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Journal of Internal Medicine Dec 2014Atherosclerosis is a silent chronic vascular pathology that is the cause of the majority of cardiovascular ischaemic events. The evolution of vascular disease involves a... (Review)
Review
Atherosclerosis is a silent chronic vascular pathology that is the cause of the majority of cardiovascular ischaemic events. The evolution of vascular disease involves a combination of endothelial dysfunction, extensive lipid deposition in the intima, exacerbated innate and adaptive immune responses, proliferation of vascular smooth muscle cells and remodelling of the extracellular matrix, resulting in the formation of an atherosclerotic plaque. High-risk plaques have a large acellular lipid-rich necrotic core with an overlying thin fibrous cap infiltrated by inflammatory cells and diffuse calcification. The formation of new fragile and leaky vessels that invade the expanding intima contributes to enlarge the necrotic core increasing the vulnerability of the plaque. In addition, biomechanical, haemodynamic and physical factors contribute to plaque destabilization. Upon erosion or rupture, these high-risk lipid-rich vulnerable plaques expose vascular structures or necrotic core components to the circulation, which causes the activation of tissue factor and the subsequent formation of a fibrin monolayer (coagulation cascade) and, concomitantly, the recruitment of circulating platelets and inflammatory cells. The interaction between exposed atherosclerotic plaque components, platelet receptors and coagulation factors eventually leads to platelet activation, aggregation and the subsequent formation of a superimposed thrombus (i.e. atherothrombosis) which may compromise the arterial lumen leading to the presentation of acute ischaemic syndromes. In this review, we will describe the progression of the atherosclerotic lesion along with the main morphological characteristics that predispose to plaque rupture, and discuss the multifaceted mechanisms that drive platelet activation and subsequent thrombus formation. Finally, we will consider the current scientific challenges and future research directions.
Topics: Atherosclerosis; Blood Coagulation; Endothelium, Vascular; Fibrinolysis; Humans; Necrosis; Plaque, Atherosclerotic; Rupture, Spontaneous; Thrombosis
PubMed: 25156650
DOI: 10.1111/joim.12296 -
European Journal of Pharmacology Dec 2017An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain... (Review)
Review
An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain results that can be extrapolated to human medicine. Moreover, it must be easy to acquire, can be maintained at a reasonable cost, is easy to handle and shares the topography of the lesions with humans. In general, animal models of atherosclerosis are based on accelerated plaque formation due to a cholesterol-rich/Western-type diet, manipulation of genes involved in the cholesterol metabolism, and the introduction of additional risk factors for atherosclerosis. Mouse and rabbit models have been mostly used, followed by pigs and non-human primates. Each of these models has its advantages and limitations. The mouse has become the predominant species to study experimental atherosclerosis because of its rapid reproduction, ease of genetic manipulation and its ability to monitor atherogenesis in a reasonable time frame. Both Apolipoprotein E deficient (ApoE) and LDL-receptor (LDLr) knockout mice have been frequently used, but also ApoE/LDLr double-knockout, ApoE3-Leiden and PCSK9-AAV mice are valuable tools in atherosclerosis research. However, a great challenge was the development of a model in which intra-plaque microvessels, haemorrhages, spontaneous atherosclerotic plaque ruptures, myocardial infarction and sudden death occur consistently. These features are present in ApoEFbn1 mice, which can be used as a validated model in pre-clinical studies to evaluate novel plaque-stabilizing drugs.
Topics: Animals; Atherosclerosis; Disease Models, Animal; Plaque, Atherosclerotic
PubMed: 28483459
DOI: 10.1016/j.ejphar.2017.05.010 -
The New England Journal of Medicine Aug 2020
Review
Topics: Acute Coronary Syndrome; Coronary Thrombosis; Humans; Inflammation; Plaque, Atherosclerotic; Rupture, Spontaneous; Tomography, Optical Coherence
PubMed: 32846063
DOI: 10.1056/NEJMra2000317 -
Immunological Reviews Nov 2014Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the... (Review)
Review
Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype.
Topics: Animals; Atherosclerosis; Cell Movement; Humans; Macrophage Activation; Macrophages; Phenotype; Plaque, Atherosclerotic; Transcription Factors
PubMed: 25319333
DOI: 10.1111/imr.12218 -
Archives of Biochemistry and Biophysics Jul 2017Heart disease ends the life of more people than any other disease in the United States. High levels of low density lipoprotein (LDL)-cholesterol cause heart diseases by... (Review)
Review
Heart disease ends the life of more people than any other disease in the United States. High levels of low density lipoprotein (LDL)-cholesterol cause heart diseases by increasing the formation of atherosclerotic plaques. Proprotein convertase subtilisin/kexin-9 (PCSK9) indirectly regulates plasma LDL levels by controlling the LDL receptor expression at the plasma membrane. PCSK9 also appears to modulate glucose intolerance, insulin resistance, abdominal obesity, inflammation, and hypertension. The magnitude of PCSK9's involvement in the onset of these metabolic abnormalities appears to be associated with age, sex, and ethnic background. Another regulator, the inducible degrader of the LDL receptor (IDOL), works by enhancing the ubiquitination of the LDL receptor. Herein, we will review the functions and regulatory mechanisms of PCSK9. The effects of PCSK9 on the LDL receptor, the relationship of this convertase with IDOL, and treatments currently available against hypercholesterolemia are also discussed.
Topics: Animals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Plaque, Atherosclerotic; Proprotein Convertase 9; Receptors, LDL; Ubiquitin-Protein Ligases
PubMed: 28587771
DOI: 10.1016/j.abb.2017.06.001 -
Journal of the American College of... Sep 2019It has been believed that most acute coronary events result from the rupture of mildly stenotic plaques, based on studies in which angiographic information was available... (Review)
Review
It has been believed that most acute coronary events result from the rupture of mildly stenotic plaques, based on studies in which angiographic information was available from many months to years before the event. However, serial studies in which angiographic data were available from the past as also within 1 to 3 months of myocardial infarction have clarified that nonobstructive lesions progressively enlarged relatively rapidly before the acute event occurred. Noninvasive computed tomography angiography imaging data have confirmed that lesions that did not progress voluminously over time rarely led to events, regardless of the extent of luminal stenosis or baseline high-risk plaque morphology. Therefore, plaque progression could be proposed as a necessary step between early, uncomplicated atherosclerosis and plaque rupture. On the other hand, it has been convincingly demonstrated that intensive lipid-lowering therapy (to a low-density lipoprotein cholesterol level of <70 mg/dl) halts plaque progression. Given the current ability to noninvasively detect the presence of early atherosclerosis, the importance of plaque progression in the pathogenesis of myocardial infarction, and the efficacy of maximum lipid-lowering therapy, it has been suggested that plaque progression is a modifiable step in the evolution of atherosclerotic plaque. A personalized approach based on the detection of early atherosclerosis can trigger the necessary treatment to prevent plaque progression and hence plaque instability. Therefore, this approach can redefine the traditional paradigm of primary and secondary prevention based on population-derived risk estimates and can potentially improve long-term outcomes.
Topics: Acute Coronary Syndrome; Acute Disease; Atherosclerosis; Disease Progression; Humans; Plaque, Atherosclerotic
PubMed: 31537271
DOI: 10.1016/j.jacc.2019.08.012 -
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 -
International Journal of Molecular... Apr 2020Atherosclerosis is a lipoprotein-driven inflammatory disorder leading to a plaque formation at specific sites of the arterial tree. After decades of slow progression,... (Review)
Review
Atherosclerosis is a lipoprotein-driven inflammatory disorder leading to a plaque formation at specific sites of the arterial tree. After decades of slow progression, atherosclerotic plaque rupture and formation of thrombi are the major factors responsible for the development of acute coronary syndromes (ACSs). In this regard, the detection of high-risk (vulnerable) plaques is an ultimate goal in the management of atherosclerosis and cardiovascular diseases (CVDs). Vulnerable plaques have specific morphological features that make their detection possible, hence allowing for identification of high-risk patients and the tailoring of therapy. Plaque ruptures predominantly occur amongst lesions characterized as thin-cap fibroatheromas (TCFA). Plaques without a rupture, such as plaque erosions, are also thrombi-forming lesions on the most frequent pathological intimal thickening or fibroatheromas. Many attempts to comprehensively identify vulnerable plaque constituents with different invasive and non-invasive imaging technologies have been made. In this review, advantages and limitations of invasive and non-invasive imaging modalities currently available for the identification of plaque components and morphologic features associated with plaque vulnerability, as well as their clinical diagnostic and prognostic value, were discussed.
Topics: Animals; Atherosclerosis; Biomarkers; Diagnostic Imaging; Disease Susceptibility; Humans; Molecular Imaging; Multimodal Imaging; Plaque, Atherosclerotic; Reproducibility of Results; Sensitivity and Specificity
PubMed: 32340284
DOI: 10.3390/ijms21082992 -
Seminars in Nuclear Medicine Mar 2023Atherosclerotic plaques progress as a result of inflammation. Both invasive and noninvasive imaging techniques have been developed to identify and characterize plaque as... (Review)
Review
Atherosclerotic plaques progress as a result of inflammation. Both invasive and noninvasive imaging techniques have been developed to identify and characterize plaque as vulnerable (more likely to rupture and cause a clinical event). Imaging techniques to identify vulnerable include identifying vessels with focal subendothelial collections of I) inflammatory cells; II) lipid/ fatty acid; III) local regions of hypoxia; IV) local expression of angiogenesis factors; V) local expression of protease; VI) intravascular foci of thrombus; hemorrhage (most often seen in the aftermath of a clinical event); VII) apoptosis and VIII) microcalcification. This review provides an overview of atherosclerotic plaque progression and tracers which can visualize specific molecules associated with vulnerability.
Topics: Humans; Plaque, Atherosclerotic; Positron-Emission Tomography; Thrombosis
PubMed: 36333157
DOI: 10.1053/j.semnuclmed.2022.08.009 -
The Lancet. Neurology Jun 2019Stroke represents a massive public health problem. Carotid atherosclerosis plays a fundamental part in the occurence of ischaemic stroke. European and US guidelines for... (Review)
Review
Stroke represents a massive public health problem. Carotid atherosclerosis plays a fundamental part in the occurence of ischaemic stroke. European and US guidelines for prevention of stroke in patients with carotid plaques are based on quantification of the percentage reduction in luminal diameter due to the atherosclerotic process to select the best therapeutic approach. However, better strategies for prevention of stroke are needed because some subtypes of carotid plaques (eg, vulnerable plaques) can predict the occurrence of stroke independent of the degree of stenosis. Advances in imaging techniques have enabled routine characterisation and detection of the features of carotid plaque vulnerability. Intraplaque haemorrhage is accepted by neurologists and radiologists as one of the features of vulnerable plaques, but other characteristics-eg, plaque volume, neovascularisation, and inflammation-are promising as biomarkers of carotid plaque vulnerability. These biomarkers could change current management strategies based merely on the degree of stenosis.
Topics: Biomarkers; Carotid Artery Diseases; Humans; Plaque, Atherosclerotic; Predictive Value of Tests; Stroke
PubMed: 30954372
DOI: 10.1016/S1474-4422(19)30035-3