From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.
Harvard University1, Aarhus University2, University of Texas at Austin3, Memorial Hermann Texas Medical Center4, National and Kapodistrian University of Athens5, University of Kentucky6, Utrecht University7, Icahn School of Medicine at Mount Sinai8, Tufts University9, Tulane University10, Armed Forces Institute of Pathology11, University of Washington12, Stanford University13, Erasmus University Rotterdam14, University of Turku15, University of Münster16, Mayo Clinic17, Emory University18, University of Bristol19, University of Ulm20, Veterans Health Administration21, University of Texas Health Science Center at Houston22, University of California, Los Angeles23, University of Pavia24, Pfizer25, University of Texas Southwestern Medical Center26, Lenox Hill Hospital27, Baylor College of Medicine28, University of Maryland, Baltimore29, Karolinska Institutet30, University of Chicago31, Cedars-Sinai Medical Center32, Northwestern University33, Indiana University34
TL;DR: The term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future and a quantitative method for cumulative risk assessment of vulnerable patients needs to be developed.
Abstract: Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.
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Veterans Health Administration1, McMaster University2, Vanderbilt University3, University of Western Ontario4, Foothills Medical Centre5, Hartford Hospital6, University of New Mexico7, Saint Louis University8, Cedars-Sinai Medical Center9, Université de Montréal10, Mayo Clinic11, United States Department of Veterans Affairs12, University of Michigan13, Christiana Care Health System14
TL;DR: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy.
Abstract: We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6). Results There were 211 primary events in the PCI group and 202 events in the medicaltherapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P = 0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P = 0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P = 0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P = 0.33). Conclusions As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657.)
4,069 citations
TL;DR: In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions.
Abstract: A b s t r ac t Background Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. Methods In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. Results The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm 2 or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P = 0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). Conclusions In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.)
2,649 citations
TL;DR: Angina/Non-ST-Elevation Myocardial Infarction : ACC/AHA 2007 Guidelines for the Management of Patients With Unstable ISSN: 1524-4539 Copyright © 2007 American Heart Association.
Abstract: Angina/Non-ST-Elevation Myocardial Infarction : ACC/AHA 2007 Guidelines for the Management of Patients With Unstable ISSN: 1524-4539 Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX doi: 10.1161/CIRCULATIONAHA.107.18194
2,605 citations
TL;DR: The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease and practical recommendations for healthcare providers and their patients are outlined.
Abstract: Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated a consistent increased risk for cardiovascular events in relation to both short- and long-term exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final section, suggestions for future research are made to address a number of remaining scientific questions.
2,213 citations
TL;DR: Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means.
Abstract: Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.
A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules).
In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 .
View this table:
Table 1
Classes of recommendations
View this table:
Table 2
Levels of evidence
The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the …
1,960 citations
Cites background from "From vulnerable plaque to vulnerabl..."
...Focal accumulation of specific plaque components such as lipid necrotic core and weakening of the fibrous cap are associated with instability.(299,300) At this point in time, it remains undetermined whether nonculprit coronary segments showing vulnerable features will merit mechanical intervention....
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References
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TL;DR: The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events.
Abstract: Background Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events. Methods We conducted a prospective, nested case–control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation. The markers included high-sensitivity C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (slCAM-1). We also studied homocysteine and several lipid and lipoprotein measurements. Cardiovascular events were defined as death from coronary heart disease, nonfatal myocardial infarction or stroke, or the need for coronay-revascularization procedures. Results Of the 12 markers measured, hs-CRP was the strongest univariate predictor of the risk of cardiovascular events; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 (95 percent confidence interval, 2.2 to 8.9). Other markers significantly associated with the risk of cardiovascular events were serum amyloid A (relative risk for the highest as compared with the lowest quartile, 3.0), slCAM-1 (2.6), interleukin-6 (2.2), homocysteine (2.0), total cholesterol (2.4), low-density lipoprotein (LDL) cholesterol (2.4), apolipoprotein B-100 (3.4), high-density lipoprotein (HDL) cholesterol (0.3), and the ratio of total cholesterol to HDL cholesterol (3.4). Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone (P<0.001). The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter (3.4 mmol per liter), the target for primary prevention established by the National Cholesterol Education Program. In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (relative risk for the highest as compared with the lowest quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.9). Conclusions The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying women at risk for cardiovascular events.
5,895 citations
"From vulnerable plaque to vulnerabl..." refers background in this paper
...Therefore, Table 2 Descriptions used by pioneers for culprit plaques [93, 94]...
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...A few such studies have been conducted or are underway [94, 154]....
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TL;DR: The reduction associated with the use of aspirin in the risk of a first myocardial infarction appears to be directly related to the level of C-reactive protein, raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease.
Abstract: Background Inflammation may be important in the pathogenesis of atherothrombosis. We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk. Methods We measured plasma C-reactive protein, a marker for systemic inflammation, in 543 apparently healthy men participating in the Physicians' Health Study in whom myocardial infarction, stroke, or venous thrombosis subsequently developed, and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial. Results Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infarction (1.51 vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38 vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis (1.26 vs. 1.13 mg per liter, P = 0.34), than among men without vascular events. The men in the quartile wit...
5,489 citations
"From vulnerable plaque to vulnerabl..." refers background in this paper
...Therefore, Table 2 Descriptions used by pioneers for culprit plaques [93, 94]...
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TL;DR: This review will reconsider the current paradigm for understanding the critical, final steps in the progression of atherosclerotic lesions, and devise a simpler classification scheme that is consistent with the AHA categories but is easier to use, able to deal with a wide array of morphological variations, and not overly burdened by mechanistic implications.
Abstract: This review will reconsider the current paradigm for understanding the critical, final steps in the progression of atherosclerotic lesions. That scheme, largely an outgrowth of observations of autopsy tissues by Davies and colleagues,1 2 asserts that the cause of death in atherosclerotic coronary artery disease is rupture of an advanced atherosclerotic lesion. Although this assumption may be partially true, recent autopsy studies suggest that it is incomplete.
To reconsider this paradigm, we reexamined the morphological classification scheme for lesions proposed by the American Heart Association (AHA).3 4 This scheme is difficult to use for 2 reasons. First, it uses a very long list of roman numerals modified by letter codes that are difficult to remember. Second, it implies an orderly, linear pattern of lesion progression. This tends to be ambiguous, because it is not clear whether there is a single sequence of events during the progression of all lesions. We have therefore tried to devise a simpler classification scheme that is consistent with the AHA categories but is easier to use, able to deal with a wide array of morphological variations, and not overly burdened by mechanistic implications.
The current paradigm is based on the belief that type IV lesions, or “atheromas,” described by the AHA are stable because the fatty, necrotic core is contained by a smooth muscle cell–rich fibrous cap. Virchow’s analysis5 in 1858 pointed out that historically, the term “atheroma” refers to a dermal cyst (“Grutzbalg”), a fatty …
3,869 citations
"From vulnerable plaque to vulnerabl..." refers background in this paper
...Plaques with a fissured cap (most of them involving a recent rupture) that did not result in occlusive thrombi may be prone to subsequent thrombosis, entailing occlusive thrombi or thromboemboli [5]....
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...These plaques are characterized by superficial erosion and platelet aggregation or fibrin deposition [5]....
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...In cases involving nonruptured plaques, plaque erosion or nodular calcification usually accompanies the luminal thrombus [5]....
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...2) that may also cause acute coronary events [5]....
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...This event may or may not be associated with severe coronary calcification and a high calcium score [5]....
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TL;DR: The histological classification of human atherosclerotic lesions found in the second part of this report led to the earlier definitions of precursor lesions, and the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes was attempted.
Abstract: This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).
3,698 citations
TL;DR: This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.
Abstract: Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease, and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden death.1 2 3 4 5 Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. The composition and vulnerability of plaque rather than its volume or the consequent severity of stenosis produced have emerged as being the most important determinants for the development of the thrombus-mediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are more unstable and rupture-prone and highly thrombogenic after disruption.6 This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.7 8
Atherosclerosis is the result of a complex interaction between blood elements, disturbed flow, and vessel wall abnormality, involving several pathological processes: inflammation, with increased endothelial permeability, endothelial activation, and monocyte recruitment9 10 11 12 13 14 ; growth, with smooth muscle cell (SMC) proliferation, migration, and matrix synthesis15 16 ; degeneration, with lipid accumulation17 18 ; necrosis, possibly related to the cytotoxic effect of oxidized lipid19 ; calcification/ossification, which may represent an active rather than a dystrophic process20 21 ; and thrombosis, with platelet recruitment and fibrin formation.1 22 23 Thrombotic factors may play a role early during atherogenesis, but a flow-limiting thrombus does not develop until mature plaques are present, which is why thrombosis often is classified as a complication rather than a genuine component of atherosclerosis.
### Mature Plaques: Atherosis and Sclerosis
As the name atherosclerosis implies, mature …
3,493 citations
"From vulnerable plaque to vulnerabl..." refers methods in this paper
...Adapted from Falk and associates [6], Davies [7], and Virmani et al....
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