Plaque Rupture Research Articles

Unraveling the complex interplay between abnormal hemorheology and shape asymmetry in flow through stenotic arteries

Background and Objective:Stenosis or narrowing of arteries due to the buildup of plaque is a common occurrence in atherosclerosis and coronary artery disease (CAD), limiting blood flow to the heart and posing substantial cardiovascular risk. While the role of geometric irregularities in arterial stenosis is well-documented, the complex interplay between the abnormal hemorheology and asymmetric shape in flow characteristics remains unexplored. Methods:This study investigates the influence of varying hematocrit (Hct) levels, often caused by conditions such as diabetes and anemia, on flow patterns in an idealized eccentric stenotic artery using computational fluid dynamics simulations. We consider three physiological levels of Hct, 25%, 45%, and 65%, representing anemia, healthy, and diabetic conditions, respectively. The numerical simulations are performed for different combinations of shape eccentricity and blood rheological parameters, and hemodynamic indicators such as wall shear stress (WSS), oscillatory shear index (OSI), are relative residence time (RRT) are calculated to assess the arterial health. Results:Our results reveal the significant influence of Hct level on stenosis progression. CAD patients with anemia are exposed to lower WSS and higher OSI, which may increase the propensity for plaque progression and rupture. However, for CAD patients with high Hct level—as is often the case in diabetes—the WSS at the minimal lumen area increases rapidly, which may also lead to plaque rupture and cause adverse events such as heart attacks. These disturbances promote endothelial dysfunction, inflammation, and thrombus formation, thereby intensifying cardiovascular risk. Conclusions:Our findings underscore the significance of incorporating hemorheological parameters, such as Hct, into computational models for accurate assessment of flow dynamics. We envision that insights gained from this study will inform the development of tailored treatment strategies and interventions in CAD patients with common comorbidities such as diabetes and anemia, thus mitigating the adverse effects of abnormal hemorheology and reducing the ever-growing burden of cardiovascular diseases.

Neutrophil count as a risk factor for cardiovascular diseases: how can we manage it?

Neutrophils activation plays a pivotal role in the pathogenesis of atherosclerotic plaque formation, progression and rupture. An association between the leukocyte count and the risk of developing myocardial infarction has been well known for many years; however, only recently did Mendelian randomization studies show that a high neutrophil count is a causal risk factor for atherosclerotic cardiovascular disease. On the other hand, experimental studies show that depletion of circulating neutrophils impairs plaque development. Clopidogrel, an antiplatelet agent, is widely used in combination with aspirin to reduce the incidence of ischemic events in patients treated with coronary stenting. Chronic treatment with this drug reduces inflammatory markers and neutrophil numbers, rarely causing severe leukopenia. The purpose of this review is to present recent evidence showing the link between neutrophil number and the development of cardiovascular diseases and to discuss how the clopidogrel-induced reduction in the neutrophil count may be a beneficial off-target effect of this drug.

Electrochemical impedance spectroscopy unmasks high-risk atherosclerotic features in human coronary artery disease.

Coronary plaque rupture remains the prominent mechanism of myocardial infarction. Accurate identification of rupture-prone plaque may improve clinical management. This study assessed the discriminatory performance of electrochemical impedance spectroscopy (EIS) in human cardiac explants to detect high-risk atherosclerotic features that portend rupture risk. In this single-center, prospective study, n = 26 cardiac explants were collected for EIS interrogation of the three major coronary arteries. Vessels in which advancement of the EIS catheter without iatrogenic plaque disruption was rendered impossible were not assessed. N = 61 vessels underwent EIS measurement and histological analyses. Plaques were dichotomized according to previously established high rupture-risk parameter thresholds. Diagnostic performance was determined via receiver operating characteristic areas-under-the-curve (AUC). Necrotic cores were identified in n = 19 vessels (median area 1.53 mm2) with a median fibrous cap thickness of 62 μm. Impedance was significantly greater in plaques with necrotic core area ≥1.75 mm2 versus <1.75 mm2 (19.8 ± 4.4 kΩ vs. 7.2 ± 1.0 kΩ, p = .019), fibrous cap thickness ≤65 μm versus >65 μm (19.1 ± 3.5 kΩ vs. 6.5 ± 0.9 kΩ, p = .004), and ≥20 macrophages per 0.3 mm-diameter high-power field (HPF) versus <20 macrophages per HPF (19.8 ± 4.1 kΩ vs. 10.2 ± 0.9 kΩ, p = .002). Impedance identified necrotic core area ≥1.75 mm2, fibrous cap thickness ≤65 μm, and ≥20 macrophages per HPF with AUCs of 0.889 (95% CI: 0.716-1.000) (p = .013), 0.852 (0.646-1.000) (p = .025), and 0.835 (0.577-1.000) (p = .028), respectively. Further, phase delay discriminated severe stenosis (≥70%) with an AUC of 0.767 (0.573-0.962) (p = .035). EIS discriminates high-risk atherosclerotic features that portend plaque rupture in human coronary artery disease and may serve as a complementary modality for angiography-guided atherosclerosis evaluation.

High Detectability of Prehospital 12-Lead Electrocardiogram in Diagnosing Spasm-Induced Acute Coronary Syndrome.

The importance of prehospital (PH) electrocardiograms (ECG) recorded by emergency medical services (EMS) for diagnosing coronary artery spasm-induced acute coronary syndrome (CS-ACS) remains unclear. We enrolled 340 consecutive patients with ACS who were transported by EMS within 12 h of symptom onset. According to Japanese Circulation Society guidelines, CS-ACS (n=48) was diagnosed with or without a pharmacological provocation test (n=34 and n=14, respectively). Obstructive coronary artery-induced ACS (OC-ACS; n=292) was defined as ACS with a culprit lesion showing 99% stenosis or >75% stenosis with plaque rupture or thrombosis observed via angiographic and intravascular imaging. Ischemic ECG findings included ST-segment deviation (elevation or depression) and negative T and U waves. In CS-ACS, the prevalence of ST-segment deviation decreased significantly from PH-ECG to emergency room (ER) ECG (77.0% vs. 35.4%; P<0.001), as did the prevalence of overall ECG abnormalities (81.2% vs. 45.8%; P<0.001). Conversely, in OC-ACS, there was a similar prevalence on PH-ECG and ER-ECG of ST-segment deviations (94.8% vs. 92.8%, respectively; P=0.057) and abnormal ECG findings (96.9% vs. 95.2%, respectively; P=0.058). Patients with abnormal PH-ECG findings that disappeared upon arrival at hospital without ER-ECG or troponin abnormalities were more frequent in the CS-ACS than OC-ACS group (20.8% vs. 1.0%; P<0.001). PH-ECG is valuable for detecting abnormal ECG findings that disappear upon arrival at hospital in CS-ACS patients.

Functional and morphological improvement of significant non-culprit coronary artery stenosis by LDL-C reduction with a PCSK9 antibody: Rationale and design of the randomized FITTER trial

Non-culprit coronary artery lesions are commonly present in patients presenting with an acute coronary syndrome (ACS). Additional stenting of non-culprit lesions in addition to the culprit lesion intends to prevent secondary events caused by these lesions. At the same time, multiple trials have demonstrated the potential of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in reducing plaque size and changing plaque composition of non-culprit lesions. Whether intensive low-density lipoprotein cholesterol (LDL-C) reduction with PCSK9 inhibitor evolocumab improves non-culprit vessel hemodynamics, reduces the risk of plaque rupture of important non-culprit lesions, and might obviate the need for additional stenting has not been investigated. The “Functional Improvement of non‐infarcT related coronary artery stenosis by Extensive LDL‐C Reduction with a PCSK9 Antibody” (FITTER) trial is a multi-center, randomized, double-blind, placebo-controlled clinical trial for patients presenting with ACS and multivessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) is performed in non-culprit vessels amenable for percutaneous coronary intervention (PCI). Coronary intervention in patients with hemodynamically important non-critical lesions (FFR: 0.67–0.85) is staged after baseline imaging using near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS). Eligible patients are randomized and treated for 12 weeks with either evolocumab or placebo, in addition to high-intensity statin therapy. Follow-up angiography with repeat FFR and IVUS-NIRS is scheduled at 12 weeks. Staged PCI is performed at the operator's discretion.The FITTER trial is the first study to evaluate the effect of maximal LDL-C reduction by the PCSK9 inhibitor evolocumab on invasively measured FFR, plaque size, and plaque composition in hemodynamically important non-culprit lesions, during a treatment period of just 12 weeks after an ACS. Currently, all patients have been included (August 2023) and data analysis is ongoing. Trial registration numberclinicaltrials.gov NCT04141579.

Changes in the Release of Endothelial Extracellular Vesicles CD144+, CCR6+, and CXCR3+ in Individuals with Acute Myocardial Infarction.

Acute myocardial infarction (AMI) results from vulnerable plaque rupture, causing ischemic cardiomyocyte necrosis and intense inflammation. Paradoxically, this inflammation releases factors that aid heart repair. Recent findings suggest a role for extracellular vesicles (EVs) in intercellular communication during post-AMI cardiac repair. However, EVs' tissue origin and chemokine profile in the blood of patients with AMI remains unclear. This study characterized the tissue origin and chemokine receptor profile of EVs in the coronary and peripheral blood of patients with AMI. The results reveal that vesicles isolated from coronary and peripheral blood plasma are enriched in tetraspanin (CD9) and express CD81+, CD90+, and CD144+. The vesicle size ranged between 145 and 162 nm, with the control group exhibiting smaller vesicles (D10) than the AMI group. Furthermore, all vesicles expressed CCR6 and CXCR3, whereas a small percentage expressed CCR4. In addition, a decrease in CXCR3 and CCR6 expression was observed in coronary and peripheral AMI blood vesicles compared with the control; however, no difference was found between AMI coronary and AMI peripheral blood vesicles. In conclusion, our study demonstrates, for the first time, changes in the number of extracellular vesicles expressing CD144+, CXCR3, and CCR6 in the peripheral circulation of patients with AMI. Extracellular vesicles present in the circulation of patients with AMI hold excellent promise as a potential diagnostic tool.

Novel Metal-Free Nanozyme for Targeted Imaging and Inhibition of Atherosclerosis via Macrophage Autophagy Activation to Prevent Vulnerable Plaque Formation and Rupture.

Atherosclerosis is a primary cause of cardiovascular and cerebrovascular diseases, with the unpredictable rupture of vulnerable atherosclerotic plaques enriched with lipid-laden macrophages being able to lead to heart attacks and strokes. Activating macrophage autophagy presents itself as a promising strategy for preventing vulnerable plaque formation and reducing the risk of rupture. In this study, we have developed a novel metal-free nanozyme (HCN@DS) that integrates the functions of multimodal imaging-guided therapy for atherosclerosis. HCN@DS has demonstrated high macrophage-targeting abilities due to its affinity toward scavenger receptor A (SR-A), along with excellent photoacoustic and photothermal imaging capabilities for guiding the precise treatment. It combines mild photothermal effects with moderate reactive oxygen species (ROS) generation to treat atherosclerosis. This controlled approach activates autophagy in atherosclerotic macrophages, inhibiting foam cell formation by reducing the uptake of oxidized low-density lipoproteins (oxLDL) and promoting efferocytosis and cholesterol efflux in macrophages. Additionally, it prevents plaque rupture by inhibiting apoptosis and inflammation within the plaque. Therefore, this metal-free nanozyme holds great potential for reducing the risk of atherosclerosis due to its high biosafety, excellent targeting ability, dual-modality imaging capability, and appropriate modulation of autophagy.

Foam Cells: The Origin of Formation and Target for Plant-derived Bioactive Compounds.

Foam cells play a crucial role in the initiation and progression of atherosclerosis, a condition marked by the development and growth of plaques that narrow blood vessel lumens. This narrowing can prevent normal blood flow and, in severe cases, lead to plaque rupture and blood clot formation, which can cause stroke or myocardial infarction. The origin of foam cells is diverse, arising from monocytes, vascular smooth muscle cells, stem/progenitor cells, and dendritic and endothelial cells. In their attempt to eliminate excess lipoproteins and cholesterol, foam cells inadvertently contribute to plaque development and rupture. Cholesterol uptake, efflux, and esterification are the major processes regulating foam cell formation. Advances in technology, such as the identification of cell-surface markers for lineage tracing and single-cell RNA sequencing, have unveiled diverse molecular mechanisms involved in the formation of foam cells from different origins, offering new insights into plaque formation and potential targets for anti-foam cell therapies. In this review, we focus on recent studies exploringthe inhibitory effects of medicinal plants and their bioactive components on foam cell formation. Various mechanisms are explored, including the inhibition of cholesterol uptake and the up-regulation of cholesterol efflux, as well as the suppression of inflammatory and adhesion activities. Emphasizing a cellular target-based therapeutic approach, this review envisions the development of innovative plant-based medications for atherosclerosis treatment.

Macrophages overexpressing interleukin‐10 target and prevent atherosclerosis: Regression of plaque formation and reduction in necrotic core

AbstractAtherosclerosis, a slowly progressing inflammatory disease, is characterized by the presence of monocyte‐derived macrophages. Interventions targeting the inflammatory characteristics of atherosclerosis hold promising potential. Although interleukin (IL)‐10 is widely acknowledged for its anti‐inflammatory effects, systemic administration of IL‐10 has limitations due to its short half‐life and significant systemic side effects. In this study, we aimed to investigate the effectiveness of an approach designed to overexpress IL‐10 in macrophages and subsequently introduce these genetically modified cells into ApoE−/− mice to promote atherosclerosis regression. We engineered RAW264.7 cells to overexpress IL‐10 (referred to as IL‐10M) using lentivirus vectors. The IL‐10M exhibited robust IL‐10 secretion, maintained phagocytic function, improved mitochondrial membrane potentials, reduced superoxide production and showed a tendency toward the M2 phenotype when exposed to inflammatory stimuli. IL‐10M can selectively target plaques in ApoE−/− mice and has the potential to reduce plaque area and necrotic core at both early and late stages of plaque progression. Moreover, there was a significant reduction in MMP9, a biomarker associated with plaque rupture, in IL‐10M‐treated plaques from both the early and late intervention groups. Additionally, the administration of IL‐10M showed no obvious side effects. This study serves as proof that cell therapy based on anti‐inflammatory macrophages might be a promising strategy for the intervention of atherosclerosis.

Development of Pro-resolving and Pro-efferocytic Nanoparticles for Atherosclerosis Therapy.

Atherosclerosis is a major contributor to cardiovascular diseases with a high global prevalence. It is characterized by the formation of lipid-laden plaques in the arteries, which eventually lead to plaque rupture and thrombosis. While the current lipid-lowering therapies are generally effective in lowering the risk of cardiovascular events, they do not address the underlying causes of disease. Defective resolution of inflammation and impaired efferocytosis are the main driving forces of atherosclerosis. Macrophages recognize cells for clearance by the expression of "eat me" and "do not eat me" signals, including the CD47-SIRPα axis. However, the "do not eat me" signal CD47 is overexpressed in atherosclerotic plaques, leading to compromised efferocytosis and secondary necrosis. In this context, prophagocytic antibodies have been explored to stimulate the clearance of apoptotic cells, but they are nonspecific and impact healthy tissues. In macrophages, downstream of signal regulatory protein α, lie protein tyrosine phosphatases, SHP 1/2, which can serve as effective targets for selectively phagocytosing apoptotic cells. While increasing the efferocytosis targets the end stages of lesion development, the underlying issue of inflammation still persists. Simultaneously increasing efferocytosis and reducing inflammation can be effective therapeutic strategies for managing atherosclerosis. For instance, IL-10 is a key anti-inflammatory mediator that enhances efferocytosis via phosphoSTAT3 (pSTAT3) activation. In this study, we developed a combination nanotherapy by encapsulating an SHP-1 inhibitor (NSC 87877) and IL-10 in a single nanoparticle platform [(S + IL)-NPs] to enhance efferocytosis and inflammation resolution. Our studies suggest that (S + IL)-NPs successfully encapsulated both agents, entered the macrophages, and delivered the agents into intracellular compartments. Additionally, (S + IL)-NPs decreased inflammation by suppressing pro-inflammatory markers and enhancing anti-inflammatory mediators. They also exhibited the potential for improved phagocytic activity via pSTAT3 activation. Our nanomedicine-mediated upregulation of the anti-inflammatory and efferocytic responses in macrophages shows promise for the treatment of atherosclerosis.

Predictors for Vulnerable Plaque in Functionally Significant Lesions

BackgroundVulnerable plaque presents prognostic implications in addition to functional significance. ObjectivesThe aim of this study was to identify relevant features of vulnerable plaque in functionally significant lesions. MethodsIn this multicenter, prospective study conducted across 5 countries, including patients who had invasive fractional flow reserve (FFR) ≤0.80, a total of 95 patients with available pullback pressure gradient (PPG) and plaque analysis on coronary computed tomographic angiography and optical coherence tomography were analyzed. Vulnerable plaque was defined as the presence of plaque rupture or thin-cap fibroatheroma on optical coherence tomography. Among the 25 clinical characteristics, invasive angiographic findings, physiological indexes, and coronary computed tomographic angiographic findings, significant predictors of vulnerable plaque were identified. ResultsMean percentage diameter stenosis, FFR, and PPG were 77.8% ± 14.6%, 0.66 ± 0.13, and 0.65 ± 0.13, respectively. Vulnerable plaque was present in 53 lesions (55.8%). PPG and FFR were identified as significant predictors of vulnerable plaque (P < 0.05 for all). PPG >0.65 and FFR ≤0.70 were significantly related to a higher probability of vulnerable plaque after adjustment for each other (OR: 6.75 [95% CI: 2.39-19.1]; P < 0.001] for PPG >0.65; OR: 4.61 [95% CI: 1.66-12.8]; P = 0.003 for FFR ≤0.70). When categorizing lesions according to combined PPG >0.65 and FFR ≤0.70, the prevalence of vulnerable plaque was 20.0%, 57.1%, 66.7%, and 88.2% in the order of PPG ≤0.65 and FFR >0.70, PPG ≤0.65 and FFR ≤0.70, PPG >0.65 and FFR >0.70, and PPG >0.65 and FFR ≤0.70 (P for trend < 0.001), respectively. ConclusionsAmong low-FFR lesions, the presence of vulnerable plaque can be predicted by PPG combined with FFR without additional anatomical or plaque characteristics. (Precise Percutaneous Coronary Intervention Plan [P3] Study; NCT03782688)

Acute exercise-induced inflammatory and thrombotic response in hypertensive patients.

Vigorous physical activity may acutely trigger the onset of an acute coronary syndrome especially in sedentary persons with established cardiovascular risk factors such as arterial hypertension. The rupture of an inflamed coronary plaque and the activation of the coagulation cascade are the main underlying mechanisms. The present study aimed to determine the effect of acute exercise on the inflammatory and thrombotic response in patients with arterial hypertension as compared to normotensive peers. After excluding patients with any inflammatory or/and coronary artery disease, a total of 60 non-treated hypertensive patients and 65 normotensive individuals underwent a maximal treadmill exercise testing. Βlood samples were drawn at rest and immediately after peak exercise. High-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), white blood cell (WBC), interleukin-6 (IL-6), and total fibrinogen (TF) levels, as well as plasminogen activator inhibitor-1 (PAI-1) activity, were measured. All biomarkers increased with exercise, except PAI-1, which decreased (P < 0.05 for the change between resting and peak exercise for all biomarkers). Αfter adjusting for relevant confounders (duration of exercise, metabolic equivalents, systolic BP, and rate-pressure product achieved at peak exercise), the normotensive group had less marked (P < 0.05) exercise-induced changes than the hypertensive group in hsCRP (7.7 vs. 8.6%), SAA (5.6 vs. 11.9%), WBC (45.0 vs. 51.7%), and PAI-1 (-17.3 vs. -20.1%) and a similar (P = NS) change in IL-6 (23.8 vs. 23.0%) and TF (8.5 vs. 8.5%). In conclusion, the acute exercise-induced inflammatory and thrombotic response seems to be more pronounced in non-treated hypertensive patients than in normotensive controls. Possible clinical implications of this finding merit further examination.

High expression levels of haem oxygenase-1 promote ferroptosis in macrophage-derived foam cells and exacerbate plaque instability

Plaque rupture with consequent thrombosis is the leading cause of acute cardiovascular events, during which macrophage death is a hallmark. Ferroptosis is a pivotal intermediate link between early and advanced atherosclerosis. Existing evidence indicates the involvement of macrophage ferroptosis in plaque vulnerability; however, the exact mechanism remains elusive. The aim of this study was to explore key ferroptosis-related genes (FRGs) involved in plaque progression and the underlying molecular mechanisms involved. The expression landscape of FRGs was obtained from atherosclerosis-related GEO datasets. Molecular mechanism studies of ferroptosis were performed using bone marrow-derived macrophages (BMDMs) and macrophage-derived foam cells (MDFCs). Bioinformatics analysis and immunohistochemistry revealed that macrophage haem oxygenase-1 (HMOX1) is the key FRG involved in plaque destabilization. Hypoxic conditions induced a significant increase in Hmox1 expression in MDFCs but not in macrophages. In addition, the beneficial or deleterious effects of Hmox1 were dependent on the degree of Hmox1 induction. Hmox1 overexpression drove inflammatory responses and ferroptotic oxidative stress in MDFCs and aggravated the plaque burden in atherosclerotic model mice. Further mechanistic investigations demonstrated that hypoxia-mediated degradation of egl-9 family hypoxia-inducible factor 3 (Egln3) stabilized Hif1a, which subsequently promoted Hmox1 transcription. Our findings suggest that high Hmox1 expression under hypoxia is deleterious to MDFC viability and plaque stability, providing a reference for the management of acute cardiovascular events.

Pathogenesis of human atheroma necrotic core: degradation of connective tissue fibers and possible involvement of cathepsin K

BackgroundAtheroma is a serious atherosclerotic lesion related to plaque rupture, thrombosis, and ischemic disease. To clarify the pathogenesis of human atheroma, particularly the formation of the liponecrotic tissue in the necrotic core, the distribution of connective tissue fibers, such as collagen and elastic fibers, and related substances was investigated in this study.MethodsAtherosclerotic lesions in human coronary arteries were classified into three categories: pathologic intimal thickening (PIT), atheroma with lipid core (ALC), and atheroma with necrotic core (ANC). PIT and ALC consisted of the lipid pool and the lipid core, respectively. The necrotic core of ANC was composed of a lipid core-like region and liponecrotic tissue containing amorphous materials and lacking cells and connective tissue fibers. The distribution of collagen type I, elastin, C-terminal crosslinked telopeptide of collagen type I (CTX-I), and cathepsin K (CatK) was investigated through immunohistochemistry. CTX-I is a fragmented peptide consisting of the C-terminal region of collagen type I that is generated by CatK. The distribution of denatured and unfolded collagen chains was also investigated through collagen hybridizing peptide staining.ResultsCollagen type I, denatured and unfolded collagen chains, and elastin were positively stained in the PIT, ALC, and lipid core-like region of ANC. However, they were negatively stained in the liponecrotic tissue of ANC. CTX-I and CatK were positively stained in all four regions, and their grade of staining appeared to show a positive relationship. Both CTX-I and CatK demonstrated higher staining grades in the liponecrotic tissue. These findings suggested that pre-existing collagen type I was severely degraded by CatK, resulting in the production of CTX-I in the liponecrotic tissue, and that pre-existing elastin was also degraded in this region. CatK was mainly found in macrophage foam cells, many of which were localized within and around the liponecrotic tissue.ConclusionsThis study suggests that the liponecrotic tissue in the necrotic core of human atheroma is formed by severe degradation of pre-existing connective tissue fibers and consequent collapse of tissue structure. This degradation is likely caused by proteolytic enzymes, such as CatK, secreted by macrophage foam cells.

OCT-based comparative evaluation of culprit lesion morphology in very young versus older adult patients with STEMI.

The clinical and pathophysiological characteristics of coronary artery disease in very young adults are poorly described. Using optical coherence tomography (OCT), we compared culprit lesion morphology in very young adult patients (≤35 years) versus older adult patients (>60 years) with ST-segment elevation myocardial infarction (STEMI). Culprit lesion morphology was classified as plaque rupture, plaque erosion, or calcified nodule. Thrombus age was subclassified into acute (intraluminal thrombus with surface irregularity) or subacute (mostly mural thrombus with a smooth surface). A total of 61 patients who underwent thrombolysis within 24 hours from symptom onset were included, with 38 (59.7%) subjects ≤35 years and 23 (40.3%) subjects >60 years of age. As an underlying mechanism of STEMI thrombosis, plaque erosion was more common in very young patients (52.6% vs 21.7%; p=0.02) while plaque rupture was more common in elderly patients (65.2% vs 36.8%; p=0.03). Acute or subacute thrombus was identified in 68.9% (42/61) of patients, with red thrombus being more frequent in very young patients. In the entire patient cohort, acute thrombus was more frequent in plaque rupture compared with plaque erosion (62.0% vs 28.0%; p=0.01), whereas subacute thrombus was more common in plaque erosion versus plaque rupture (52.0% vs 10.3%; p=0.0008). OCT showed that plaque erosion and plaque rupture were the most common underlying STEMI mechanisms in very young patients and older patients, respectively, and that subjects with plaque erosion had greater evidence of subacute thrombus.

Serum LOXL2 is Elevated and an Independent Biomarker in Patients with Coronary Artery Disease.

Arterial stiffness is associated with accelerated progression of atherosclerosis and plaque rupture. Lysyl oxidase-like 2 (LOXL2) plays a vital role in inflammatory responses, matrix deposition and arterial stiffness. This study assessed the correlation between the serum LOXL2 concentration and disease severity, inflammation, and endothelial dysfunction of coronary artery disease (CAD). The study included 143 CAD patients and 150 non-CAD patients who underwent coronary angiography. Medical records, demographic and clinical baseline parameters were collected. Serum LOXL2 levels were measured using an ELISA kit. CAD patients had higher serum LOXL2 levels than non-CAD patients, and LOXL2 levels were associated with severity of coronary lesions. Serum LOXL2 level was positively correlated with low-density lipoprotein cholesterol (LDL-C) (r=0.161, P=0.054), systolic blood pressure (SBP) (r=0.175, P=0.036), high-sensitivity C-reactive protein (hs-CRP) (r=0.177, P=0.035), intima-media thickness (IMT) (r=0.190, P=0.023), and brachial-ankle pulse wave velocity (baPWV) (r=0.203, P=0.015), while negatively associated with high-density lipoprotein cholesterol (HDL-C) (r=-0.191, P=0.023) and flow-mediated dilation (FMD) (r=-0.183, P=0.028) in CAD patients. Multivariate logistic regression showed that LOXL2 is independently correlated with LDL-C (OR=3.380; 95% CI=1.258-9.082; P=0.016), hs-CRP (OR=10.988; 95% CI=1.962-61.532; P=0.006), TC (OR=2.229; 95% CI=1.005-4.944; P=0.049), IMT (OR=72.719; 95% CI=2.313-2286.008; P=0.015), and baPWV (OR=1.002; 95% CI=1.001-1.004; P=0.005) in CAD patients. The receiver operating characteristic (ROC) curve showed that the best cut-off for CAD as serum LOXL2 is 275.35 pg/mL, with sensitivity and specificity of 77.6% and 84%, respectively. Our data demonstrated that LOXL2 could be a potential biomarker and independent risk factor for CAD patients.

Association of neutrophil extracellular traps burden with clinical and angiographic characteristics in patients with ST-elevation myocardial infarction

BackgroundThe precise triggers for atherosclerotic plaque rupture and the underlying pathophysiology of coronary thrombogenesis remain elusive. Polymorphonuclear neutrophils, particularly their formation of neutrophil extracellular traps (NETs), have garnered attention in the context of coronary atherothrombosis. This study sought to explore the association of NETs burden with clinical and angiographic characteristics in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI) and thrombus aspiration (TA). MethodsFor this study, 336 consecutive STEMI patients undergoing pPCI were considered for TA. Aspirated thrombi underwent histological analysis and NETs quantification via immunohistochemistry. Potential associations of clinical variables and angiographic outcomes with NETs burden were assessed. ResultsManual TA was selectively performed in 72 cases with increased thrombotic burden, and 60 thrombi were suitable for analysis and included in the current study. Most thrombi specimens displayed lytic features (63%), and almost three out of four were identified as white thrombi. Increased NETs burden was significantly associated with prolonged pain-to-balloon time (>300 min), OR = 10.29 (95% CI 2.11–42.22, p = 0.001), and stress-induced hyperglycemia OR = 6.58 (95% CI 1.23–52.63, p < 0.01) after multivariate regression analysis. Additionally, distal embolization, and left ventricular ejection fraction ≤40% were more frequent among patients with an elevated NETs burden OR = 16.9 (95% CI 4.23–44.52, p < 0.01) and OR = 3.2 (95% CI 1.05–12.1, p = 0.05), respectively. ConclusionElevated NETs burden in STEMI thrombi may be due to delayed reperfusion and stress-induced hyperglycemia, and it is associated with an increased risk of distal embolization and lower left ventricular ejection fraction. Further research is needed to elucidate the role of NETs as a potential therapeutic target in acute atherothrombosis.

Single-Cell Time-Resolved Metabolomics and Lipidomics Reveal Apoptotic and Ferroptotic Heterogeneity during Foam Cell Formation.

Macrophage-derived foam cells play a crucial role in plaque formation and rupture during the progression of atherosclerosis. Traditional studies have often overlooked the heterogeneity of foam cells, focusing instead on populations of cells. To address this, we have developed time-resolved, single-cell metabolomics and lipidomics approaches to explore the heterogeneity of macrophages during foam cell formation. Our dynamic metabolomic and lipidomic analyses revealed a dual regulatory axis involving inflammation and ferroptosis. Further, single-cell metabolomics and lipidomics have delineated a continuum of macrophage states, with varied susceptibilities to apoptosis and ferroptosis. Single-cell transcriptomic profiling confirmed these divergent fates, both in established cell lines and in macrophages derived from peripheral blood monocytes. This research has uncovered the complex molecular interactions that dictate these divergent cell fates, providing crucial insights into the pathogenesis of atherosclerosis.

The role of inflammatory response in the development of atherosclerosis, myocardial infarction, and remodeling

Inflammation is an intrinsic part of the body’s immune response, significantly influencing a myriad of physiological and pathological processes. There is now clinical and experimental evidence suggesting that inflammation accelerates atherosclerosis and its associated complications. The presence of macrophages, T and B cells inside the atherosclerotic plaque fueled this concept and steered subsequent research endeavors toward understanding the pathophysiology of atherosclerosis including plaque formation and destabilization leading to plaque rupture resulting in myocardial injury and remodeling. Understanding the mechanism behind atherosclerosis will aid in developing appropriate treatment interventions. Shifting research and drug development from a singular focus on cholesterol-lowering agents to include adjunctive anti-inflammatory therapies is crucial. Targeting a root cause, i.e., inflammation, will help decrease the incidence and progression of atherosclerosis and improve patient outcomes. In this review, we aim to discuss the current understanding of the intricate role of inflammation in the pathogenesis of atherosclerosis, myocardial infarction, and cardiac remodeling. This synthesis will encompass an exploration of the various inflammatory cells involved, the intricate network of chemokines orchestrating inflammatory responses, and the pathways that underpin these cardiovascular conditions. Furthermore, we will explore promising diagnostic and therapeutic strategies aimed at addressing inflammation in cardiovascular diseases. These include interventions such as colchicine, monoclonal antibodies, and nanoparticles designed to deliver and accumulate drugs at the molecular level within cells.

Causal relationship between immune cells and risk of myocardial infarction: evidence from a Mendelian randomization study.

Atherosclerotic plaque rupture is a major cause of heart attack. Previous studies have shown that immune cells are involved in the development of atherosclerosis, but different immune cells play different roles. The aim of this study was to investigate the causal relationship between immunological traits and myocardial infarction (MI). To assess the causal association of immunological profiles with myocardial infarction based on publicly available genome-wide studies, we used a two-sample mendelian randomization (MR) approach with inverse variance weighted (IVW) as the main analytical method. Sensitivity analyses were used to assess heterogeneity and horizontal pleiotropy. A two-sample MR analysis was conducted using IVW as the primary method. At a significance level of 0.001, we identified 47 immunophenotypes that have a significant causal relationship with MI. Seven of these were present in B cells, five in cDC, four in T cells at the maturation stage, six in monocytes, five in myeloid cells, 12 in TBNK cells, and eight in Treg cells. Sensitivity analyses were performed to confirm the robustness of the MR results. Our results provide strong evidence that multiple immune cells have a causal effect on the risk of myocardial infarction. This discovery provides a new avenue for the development of therapeutic treatments for myocardial infarction and a new target for drug development.