Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 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

In the past decade, impressive strides have been made in the diagnosis and management of atherosclerotic, aneurysmal, and thromboembolic diseases, thanks in large part to the explosive growth in both vascular biology and clinical vascular medicine. We review what we consider to be the top 12 advances in this field: the discovery of nitric oxide, the metabolic syndrome, new thrombophilic disorders, therapeutic angiogenesis, endoluminal treatment of chronic venous disease, and a variety of drugs, including sildenafil, cilostazol, low-molecular-weight heparins, oral direct thrombin inhibitors, clopidogrel, statins, and angiotensin-converting enzyme inhibitors and angiotensin-receptor blocking agents.
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PMID:The top 12 advances in vascular medicine. 1576 Feb 60

We have progressively analysed three studies of coronary heart disease (CHD) for a variant in EPCR (Ser219Gly). Initially, in a prospective study, NPHSII, while no overall CHD-risk was identified in heterozygotes, homozygotes for 219Gly exhibited a three-fold elevated risk (HR 3.3, CI 1.22-8.96). In diabetics within NPHSII, there was a suggestion that 219Gly+ was associated with elevated CHD-risk (HR 1.89, CI 0.39-9.06) although numbers were small. To further assess the effect of the variant in diabetes, a case-control study of MI, HIFMECH, was used, in which previous analysis had defined a group with metabolic syndrome, by factor analysis. A significant CHD-risk interaction was identified between genotype and the 'metabolic syndrome' factor (interaction p=0.009). To further assess CHD-risk for this variant in type-2 diabetes and to assess the effect of the variant upon thrombin generation and plasma levels of soluble EPCR, a cross-sectional study of type-2 diabetes was used. A significant CHD-risk was identified for European Whites (OR 2.84, CI 1.38-5.85) and Indian Asians in this study (OR 1.6, CI 1.00-2.57) and the frequency of 219Gly was two-fold higher in Indian Asians. Soluble EPCR levels were strongly associated with genotype, with homozygotes for 219Gly having four-fold higher levels (p<0.0001). In vitro studies of EPCR-transfected cells suggested increased basal release of sEPCR from cells expressing the 219Gly EPCR phenotype. Furthermore, in base-line samples from NPHSII and in the diabetic study, a significant increase in prothrombin F1+2 level was observed for 219Gly. The increased CHD-risk and thrombin generation appears to be acting through increased shedding of the Gly allele from the cell surface.
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PMID:EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro. 1592 88

We investigated the effect of a high walnut and cashew diet on haemostatic variables in people with the metabolic syndrome. Factor analysis was used to determine how the haemostatic variables cluster with other components of the metabolic syndrome and multiple regression to determine possible predictors. This randomized, control, parallel, controlled-feeding trial included 68 subjects who complied with the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol criteria. After a 3-week run-in following the control diet, subjects were divided into three groups receiving either walnuts or cashews (20 energy%) or a control diet for 8 weeks. The nut intervention had no significant effect on von Willebrand factor antigen, fibrinogen, factor VII coagulant activity, plasminogen activator inhibitor 1 activity, tissue plasminogen activator activity or thrombin activatable fibrinolysis inhibitor. Statistically, fibrinogen clustered with the body-mass-correlates and acute phase response factors, and factor VII coagulant activity clustered with high-density lipoprotein cholesterol (HDL-C). Tissue plasminogen activator activity, plasminogen activator inhibitor 1 activity and von Willebrand factor antigen clustered into a separate endothelial function factor. HDL-C and markers of obesity were the strongest predictors of the haemostatic variables. We conclude that high walnut and cashew diets did not influence haemostatic factors in this group of metabolic syndrome subjects. The HDL-C increase and weight loss may be the main focus of dietary intervention for the metabolic syndrome. Furthermore, diet composition may have only limited effects if weight loss is not achieved.
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PMID:Clustering of haemostatic variables and the effect of high cashew and walnut diets on these variables in metabolic syndrome patients. 1609 34

We investigated whether, in primary prevention patients with metabolic syndrome, statins affect the platelet protease-activated receptor-1 (PAR-1) thrombin receptor by performing serial measurements of its activity and the antigen expression level by flow cytometry before and during treatment. Recent data from randomized trials of statins are compatible with the possibility of clinically relevant pleiotropic effects. The use of statins is associated with a reduced thrombosis burden and diminished platelet activity, as shown in animal models and in vitro studies. Seventy patients with the metabolic syndrome who were not taking antiplatelet agents were assigned consecutively at starting doses at the discretion of the responsible clinician to 1 of 6 statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin) or to a no-statin group for 6 weeks. Platelet expression of intact (SPAN12 antibody) and cleaved (WEDE15) PAR-1 thrombin receptors were assessed by flow cytometry at baseline and at weeks 4 and 6 of treatment. At baseline, no difference was found in receptor expression. However, after 4 weeks of treatment, all statins had significantly inhibited (46% to 55%) the activated epitope of PAR-1 expression. After 6 weeks, inhibition remained, despite a slight rebound (22% to 37%). Also, a delayed pattern of inhibition of the intact PAR-1 receptor epitope was found. In conclusion, all statins inhibited the activity and antigen level of the platelet PAR-1 thrombin receptor, which has a major role in regulating platelet activity and thrombin formation. These observational data offer a plausible mechanism for the recently demonstrated pleiotropic effects of statins that may contribute to early clinical benefit.
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PMID:Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study). 1663 6

The results of the two arms of the Women's Health Initiative (WHI) study allow a comparative assessment of the contribution of the progestogen component to the changes in risk of cardiovascular disease and cancer during treatment of postmenopausal women with conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). However, the high proportion of older and overweight or obese women compromises any conclusions, since we estimate that 50% of the women would have the metabolic syndrome. In overweight postmenopausal women with hyperinsulinemia, the risk of breast cancer is elevated and cannot be increased further by hormone replacement therapy (HRT). Therefore, the non-significant, but consistent reduction in breast cancer risk during treatment with CEE alone might be based on an improvement of hyperinsulinemia. The 24% increase in breast cancer risk in the CEE/MPA group can be regarded as an artifact due to very low numbers of breast cancer diagnoses in the placebo group of women who had received HRT prior to the WHI study. The elevated risk of venous thromboembolism and the transient increase in the risk of coronary heart disease (CHD) during treatment with CEE/MPA but not CEE alone suggests a direct effect of MPA on the vessel wall. MPA has been demonstrated to upregulate the thrombin receptor, the thrombin-induced production of tissue factor and procoagulatory activity in the vessel wall owing to its glucocorticoid activity. In contrast, CEE alone reduced non-significantly the risk of CHD in women aged 50-59 years, suggesting that primary prevention is possible if estrogen replacement therapy is initiated early. As clinical studies on the effect of different progestogens combined with estrogens are scarce, a possible superiority of progestogens other than MPA remains to be proven.
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PMID:The effect of medroxyprogesterone acetate on estrogen-dependent risks and benefits--an attempt to interpret the Women's Health Initiative results. 1678 55

There is a considerable body of evidence supporting an association between hypertriglyceridaemia, a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade. Fibrinolysis is also less efficient when thrombin is generated. Thrombin induces thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor is a carboxypeptidase that cleaves the carboxylic lysine residues on fibrin, thereby abolishing the critical binding site for tPA-plasminogen decreasing plasmin formation. Thus the evidence is supportive of dysregulated coagulation, and impaired fibrinolysis with a predisposition to atherothrombosis, in conditions such as the metabolic syndrome, in which there are increased concentrations of VLDL and remnant lipoproteins. The purpose of this review is to describe the current evidence supporting a procoagulant state induced by VLDL and remnant lipoproteins. The role of these lipoprotein classes in (1) platelet activation; (2) the intrinsic coagulation cascade, and (3) clot formation and fibrinolysis is discussed.
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PMID:Effects of VLDL and remnant particles on platelets. 1687 77

The composition of an atherosclerotic plaque is an important determinant of plaque stability. Unstable rupture-prone plaques are characterized by a thin fibrous cap that contains few muscle cells. Several lines of evidence suggest that macrophage activation in the unstable shoulder of the plaque could contribute to plaque rupture by releasing toxic factors, possibly nitric oxide (NO), to smooth muscle cells. These macrophages are also involved in the uptake of apoptotic cells (AC) and the inefficient removal of the latter might contribute to the formation of the necrotic core through accumulation of necrotic debris. Furthermore, these AC rapidly expose phosphatidylserine on their surface, which is a potent substrate for the generation of thrombin and activation of the coagulation cascade. The following new insights in the etiopathogenesis of atherothrombosis will be discussed: (1) Human atherosclerotic plaques contain amyloid precursor protein (APP) and beta-amyloid peptide, which is cleaved from APP and which has been extensively studied in Alzheimer's disease. Macrophages phagocytose platelets,which contain APP in their alpha-granules and this platelet derived APP is subsequently proteolytically processed in these macrophages into beta-amyloid The latter is involved in the upregulation of the inducible NO-synthase which results in an increased production of toxic amounts of NO. (2) Phagocytosis of the pro-coagulant ACS is severely impaired in advanced human atherosclerotic plaques. Several factors present in the atherosclerotic lesion,such as accumulation of indigestible material in the macrophage cytoplasm,oxidative stress,and the presence of oxidized LDL or oxidized erythrocytes may contribute to the impairment of phagocytosis. (3) In order to study the impact of the impaired phagocytosis by the macrophages on the atherosclerotic lesion development,a double knock-out mouse was created which spontaneously develops atherosclerosis combined with a deficient phagocytotic capacity. Completely unexpected the double-knock out mouse developed an until now not described phenotype resembling the metabolic syndrome including a spectacular increase in body weight,accumulation of abdominal fat and fat in the liver and increased plasma levels of cholesterol. Furthermore the atherosclerotic lesions demonstrated a striking different morphology as compared to the lesions present in mice which spontaneously develop atherosclerosis.
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PMID:[New insights into the etiopathogenesis of atherosclerosis and atherothrombosis]. 1717 27

The primary target receptor for thiazolidinediones (TZDs) or peroxisome proliferator-activated receptor gamma (PPARgamma) agonists is a transcription factor in the nucleus of adipocytes and other metabolically active cells, where they improve insulin sensitivity and glucose utilization. TZDs are also able to modify gene expression in macrophages, smooth muscle cells, and endothelial cells. Although PPARgamma is considered to be a nuclear receptor, enucleate platelets also highly express this receptor. The aim of this review is to present the current understanding of a direct or indirect effect of TZDs on platelet function. By means of a comprehensive literature search (January 1990-June 2006), publications were obtained that contained specific information about in vitro and in vivo effects of TZDs on platelet function. The effects were studied for different risk biochemical markers, i.e., proteins found to be elevated in the state of procoagulant inflammation and endothelial dysfunction. Improvement of platelet function was reported for all TZDs-troglitazone, pioglitazone, and rosiglitazone. The described effects included reduction of platelet aggregation, suppression of thrombin-induced protein kinase C-alpha and -beta activation, decrease in plasma P-selectin and platelet P-selectin expression, increase in nitric oxide production, inhibition of the Rho/Rho kinase pathway, and inhibition of tissue factor- and platelet-activating factor-induced morphological changes in macrophages. These findings appeared in parallel with reduction of the plasma concentrations of pro-inflammatory risk markers. TZDs seem to have a direct pleiotropic positive influence on platelet function and coagulation and may be helpful in treating the prothrombotic state observed in patients with type 2 diabetes and metabolic syndrome.
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PMID:Review of the pleiotropic effects of peroxisome proliferator-activated receptor gamma agonists on platelet function. 1793 Oct 49

The synthetic cannabinoid CB1 receptor antagonist rimonabant (sold in the United Kingdom under the brand name Acomplia) was reported to improve the profile of cardiovascular risk factors in obese patients with the metabolic syndrome, a cluster of metabolic disorders that often precedes the onset of type II diabetes. Rimonabant is shown in the current issue of British Journal of Pharmacology to attenuate weight gain in Zucker rats, an experimental model of insulin resistance. Neutrophil and monocyte counts were lowered by rimonabant administration. Both platelet activation (by ADP) and aggregation (in response to thrombin) were inhibited. Circulating pro-inflammatory cytokine levels (monocyte chemotactic protein 1, MCP1 and Regulated upon Activation, Normal T-cell Expressed and Secreted, RANTES) were also reduced. Furthermore, fibrinogen levels returned to normal. These favourable anti-inflammatory and anti-thrombotic actions imply for rimonabant a peripheral, direct action on some cardiovascular risk factors.
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PMID:Rimonabant in rats with a metabolic syndrome: good news after the depression. 1846 48


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