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Frontiers in Immunology 2022Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages...
Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages are effector cells and accumulate to the damaged and inflamed sites of arteries to internalize native and chemically modified lipoproteins to transform them into cholesterol-loaded foam cells. Foam cell formation is determined by the capacity of phagocytosis, migration, scavenging, and the features of phenotypes. Macrophages are diverse, and the subsets and functions are controlled by their surrounding microenvironment. Generally, macrophages are divided into classically activated (M1) and alternatively activated (M2). Recently, intraplaque macrophage phenotypes are recognized by the stimulation of CXCL4 (M4), oxidized phospholipids (Mox), hemoglobin/haptoglobin complexes [HA-mac/M(Hb)], and heme (Mhem). The pro-atherogenic or anti-atherosclerotic phenotypes of macrophages decide the progression of AS. Besides, apoptosis, necrosis, ferroptosis, autophagy and pyrotopsis determine plaque formation and cardiovascular vulnerability, which may be associated with macrophage polarization phenotypes. In this review, we first summarize the three most popular hypotheses for AS and find the common key factors for further discussion. Secondly, we discuss the factors affecting macrophage polarization and five types of macrophage death in AS progression, especially ferroptosis. A comprehensive understanding of the cellular and molecular mechanisms of plaque formation is conducive to disentangling the candidate targets of macrophage-targeting therapies for clinical intervention at various stages of AS.
Topics: Atherosclerosis; Foam Cells; Humans; Macrophage Activation; Macrophages; Plaque, Atherosclerotic
PubMed: 35432323
DOI: 10.3389/fimmu.2022.843712 -
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 -
Pharmacology & Therapeutics Apr 2019Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid...
Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic "writers", "readers", and "erasers". Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics.
Topics: Animals; Atherosclerosis; Epigenesis, Genetic; Humans; Immunity; RNA, Untranslated; Risk Factors
PubMed: 30439455
DOI: 10.1016/j.pharmthera.2018.11.003 -
Cureus Apr 2023The main risk factor for atherosclerotic cardiovascular disease is smoking. Nicotine and carbon monoxide are two dangerous substances that are found in cigarette smoke.... (Review)
Review
The main risk factor for atherosclerotic cardiovascular disease is smoking. Nicotine and carbon monoxide are two dangerous substances that are found in cigarette smoke. The increased heart rate can have an almost instantaneous impact on the heart and blood vessels. Smoking is well known to cause oxidative stress, endanger the lining of the arteries, and accelerate the accumulation of fatty plaque in the blood vessels. It raises the danger of sudden thrombotic events, inflammatory alterations, and low-density lipoprotein oxidation. The smoke's carbon monoxide decreases the blood's capacity to deliver oxygen, adding to the heart's stress. Notably, these risks increase when diabetes, hypertension, high cholesterol, and glucose intolerance are present. It has a detrimental effect on peripheral blood vessels, raising the possibility of thromboangiitis obliterans. Stroke risk is known to be increased by smoking. As compared to those who continue to smoke, those who give up smoking have a much longer life expectancy. Chronic cigarette smoking has been shown to affect the macrophages' ability to remove cholesterol. Abstinence from smoking enhances the function of high-density lipoproteins and cholesterol efflux, lowering the risk of plaque buildup. In this review, we present the most recent information regarding the causal relationship between smoking and cardiovascular health as well as the long-term advantages of quitting.
PubMed: 37234135
DOI: 10.7759/cureus.38073 -
JACC. Cardiovascular Imaging Dec 2023The clinical value of high-risk coronary plaque characteristics (CPCs) to inform intensified medical therapy or revascularization of non-flow-limiting lesions remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The clinical value of high-risk coronary plaque characteristics (CPCs) to inform intensified medical therapy or revascularization of non-flow-limiting lesions remains uncertain.
OBJECTIVES
The authors performed a systematic review and meta-analysis to study the prognostic impact of CPCs on patient-level and lesion-level major cardiovascular adverse events (MACE).
METHODS
Thirty studies (21 retrospective, 9 prospective) with 30,369 patients evaluating the association of CPCs with MACE were included. CPCs included high plaque burden, low minimal lumen area, thin cap fibroatheroma, high lipid core burden index, low-attenuation plaque, spotty calcification, napkin ring sign, and positive remodeling.
RESULTS
CPCs were evaluated with the use of intracoronary modalities in 9 studies (optical coherence tomography in 4 studies, intravascular ultrasound imaging in 3 studies, and near-infrared spectroscopy intravascular ultrasound imaging in 2 studies) and by means of coronary computed tomographic angiography in 21 studies. CPCs significantly predicted patient-level and lesion-level MACE in both unadjusted and adjusted analyses. For most CPCs, accuracy for MACE was modest to good at the patient level and moderate to good at the lesion level. Plaques with more than 1 CPC had the highest accuracy for lesion-level MACE (AUC: 0.87). Because the prevalence of CPCs among plaques was low, estimated positive predictive values for lesion-level MACE were modest. Results were mostly consistent across imaging modalities and clinical presentations, and in studies with prevailing hard outcomes.
CONCLUSIONS
Characterization of CPCs identifies high-risk atherosclerotic plaques that place lesions and patients at risk for future MACE, albeit with modest sensitivity and positive predictive value (Coronary Plaque Characteristics Associated With Major Adverse Cardiovascular Events Among Atherosclerotic Patients and Lesions; CRD42021251810).
Topics: Humans; Plaque, Atherosclerotic; Coronary Artery Disease; Coronary Angiography; Retrospective Studies; Prospective Studies; Coronary Vessels; Predictive Value of Tests; Ultrasonography, Interventional
PubMed: 37804276
DOI: 10.1016/j.jcmg.2023.08.006 -
Cardiovascular Diabetology Jul 2023The TyG index is an indicator of insulin resistance (IR), which is associated with the development and prognosis of cardiovascular disease. This study aimed to summarize... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The TyG index is an indicator of insulin resistance (IR), which is associated with the development and prognosis of cardiovascular disease. This study aimed to summarize the relationship between the TyG index and the risk, severity, and prognosis of coronary artery disease (CAD) by performing a systematic review and meta-analysis.
METHODS
The PubMed, EMBASE, The Cochrane Library, and Web of Science databases were searched for articles published from inception until May 1, 2023. Cross-sectional studies, retrospective or prospective cohort studies recruiting patients with CAD were included. For the analysis of CAD severity, the outcomes were coronary artery calcification, coronary artery stenosis, coronary plaque progression, multi-vessel CAD, and in-stent re-stenosis. For the analysis of CAD prognosis, the primary outcome was major adverse cardiovascular events (MACE).
RESULTS
Forty-one studies were included in this study. Compared to patients with the lowest TyG index, those with the highest TyG index had a higher CAD risk [odds ratio (OR): 1.94, 95% confidence interval (CI) 1.20-3.14, I = 91%, P = 0.007]. Additionally, these patients were more likely to have stenotic coronary arteries (OR: 3.49, 95% CI 1.71-7.12, I = 0%, P = 0.0006), progressed plaques (OR: 1.67, 95% CI 1.28-2.19, I = 0%, P = 0.002), and with more vessels involved (OR: 2.33, 95% CI 1.59-3.42, I = 0%, P < 0.0001). When calculated as a categorized variable, it appears that acute coronary syndrome (ACS) patients with higher TyG index levels may have a higher incidence rate of MACE [hazard ratio (HR): 2.09, 95% CI 1.68-2.62, I = 87%, P < 0.00001], whereas chronic coronary syndrome (CCS) or stable CAD patients with higher TyG index levels showed a trend towards an increased incidence rate of MACE (HR: 1.24, 95% CI 0.96-1.60, I = 85%, P = 0.09). When calculated as a continuous variable, ACS patients had an HR of 2.28 per 1-unit/1-standard deviation increment of the TyG index (95% CI 1.44-3.63, I = 95%, P = 0.0005). Similarly, CCS or stable CAD patients had an HR of 1.49 per 1-unit/1-standard deviation increment of the TyG index (95% CI 1.21-1.83, I = 75%, P = 0.0001). Myocardial infarction with non-obstructive coronary arteries patients had an HR of 1.85 per 1-unit increment of the TyG index (95% CI 1.17-2.93, P = 0.008).
CONCLUSIONS
The TyG index is a simple new synthetic index that has been proven to be a valuable tool in the whole-course management of CAD patients. Patients with higher TyG index levels are at a higher risk of CAD, more severe coronary artery lesions, and worse prognosis compared to those with lower TyG index levels.
Topics: Humans; Coronary Artery Disease; Glucose; Retrospective Studies; Triglycerides; Prospective Studies; Cross-Sectional Studies; Risk Factors; Risk Assessment; Prognosis; Plaque, Atherosclerotic; Acute Coronary Syndrome; Blood Glucose; Biomarkers
PubMed: 37415168
DOI: 10.1186/s12933-023-01906-4 -
Stroke Oct 2023Although coronary calcification quantification is an established approach for cardiovascular risk assessment, the value of quantifying carotid calcification is less... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although coronary calcification quantification is an established approach for cardiovascular risk assessment, the value of quantifying carotid calcification is less clear. As a result, we performed a systematic review and meta-analysis to evaluate the association between extracranial carotid artery plaque calcification burden and ipsilateral cerebrovascular ischemic events.
METHODS
A comprehensive literature search was performed in the following databases: Ovid MEDLINE(R) 1946 to July 6, 2022; OVID Embase 1974 to July 6, 2022; and The Cochrane Library (Wiley). We performed meta-analyses including studies in which investigators performed a computed tomography assessment of calcification volume, percentage, or other total calcium burden summarizable in a single continuous imaging biomarker and determined the association of these features with the occurrence of ipsilateral stroke or transient ischemic attack.
RESULTS
Our overall meta-analysis consisted of 2239 carotid arteries and 9 studies. The presence of calcification in carotid arteries ipsilateral to ischemic stroke or in stroke patients compared with asymptomatic patients did not demonstrate a significant association with ischemic cerebrovascular events (relative risk of 0.75 [95% CI, 0.44-1.28]; =0.29). When restricted to studies of significant carotid artery stenosis (>50%), the presence of calcification was associated with a reduced risk of ischemic stroke (relative risk of 0.56 [95% CI, 0.38-0.85]; =0.006). When the analysis was limited to studies of patients with mainly nonstenotic plaques, there was an increased relative risk of ipsilateral ischemic stroke of 1.72 ([95% CI, 1.01-2.91]; =0.04). Subgroup meta-analyses of total calcium burden and morphological features of calcium showed wide variability in their strength of association with ischemic stroke and demonstrated significant heterogeneity.
CONCLUSIONS
The presence of calcification in carotid plaque confers a reduced association with ipsilateral ischemic events, although these results seem to be limited among carotid arteries with higher degrees of stenosis. Adoption of carotid calcification measures in clinical decision-making will require additional studies providing more reproducible and standardized methods of calcium characterization and testing these imaging strategies in prospective studies.
Topics: Humans; Prospective Studies; Calcium; Brain Ischemia; Stroke; Carotid Arteries; Carotid Artery Diseases; Plaque, Atherosclerotic; Carotid Stenosis; Risk Assessment; Calcinosis; Ischemic Stroke; Risk Factors
PubMed: 37638399
DOI: 10.1161/STROKEAHA.123.042807 -
Frontiers in Cardiovascular Medicine 2023Individuals diagnosed with atherosclerotic cardiovascular disease (ACD) are exposed to an increased risk of cardiovascular events. Reducing low-density lipoprotein... (Review)
Review
INTRODUCTION
Individuals diagnosed with atherosclerotic cardiovascular disease (ACD) are exposed to an increased risk of cardiovascular events. Reducing low-density lipoprotein cholesterol (LDL-C) levels has been established as an effective approach to mitigate these risks. However, a comprehensive and up-to-date meta-analysis investigating the LDL-C-lowering effectiveness and the impact on coronary atherosclerotic plaque compositions of Ezetimibe has been lacking.
METHODS
We conducted a systematic review by meticulously analyzing databases such as MEDLINE, EMBASE, and the Cochrane CENTRAL for randomized controlled trials that evaluated the efficacy of ezetimibe in lowering LDL-C levels and its influence on coronary atherosclerotic plaques among individuals with ACD. This review encompassed studies available until August 1, 2023. In our analysis, we employed the weighted mean difference (WMD) as the aggregated statistical measure, accompanied by the corresponding 95% confidence interval (CI).
RESULTS
We encompassed a total of 20 eligible studies. Our findings unveiled that the combined therapy involving ezetimibe alongside statins led to a more substantial absolute decrease in LDL-C in comparison to using statins alone. This difference in means amounted to (-14.06 mg/dl; 95% CI -18.0 to -10.0; = 0.0001). Furthermore, upon conducting subgroup analyses, it became evident that the intervention strategies proved effective in diminishing the volume of dense calcification (DC) in contrast to the control group.
CONCLUSIONS
Our study findings indicate that the inclusion of ezetimibe in conjunction with statin therapy leads to a modest yet meaningful additional reduction in LDL-C levels when compared to using statins in isolation. Importantly, the introduction of ezetimibe resulted in a significant decrease in the volume of DC. However, it is worth noting that further investigation is warranted to delve deeper into this phenomenon.
PubMed: 38075958
DOI: 10.3389/fcvm.2023.1269172 -
Frontiers in Cardiovascular Medicine 2023Carotid atherosclerotic plaque is an important independent risk factor for stroke. Apolipoprotein E (APOE) influences cholesterol levels and certain isoforms are...
INTRODUCTION
Carotid atherosclerotic plaque is an important independent risk factor for stroke. Apolipoprotein E (APOE) influences cholesterol levels and certain isoforms are associated with increased carotid atherosclerosis, though the exact association between APOE and carotid plaque is uncertain. The study aimed to evaluate the association between APOE and carotid plaque.
METHODS
A systematic review was performed to retrieve all studies which examined the association between carotid plaque and APOE. This study was conducted in accordance with the PRISMA guidelines. Independent readers extracted the relevant data from each study including the type of imaging assessment, plaque definition, frequency of APOE E4 carrier status and type of genotyping. Meta-analyses with an assessment of study heterogeneity and publication bias were performed. Results were presented in a forest plot and summarized using a random-effects model.
RESULTS
After screening 838 studies, 17 studies were included for systematic review. A meta-analysis of 5 published studies showed a significant association between 4 homozygosity and carotid plaque [odds ratio (OR), 1.53; 95% CI, 1.16, 2.02; = .003]. Additionally, there was a significant association between patients possessing at least one 4 allele, heterozygotes or homozygotes, and carotid plaque (OR, 1.25; 95% CI, 1.03, 1.52; = .03). Lastly, there was no association between 4 heterozygosity and carotid plaque (OR, 1.08; 95% CI, 0.93, 1.26; = .30).
CONCLUSION
APOE 4 allele is significantly associated with extracranial carotid atherosclerotic plaque, especially for homozygous individuals.
PubMed: 38034385
DOI: 10.3389/fcvm.2023.1155916 -
Brain Circulation 2022Carotid stenosis is an important contributor to ischemic stroke risk with resultant significant impact on neurological disability and death in adults and with worldwide... (Review)
Review
Carotid stenosis is an important contributor to ischemic stroke risk with resultant significant impact on neurological disability and death in adults and with worldwide implications. Management of carotid stenosis is impacted by whether there are associated symptoms along with the degree of stenosis. Understanding of the pathogenesis of carotid atherosclerosis or stenosis is important in management of carotid stenosis. Atherosclerotic plaque formation is a chronic insidious process with a number of potential contributors to the formation of such a plaque. The definition of atherosclerosis is not simply limited to abnormal deposition of lipid but also includes a chronic, complex, inflammatory process. Molecularly, in atherosclerosis, there is decreasing nitric oxide (NO) bioavailability, activity and/or expression of endothelial NO synthase, or increasing degradation of NO secondary to enhanced superoxide production. These above changes cause endothelial dysfunction leading to formation of foam cell followed by formation on lipid plaque. After lipid plaque formation, stable or unstable atherosclerotic plaque is formed depending on the calcium deposition over the lipid plaque. It continues to be clearly established that carotid intervention for symptomatic high-grade carotid stenosis is best managed with intervention either by carotid endarterectomy or carotid stenting. However, asymptomatic carotid stenosis is the subject of considerable controversy in terms of optimal management. This review of carotid atherosclerosis is an attempt to incorporate the information provided by more recent studies on pathogenesis and management which may help in the decision-making process for optimal management for protection against stroke.
PubMed: 36267431
DOI: 10.4103/bc.bc_36_22