressed the mRNA expression of Tnf and the release of activated matrix metalloproteinase 9, which increased plaque vulnerability. In contrast, the stimulation of Dll1-Notch by recombinant Dll1 induced Il1b, Il6, and Tnf expression in macrophages, as well as NF-κB activation. An exploratory transcriptome analysis of atherosclerotic arteries suggested that Dll1-Notch signaling regulates the expression of genes associated with inflammation and mitosis.

Conclusions: These results indicate that Dll1 promotes the pathobiology of atherosclerosis from the initial lesion development to plaque destabilization in advanced atherosclerotic lesions.

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.

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.