-
The New England Journal of Medicine Mar 2024Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends... (Comparative Study)
Comparative Study Observational Study
BACKGROUND
Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking.
METHODS
We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs.
RESULTS
A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 μg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 μg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001).
CONCLUSIONS
In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).
Topics: Humans; Carotid Stenosis; Microplastics; Myocardial Infarction; Plaque, Atherosclerotic; Plastics; Prospective Studies; Stroke; Heart Disease Risk Factors; Endarterectomy, Carotid; Carotid Artery Diseases; Follow-Up Studies
PubMed: 38446676
DOI: 10.1056/NEJMoa2309822 -
Cell Death & Disease Oct 2023Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow... (Review)
Review
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Macrophages; Apoptosis; Myocardial Infarction
PubMed: 37863894
DOI: 10.1038/s41419-023-06206-z -
JAMA Cardiology Aug 2023Recurrent coronary events in patients with recent myocardial infarction remain a major clinical problem. Noninvasive measures of coronary atherosclerotic disease...
IMPORTANCE
Recurrent coronary events in patients with recent myocardial infarction remain a major clinical problem. Noninvasive measures of coronary atherosclerotic disease activity have the potential to identify individuals at greatest risk.
OBJECTIVE
To assess whether coronary atherosclerotic plaque activity as assessed by noninvasive imaging is associated with recurrent coronary events in patients with myocardial infarction.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, longitudinal, international multicenter cohort study recruited participants aged 50 years or older with multivessel coronary artery disease and recent (within 21 days) myocardial infarction between September 2015 and February 2020, with a minimum 2 years' follow-up.
INTERVENTION
Coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography.
MAIN OUTCOMES AND MEASURES
Total coronary atherosclerotic plaque activity was assessed by 18F-sodium fluoride uptake. The primary end point was cardiac death or nonfatal myocardial infarction but was expanded during study conduct to include unscheduled coronary revascularization due to lower than anticipated primary event rates.
RESULTS
Among 2684 patients screened, 995 were eligible, 712 attended for imaging, and 704 completed an interpretable scan and comprised the study population. The mean (SD) age of participants was 63.8 (8.2) years, and most were male (601 [85%]). Total coronary atherosclerotic plaque activity was identified in 421 participants (60%). After a median follow-up of 4 years (IQR, 3-5 years), 141 participants (20%) experienced the primary end point: 9 had cardiac death, 49 had nonfatal myocardial infarction, and 83 had unscheduled coronary revascularizations. Increased coronary plaque activity was not associated with the primary end point (hazard ratio [HR], 1.25; 95% CI, 0.89-1.76; P = .20) or unscheduled revascularization (HR, 0.98; 95% CI, 0.64-1.49; P = .91) but was associated with the secondary end point of cardiac death or nonfatal myocardial infarction (47 of 421 patients with high plaque activity [11.2%] vs 19 of 283 with low plaque activity [6.7%]; HR, 1.82; 95% CI, 1.07-3.10; P = .03) and all-cause mortality (30 of 421 patients with high plaque activity [7.1%] vs 9 of 283 with low plaque activity [3.2%]; HR, 2.43; 95% CI, 1.15-5.12; P = .02). After adjustment for differences in baseline clinical characteristics, coronary angiography findings, and Global Registry of Acute Coronary Events score, high coronary plaque activity was associated with cardiac death or nonfatal myocardial infarction (HR, 1.76; 95% CI, 1.00-3.10; P = .05) but not with all-cause mortality (HR, 2.01; 95% CI, 0.90-4.49; P = .09).
CONCLUSIONS AND RELEVANCE
In this cohort study of patients with recent myocardial infarction, coronary atherosclerotic plaque activity was not associated with the primary composite end point. The findings suggest that risk of cardiovascular death or myocardial infarction in patients with elevated plaque activity warrants further research to explore its incremental prognostic implications.
Topics: Humans; Male; Female; Plaque, Atherosclerotic; Prospective Studies; Cohort Studies; Sodium Fluoride; Coronary Artery Disease; Myocardial Infarction; Death
PubMed: 37379010
DOI: 10.1001/jamacardio.2023.1729 -
American Heart Journal Oct 2023Acute coronary syndromes are commonly caused by the rupture of vulnerable plaque, which often appear angiographically not severe. Although pharmacologic management is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acute coronary syndromes are commonly caused by the rupture of vulnerable plaque, which often appear angiographically not severe. Although pharmacologic management is considered standard therapy for stabilizing plaque vulnerability, the potential role of preventive local treatment for vulnerable plaque has not yet been determined. The PREVENT trial was designed to compare preventive percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) with OMT alone in patients with functionally nonsignificant high-risk vulnerable plaques.
METHODS
The PREVENT trial is a multinational, multicenter, prospective, open-label, active-treatment-controlled randomized trial. Eligible patients have at least 1 angiographically significant stenosis (diameter stenosis >50% by visual estimation) without functional significance (fractional flow reserve [FFR] >0.80). Target lesions are assessed by intracoronary imaging and must meet at least 2 imaging criteria for vulnerable plaque; (1) minimal lumen area <4.0 mm; (2) plaque burden >70%; (3) maximal lipid core burden index in a 4 mm segment >315 by near infrared spectroscopy; and (4) thin cap fibroatheroma as determined by virtual histology or optical coherence tomography. Enrolled patients are randomly assigned in a 1:1 ratio to either preventive PCI with either bioabsorbable vascular scaffolds or metallic everolimus-eluting stents plus OMT or OMT alone. The primary endpoint is target-vessel failure, defined as the composite of death from cardiac causes, target-vessel myocardial infarction, ischemic-driven target-vessel revascularization, or hospitalization for unstable or progressive angina, at 2 years after randomization.
RESULTS
Enrollment of a total of 1,608 patients has been completed. Follow-up of the last enrolled patient will be completed in September 2023 and primary results are expected to be available in early 2024.
CONCLUSIONS
The PREVENT trial is the first large-scale, randomized trial to evaluate the effect of preventive PCI on non-flow-limiting vulnerable plaques containing multiple high-risk features that is appropriately powered for clinical outcomes. PREVENT will provide compelling evidence as to whether preventive PCI of vulnerable plaques plus OMT improves patient outcomes compared with OMT alone.
CLINICAL TRIAL REGISTRATION
URL: https://www.
CLINICALTRIALS
gov. Unique identifier: NCT02316886.
KEY POINTS
The PREVENT trial is the first, large-scale randomized clinical trial to evaluate the effect of preventive PCI on non-flow-limiting vulnerable plaque with high-risk features. It will provide compelling evidence to determine whether PCI of focal vulnerable plaques on top of OMT improves patient outcomes.
Topics: Humans; Plaque, Atherosclerotic; Fractional Flow Reserve, Myocardial; Coronary Angiography; Percutaneous Coronary Intervention; Constriction, Pathologic; Treatment Outcome; Prospective Studies; Coronary Artery Disease
PubMed: 37271356
DOI: 10.1016/j.ahj.2023.05.017 -
Ageing Research Reviews Sep 2023Macrophages are crucial in the progression of atherosclerotic cardiovascular disease (ASCVD). In the atherosclerotic lesions, macrophages play a central role in... (Review)
Review
Macrophages are crucial in the progression of atherosclerotic cardiovascular disease (ASCVD). In the atherosclerotic lesions, macrophages play a central role in maintaining inflammatory response, promoting plaque development, and facilitating thrombosis. Increasing studies indicate that metabolic reprogramming and immune response mediate macrophage functional changes in all stages of atherosclerosis. In this review article, we explain how metabolic changes in glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, fatty acid synthesis, fatty acid oxidation, and cholesterol metabolism regulate macrophage function in atherosclerosis. We discuss how immune response to oxidized lipids regulate macrophage function in atherosclerosis. Additionally, we explore how abnormal metabolism leads to macrophage mitochondrial dysfunction in atherosclerosis.
Topics: Humans; Macrophages; Atherosclerosis; Plaque, Atherosclerotic; Immunity; Fatty Acids
PubMed: 37379970
DOI: 10.1016/j.arr.2023.101993 -
JAMA Cardiology Oct 2023The association between changes in atherosclerotic plaque induced by lipid-lowering therapies (LLTs) and reduction in major adverse cardiovascular events (MACEs) remains... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The association between changes in atherosclerotic plaque induced by lipid-lowering therapies (LLTs) and reduction in major adverse cardiovascular events (MACEs) remains controversial.
OBJECTIVE
To evaluate the association between coronary plaque regression assessed by intravascular ultrasound (IVUS) and MACEs.
DATA SOURCES
A comprehensive, systematic search of publications in PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was performed.
STUDY SELECTION
Clinical prospective studies of LLTs reporting change in percent atheroma volume (PAV) assessed by IVUS and describing MACE components were selected.
DATA EXTRACTION AND SYNTHESIS
Reporting was performed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The association between mean change in PAV and MACEs was analyzed by meta-regression using mixed-effects, 2-level binomial logistic regression models, unadjusted and adjusted for clinical covariates, including mean age, baseline PAV, baseline low-density lipoprotein cholesterol level, and study duration.
MAIN OUTCOME AND MEASURES
Mean PAV change and MACE in intervention and comparator arms were assessed in an updated systematic review and meta-regression analysis of IVUS trials of LLTs that also reported MACEs.
RESULTS
This meta-analysis included 23 studies published between July 2001 and July 2022, including 7407 patients and trial durations ranging from 11 to 104 weeks. Mean (SD) patient age ranged from 55.8 (9.8) to 70.2 (7.6) years, and the number of male patients from 245 of 507 (48.3%) to 24 of 26 (92.3%). Change in PAV across 46 study arms ranged from -5.6% to 3.1%. The number of MACEs ranged from 0 to 72 per study arm (17 groups [37%] reported no events, 9 [20%] reported 1-2 events, and 20 [43%] reported ≥3 events). In unadjusted analysis, a 1% decrease in mean PAV was associated with 17% reduced odds of MACEs (unadjusted OR, 0.83; 95% CI, 0.71-0.98; P = .03), and with a 14% reduction in MACEs in adjusted analysis (adjusted OR, 0.86; 95% CI, 0.75-1.00; P = .050). Further adjustment for cardiovascular risk factors showed a 19% reduced risk (adjusted OR, 0.81; 95% CI, 0.68-0.96; P = .01) per 1% decrease in PAV. A 1% reduction of PAV change between intervention and comparator arms within studies was also associated with a significant 25% reduction in MACEs (OR, 0.75; 95% CI, 0.56-1.00; P = .046).
CONCLUSIONS AND RELEVANCE
In this meta-analysis, regression of atherosclerotic plaque by 1% was associated with a 25% reduction in the odds of MACEs. These findings suggest that change in PAV could be a surrogate marker for MACEs, but given the heterogeneity in the outcomes, additional data are needed.
Topics: Humans; Male; Middle Aged; Plaque, Atherosclerotic; Coronary Artery Disease; Prospective Studies; Regression Analysis
PubMed: 37647074
DOI: 10.1001/jamacardio.2023.2731 -
Biomedicine & Pharmacotherapy =... Nov 2023The mechanisms of Salvia miltiorrhiza (SM) and Tanshinone IIA (Tan IIA) in the treatment of atherosclerosis was examined by combining network pharmacology and molecular...
The mechanisms of Salvia miltiorrhiza (SM) and Tanshinone IIA (Tan IIA) in the treatment of atherosclerosis was examined by combining network pharmacology and molecular biology experiments. The TCMSP and BATMAN-TCM databases provided 104 SM candidate ingredients and 813 target genes, while GEO and GeneCards databases identified 35 overlapping targets between SM and coronary artery disease (CAD). From these data, we constructed a CAD-target-active ingredient network, and using Gene Ontology (GO) and KEGG pathway analysis, 211 GO terms and 43 pathways were identified, which facilitated the construction of a key active ingredient-target-pathway network. We then constructed a protein-protein interaction (PPI) network and performed molecular docking simulations between Tan IIA and 10 key target proteins to analyze the interactions between the molecule and the protein. SM was found to alleviate CAD by reducing the expression of key pro-inflammatory factors, such as COX-2 (PTGS2), MMP9, ICAM1, TNF-α, and NF-κB. Tan IIA was identified as the primary effective component of SM in treating CAD, with TNF and PTGS2 being its main targets. We further validated these findings using in vitro/in vivo experiments. The results showed that both SM and Tan IIA attenuated the buildup of plaque and the accumulation of lipids in ApoE mice. In addition, SM and Tan IIA reduced vascular inflammatory factors expression in ApoE mice and ox-LDL-cultured HUVECs. Furthermore, our findings showed that Tan IIA reduced vascular endothelial inflammation and prevented plaque formation via COX-2/TNF-a/NF-κB signaling pathway. We have demonstrated for the first time that Tan IIA plays a vital role in attenuating atherosclerosis by downregulating COX-2 expression.
Topics: Mice; Animals; Plaque, Atherosclerotic; NF-kappa B; Cyclooxygenase 2; Salvia miltiorrhiza; Molecular Docking Simulation; Atherosclerosis; Inflammation; Apolipoproteins E
PubMed: 37713995
DOI: 10.1016/j.biopha.2023.115501 -
Journal of Atherosclerosis and... Jul 2023Intracranial branch atheromatous disease (BAD) is a pathological condition characterized by the occlusion of a relatively large perforating branch (700-800 µm) near the... (Review)
Review
Intracranial branch atheromatous disease (BAD) is a pathological condition characterized by the occlusion of a relatively large perforating branch (700-800 µm) near the orifice of a parent artery due to atherosclerotic plaque-based thrombus (microatheroma). BAD is refractory to treatment and follows a course of progressive exacerbation, especially motor paralysis. Uniform treatment for common atherothrombotic cerebral infarction or lacunar infarction does not prevent the progressive exacerbation of BAD, and consequently affects functional prognosis. To date, various combinations of treatments have been investigated and proposed to attenuate the worsening symptoms of BAD. However, no therapy with established efficacy is yet available for BAD. Since it is the most difficult condition to treat in the area of cerebral infarction, the establishment of optimal treatment methods for BAD is keenly awaited. This review presents an overview of the acute treatments available for BAD and discusses the prospects for optimal treatment.
Topics: Plaque, Atherosclerotic; Humans; Intracranial Thrombosis; Cerebral Infarction; Stroke, Lacunar; Dual Anti-Platelet Therapy
PubMed: 37183021
DOI: 10.5551/jat.RV22003 -
Nature Reviews. Cardiology May 2024Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable... (Review)
Review
Atherosclerosis is a progressive inflammatory disorder of the arterial vessel wall characterized by substantial infiltration of macrophages, which exert both favourable and detrimental functions. Early in atherogenesis, macrophages can clear cytotoxic lipoproteins and dead cells, preventing cytotoxicity. Efferocytosis - the efficient clearance of dead cells by macrophages - is crucial for preventing secondary necrosis and stimulating the release of anti-inflammatory cytokines. In addition, macrophages can promote tissue repair and proliferation of vascular smooth muscle cells, thereby increasing plaque stability. However, advanced atherosclerotic plaques contain large numbers of pro-inflammatory macrophages that secrete matrix-degrading enzymes, induce death in surrounding cells and contribute to plaque destabilization and rupture. Importantly, macrophages in the plaque can undergo apoptosis and several forms of regulated necrosis, including necroptosis, pyroptosis and ferroptosis. Regulated necrosis has an important role in the formation and expansion of the necrotic core during plaque progression, and several triggers for necrosis are present within atherosclerotic plaques. This Review focuses on the various forms of programmed macrophage death in atherosclerosis and the pharmacological interventions that target them as a potential means of stabilizing vulnerable plaques and improving the efficacy of currently available anti-atherosclerotic therapies.
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Macrophages; Apoptosis; Necrosis
PubMed: 38163815
DOI: 10.1038/s41569-023-00957-0 -
Biomedicine & Pharmacotherapy =... Feb 2024Ferroptosis is a newly identified form of non-apoptotic programmed cell death, characterized by the iron-dependent accumulation of lethal lipid reactive oxygen species... (Review)
Review
Ferroptosis is a newly identified form of non-apoptotic programmed cell death, characterized by the iron-dependent accumulation of lethal lipid reactive oxygen species (ROS) and peroxidation of membrane polyunsaturated fatty acid phospholipids (PUFA-PLs). Ferroptosis is unique among other cell death modalities in many aspects. It is initiated by excessive oxidative damage due to iron overload and lipid peroxidation and compromised antioxidant defense systems, including the system Xc/ glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and the GPX4-independent pathways. In the past ten years, ferroptosis was reported to play a critical role in the pathogenesis of various cardiovascular diseases, e.g., atherosclerosis (AS), arrhythmia, heart failure, diabetic cardiomyopathy, and myocardial ischemia-reperfusion injury. Studies have identified dysfunctional iron metabolism and abnormal expression profiles of ferroptosis-related factors, including iron, GSH, GPX4, ferroportin (FPN), and SLC7A11 (xCT), as critical indicators for atherogenesis. Moreover, ferroptosis in plaque cells, i.e., vascular endothelial cell (VEC), macrophage, and vascular smooth muscle cell (VSMC), positively correlate with atherosclerotic plaque development. Many macromolecules, drugs, Chinese herbs, and food extracts can inhibit the atherogenic process by suppressing the ferroptosis of plaque cells. In contrast, some ferroptosis inducers have significant pro-atherogenic effects. However, the mechanisms through which ferroptosis affects the progression of AS still need to be well-known. This review summarizes the molecular mechanisms of ferroptosis and their emerging role in AS, aimed at providing novel, promising druggable targets for anti-AS therapy.
Topics: Humans; Ferroptosis; Atherosclerosis; Plaque, Atherosclerotic; Glutathione; Iron; Lipid Peroxidation; Reactive Oxygen Species; Hyperaldosteronism
PubMed: 38171246
DOI: 10.1016/j.biopha.2023.116112