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The Biochemical Journal May 2016The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood... (Review)
Review
The formation of atherosclerotic plaques in the large and medium sized arteries is classically driven by systemic factors, such as elevated cholesterol and blood pressure. However, work over the past several decades has established that atherosclerotic plaque development involves a complex coordination of both systemic and local cues that ultimately determine where plaques form and how plaques progress. Although current therapeutics for atherosclerotic cardiovascular disease primarily target the systemic risk factors, a large array of studies suggest that the local microenvironment, including arterial mechanics, matrix remodelling and lipid deposition, plays a vital role in regulating the local susceptibility to plaque development through the regulation of vascular cell function. Additionally, these microenvironmental stimuli are capable of tuning other aspects of the microenvironment through collective adaptation. In this review, we will discuss the components of the arterial microenvironment, how these components cross-talk to shape the local microenvironment, and the effect of microenvironmental stimuli on vascular cell function during atherosclerotic plaque formation.
Topics: Animals; Atherosclerosis; Endothelium, Vascular; Humans; Models, Biological; Plaque, Atherosclerotic; Risk Factors
PubMed: 27208212
DOI: 10.1042/BJ20150844 -
Molecules (Basel, Switzerland) Aug 2019Atherosclerosis is a chronic long-lasting vascular disease leading to myocardial infarction and stroke. Vulnerable atherosclerotic (AS) plaques are responsible for these... (Review)
Review
Atherosclerosis is a chronic long-lasting vascular disease leading to myocardial infarction and stroke. Vulnerable atherosclerotic (AS) plaques are responsible for these life-threatening clinical endpoints. To more successfully work against atherosclerosis, improvements in early diagnosis and treatment of AS plaque lesions are required. Vulnerable AS plaques are frequently undetectable by conventional imaging because they are non-stenotic. Although blood biomarkers like lipids, C-reactive protein, interleukin-6, troponins, and natriuretic peptides are in pathological ranges, these markers are insufficient in detecting the critical perpetuation of AS anteceding endpoints. Thus, chances to treat the patient in a preventive way are wasted. It is now time to solve this dilemma because clear results indicate a benefit of anti-inflammatory therapy per se without modification of blood lipids (CANTOS Trial, NCT01327846). This fact identifies modulation of immune-mediated inflammation as a new promising point of action for the eradication of fatal atherosclerotic endpoints.
Topics: Adaptive Immunity; Animals; Biomarkers; Disease Susceptibility; Humans; Immune System; Immunity, Innate; Inflammation; Matrix Metalloproteinases; Neovascularization, Pathologic; Plaque, Atherosclerotic
PubMed: 31450823
DOI: 10.3390/molecules24173072 -
Experimental Biology and Medicine... Dec 2021Cardiovascular and cerebrovascular diseases, such as coronary heart disease and stroke, caused by atherosclerosis have become the "number one killer", seriously... (Review)
Review
Cardiovascular and cerebrovascular diseases, such as coronary heart disease and stroke, caused by atherosclerosis have become the "number one killer", seriously endangering human health in developing and developed countries. Atherosclerosis mainly occurs in large and medium-sized arteries and involves intimal thickening, accumulation of foam cells, and formation of atheromatous plaques. Autophagy is a cellular catabolic process that has evolved to defend cells from the turnover of intracellular molecules. Autophagy is thought to play an important role in the development of plaques. This review focuses on studies on autophagy in cells involved in the formation of atherosclerotic plaques, such as monocytes, macrophages, endothelial cells, dendritic cells, and vascular smooth muscle cells, indicating that autophagy plays an important role in plaque development. We mainly discuss the roles of autophagy in these cells in maintaining the stability of atherosclerotic plaques, providing a reference for the next steps to unravel the mechanisms of atherogenesis.
Topics: Animals; Atherosclerosis; Autophagy; Humans; Plaque, Atherosclerotic
PubMed: 34407677
DOI: 10.1177/15353702211038894 -
Journal of Biomechanics Apr 2019The catastrophic mechanical rupture of an atherosclerotic plaque is the underlying cause of the majority of cardiovascular events. The infestation of vascular... (Review)
Review
The catastrophic mechanical rupture of an atherosclerotic plaque is the underlying cause of the majority of cardiovascular events. The infestation of vascular calcification in the plaques creates a mechanically complex tissue composite. Local stress concentrations and plaque tissue strength properties are the governing parameters required to predict plaque ruptures. Advanced imaging techniques have permitted insight into fundamental mechanisms driving the initiating inflammatory-driven vascular calcification of the diseased intima at the (sub-) micron scale and up to the macroscale. Clinical studies have potentiated the biomechanical relevance of calcification through the derivation of links between local plaque rupture and specific macrocalcification geometrical features. The clinical implications of the data presented in this review indicate that the combination of imaging, experimental testing, and computational modelling efforts are crucial to predict the rupture risk for atherosclerotic plaques. Specialised experimental tests and modelling efforts have further enhanced the knowledge base for calcified plaque tissue mechanical properties. However, capturing the temporal instability and rupture causality in the plaque fibrous caps remains elusive. Is it necessary to move our experimental efforts down in scale towards the fundamental (sub-) micron scales in order to interpret the true mechanical behaviour of calcified plaque tissue interactions that is presented on a macroscale in the clinic and to further optimally assess calcified plaques in the context of biomechanical modelling.
Topics: Biomechanical Phenomena; Calcinosis; Humans; Models, Biological; Plaque, Atherosclerotic; Rupture
PubMed: 30904335
DOI: 10.1016/j.jbiomech.2019.03.005 -
Pharmacology & Therapeutics Dec 2022Atherosclerotic plaques associated with acute coronary syndromes (ACS), i.e. culprit lesions, frequently feature a ruptured fibrous cap with thrombotic complications. On... (Review)
Review
Atherosclerotic plaques associated with acute coronary syndromes (ACS), i.e. culprit lesions, frequently feature a ruptured fibrous cap with thrombotic complications. On imaging, these plaques exhibit a low attenuation, lipid-rich, necrotic core containing cholesterol crystals and are inherently unstable. Indeed, cholesterol crystals are causally associated with plaque vulnerability in vivo; their formation results from spontaneous self-assembly of cholesterol molecules. Cholesterol homeostasis is a central determinant of the physicochemical conditions leading to crystal formation, which are favored by elevated membrane free cholesterol content in plaque endothelial cells, smooth muscle cells, monocyte-derived macrophages, and foam cells, and equally by lipid oxidation. Emerging evidence from imaging trials in patients with coronary heart disease has highlighted the impact of intervention involving the omega-3 fatty acid, eicosapentaenoic acid (EPA), on vulnerable, low attenuation atherosclerotic plaques. Thus, EPA decreased features associated with unstable plaque by increasing fibrous cap thickness in statin-treated patients, by reducing lipid volume and equally attenuating intraplaque inflammation. Importantly, atherosclerotic plaques rapidly incorporate EPA; indeed, a high content of EPA in plaque tissue is associated with decreased plaque inflammation and increased stability. These findings are entirely consistent with the major reduction seen in cardiovascular events in the REDUCE-IT trial, in which high dose EPA was administered as its esterified precursor, icosapent ethyl (IPE); moreover, clinical benefit was proportional to circulating EPA levels. Eicosapentaenoic acid is efficiently incorporated into phospholipids, where it modulates cholesterol-enriched domains in cell membranes through physicochemical lipid interactions and changes in rates of lipid oxidation. Indeed, biophysical analyses indicate that EPA exists in an extended conformation in membranes, thereby enhancing normal cholesterol distribution while reducing propagation of free radicals. Such effects mitigate cholesterol aggregation and crystal formation. In addition to its favorable effect on cholesterol domain structure, EPA/IPE exerts pleiotropic actions, including antithrombotic, antiplatelet, anti-inflammatory, and proresolving effects, whose plaque-stabilizing potential cannot be excluded. Docosahexaenoic acid is distinguished from EPA by a higher degree of unsaturation and longer carbon chain length; DHA is thus predisposed to changes in its conformation with ensuing increase in membrane lipid fluidity and promotion of cholesterol aggregation into discrete domains. Such distinct molecular effects between EPA and DHA are pronounced under conditions of high cellular cholesterol content and oxidative stress. This review will focus on the formation and role of cholesterol monohydrate crystals in destabilizing atherosclerotic plaques, and on the potential of EPA as a therapeutic agent to attenuate the formation of deleterious cholesterol membrane domains and of cholesterol crystals. Such a therapeutic approach may translate to enhanced plaque stability and ultimately to reduction in cardiovascular risk.
Topics: Humans; Eicosapentaenoic Acid; Plaque, Atherosclerotic; Endothelial Cells; Docosahexaenoic Acids; Cholesterol; Inflammation
PubMed: 35772589
DOI: 10.1016/j.pharmthera.2022.108237 -
European Journal of Pharmacology Dec 2017Acute cardiovascular events, due to rupture or erosion of an atherosclerotic plaque, represent the major cause of morbidity and mortality in patients. Growing evidence... (Review)
Review
Acute cardiovascular events, due to rupture or erosion of an atherosclerotic plaque, represent the major cause of morbidity and mortality in patients. Growing evidence suggests that plaque neovascularization is an important contributor to plaque growth and instability. The vessels' immaturity, with profound structural and functional abnormalities, leads to recurrent intraplaque hemorrhage. This review discusses new insights of atherosclerotic neovascularization, including the effects of leaky neovessels on intraplaque hemorrhage, both in experimental models and humans. Furthermore, modalities for in vivo imaging and therapeutic interventions to target plaque angiogenesis will be discussed.
Topics: Animals; Hemorrhage; Humans; Molecular Imaging; Neovascularization, Pathologic; Plaque, Atherosclerotic
PubMed: 28435093
DOI: 10.1016/j.ejphar.2017.04.028 -
Current Atherosclerosis Reports Aug 2016Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification... (Review)
Review
Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification is a more active process, involving complex signaling pathways and bone-like genetic programs. Initially, imaging of atherosclerotic calcification was limited to gross assessment of calcium burden, which is associated with total atherosclerotic burden and risk of cardiovascular mortality and of all cause mortality. More recently, sophisticated molecular imaging studies of the various processes involved in calcification have begun to elucidate information about plaque calcium composition and consequent vulnerability to rupture, leading to hard cardiovascular events like myocardial infarction. As such, there has been renewed interest in imaging calcification to advance risk assessment accuracy in an evolving era of precision medicine. Here we summarize recent advances in our understanding of the biologic process of atherosclerotic calcification as well as some of the molecular imaging tools used to assess it.
Topics: Animals; Calcinosis; Humans; Molecular Imaging; Plaque, Atherosclerotic; Precision Medicine
PubMed: 27339750
DOI: 10.1007/s11883-016-0601-6 -
International Journal of Molecular... Mar 2021Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of... (Review)
Review
Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years-in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.
Topics: Animals; Atherosclerosis; Epigenesis, Genetic; Humans; Inflammation; Lipoproteins, LDL; Macrophage Activation; Plaque, Atherosclerotic
PubMed: 33805303
DOI: 10.3390/ijms22073513 -
Current Atherosclerosis Reports Oct 2020Inflammatory cytokines play a major role in atherosclerotic plaque progression. This review summarizes the rationale for personalized anti-inflammatory therapy. (Review)
Review
PURPOSE OF THE REVIEW
Inflammatory cytokines play a major role in atherosclerotic plaque progression. This review summarizes the rationale for personalized anti-inflammatory therapy.
RECENT FINDINGS
Systemic inflammatory parameters may be used to follow the clinical outcome in primary and secondary prevention. Medical therapy, both in patients with stable cardiovascular disease, or with acute events, may be tailored taking into consideration the level and course of systemic inflammatory mediators. There is significant space for improvement in primary prevention and in the treatment of patients who have suffered from severe cardiovascular events, paying attention to not only blood pressure and cholesterol levels but also including inflammatory parameters in our clinical analysis. The potential exists to alter the course of atherosclerosis with anti-inflammatory drugs. With increased understanding of the specific mechanisms that regulate the relationship between inflammation and atherosclerosis, new, more effective and specific anti-inflammatory treatment may become available.
Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cytokines; Disease Progression; Humans; Inflammation; Inflammation Mediators; Mice; Plaque, Atherosclerotic; Secondary Prevention; Treatment Outcome
PubMed: 33025148
DOI: 10.1007/s11883-020-00891-3 -
Journal of Ultrasound Sep 2022The aim of the proposed study was to conduct a feasibility study using a flat rectangular (2 × 10 mm) transducer operating at 4.0 MHz for creating thermal lesions...
PURPOSE
The aim of the proposed study was to conduct a feasibility study using a flat rectangular (2 × 10 mm) transducer operating at 4.0 MHz for creating thermal lesions in an arterial atherosclerotic plaque phantom. The proposed method can be used in the future for treating atherosclerotic plaques in human arteries.
MATERIALS AND METHODS
The flat rectangular transducer was firstly assessed in agar/silica evaporated milk phantom, polyacrylamide phantom and freshly excised turkeytissue phantom. Then, the same transducer was assessed in an arterial atherosclerotic plaque phantom which was created in the laboratory with a very low cost. The recipe of the atherosclerotic plaque phantom was 4% w/v agar, 1% w/v gypsum, 2% w/v butter and 93% water. The amount of plaque removal was evaluated visually and using an X-Ray system.
RESULTS
It was shown that the flat rectangular transducer can create thermal lesions on the agar/silica evaporated milk phantom, polyacrylamide phantom and in excised tissue. The size of the lesions matches the geometry of the transducer. Moreover, this transducer destroyed 27.1% of the atherosclerotic plaque phantom with 8 W acoustical power and 30 s duration.
CONCLUSIONS
This feasibility study demonstrated that atherosclerotic plaque can be destroyed using a very small flat rectangular (2 × 10 mm) transducer in a very small time interval of 30 s. In future clinical trials the transducer will be incorporated in a catheter which will be inserted intravascular (1-3 mm) wide and can be used to treat atherosclerotic plaques in the coronary arteries.
Topics: Agar; Coronary Vessels; Humans; Phantoms, Imaging; Plaque, Atherosclerotic; Silicon Dioxide
PubMed: 35098435
DOI: 10.1007/s40477-022-00658-3