Intraplaque haemorrhages as the trigger of plaque vulnerability
TL;DR: Recent studies strengthen the concept that the intraplaque neovascularization and bleeding are events that could play a major role in plaque progression and leucocyte infiltration, and may also serve as a measure of risk for the development of future events.
Abstract: Atherothrombosis remains one of the main causes of morbidity and mortality in the western countries. Human atherothrombotic disease begins early in life in relation to circulating lipid retention in the inner vascular wall. Risk factors enhance the progression towards clinical expression: dyslipidaemia, diabetes, smoking, hypertension, ageing, etc. The evolution from the initial lipid retention in the arterial wall to clinical events is a continuum of increasingly complex biological processes. Current strategies to fight the consequences of atherothrombosis are orientated either towards the promotion of a healthy life style and preventive treatment of risk factors, or towards late interventional strategies. Despite this therapeutic arsenal, the incidence of clinical events remains dramatically high, dependent, at least in part, on the increasing frequency of type 2 diabetes and ageing. But some medical treatments, focusing only on prevention of the metabolic risk, have failed to reduce cardiovascular mortality, thus illustrating that our understanding of the pathophysiology of human atherothrombosis leading to clinical events remain incomplete. New paradigms are now emerging which may give rise to novel experimental strategies to improve therapeutic efficacy and prediction of disease progression. Recent studies strengthen the concept that the intraplaque neovascularization and bleeding (Figure 1, upper panel) are events that could play a major role in plaque progression and leucocyte infiltration, and may also serve as a measure of risk for the development of future events. The recent advances in our understanding of IntraPlaque Hemorrhage as a critical event in triggering acute clinical events have important implications for clinical research and possibly future clinical practice.
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TL;DR: The medial VSMC is the organizer of the inwardly directed angiogenic response arising from the adventitia by overexpressing vascular endothelial growth factor in response to lipid-stimulated peroxisome proliferator-activated receptor-γ, and probably also the organizers of the adventitial immune response by secreting chemokines.
Abstract: Vascular smooth muscle cells (VSMCs) are the stromal cells of the vascular wall, continually exposed to mechanical signals and biochemical components generated in the blood compartment. They are involved in all the physiological functions and the pathological changes taking place in the vascular wall. Owing to their contractile tonus, VSMCs of resistance vessels participate in the regulation of blood pressure and also in hypertension. VSMCs of conduit arteries respond to hypertension-induced increases in wall stress by an increase in cell protein synthesis (hypertrophy) and extracellular matrix secretion. These responses are mediated by complex signalling pathways, mainly involving RhoA and extracellular signal-regulated kinase1/2. Serum response factor and miRNA expression represent main mechanisms controlling the pattern of gene expression. Ageing also induces VSMC phenotypic modulation that could have influence on cell senescence and loss of plasticity and reprogramming. In the early stages of human atheroma, VSMCs support the lipid overload. Endocytosis/phagocytosis of modified low-density lipoproteins, free cholesterol, microvesicles, and apoptotic cells by VSMCs plays a major role in the progression of atheroma. Migration and proliferation of VSMCs in the intima also participate in plaque progression. The medial VSMC is the organizer of the inwardly directed angiogenic response arising from the adventitia by overexpressing vascular endothelial growth factor in response to lipid-stimulated peroxisome proliferator-activated receptor-γ, and probably also the organizer of the adventitial immune response by secreting chemokines. VSMCs are also involved in the response to proteolytic injury via their ability to activate blood-borne proteases, to secrete antiproteases, and to clear protease/antiprotease complexes.
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Cites background from "Intraplaque haemorrhages as the tri..."
...responsible for erythrocyte leakage and haemorrhages and participates in leucocyte extravasation into the newly vascularized plaques.(68) In a recent study, Ho-Tin-Noé et al....
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...repeated intraplaque haemorrhages, the main determinants of plaque expansion, ultimately leading to plaque rupture and thrombosis.(68) VSMCs, as the vascular stromal cells, are involved in all stages of the...
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TL;DR: CD14++CD16+ monocytes independently predicted cardiovascular events in subjects referred for elective coronary angiography, suggesting they may become a target cell population for new therapeutic strategies in atherosclerosis.
473 citations
TL;DR: Current knowledge on the role of extracellular vesicles in coronary artery disease, and their emerging potential as biomarkers and therapeutic agents are summarized.
Abstract: Membrane vesicles released in the extracellular space are composed of a lipid bilayer enclosing soluble cytosolic material and nuclear components. Extracellular vesicles include apoptotic bodies, exosomes, and microvesicles (also known previously as microparticles). Originating from different subcellular compartments, the role of extracellular vesicles as regulators of transfer of biological information, acting locally and remotely, is now acknowledged. Circulating vesicles released from platelets, erythrocytes, leukocytes, and endothelial cells contain potential valuable biological information for biomarker discovery in primary and secondary prevention of coronary artery disease. Extracellular vesicles also accumulate in human atherosclerotic plaques, where they affect major biological pathways, including inflammation, proliferation, thrombosis, calcification, and vasoactive responses. Extracellular vesicles also recapitulate the beneficial effect of stem cells to treat cardiac consequences of acute myocardial infarction, and now emerge as an attractive alternative to cell therapy, opening new avenues to vectorize biological information to target tissues. Although interest in microvesicles in the cardiovascular field emerged about 2 decades ago, that for extracellular vesicles, in particular exosomes, started to unfold a decade ago, opening new research and therapeutic avenues. This Review summarizes current knowledge on the role of extracellular vesicles in coronary artery disease, and their emerging potential as biomarkers and therapeutic agents.
363 citations
TL;DR: The roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction are considered, by providing an evaluation of the known and emerging inflammatory pathways.
Abstract: Inflammatory processes are firmly established as central to the development and complications of cardiovascular diseases. Elevated levels of inflammatory markers have been shown to be predictive of future cardiovascular events. The specific targeting of these processes in experimental models has been shown to attenuate myocardial and arterial injury, reduce disease progression, and promote healing. However, the translation of these observations and the demonstration of clear efficacy in clinical practice have been disappointing. A major limitation might be that tools currently used to measure 'inflammation' are insufficiently precise and do not provide information about disease site and activity, or discriminate between functionally important activation pathways. The challenge, therefore, is to make measures of inflammation that are more meaningful, and which can guide specific targeted therapies. In this Review, we consider the roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction, by providing an evaluation of the known and emerging inflammatory pathways. We highlight contemporary techniques to characterize and quantify inflammation, and consider how they might be used to guide specific treatments. Finally, we discuss emerging opportunities in the field, including their current limitations and challenges that are the focus of ongoing study.
348 citations
TL;DR: The current understanding of the pathophysiological mechanisms involved in atherogenesis is discussed – from fatty streaks to complex and vulnerable atheromas – and the molecular machinery used by platelets to regulate the atherogenic process, thrombosis and its clinical implications are highlighted.
Abstract: Atherosclerosis is the underlying reason for nearly all causes of coronary artery disease and peripheral arterial disease and many cases of stroke. Atherosclerosis is a systemic inflammatory process characterised by the accumulation of lipids and macrophages/lymphocytes within the intima of large arteries. The deposition of these blood borne materials and the subsequent thickening of the wall often significantly compromise the residual lumen leading to ischaemic events distal to the arterial stenosis. However, these initial fatty streak lesions may also evolve into vulnerable plaques susceptible to rupture or erosion. Plaque disruption initiates both platelet adhesion and aggregation on the exposed vascular surface and the activation of the clotting cascade leading to the so-called atherothrombotic process. Yet, platelets have also been shown to be transporters of regulatory molecules (micro-RNA), to drive the inflammatory response and mediate atherosclerosis progression. Here we discuss our current understanding of the pathophysiological mechanisms involved in atherogenesis - from fatty streaks to complex and vulnerable atheromas - and highlight the molecular machinery used by platelets to regulate the atherogenic process, thrombosis and its clinical implications.
275 citations
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TL;DR: Atherosclerosis is an inflammatory disease as discussed by the authors, and it is a major cause of death in the United States, Europe, and much of Asia, despite changes in lifestyle and use of new pharmacologic approaches to lower plasma cholesterol concentrations.
Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .
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"Intraplaque haemorrhages as the tri..." refers background in this paper
...and on the inflammatory response mainly represented by leucocyte extravasation observed within the complicated plaque.(9)...
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TL;DR: This chapter describes the most important sources and the types of data the AHA uses from them and other government agencies to derive the annual statistics in this Update.
Abstract: 1. About These Statistics…e70
2. Cardiovascular Diseases…e72
3. Coronary Heart Disease, Acute Coronary Syndrome, and Angina Pectoris…e89
4. Stroke…e99
5. High Blood Pressure…e111
6. Congenital Cardiovascular Defects…e116
7. Heart Failure…e119
8. Other Cardiovascular Diseases…e122
9. Risk Factor: Smoking/Tobacco Use…e128
10. Risk Factor: High Blood Cholesterol and Other Lipids…e132
11. Risk Factor: Physical Inactivity…e136
12. Risk Factor: Overweight and Obesity…e139
13. Risk Factor: Diabetes Mellitus…e143
14. End-Stage Renal Disease and Chronic Kidney Disease…e149
15. Metabolic Syndrome…e151
16. Nutrition…e153
17. Quality of Care…e155
18. Medical Procedures…e159
19. Economic Cost of Cardiovascular Diseases…e162
20. At-a-Glance Summary Tables…e164
21. Glossary and Abbreviation Guide…e168
Writing Group Disclosures…e171
Appendix I: List of Statistical Fact Sheets:
http://www.americanheart.org/presenter.jhtml?identifier=2007
We thank Drs Robert Adams, Philip Gorelick, Matt Wilson, and Philip Wolf (members of the Statistics Committee or Stroke Statistics Subcommittee); Brian Eigel; Gregg Fonarow; Kathy Jenkins; Gail Pearson; and Michael Wolz for their valuable comments and contributions. We would like to acknowledge Tim Anderson and Tom Schneider for their editorial contributions and Karen Modesitt for her administrative assistance.
# 1. About These Statistics {#article-title-2}
The American Heart Association (AHA) works with the Centers for Disease Control and Prevention’s National Center for Health Statistics (CDC/NCHS); the National Heart, Lung, and Blood Institute (NHLBI); the National Institute of Neurological Disorders and Stroke (NINDS); and other government agencies to derive the annual statistics in this Update. This chapter describes the most important sources and the types of data we use from them. For more details and an alphabetical list of abbreviations, see Chapter 21 of this document, the Glossary and Abbreviation Guide.
The surveys used are:
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TL;DR: Criteria for assessment of death, myocardial infarction, repeat revascularization, and stent thrombosis were developed and provide consistency across studies that can facilitate the evaluation of safety and effectiveness of these devices.
Abstract: Background— Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end points, differences in definitions and timing of assessment have created confusion in interpretation. Methods and Results— The Academic Research Consortium is an informal collaboration between academic research organizations in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006, sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs, were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of considerations from historical legacy to key pathophysiological mechani...
4,994 citations
"Intraplaque haemorrhages as the tri..." refers background in this paper
...Current strategies to fight the consequences of atherothrombosis are orientated either towards the promotion of a healthy life style(1) and preventive treatment of risk factors, or towards late interventional strategies.(2) Despite this therapeutic arsenal, the incidence of clinical events remains dramatically high,(3) dependent, at least in part, on the increasing frequency of type 2 diabetes and ageing....
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