Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rate of cardiac deaths that are sudden is approximately 50%, and decreases with age. The causes of sudden cardiac death are diverse, and are a function of age. In children and adolescents, coronary anomalies, hypertrophic cardiomyopathy and myocarditis are frequent substrates for lethal arrhythmias; in adults, coronary atherosclerosis and acquired forms of cardiomyopathy are the most common findings at autopsies of sudden cardiac death. This review focuses on coronary causes of sudden cardiac death, especially congenital coronary artery anomalies, which result in sudden death almost exclusively in adults younger than age 35, and coronary thrombosis. The most lethal coronary artery anomaly is the left coronary artery arising from the right sinus of Valsalva; this anomaly often results in fatal arrhythmias, often with exercise. The right coronary artery arising from the left sinus of Valsalva may also be lethal in adolescents and young adults, but, unlike the anomalous left, is more often an incidental finding at autopsy. Approximately 60% of sudden coronary death is caused by coronary thrombosis, the rest die with severe coronary disease in the absence of thrombosis. The two major substrates of coronary thrombosis are plaque rupture and plaque erosion, and are not only different pathologically, but are seen in patients with divergent risk factor profiles. Plaque rupture is the most common cause of fatal coronary thrombus, and is characterized by necrotic core with a thin fibrous cap, infiltrated by macrophages. The factors that result in plaque instability and rupture are largely unknown, and are under intense scrutiny; morphologic studies have identified serum lipid abnormalities as a key risk factor in the development of plaque rupture. Plaque erosion, in contrast to plaque rupture, is seen in younger men and women, is not associated with lipid abnormalities, and does not result from exposure of the lipid core to the lumen. The heterogeneity of the atherosclerotic plaque and the diverse mechanics of plaque progression and thrombosis have only been relatively recently explored, and are largely elucidated by autopsy studies of victims of sudden coronary death.
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PMID:Sudden cardiac death. 1167 58

The cardiovascular system is an internal flow loop with multiple branches circulating a complex liquid. The hallmarks of blood flow in arteries are pulsatility and branches, which cause wall stresses to be cyclical and nonuniform. Normal arterial flow is laminar, with secondary flows generated at curves and branches. Arteries can adapt to and modify hemodynamic conditions, and unusual hemodynamic conditions may cause an abnormal biological response. Velocity profile skewing can create pockets in which the wall shear stress is low and oscillates in direction. Atherosclerosis tends to localize to these sites and creates a narrowing of the artery lumen--a stenosis. Plaque rupture or endothelial injury can stimulate thrombosis, which can block blood flow to heart or brain tissues, causing a heart attack or stroke. This small lumen and elevated shear rate in a stenosis create conditions that accelerate platelet accumulation and occlusion. The relationship between thrombosis and fluid mechanics is complex, especially in the post-stenotic flow field. New convection models have been developed to predict clinical from platelet thrombosis in diseased arteries. Future hemodynamic studies should address the complex mechanics of flow-induced, large-scale wall motion and convection of semisolid particles and cells in flowing blood.
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PMID:Fluid mechanics of vascular systems, diseases, and thrombosis. 1170 91

An immune and inflammatory response involving endothelial and smooth muscle cells accompanies the accumulation of lipids and fibrous materials in atheromatous arteries. The inflammatory response involves not only the intrinsic cells of the artery wall, but also circulating leukocytes. Lymphocytes as well as macrophages participate importantly in this disease process. Plaque composition and vulnerability have emerged as more critical determinants of plaque rupture than the degree of lumenal stenosis. Thus, plaque biology has proven more important than gross morphology in determining the clinical consequences of the disease. Rupture of the atherosclerotic plaque, its thrombotic complications, and their sequelae have gained increased recognition as the proximate causes of disability and death due to related syndromes such as acute myocardial infarction. Arterial thromboses occur much more readily in arteries damaged or distorted by the atherosclerotic process. The consequences of a given plaque disruption and subsequent thrombus formation will depend on both "systemic" or fluid phase determinants and local "solid state" factors. The complex heterogeneous structure of thrombi includes fibrin, platelets, erythrocytes, and leukocytes. The local balance of proteases and inhibitors on the fibrin and cell surfaces will determine thrombus stability and persistence. Enhanced understanding of the processes involved in the development and progression of atherosclerosis and its complications will surely provide areas that can be targeted in the treatment of the disease.
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PMID:Inflammation and atherothrombosis. 1179 64

Plaque disruption with superimposed thrombosis is the main cause of acute coronary events such as acute myocardial infarction and unstable angina. Among other factors, tissue factor seems to play an important role determining plaque thrombogenicity. Tissue factor is a potent initiator of the coagulation cascade situated within the vessel wall and is highly exposed to the blood after plaque rupture. Several mediators involved in the process of atherosclerotic plaque formation are capable of inducing tissue factor expression in cells such as monocytes, macrophages and endothelial cells, which under normal conditions do not express tissue factor or to a limited extent only. The increased expression of tissue factor is not limited to the plaque but is also found in circulating monocytes in patients with acute coronary syndromes. In addition, studies have shown an important contribution of tissue factor in the pathogenesis of thrombosis and restenosis after balloon angioplasty. Recent basic studies focus on the therapeutic inhibition of tissue factor. Specific and non-specific inhibitors of tissue factor or the tissue factor/factor VIIa complex have been developed or identified, and have been tested in experimental studies. Clinical studies are currently being initiated. In this review, we present the current knowledge on the role of tissue factor in atherosclerosis, arterial intervention and potential pharmacological approaches, with focus on acute coronary syndromes.
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PMID:Tissue factor and coronary artery disease. 1182 81

Intima-media thickness (IMT) is commonly used as a surrogate marker for coronary artery disease (CAD). However, use of this parameter is a problem because (1) it assumes uniform thickness throughout the blood vessel, and (2) it detects changes primarily in the media, whereas atherosclerosis is a focal phenomenon that is confined to the intima. As an alternative to IMT, we have investigated the use of ultrasound measurements of plaque area and plaque volume as surrogate outcomes for CAD. Plaque area is a sensitive predictor of coronary disease progression and is closely associated with CAD. Clinical studies have shown that the sample size needed to detect atherosclerosis progression is sufficiently small to make this a useful assessment in clinical trials. Plaque volume, as measured by 3-dimensional ultrasound, may offer an even better means of assessing atherosclerosis. Plaque volume assessments are highly accurate and the data can be saved on a compact disc for central reading. Because of the high degree of accuracy and the increased size of plaque volume relative to plaque area or IMT, it is likely that only a small sample size will be required to detect clinically meaningful differences in plaque volume in a clinical trial.
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PMID:Ultrasound measurement of carotid plaque as a surrogate outcome for coronary artery disease. 1187 61

Angiography has major limitations in its ability to assess coronary disease. Intravascular ultrasound (IVUS) offers unique capabilities to assess coronary atherosclerotic burden. The tomographic orientation of ultrasound enables visualization of the full vessel wall, as opposed to the 2-dimensional projection of the lumen provided by angiography. The equipment required to perform coronary IVUS consists of a catheter with a miniaturized transducer and a console to reconstruct the image. High ultrasound frequencies are used, typically, 30 to 40 MHz, which provides excellent theoretical resolution. IVUS has been performed safely in a wide variety of clinical situations. Vessels with classic atherosclerosis exhibit a diversity of abnormal features that reflect the severity, composition, and distribution of the atheromata. Plaque rupture is sometimes evident in ultrasound examination of the culprit lesions after an acute coronary syndrome. Most laboratories routinely perform cross-sectional area measurements of the lumen and external elastic membrane boundaries and calculate atheroma area. IVUS commonly detects atherosclerosis at angiographically normal sites. It has contributed substantially to our understanding of remodeling and has shown that positive remodeling is more prevalent in unstable lesions. Studies in patients early after transplantation have shown the presence of advanced atherosclerosis in their apparently normal donors. In addition, the application of IVUS in detecting the rate of progression or regression of existing atherosclerosis is among the most dynamic areas of development. IVUS is likely to emerge as the "gold standard" in the study of atherosclerosis progression-regression over the next few years.
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PMID:Application of intravascular ultrasound to characterize coronary artery disease and assess the progression or regression of atherosclerosis. 1187 65

Increased intima-media thickness and plaque development in the extracranial carotid arteries reportedly correlate well with the prevalence of coronary artery diseases. The location of these atherosclerotic lesions in the carotid artery varies with age in patients with coronary artery atherosclerosis. Intima-media thickness, plaque, and calcification in the common carotid artery and bifurcation were assessed with high-resolution B-mode ultrasonography. Forty patients with severe atherosclerosis of the coronary artery and 56 healthy control subjects with no risk factors for coronary atherosclerosis were included in this study. The subjects were divided into a middle-age group (40-59 yr) and an old-age group (60-79 yr). In both groups, the intimamedia thickness in the patients was significantly higher than that in the controls. Intima-media thickness of at least 0.7 mm in the middle-age group and at least 1.0 mm in the old-age group was specific and positively predictive of coronary artery disease. Plaque (> 1.0 mm) and calcification were more significant in patients than in controls. In the middle-age group, intimamedia thickness in the common carotid artery was correlated with coronary atherosclerotic severity. Conversely, in the old-age group, the presence of plaque and calcification at the bifurcation was correlated with coronary atherosclerotic severity. The characteristic manifestation of the atherosclerotic lesion in the carotid artery varied with age in patients with coronary artery disease.
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PMID:Ultrasonic correlates of common carotid atherosclerosis in patients with coronary artery disease. 1195 8

Autopsy data demonstrate a correlation between subclinical aortic atherosclerosis and cardiovascular disease. Therefore, noninvasive cardiovascular magnetic resonance (CMR) of subclinical atherosclerosis may provide a novel measure of cardiovascular risk, but it has not been applied to an asymptomatic population-based cohort to establish age- and sex-specific normative data. Participants in the Framingham Heart Study offspring cohort who were free of clinically apparent coronary disease were randomly sampled from strata of sex, quartiles of age, and quintiles of Framingham Coronary Risk Score. Subjects (n=318, aged 60+/-9 years, range 36 to 78 years, 51% women) underwent ECG-gated T2-weighted black-blood thoracoabdominal aortic CMR scanning. CMR evidence of aortic atherosclerosis was noted in 38% of the women and 41% of the men. Plaque prevalence and all measures of plaque burden increased with age group and were greater in the abdomen than in the thorax for both sexes and across all age groups. In addition, the Framingham Coronary Risk Score was significantly correlated with all plaque prevalence and burden measures for women but only for men after age adjustment. These noninvasive CMR data extend the prior autopsy-based prevalence estimates of subclinical atherosclerosis and may help to lay the foundation for future studies of risk stratification and treatment of affected individuals.
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PMID:Age and sex distribution of subclinical aortic atherosclerosis: a magnetic resonance imaging examination of the Framingham Heart Study. 1200 1

Apolipoprotein A-I(Milano) (AIM), a natural variant of human apolipoprotein A-I, confers to carriers a significant protection against vascular disease. In previous studies, administration of recombinant AIM-phospholipid (AIM-PL) complexes to hypercholesterolemic rabbits markedly inhibited neointimal formation after arterial injury; moreover, repeated injections of AIM-PL in apoE-deficient mice significantly reduced atherosclerosis progression. The objective of the present study was to determine if a single localized infusion of AIM-PL complexes administered directly to atheromatous lesions could promote plaque regression. Lipid-rich, atheromatous plaques were generated at both common carotid arteries of 25 rabbits by applying a perivascular electric injury, followed by 1.5% cholesterol diet for 90 days. Rabbits were infused with either saline, phospholipid vesicles, or 3 different AIM-PL doses (250, 500, or 1000 mg of protein) delivered through an intravascular ultrasound (IVUS) catheter positioned at the origin of the right carotid. The lesions at the left carotid artery were therefore exposed to the agents systemically. Infusion of AIM-PL at the 2 highest doses caused reduction of right carotid artery plaque area by the end a 90-minute infusion as assessed by IVUS analysis. Plaque area regression was confirmed by histology in carotid arteries receiving direct (500 and 1000 mg doses) and systemic (500 mg dose) delivery, 72 hours after the start of the treatment. Plaque lipid content was associated with significant and similar decreases in Oil Red O staining in both arteries. These results suggest AIM-PL complexes enhanced lipid removal from arteries is the mechanism responsible for the observed plaque changes.
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PMID:Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. 1201 63

The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-beta, and a pivotal role for TGF-beta in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-beta inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-beta receptor II (TGFbetaRII:Fc), which inhibits TGF-beta signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 microg, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-beta signaling treatment resulted in a prominent increase in CD3- and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGFbetaRII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGFbetaRII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-beta in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.
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PMID:Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. 1206 7


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