PANoptosis in atherosclerotic plaques: Molecular mechanisms, clinical significance, and therapeutic potential.

Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.

Exploring potential mechanism of Chuanzhi Qingyu recipe for vulnerable atherosclerosis plaques based on UPLC-Q-TOF-MSE, systems biology strategy, and experimental validation.

Long-term prognostic value of residual lipid burden in acute myocardial infarction.

Atherosclerotic plaque destabilization is promoted by inflammatory cell recruitment, tissue cell death, and mechanical weakening. Neutrophils drive vascular tissue injury and perpetuate inflammation and represent a viable therapeutic opportunity. Here, we identify a distinct subset of activated neutrophils within atherosclerotic lesions that express the chemokine receptor CCR2 (C-C chemokine receptor type 2), which directs their migration toward areas enriched with smooth muscle cells and contributes to plaque instability. Flow cytometry and single-cell transcriptomic analysis of CCR2+ neutrophils within murine and human atherosclerotic plaques. Tracking of CCR2+ neutrophil in hypercholesterolemic Ldlr-/- mice and in mice reconstituted with Ccr2GFP/- bone marrow. In vivo reactive oxygen species and neutrophil extracellular trap analysis in lipopolysaccharide-induced peritonitis. In vitro migration assays of neutrophils deficient for or treated with a specific antagonist against chemokine receptors. In vivo neutrophil recruitment and features of atherosclerotic plaque vulnerability analysis on CCR2 and CCL2 (C-C motif chemokine ligand 2) blockade in a model of advanced atherosclerosis in Apoe-/- mice. CCR2+ neutrophils preferentially populate mouse and human atherosclerotic lesions and display a proinflammatory phenotype with enhanced capacity for reactive oxygen species production and neutrophil extracellular trap release. Genetic or pharmacological CCR2 inhibition reduced neutrophil migration and infiltration to the atherosclerotic lesion, reducing their presence in smooth muscle cell-rich areas. Consistently, neutralization of the CCR2 ligand CCL2 decreased lesional neutrophil numbers and preserved fibrous cap integrity by increasing smooth muscle cell content and decreasing features associated with plaque instability. Our data suggest that a subset of CCR2-expressing neutrophils senses smooth muscle cell-derived CCR2 ligands to infiltrate and promote vulnerable atherosclerotic lesions. These results support that neutrophil functional heterogeneity within the atherosclerotic lesions alters lesion stability. Specific targeting thereof may improve plaque stability without impacting host defense.

Volumetric diffusion and fat imaging of symptomatic carotid plaques on seven tesla magnetic resonance imaging.

Plaque-to-artery signal intensity ratio on time-of-flight magnetic resonance angiography (TOF-MRA) as a predictor of postoperative ischemic lesions after carotid artery stenting.

Immune gene MMP9 as a potential key mediator in TCDD exposure-associated atherosclerosis: An integrated study based on network toxicology and experimental validation.

The quantitative flow ratio (QFR)-derived pullback pressure gradient (PPG) characterizes the pathophysiological patterns of coronary atherosclerosis. This study investigated the plaque morphologies associated with these disease patterns. This study used the institutional QFR-PPG database registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000056097). Patients who underwent elective stenting with pre-procedural optical coherence tomography and near-infrared spectroscopy intravascular ultrasound were included. Offline QFR and QFR-PPG analyses were performed, and the lesions were stratified into tertiles. A total of 168 de novo lesions were analyzed in this study. The QFR tertiles were defined as severe (＜0.61), moderate (0.61-0.71), and mild (＞0.71); the QFR-PPG tertiles were defined as diffuse (＜0.66), intermediate (0.66-0.79), and focal (＞0.79). The Severe QFR tertiles exhibited a smaller minimum lumen area (MLA) and higher frequencies of thin-cap fibroatheroma (TCFA) and layered plaque. In contrast, across the QFR-PPG tertiles, MLA and TCFA frequencies were similar, whereas the diffuse group exhibited more layered plaques and larger calcium angles. The maximum lipid-core burden index did not vary across the QFR-PPG tertiles. A multivariable analysis identified MLA and TCFA as independent predictors of QFR, while layered plaque and calcium angle independently predicted QFR-PPG. However, the lipidic features were not independent predictors of QFR. Multimodal intracoronary imaging demonstrated that QFR reflects luminal narrowing and the features of vulnerable plaques. Conversely, QFR-PPG reflects disease diffuseness, characterized by layered plaques and calcium burden rather than lipid-rich features.

Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque. Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography-based measures of coronary artery calcium score and segment involvement score. We identified 156 significant associations (P<0.05) between lipid metabolites and coronary plaque characteristics across 39 metabolic pathways. Sphingomyelins were inversely associated with all plaque metrics, and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1), a phosphatidylethanolamine, was positively associated with all plaque metrics. After correcting for multiple testing, 27 lipid species across 7 pathways remained significant (q<0.05). The majority were linked to pan-coronary lipid burden, with the strongest inverse association observed for sphingomyelin d18:1/22:1, d18:2/22:0, and d16:1/24:1. Similar inverse patterns were seen for select dihydrosphingomyelins and fatty acid dicarboxylates. In contrast, 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) remained positively associated with pan-coronary lipid. In the SCAPIS validation cohort, 19 of the 27 significant lipid associations were successfully replicated (q<0.05). This study is the first to demonstrate that sphingomyelins are negatively and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) positively associated with vulnerable coronary plaque features based on multimodality intracoronary imaging in patients with myocardial infarction. Moreover, these associations were validated in a large cohort using coronary computed tomography angiography-derived measures of plaque burden. These novel results may enable the development of new diagnostic and therapeutic strategies.

ABSTRACT Background Low-echo plaques are closely related to stroke. Non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is a novel lipid metabolism indicator. This study aims to evaluate the predictive value of NHHR for identifying vulnerable plaques. Methods This study retrospectively collected data from 3,339 patients with carotid plaque. We used multivariable logistic regression and restricted cubic spline (RCS) method to evaluate the association between NHHR and high-risk plaques. The feature variables were determined through Boruta feature selection, and verified using the Shapley Additive Interpretation (SHAP) method. We constructed 9 machine learning model to further explore the ability of NHHR to predict high-risk plaques. Results The results of the multivariable logistic regression analysis showed a significant positive association between NHHR and high-risk plaques: In the three-category model (low/medium-high/high-risk plaques), patients with high NHHR had a 57.3% increased risk of developing high-risk plaques compared to those with low NHHR (OR = 1.573, 95% CI: 1.266–1.955; p < 0.001); while in the binary model (non-high-risk/high-risk plaques), the risk of developing high-risk plaques in the high NHHR group increased by 80.2% (OR = 1.802, 95% CI: 1.369–2.378; p < 0.001). RCS also revealed that NHHR was significantly and linearly associated with high-risk plaques. In machine learning, NHHR could be used as a new non-invasive screening indicator for plaque risk (RF model: AUC = 0.68). Conclusions Higher NHHR is significantly associated with high-risk carotid plaques. NHHR has strong potential as a convenient and non-invasive auxiliary screening indicator, especially suitable for scenarios where ultrasound examination is not accessible or requires frequent monitoring.

Despite advances in percutaneous coronary intervention (PCI) and contemporary secondary prevention, recurrent cardiovascular events remain a major clinical challenge. Increasing evidence suggests that persistent vascular inflammation contributes to residual cardiovascular risk after PCI, even in patients receiving optimal lipid-lowering therapy. Recent studies have highlighted the clinical relevance of inflammatory biomarkers, plaque vulnerability, and intracoronary imaging findings in predicting adverse cardiovascular outcomes. In addition, anti-inflammatory therapeutic strategies have emerged as promising approaches for residual risk reduction. This review summarizes current insights into the mechanisms, assessment, and potential therapeutic implications of residual inflammatory risk after PCI.

Plaque characteristics and clinical outcomes of non-culprit long lesions in patients with acute myocardial infarction.

Jianpi Qutan Formula attenuates vulnerable plaques by regulating IGFBP3.

Integrated Coronary CT Angiography Assessment of Plaque Vulnerability and Clinical Outcomes: The Morphology-Inflammation-Burden (MIB) Score.

CL-316243 facilitates stable atherosclerotic plaque phenotypes in association with suppression of perivascular adipose tissue ferroptosis via upregulating C/EBP\u03b2

Acute cardiovascular events driven by atherosclerosis primarily originate from thrombosis triggered by vulnerable plaque rupture or endothelial erosion. Endothelial barrier destabilization-characterized by glycocalyx impairment, intercellular junction disassembly, and abnormal cytoskeletal tension-is a core upstream pathological stage that promotes atherogenic lipoprotein leakage, inflammatory cell infiltration, and matrix degradation. Hemodynamics, primarily through wall shear stress (WSS), shape the spatial distribution and plaque phenotypes of atherosclerosis; notably, low or oscillatory shear stress is associated with, and in experimental systems can promote, pro-inflammatory, pro-oxidant and pro-permeability endothelial phenotypes that contribute to plaque initiation and vulnerability. Conversely, regular exercise training, as an intervention that modulates hemodynamics, is widely suggested to promote anti-inflammatory, antioxidant, and antithrombotic endothelial phenotypes by significantly increasing antegrade shear stress and reducing detrimental retrograde/oscillatory shear stress. With a central focus on the axis of "exercise-shear stress-glycocalyx-cytoskeleton/junction-permeability-plaque stability," this review integrates evidence from in vitro flow chambers, animal models and human studies to critically discuss: (1) the spatiotemporal heterogeneity of WSS and its relationship with plaque vulnerability; (2) the composition, barrier function, and plasticity of the glycocalyx as the primary interface for shear stress; (3) the mechanosensory complexes at the glycocalyx and junctions that transduce shear stimuli to protective pathways such as Phosphoinositide 3-kinase (PI3K)-Akt-endothelial nitric oxide synthase (eNOS) and Krüppel-like factor 2 (KLF2), thereby stabilizing adherens/tight junctions; (4) how improved barrier homeostasis promotes the maintenance of the fibrous cap collagen scaffold by reducing lipoprotein leakage and dampening the inflammation-matrix metalloproteinase (MMP) axis. Finally, this review highlights the boundary conditions of the biological effects of shear stress: low/oscillatory shear stress is primarily associated with plaque initiation and susceptible sites, whereas focal, extremely high WSS in established stenotic lesions may contribute to late-stage high-risk remodeling. Therefore, the protective hemodynamic adaptations induced by exercise should not be simply equated with the pathologically high WSS found at stenotic sites.

A score system to determine the five-year survival in patients with asymptomatic carotid stenosis under best medical therapy: results from the CARAS study.

Carotid artery calcification is commonly assessed on computed tomography angiography (CTA) using a threshold of ≥130 Hounsfield units (HU), yet this may overestimate its volume and merge distinct calcifications due to blooming and partial-volume effects. The aim of our study was to determine the effect of incrementally increasing segmentation thresholds on the number of clusters and calcification morphology on CTA in patients with carotid atherosclerosis. In a cross-sectional study of 107 carotid atherosclerotic plaques on CTA, three-dimensional calcification masks at the carotid bifurcation were segmented using incremental thresholds from 130 to 1000 HU. For each calcification cluster, volume, eccentricity, compactness, aspect ratio, and mean attenuation were quantified. Associations between features were assessed using Spearman correlation, and changes in cluster number and inter-parameter relationships across thresholds were analyzed. The total number of calcification clusters increased at HU ranges between 130 (n = 149) to 450-500 HU (n = 188), reflecting improved separation of clusters at 450-500 HU, and decreased at thresholds above 500 HU as low-attenuation clusters were excluded. Inter-parameter correlations changed markedly between 130 and 250-400 HU, after which relationships stabilized, indicating more consistent morphology. CTA segmentation HU thresholds for calcifications substantially influence the apparent number, volume, and morphological parameters of carotid calcifications. These findings suggest that 130 HU may misrepresent calcification burden, whereas thresholds of ∼300 HU may provide more accurate and better representation of the morphology of calcification clusters. Future studies examining the role of calcifications in plaque vulnerability should account for the influence of attenuation thresholds during calcification segmentation.

Intracranial atherosclerotic stenosis (ICAS) causes ischemia, predominantly from downstream hemodynamic compromise or perforator artery occlusion. We compared plaque morphology and composition between these mechanisms using high resolution vessel wall imaging (HR-VWI) and optical coherence tomography (OCT). We enrolled 39 patients with symptomatic ICAS presenting with cerebral infarction or transient ischemic attack (TIA). All patients underwent HR-VWI and OCT. Based on diffusion weighted imaging (DWI) and CT perfusion (CTP), patients were classified as: (1) hypoperfusion type-watershed infarction on DWI or TIA with distal hypoperfusion on CTP; or (2) perforator type-an infarct confined to a single perforator territory on DWI. Plaque features were compared between groups, and multivariable logistic regression identified imaging markers independently associated with perforator-type events. On HR-VWI, perforator-type plaques more often exhibited intraplaque hemorrhage (IPH; 52.9% vs 13.6%; P=0.008), plaque ulceration (47.1% vs 13.6%; P=0.033), and a higher eccentric index (0.63±0.13 vs 0.48 (IQR 0.34); P=0.028) than hypoperfusion-type plaques. On OCT, perforator-type lesions had thinner fibrous caps (60 µm (IQR 50-80) vs 90±30 µm; P=0.004) and more frequent superficial thrombus (35.3% vs 4.5%; P=0.030) and cholesterol crystals (52.9% vs 18.2%; P=0.022). In multivariable analysis, thinner caps (per 10 µm increase, OR 0.663, 95% CI 0.481 to 0.914, P=0.012) and IPH (OR 9.703, 95% CI 1.508 to 62.429, P=0.017) were independently associated with perforator-type stroke. Plaques causing perforator artery occlusion showed a vulnerable phenotype characterized by a thin fibrous cap and IPH on multimodal imaging, distinguishing them from plaques underlying hemodynamic ischemia. These features may support mechanism specific risk stratification in ICAS.