Atherosclerosis Research Articles

Dual-mode-driven nanomotors targeting inflammatory macrophages for the MRI and synergistic treatment of atherosclerosis

With the progress of atherosclerosis (AS), the arterial lumen stenosis and compact plaque structure, the thickening intima and the narrow gaps between endothelial cells significantly limit the penetration efficiency of nanoprobe to plaque, weakening the imaging sensitivity and therapy efficiency. Thus, in this study, a H2O2-NIR dual-mode nanomotor, Gd-doped mesoporous carbon nanoparticles/Pt with rapamycin (RAPA) loading and AntiCD36 modification (Gd-MCNs/Pt-RAPA-AC) was constructed. The asymmetric deposition of Pt on Gd-MCNs catalyzed H2O2 at the inflammatory site to produce O2, which could promote the self-motion of the nanomotor and ease inflammation microenvironment of AS plaque. Near-infrared (NIR) laser irradiation promoted the photothermal conversion of Gd-MCNs to generate the thermal propulsion of nanomotor and photothermal ablation of inflammatory macrophages. Meanwhile, the modification of AntiCD36 to bind with inflammatory macrophages further promotes the targeting effect. The released RAPA could inhibit the inflammatory side effects caused by photothermal effects, and promote macrophage autophagy to hinder the development of AS. The dual-mode propulsion nanomotors combining with the synergistic therapy of photothermal treatment, anti-inflammatory and pro-autophagy provided improved theranositc effect of AS.Graphical abstract

Characterizing High-Risk Enrollment Criteria and Impact on Clinical Outcomes in a Large Randomized Clinical Trial: Insights From the TWILIGHT Trial.

The TWILIGHT trial showed that, among high-risk patients who underwent percutaneous coronary intervention (PCI) and were event-free at 3 months, ticagrelor monotherapy versus ticagrelor plus aspirin reduced bleeding without increasing ischemic events. This post-hoc analysis describes the risk profiles and outcomes of patients enrolled in the TWILIGHT trial. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, and the key secondary outcome was a composite of death, myocardial infarction, or stroke within one year after randomization. The proportion of patients (n=7,119) fulfilling ≤3, 4, 5, or ≥6 risk factors was 21.5%, 32.7%, 27.4%, and 18.4%, respectively. Troponin-positive acute coronary syndrome (ACS) was the most prevalent clinical criterion (64.9%), and multivessel disease (MVD) was the most prevalent angiographic criterion (66.5%). The most frequent intersection of criteria was the combination of troponin-positive ACS, atherosclerotic vascular disease, MVD, left main or proximal anterior descending lesion, and stent length >30 mm. A stepwise increase in ischemic but not in bleeding risk was noted with an increasing number of high-risk criteria. Compared with ticagrelor plus aspirin, ticagrelor monotherapy reduced bleeding regardless of the number of risk factors (≤3-RF: 3.5% vs. 5.8%, HR 0.59, 95% CI [0.38-0.93]; 4-RF: 3.7% vs. 6.4%, HR 0.57, 95% CI [0.37-0.86]; 5-RF: 3.8% vs. 8.6%, HR 0.44, 95% CI [0.29-0.66]; ≥6-RF: 5.3% vs. 7.9%, HR 0.65, 95% CI [0.44-0.96]; p-interaction=0.56) without significantly increasing the ischemic risk (≤3-RF: 1.6% vs. 2.1%, HR 0.75, 95% CI [0.38-1.50]; 4-RF: 3.5% vs. 2.2%, HR 1.58, 95% CI [0.91-2.75]; 5-RF: 4.1% vs. 5.0%, HR 0.80, 95% CI [0.51-1.24]; ≥6-RF: 6.7% vs. 6.9%, HR 0.98, 95% CI [0.67-1.43]; p-interaction=0.22). In the TWILIGHT trial, the high-risk features correlated more strongly with ischemic than with bleeding risk. Nonetheless, the benefits of ticagrelor compared with ticagrelor plus aspirin were consistent, irrespective of the number of high-risk features. These findings are only applicable to patients who are event-free at 3 months after PCI. The trial was registered with ClinicalTrials.gov, NCT02270242.

Intermittent fasting inhibits platelet activation and thrombosis through the intestinal metabolite indole-3-propionate

Abstract Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting (IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E (ApoE) knockout (ApoE−/−) mice, by enhancing intestinal flora production of indole-3-propionic acid (IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor (PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia-reperfusion injury in ApoE−/− mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathway.

Health improvements by Understanding Residual Risk In CAd and NEw targets for prevention/treatment: Rationale and Research Protocol of the HURRICANE project

Abstract Optimal medical treatment in patients with stable coronary artery disease reduced morbidity and mortality but left a substantial residual risk of disease progression and events. According to recent evidence, insulin resistance or pre-diabetes together with elevated levels of triglycerides, low levels and functionality of high-density lipoprotein cholesterol, often associated with a chronic inflammatory state, are deemed to be relevant components of cardiometabolic and vascular residual risk. In the present project we aim at discovering specific individual genetic/molecular profiles subtending emerging cardiometabolic and vascular risk patterns and associated with more severe stable coronary artery disease phenotypes. To this end we will analyse clinical data, blood samples and imaging data already gathered in a retrospective population of 561 patients with suspected stable coronary disease and will develop integrated predictive models of severity and extent of disease defined by qualitative and quantitative analysis of coronary plaques by cardiac computed tomography. The new predictive models, which will incorporate relevant clinical and genetic/molecular variables associated with more severe coronary atherosclerosis, will be validated in a similar prospective population of patients and extended to the prediction of progression (at 1-year follow-up) of coronary disease phenotypes, occurring despite optimal medical treatment. ClinicalTrials.gov ID: NCT06601153

HYQTD Drug-containing Serum Alleviates H2O2-induced Endothelial Oxidative Damage by Increasing Mitochondrial ATP Synthesis and Inhibiting ROS.

Atherosclerosis (AS) is caused by the endothelium injury associated with oxidative stress. Previous studies have shown that the Phlegm-Eliminating and Stasis- Transforming Decoction (Huayu Qutan Decoction, HYQTD) has mitochondrial protective function. The objective of this research was to explore how HYQTD drug-containing serum (HYQTD-DS) could potentially protect mitochondrial energy production in endothelial cells (ECs) from injury caused by hydrogen peroxide (H2O2)-induced oxidative damage in AS through SIRT1/PGC-1α/ Nrf2 pathway. After preparation of containing serum, the cells were divided into various categories, such as control group, H2O2 group (an oxidative damage model), HYQTD group, Selisistat (EX527, a SIRT1 inhibitor) combined with H2O2 group, and EX527 combined with HYQTD group. The evaluation of oxidative stress involved measuring reactive oxygen species (ROS) and malondialdehyde (MDA) generation, as well as Superoxide Dismutase (SOD) activity. Mitochondrial function and ultrastructure were measured by Transmission electron microscopy (TEM), mitochondrial membrane potential (MMP), rate of oxygen consumption (OCR), respiratory chain complex activities, and ATP production. The key proteins and gene levels in the SIRT1/PGC-1α/Nrf2 pathway was quantified by quantitative real-time PCR (RT-PCR) and Western blotting analysis. We found oxidative stress, mitochondrial damage, and mitochondrial energy disorder in H2O2-induced ECs. However it indicated a marked reversal after pretreated with HYQTD-DS. Mechanistically, EX527 induced increased oxidative stress, worse mitochondrial dysfunction, and less ATP synthesis. We demonstrated that HYQTD-DS attenuated oxidative stress, improved mitochondrial function, and up-regulated mitochondrial ATP synthesis by activating SIRT1/PGC- 1α/Nrf2 pathway-induced mitochondrial biogenesis and its downstream NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDV2).

Coronary CT angiography-guided management of patients with stable chest pain: 10-year outcomes from the SCOT-HEART randomised controlled trial in Scotland.

The Scottish Computed Tomography of the Heart (SCOT-HEART) trial demonstrated that management guided by coronary CT angiography (CCTA) improved the diagnosis, management, and outcome of patients with stable chest pain. We aimed to assess whether CCTA-guided care results in sustained long-term improvements in management and outcomes. SCOT-HEART was an open-label, multicentre, parallel group trial for which patients were recruited from 12 outpatient cardiology chest pain clinics across Scotland. Eligible patients were aged 18-75 years with symptoms of suspected stable angina due to coronary heart disease. Patients were randomly assigned (1:1) to standard of care plus CCTA or standard of care alone. In this prespecified 10-year analysis, prescribing data, coronary procedural interventions, and clinical outcomes were obtained through record linkage from national registries. The primary outcome was coronary heart disease death or non-fatal myocardial infarction on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov (NCT01149590) and is complete. Between Nov 18, 2010, and Sept 24, 2014, 4146 patients were recruited (mean age 57 years [SD 10], 2325 [56·1%] male, 1821 [43·9%] female), with 2073 randomly assigned to standard care and CCTA and 2073 to standard care alone. After a median of 10·0 years (IQR 9·3-11·0), coronary heart disease death or non-fatal myocardial infarction was less frequent in the CCTA group compared with the standard care group (137 [6·6%] vs 171 [8·2%]; hazard ratio [HR] 0·79 [95% CI 0·63-0·99], p=0·044). Rates of all-cause, cardiovascular, and coronary heart disease death, and non-fatal stroke, were similar between the groups (p>0·05 for all), but non-fatal myocardial infarctions (90 [4·3%] vs 124 [6·0%]; HR 0·72 [0·55-0·94], p=0·017) and major adverse cardiovascular events (172 [8·3%] vs 214 [10·3%]; HR 0·80 [0·65-0·97], p=0·026) were less frequent in the CCTA group. Rates of coronary revascularisation procedures were similar (315 [15·2%] vs 318 [15·3%]; HR 1·00 [0·86-1·17], p=0·99) but preventive therapy prescribing remained more frequent in the CCTA group (831 [55·9%] of 1486 vs 728 [49·0%] of 1485 patients with available data; odds ratio 1·17 [95% CI 1·01-1·36], p=0·034). After 10 years, CCTA-guided management of patients with stable chest pain was associated with a sustained reduction in coronary heart disease death or non-fatal myocardial infarction. Identification of coronary atherosclerosis by CCTA improves long-term cardiovascular disease prevention in patients with stable chest pain. The Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Edinburgh and Lothian's Health Foundation Trust, British Heart Foundation, and Heart Diseases Research Fund.

Minimal extra-cardiac atherosclerosis present in young people with sudden cardiac death due to coronary artery disease.

To define the association between severe coronary artery disease and widespread atherosclerosis in younger individuals. Individuals aged 1-50 years with sudden cardiac death (SCD) from 2019-23, autopsy-proven to be due to coronary artery disease, were identified using the state-wide EndUCD registry. Presence of extra-coronary atherosclerosis greater than modified American Heart Association class III was assessed in 5 arterial beds (intra-cerebral vessels, aorta, carotid, renal and femoral arteries). 3,044 individuals experienced SCD; 356 were due to coronary artery disease and 64 (18.0%) had extra-coronary plaque. Plaque was identified in aorta (61/356 patients, 17.1%), carotid arteries (9/356, 2.5%), iliofemoral arteries (11/356, 3.1%), intracerebral arteries (4/153, 2.6%) and renal arteries (6/356 patients, 1.7%). The only feature associated with extra-coronary plaque was older age (median 47.8 vs 44.4 years, p=0.0002). Patients with extra-coronary plaque had higher rates of cardiomegaly (67.2% vs 50.7%, p=0.022), cardiac fibrosis indicative of previous myocardial infarction (45.3% vs 31.2%, p=0.030) and multi-vessel coronary disease (72.6% vs 55.6%, p=0.014). Fewer than 1 in 5 people aged 1-50 years experiencing SCD from a coronary cause exhibit extra-coronary plaque, suggesting that in young people severe atherosclerosis is not necessarily a systemic disease. This limits the utility of screening for carotid or aortic plaque to predict coronary atherosclerosis on an individual level. Individuals with extra-coronary plaque were older with more established coronary disease.

MiR-125b-5p ameliorates ox-LDL-induced vascular endothelial cell dysfunction by negatively regulating TNFSF4/TLR4/NF-κB signaling

BackgroundOxidized low-density lipoprotein (ox-LDL)-induced endothelial cell dysfunction plays a crucial role in the progression of atherosclerosis (AS). Although miR-125b-5p is known to be involved in cardiovascular and cerebrovascular disorders, its function in ox-LDL-induced endothelial injury is still not well understood.MethodsAn in vitro AS cell model was established by exposing human umbilical vein endothelial cells (HUVECs) to 100 µg/mL ox-LDL for 24 h. A series of functional assays, including CCK-8 assay, flow cytometry, MDA and SOD kits, capillary-like network formation assay and ELISA assay were performed in vitro. TNFSF4/TLR4/NF-κB pathway-related protein expressions were measured by Western blot. Molecular mechanisms were elucidated through quantitative real-time PCR, western blot analysis, and luciferase reporter assays.ResultsOur investigation revealed that exposure to ox-LDL led to a downregulation in miR-125b-5p, while upregulating the expression of tumor necrosis factor (ligand) superfamily, member 4 (TNFSF4), TLR4, p-p65 and p-IkBa in HUVECs in a dose-dependent manner. We confirmed TNFSF4 as a direct target of miR-125b-5p. Ox-LDL exposure led to decreased cell viability and angiogenic capacity, along with increased apoptosis, inflammation, and oxidative stress in HUVECs. These effects were reversed by overexpressing miR-125b-5p or knocking down TNFSF4. Overexpression of TNFSF4 significantly reversed the effects brought about by miR-125b-5p in HUVECs exposed to ox-LDL. Moreover, miR-125b-5p inactivated the TLR4/NF-κB signaling pathway by negatively regulating TNFSF4.ConclusionsIn summary, our findings demonstrate that miR-125b-5p possessed an anti-inflammatory and anti-apoptosis against ox-LDL-induced HUVEC injury by regulating the TNFSF4/TLR4/NF-κB signaling, indicating that miR-125b-5p may have an important therapeutic function for AS.

Systematic Coronary Risk Evaluation 2 (SCORE2), arterial stiffness, and subclinical coronary atherosclerosis in a population-based study

Aim To investigate the association between Systematic Coronary Risk Evaluation 2 (SCORE2) and subclinical damage in two vascular beds: atherosclerosis in the coronary arteries and aortic arterial stiffness, in a large population-based cohort without cardiovascular disease or diabetes. Methods Design: A cross-sectional study based on Swedish CArdio Pulmonary bioImaging Study (SCAPIS) data. Study population: A population-based cohort of 3087 participants aged 50–64. Outcome Pulse Wave Velocity (PWV) was measured, and aortic arterial stiffness was defined as PWV≥ 10 m/s. Coronary artery calcium score (CACS) was determined by coronary computed tomography and clinically significant coronary calcification was defined as CACS > 100. Results The prevalence of arterial stiffness was 6.6% in the low-moderate SCORE2 risk group, 31.0% in the high-risk group, and 53.3% in the very high-risk group. The prevalence of coronary calcification was 4.5%, 18.5% 23.0%, respectively. There was a modest overlap between arterial stiffness and coronary calcification in all SCORE2 risk groups. When comparing the high SCORE2 risk group with the low-moderate risk group, the Odds ratio (OR) was 6.4, 95% confidence interval (CI 5.1–8.0) for arterial stiffness and 4.8 (CI 3.7–6.3) for coronary calcification. When comparing the very high SCORE2 risk group to the low-moderate group, the OR was 16.2 (CI 11.3–23.1) for arterial stiffness and 6.4 (CI 4.2–9.7) for coronary calcification. Conclusion Our study shows that high cardiovascular risk according to SCORE2 is associated with increased arterial stiffness and significant coronary calcification in a population without prevalent cardiovascular disease or diabetes. This knowledge can be useful in primary care, where SCORE2 is frequently used as a risk prediction tool. The modest overlap between arterial stiffness and coronary calcification suggests that CACS and PWV describe different types of vascular damage.

Association Between Triglyceride-Glucose Index and Carotid Plaque Stability in Different Glycemic Status: A Single-Center Retrospective Study.

The triglyceride-glucose (TyG) index has been proposed as a reliable marker of insulin resistance. However, its value in patients with carotid plaque stability remains unclear. This study investigated the association between the TyG index and unstable carotid plaque. A total of 12 068 participants were enrolled. Carotid ultrasound was used to determine the stability of carotid plaque. Logistic regression was used to analyze the relationship between the TyG index and unstable carotid plaque. The relationship between the TyG index and unstable carotid plaque was evaluated according to sex, age, and glucose metabolism states. Further, the dose-response relationship between the TyG index and unstable carotid plaque was also determined by restrictive cubic splines. Of the 12 068 participants, 11 601 had stable carotid plaque and 467 had unstable carotid plaque. In several different adjustment models, the TyG index is significantly related to the risk of unstable carotid plaque. The association between the TyG index and an unstable carotid plaque was similar between men and women, despite the fact that the odds ratio (OR) tended to be higher in men (OR, 2.80 [95% CI, 2.04-3.83]) than women (OR, 2.07 [95% CI, 1.51-2.82]), and higher in older patients (aged >60 years; (OR, 3.59 [95% CI, 2.74-4.70]) than middle-aged patients (aged ≤60 years) (OR, 2.00 [95% CI, 1.36-2.95]). The TyG index of patients with different glycemic status was significantly correlated with the risk of unstable carotid plaque, among which the OR value of diabetes (OR, 2.51 [95% CI, 1.87-3.36]) was the highest. The restrictive cubic spline analysis indicated a nonlinear relationship between the TyG index and unstable carotid plaque, with TyG index >8.63 identified as an independent risk factor for unstable carotid plaque. The TyG index has a significant association with unstable carotid plaque. The association between the TyG index and unstable carotid plaque is similar between men and women, and the association in older patients is higher than that in middle-aged patients. In different glycemic status, the association between the TyG index and unstable carotid plaque is highest in patients with diabetes.

The Metabolite Indole-3-Acetic Acid of Bacteroides Ovatus Improves Atherosclerosis by Restoring the Polarisation Balance of M1/M2 Macrophages and Inhibiting Inflammation.

Emerging research has highlighted the significant role of the gut microbiota in atherosclerosis (AS), with microbiota-targeted interventions offering promising therapeutic potential. A central component of this process is gut-derived metabolites, which play a crucial role in mediating the distal functioning of the microbiota. In this study, a comprehensive microbiome-metabolite analysis using fecal and serum samples from patients with atherosclerotic cardiovascular disease and volunteers with risk factors for coronary heart disease and culture histology is performed, and identified the core strain Bacteroides ovatus (B. ovatus). Fecal microbiota transplantation experiments further demonstrated that the gut microbiota significantly influences AS progression, with B. ovatus alone exerting effects comparable to volunteer feces from volunteers. Notably, B. ovatus alleviated AS primarily by restoring the intestinal barrier and enhancing bile acid metabolism, particularly through the production of indole-3-acetic acid (IAA), a tryptophan-derived metabolite. IAA inhibited the TLR4/MyD88/NF-κB pathway in M1 macrophages, promoted M2 macrophage polarisation, and restored the M1/M2 polarisation balance, ultimately reducing aortic inflammation. These findings clarify the mechanistic interplay between the gut microbiota and AS, providing the first evidence that B. ovatus, a second-generation probiotic, can improve bile acid metabolism and reduce inflammation, offering a theoretical foundation for future AS therapeutic applications involving this strain.

Mutual mediation effects of homocysteine and PCSK9 on coronary lesion severity in patients with acute coronary syndrome: interplay with inflammatory and lipid markers

BackgroundHomocysteine (Hcy) and the proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly contribute to atherosclerosis (AS) as well as coronary lesion severity. Our previous work demonstrated that Hcy upregulates PCSK9, accelerating lipid accumulation and AS. A PCSK9 antagonist reduces plasma Hcy levels in ApoE−/− mice. These findings suggest complex roles for both Hcy and PCSK9 in AS. This study investigated the mutual mediating influence of Hcy together with PCSK9 on coronary lesion severity among individuals diagnosed with acute coronary syndrome (ACS), focusing on their interplay with inflammatory and lipid-related markers.MethodsThis cross-sectional study encompassed 617 individuals diagnosed with ACS. Baseline characteristics, including inflammatory and lipid-related markers, were compared between individuals with non-severe (SYNTAX score ≤ 22) and severe (SYNTAX score > 22) coronary lesions. To evaluate both the impacts of Hcy and PCSK9 on coronary lesions severity, multivariate logistic regression along with mediation analyses were utilized. The robustness of the findings was validated by conducting subgroup analyses and sensitivity tests.ResultsPatients with severe conditions showed higher levels of Hcy, PCSK9, and inflammatory markers compared to non-severe cases. Both Hcy and PCSK9 levels were independently linked to a heightened risk of severe coronary lesions(ORs: 1.03–1.04 and 1.01–1.02, respectively, all P < 0.001). PCSK9 mediated 34.04% of Hcy’s effect on coronary lesion severity, whereas Hcy mediated 31.39% of PCSK9’s effect, indicating significant mutual mediation between these biomarkers. Subgroup analyses revealed consistent associations, with notable interactions based on creatinine levels for Hcy and gender, smoking status, and diagnosis for PCSK9. Sensitivity analyses confirmed the robustness of the mediation effects.ConclusionsThese findings emphasize the mutual mediating effects of Hcy and PCSK9 on coronary lesion severity in patients suffering from ACS. These results highlight the complex interactions between lipid metabolism and inflammation in the pathophysiology of ACS, suggesting that targeting both Hcy and PCSK9 may offer novel therapeutic strategies to mitigate severe coronary lesions among high-risk patients.

New AIE Emitters from the Unexpected Boron Tribromide/Boron Trichloride‐mediated Cyclization Reaction and Application for Fluorescence Imaging of Lipid Droplets

ABSTRACTThe aberrant behavior of lipid droplets (LDs) is often indicative of cellular dysfunction, which may contribute to the development of a range of diseases, particularly metabolic dysfunction‐associated steatotic liver disease (MASLD) and atherosclerosis (AS). Consequently, there is an urgent need to develop fluorescence probes targeting LDs to monitor the progression of disease. In this study, an unanticipated one‐pot boron tribromide (BBr₃)/boron trichloride (BCl₃)‐promoted cyclization reaction was discovered, yielding a bromo‐/chloro‐substituted triphenylamine (TPA) derivative (TPA‐Br/TPA‐Cl). TPA‐Br was successfully transformed into new TPA‐containing donor‐acceptor (D–A) molecules which show typical aggregation induced emission (AIE) property. Among these new AIE emitters, TPA‐N shows the most promising LDs targeting specificity, lowest toxicity and best photo‐stability. Ex vivo studies further demonstrate that TPA‐N can be used to fluorescence image fatty liver and AS plaque quickly and effectively.

Mechanism of HJ11 Decoction in the Treatment of Atherosclerosis Based on Network Pharmacology and Experimental Validation.

HJ11 (HJ11 decoction), which is based on the traditional prescription Si-Miao-Yong-An decoction, has exerted a remarkable effect on atherosclerosis (AS). Nevertheless, the main components and underlying mechanisms of HJ11 for treating AS remain unclear. This study was designed to elucidate the mechanism of HJ11 in the treatment of AS through network pharmacology and in vivo experimental validation. Network pharmacology was employed to explore the primary bioactive components and targets of HJ11. AS-related genes were obtained from the GeneCards and DisGeNET databases and screened for intersections with HJ11. A herb-compound-target interaction network was constructed by Cytoscape 3.9.1, and molecular docking analyses were constructed on key targets. By using a mouse model, the mechanism of action of HJ11 was further confirmed. A total of 231 active components of HJ11, 1681 AS-related genes, and 156 common targets were identified. Through the establishment of numerous networks, it was discovered that the main association of the mechanism of HJ11 in AS therapy pertained to anti-inflammation. Important substances included quercetin, kaempferol, and luteolin, while TNF-α, AKT1, IL-6, and VEGFA were the main targets. Molecular docking demonstrated that there were favorable binding interactions between active drugs (quercetin, kaempferol, and luteolin) and targets (TNF-α, AKT1, IL-6, and VEGFA). In the in vivo study, HJ11 reduced the expression of TNF-α, AKT1, IL-6, and VEGFA at both the mRNA and protein levels, inhibited atherosclerotic lesions in AS mouse models, and retarded the development of retroarterioid sclerosis. HJ11 can inhibit inflammation and the progression of AS, and the mechanism might involve downregulating the expression of TNF-α, AKT1, IL-6, and VEGFA.

Microbiome and atherosclerosis: state of the problem

Objective. To study modern ideas about the influence of the intestinal microbiome, oral cavity and atherosclerotic plaque on the development and progression of atherosclerosis (AS). Design and methods. The literature review was carried out by analyzing scientific publications in PubMed, meta-analyses, randomized clinical trials, as well as guidelines and review articles within the period from 1997 to 2024. This review examines modern ideas about the above-mentioned non-traditional risk factors (RF) for AS. Conclusions. AS is a disease with a multifactorial pathogenesis. Understanding the role of both classical and non-classical RF in the development of atherosclerotic vascular disease is important for the development of effective preventive and therapeutic measures. Among the non-classical RF for AS is the role of the intestinal and oral microbiome. The fundamental mechanisms of the influence of the microbiota of the oral cavity and intestines on the development of AS include the following: the direct damaging effect of lipopolysaccharides and bacterial toxins on the vascular wall, the influence of microbial metabolites and increased permeability of the intestinal wall on the translocation of bacterial toxins into the systemic bloodstream, as well as the development of chronic lowlevel systemic inflammation and endothelial dysfunction. This review examines modern ideas about the abovedescribed non-traditional RF for AS.

Astaxanthin-loaded polylactic acid-glycolic acid nanoparticles alleviates atherosclerosis by suppressing macrophage ferroptosis via the NRF2/SLC7A11/GPX4 pathway.

Astaxanthin (ASX), a fat-soluble carotenoid mainly sourced from Haematococcus pluvialis, shows promise for clinical applications in chronic inflammatory diseases. This study investigates whether ASX can mitigate atherosclerosis (AS) by modulating macrophage ferroptosis and provides astaxanthin-loaded polylactic acid-glycolic acid nanoparticles (ASX-PLGA NPs) as comparison. ApoE-/- mice were fed a high-fat diet with ASX or statin intervention. Plaque area, lipid aggregation, collagen content, and ferroptosis-related indicators were assessed. Moreover, ASX-PLGA NPs were synthesized and characterized and were used to pretreat macrophages induced with oxidized low-density lipoprotein (ox-LDL). Indicators linked to ferroptosis and oxidative stress were detected. Finally, the expression of nuclear factor erythroid -related factor 2 (NRF2) was evaluated. ASX intervention significantly delayed the progression of AS plaques, characterized by reductions in plaque area and increased collagen fibers. The observed improvements in AS were consistent with statins. ASX-PLGA NPs demonstrate good safety and stability and have better therapeutic effects than ASX alone. Indicators linked to ferroptosis and oxidative stress were significantly improved in groups containing ASX in vivo and vitro. Additionally, ASX facilitated the nuclear translocation of NRF2, which could be attenuated with ML385, a specific inhibitor of NRF2. ASX-PLGA NPs have better therapeutic effects than ASX alone. The regulation of NRF2/SLC7A11/GPX4 represents a novel mechanism by which ASX can counteract ferroptosis and impede AS progression.

NLRC5 in Macrophages Promotes Atherosclerosis in Acute Coronary Syndrome by Regulating STAT3 Expression.

The mortality rate of cardiovascular and cerebrovascular diseases ranks first among all causes. This study elucidated the role and potential mechanism of the NLRC5 gene in atherosclerosis (AS). We enrolled patients (number = 30) diagnosed with AS and healthy volunteers (number = 30) as controls from our hospital. In patients with AS, the levels of serum NLRC5 were up-regulated (Fig.1A) and positively correlated with CIMT/CRP. In a mouse model of AS, the expression of serum NLRC5 mRNA was increased at 6 or 12weeks after inducing AS. The expression of NLRC5 protein was found to be elevated in a mouse model of AS. The inhibition of NLRC5 reduced development of AS in ApoE-/- Mice. Reducing NLRC5 inhibited the polarization of M2 macrophages and shifted macrophages towards proinflammatory M1 phenotype. STAT3 was identified as a target of NLRC5, with NLRC5 protein expression shown to reduce STAT3 ubiquitination. Methylation promoted NLRC5 DNA stability in vitro model of AS. Sh-NLRC5 increased M1/M2 macrophage ratio, foam cell formation and ox-LDL uptake. STAT3 reduced the effects of sh-NLRC5-mediated M1/M2 macrophage ratio in model of AS. These data confirmed that NLRC5 in macrophages promotes atherosclerosis in acute coronary syndrome by regulating STAT3 expression. This suggests that NLRC5 could be a potential target for the treatment of premature AS.

Screening for Subclinical Atherosclerosis in Patients with Familial Hypercholesterolemia: Insights and Implications.

Background/Objectives: Familial hypercholesterolemia (FH) is a monogenic dyslipidemia that leads to early cardiovascular events. Subclinical atherosclerosis refers to the formation of atheromatous plaques in arterial beds before any clinical events. In our study, we investigated the presence, extent, and independent predictors of subclinical atherosclerosis among patients diagnosed with FH. Methods: This was a single-center, prospective, and cross-sectional study. This original study included 215 patients diagnosed with FH from a cohort of 1145 individuals assessed according to the Dutch Lipid Clinical Network (DLCN) criteria. Carotid and femoral ultrasonography were performed, and the coronary artery calcium score was measured to screen for subclinical atherosclerosis. Apolipoprotein A-I, apolipoprotein B, and lipoprotein (a) were analyzed using the nephelometric method. Results: The study cohort comprised 136 females (63%) with a mean age of 54 (43-62) years. The stigmata rate was 18%. The rate of statin use during subclinical atherosclerosis screening was 32% and only eight patients (4%) attained LDL-C values < 70 mg/dL. Subclinical atherosclerosis was observed in 148 patients (69%), with rates of 48%, 47.5%, and 40.5% in the coronary arteries, carotid bifurcation, and femoral bifurcation, respectively. Advanced age, male sex, high pretreatment low-density lipoprotein-cholesterol (LDL-C) level, diabetes, and a low Apo A-I/Apo B ratio were identified as independent predictors of subclinical atherosclerosis. Lp(a) levels ≥ 30 mg/dL predicted coronary atherosclerosis, while diabetes and low Apo A-I/Apo B ratios predicted carotid atherosclerosis, and smoking predicted femoral atherosclerosis. Conclusions: Subclinical atherosclerosis is prevalent, and medication adherence remains suboptimal among FH patients. Screening for subclinical atherosclerosis may impact the treatment strategies, via an increase in physician commitment to treatment protocols and improving patient compliance.

Osteoprotegerin as an Emerging Biomarker of Carotid Artery Stenosis? A Scoping Review with Meta-Analysis.

Objective: In developed countries, stroke is the fifth cause of death, with a high mortality rate, and with recovery to normal neurological function in one-third of survivors. Atherosclerotic occlusive disease of the extracranial part of the internal carotid artery and related embolic complications are common preventable causes of ischemic stroke (IS), attributable to 7-18% of all first-time cases. Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor (TNFR) superfamily, is considered a modulator of vascular calcification linked to vascular smooth muscle cell proliferation and collagen production in atherosclerotic plaques. Therefore, OPG emerges as a potential biomarker (BM) of calcified carotid plaques and carotid artery stenosis (CAS). Methods: We performed a literature search of PubMed on OPG in CAS and atherosclerosis published until 2024. Results: Increased levels of serum OPG were reported in both patients with symptomatic and asymptomatic CAS, and higher values were observed in those with unstable atherosclerotic plaques. Notably, increased OPG levels were observed regardless of the location of atherosclerosis, including coronary and other peripheral arteries. In addition, chronic kidney disease, the most significant confounder disturbing the association between vascular damage and circulating OPG levels, decreases the usefulness of OPG as a BM in CAS. Conclusions: Osteoprotegerin may be considered an emerging BM of global rather than cerebrovascular atherosclerosis. Its diagnostic significance in identifying patients with asymptomatic CAS and their monitoring is limited.

Potential of low apolipoprotein A-I as a surrogate marker of vulnerable carotid artery plaques.

Recent studies suggested that the medical control of atherogenic lipoproteins is not sufficient for stroke prevention. A low apolipoprotein A-I (apoA-I) level may play a crucial role in the anti-atherogenic effects of high-density lipoprotein (HDL-C) and may also be associated with symptomatic vulnerable plaques in carotid artery stenosis. Therefore, the present study investigated the relationship between apoA-I levels and the status of carotid artery stenosis. Ninety-one patients with carotid artery stenosis were examined. The status of carotid artery plaques was divided into symptomatic (n= 47) and asymptomatic (n= 44). We examined patient profiles, including comorbidities, and laboratory lipid data, and plaque features visualized by ultrasonography, MRI, and digital subtraction angiography. The relationships between plaque instability and risk factors for carotid artery stenosis were investigated. No significant differences were observed in the profiles of symptomatic and asymptomatic patients. Regarding plaque features, ulceration, low echo luminance, and a high signal intensity in plaques on T1-weighted images correlated with symptomatic plaques. ApoA-I, total cholesterol, and non-HDL-C levels were significantly lower in symptomatic patients than in asymptomatic patients. A multivariate logistic regression analysis identified low ApoA-I levels, ulceration, and low echo luminance as predictive factors for symptomatic carotid artery stenosis. Diagnostic accuracy for predicting symptomatic carotid stenosis was 0.84 when the following four factors were combined: ulceration, low echo luminance, a high signal intensity on T1-weighted images, and the level of apoA-I. A low apoA-I level was associated with symptomatic carotid artery stenosis. Therefore, ApoA-I levels have potential as a surrogate marker to detect unstable carotid artery plaques.