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)

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.
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PMID:[Blood coagulation and fibrinolysis in arteriosclerosis]. 1041 53

This review discusses three stages in the life history of an atheroma: initiation, progression and complication. Recruitment of mononuclear leucocytes to the intima characterizes initiation of the atherosclerotic lesion. Specific adhesion molecules expressed on the surface of vascular endothelial cells mediate leucocyte adhesion: the selectins and members of the immunoglobulin superfamily such as vascular cell adhesion molecule-1 (VCAM-1). Once adherent, the leucocytes enter the artery wall directed by chemoattractant chemokines such as macrophage chemoattractant protein-1 (MCP-1). Modified lipoproteins contain oxidized phospholipids which can elicit expression of adhesion molecule and cytokines implicated in early atherogenesis. Progression of atheroma involves accumulation of smooth muscle cells which elaborate extracellular matrix macromolecules. These processes appear to result from an eventual net positive balance of growth stimulatory versus growth inhibitory stimuli, including proteins (cytokines and growth factors) and small molecules (e.g. prostanoids and nitric oxide). The clinically important complications of atheroma usually involve thrombosis. Arterial stenoses by themselves seldom cause acute unstable angina or acute myocardial infarction. Indeed, sizeable atheroma may remain silent for decades or produce only stable symptoms such as angina pectoris precipitated by increased demand. Recent research has furnished new insight into the molecular mechanisms that cause transition from the chronic to the acute phase of atherosclerosis. Thrombus formation usually occurs because of a physical disruption of atherosclerotic plaque. The majority of coronary thromboses result from a rupture of the plaque's protective fibrous cap, which permits contact between blood and the highly thrombogenic material located in the lesion's lipid core, e.g. tissue factor. Interstitial collagen accounts for most of the tensile strength of the plaque's fibrous cap. The amount of collagen in the lesion's fibrous cap depends upon its rate of biosynthesis stimulated by factors released from platelets (e.g. transforming growth factor beta or platelet-derived growth factor), but inhibited by gamma interferon, a product of activated T cells found in plaques. Degradation by specialized enzymes (matrix metalloproteinases) also influences the level of collagen in the plaque's fibrous cap. Such studies illustrate how the application of cellular and molecular approaches has fostered a deeper understanding of the pathogenesis of atherosclerosis. This increased knowledge of the basic mechanisms enables us to understand how current therapies for atherosclerosis may act. Moreover, the insights derived from recent scientific advances should aid the discovery of new therapeutic targets that would stimulate development of novel treatments. Such new treatments could further reduce the considerable burden of morbidity and mortality due to this modern scourge, and reduce reliance on costly technologies that address the symptoms rather than the cause of atherosclerosis.
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PMID:Changing concepts of atherogenesis. 1076 52

Ultrasound at high energy, as distinct from the low energy used in ultrasound imaging, has found many uses in varied branches of medicine and surgery. Clinical trials of catheter-delivered, high-energy, low-frequency (kHz) ultrasound over the past 6 years have shown the safety of this modality in the treatment of coronary artery disease and have identified a number of indications in which its use, as an adjunct to conventional percutaneous transluminal coronary angioplasty (PTCA) techniques, may offer therapeutic advantages. Thrombus-mediated conditions--such as myocardial infarction, chronic total occlusion, and atherosclerosis in small vessels--appear to derive particular benefit from ultrasound treatment. Recent developments in these fields are reviewed.
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PMID:New Developments in Therapeutic Ultrasound-Assisted Coronary Angioplasty. 1109 35

Structural changes in blood vessels associated with atherosclerosis are at the onset of arterial thrombosis. Thrombi form at the sites of plaque rupture. Plateletrich masses accumulate in the vessel lumen perturb blood flow, thereby aggravating ischemic syndromes. Other local modifications include the recruitment of cells with inflammatory and immunologic potential, showing how complicated this process is. The demonstration that aspirin lowered the number of thrombotic events was an important step in proving the value of anti-platelet therapy. Since then, newer strategies involving drugs acting on the fibrinogen receptor (the GPIIb-IIIa complex) or on ADP receptors have evolved largely as a result of the increased knowledge of the biological pathways of platelet aggregation. These drugs have given superior results in many international trials and their usefulness in interventional cardiology has been proven. Such encouraging progress also incites efforts to find new and improved targets for anti-platelet therapy as well as testing new associations of existing anti-platelet drugs which may also be used with anticoagulant therapies, and in the future, be combined with drugs directly preventing restenosis.
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PMID:[From the physiopathology of thrombosis to therapeutic targets]. 1179 61

Despite considerable evidence suggesting that hypertension contributes to the development and progression of atherosclerosis, the causative links remain unclear. We have tested the effects of chronic hypertension induced by suprarenal aortic constriction on the development of atherosclerosis in apolipoprotein E-deficient (Apoe-/-) mice. Compared with a sham operation, narrowing the aortic luminal diameter by 33% increased blood pressure proximal to the constriction by approximately 15 mm Hg, but the pressures distal to the constriction were unchanged. Kidney renin mRNA and plasma renin activity were also unaffected. Compared with plaque size after the sham operation, atherosclerotic plaque size in the aortic root 8 weeks after coarctation was increased to 245% and 152% in males and females, respectively. Aortic segments at the constriction were free of atherosclerotic deposits, but segments proximal to the constriction were dilated and had atherosclerotic lesions. Thrombi were present immediately below the constriction in Apoe-/- and wild-type vessels. Surprisingly, compared with wild-type mice, the Apoe-/- mice were more susceptible to the cardiac hypertrophy and dysfunction induced by pressure overload. Thus, aortic coarctation exacerbates atherosclerosis in vessels proximal to the constriction without a concomitant increase in the renin-angiotensin system. Our study also suggests that apolipoprotein E plays an important role in modulating cardiac hypertrophy.
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PMID:Aortic constriction exacerbates atherosclerosis and induces cardiac dysfunction in mice lacking apolipoprotein E. 1188 92

Epidemiological studies suggest the high fat content of the Western diet to be responsible for atherosclerosis and its thrombotic complications. Despite such a prevailing view, few animal experiments have so far succeeded in demonstrating enhanced thrombogenicity due to a high fat diet. Even a high fat and a very high cholesterol (1%) diet has failed to demonstrate an enhanced thrombotic reaction in rodents and rabbits. The aim of the present study was twofold. First, we wanted to establish a new, sensitive and specific thrombosis model in mice, which can then be used to study the effect of diets. Second, we intended to employ such a thrombosis model in investigations into the effect of high or low fat diets on thrombosis. The technique described uses a laser to induce thrombus formation in the exposed carotid artery of apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Thrombus formation was recorded on video, analysed by computer, and the size of thrombus was calculated by image analysis software. Thrombotic status was evaluated by analysing a total of 61 individual images of the thrombotic reaction, which were taken over 600 s. The severity of atherosclerosis was assessed by image analysis of the stained elastic fibers. Two kinds of diets were used: the Western type, high fat diet contained 20% fat (w/w) and 0.05% cholesterol (w/w); the low fat diet contained 7% fat, without cholesterol. These diets were on the basis of AIN93G and were given to mice for 4 or 8 weeks. The high fat diet significantly enhanced both the thrombotic reaction and the development of atherosclerosis as compared with the low fat diet.
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PMID:A new model to evaluate the diet-induced prothrombotic state, using He-Ne laser-induced thrombogenesis in the carotid artery of apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. 1219 1

As blood clots it goes through predictable stages that reflect the oxygenation state of hemoglobin within the red cells. One of these stages results in the formation of methemoglobin. This substance acts an endogenous contrast agent when imaged using a T1-weighted magnetic resonance sequence (Magnetic Resonance Direct Thrombus Imaging, MRDTI) - appearing as high signal. MRDTI can therefore be used to detect subacute thrombosis. This technique has been applied in a number of clinical settings arising as a result of thrombosis. Deep vein thrombosis and pulmonary embolism are both readily detected using MRDTI, providing a single imaging modality for the detection of venous thromboembolic disease. The technique is also effective in the peripheral arterial tree. Furthermore, thrombosis within vessel wall atherosclerosis is a marker of vulnerable plaque likely to produce symptoms. The MRDTI technique has thus proved useful in identifying complicated plaque in the carotid arteries in the setting of transient and permanent cerebral ischemia. MRDTI therefore holds promise as a technique that is capable of detecting high risk vessel wall disease prior to significant or permanent end organ damage. Because of the non-invasive nature of magnetic resonance imaging (MRI), application of MRDTI in the research setting for the monitoring of therapeutic interventions in a wide number of settings within vascular disease is very appealing.
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PMID:Magnetic resonance direct thrombus imaging. 1287 Dec 74

Platelets play a primary role in thrombus formation after plaque rupture. Platelets recognize the exposed collagen via Von Willebrand factor (VWF) and become activated. Saratin, an inhibitor of the VWF-dependent binding of platelets to collagen, may reduce the thrombotic risk associated to atherosclerosis. Our objective was to evaluate the antithrombotic effects of local treatment with saratin on human atherosclerotic lesions. Thrombus formation was assessed by the deposition of (111)In-platelets on different human atherosclerotic lesions under three local shear conditions (800,1700 and 3400/s) with blood derived from catheterized pigs. Human atherosclerotic lesions were locally treated with saratin (30 microg/ml) at 37 degrees C for 5 min and placed in the chamber. Under stenotic shear conditions of 800/s, saratin significantly (p<0.05) reduced platelet deposition triggered by human denuded vessel wall (44%), fatty streaks (47%), severely damaged vessel (50%) and atherosclerotic plaque (57%). Thrombus characterization by immunohistochemistry showed also a reduction in fibrin deposition in treat-ed vessels. These results suggest that the local site-specific treatment with saratin inhibits atherosclerotic plaque thrombogenicity at haemodynamic conditions typical of moderately stenotic coronary arteries.
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PMID:Antithrombotic effects of saratin on human atherosclerotic plaques. 1521 61

Cardiovascular disease is the leading cause for mortality and morbidity in the western world. Arterial thrombosis has multiple origins and may present with different clinical presentations such as acute coronary syndromes, stroke, and peripheral embolization. Furthermore, thrombotic complications may occur during percutaneous interventions. The underlying causes range from atherosclerosis with plaque rupture or erosion, embolization, stasis and hypercoagulable states. Thrombotic complications lead to activation of the intrinsic coagulation system and to platelet aggregation. Despite the development of effective platelet inhibitors, there is still the need for an optimal anticoagulation regimen. While unfractionated heparin is the most commonly used antithrombotic agent, which has major inherent limitations. Direct thrombin inhibitors and anti factor Xa agents are agents which may overcome the limitation of unfractionated heparin. The potential advantages of these new compounds are discussed on the basis of available clinical data in patients with coronary artery disease.
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PMID:Thrombin inhibitors and anti-factor Xa agents in the treatment of arterial occlusion. 1707 89

Over the last quarter of a century, therapy for acute coronary syndromes has rapidly evolved. The major causative factor for acute coronary syndromes, particularly acute myocardial infarction, is now recognised to be coronary thrombosis and therapies using thrombolytic agents to dissolve thrombus or percutaneous coronary interventions (angioplasty and stenting) to mechanically disrupt thrombus and restore vessel patency are now routine. The precipitant for coronary thrombus is believed to be atherosclerotic plaque rupture. Plaque rupture has been demonstrated at autopsy in humans and in vivo in an experimental animal model for atherosclerosis. Thrombus formed at these sites is platelet rich and anti-platelet therapy has an established role in the treatment of cardiovascular disease. The study of platelet membrane glycoproteins, which mediate platelet adhesion and aggregation, has resulted in specific therapies. Future directions for research with clinical relevance include the development of markers for plaque instability.
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PMID:Thrombosis and thrombolysis: platelet membrane glycoproteins. 1744 23


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