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 description of two additional cases of coronary artery disease in haemophiliacs is reported. Both patients are affected by mild haemophilia A. The first one was not aware of his coagulation disorder and therefore he had never been treated with FVIII concentrates, despite the occurrence of severe and recurrent articular and gastric bleeding episodes. He underwent cardiac catheterization that gave evidence of extensive coronary atherosclerosis. Percutaneous transluminal coronary angioplasty (PTCA) was then performed. The second patient had an inferior myocardial infarction. Influence of cardiovascular risk factors in haemophiliacs and the possible role of thrombosis in the pathogenesis of atherosclerosis are discussed.
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PMID:Mild haemophilia A fails to protect from coronary artery disease: the report of two cases. 811 30

We hypothesized that patients with hemophilia or von Willebrand disease might be protected from atherosclerosis because of their coagulation defect. We studied 40 subjects affected by these two coagulation diseases using echocolor Doppler of the abdominal aorta and leg arteries, and compared the results with those obtained in 40 control patients who were homogenous with study patients in terms of sex, age, and risk factors for atherosclerosis. The probands presented a lower number of plaques than the 40 control subjects in the aorta and in the leg arteries. The most serious hemophilic patients had fewer plaques than controls or than patients with mild hemophilia. Both hemophilia and von Willebrand disease seem to protect against atherosclerosis.
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PMID:Hemophilia A, von Willebrand disease, and atherosclerosis of abdominal aorta and leg arteries: factor VIII and von Willebrand factor defects appear to protect abdominal aorta and leg arteries from atherosclerosis. 1169 15

Whether carriers of hemophilia are protected against the development of atherosclerosis is controversial. In a case-control study, the presence of atherosclerosis was assessed and quantified with echo-color Doppler of all explorable arterial districts in 50 carriers of hemophilia and in 50 age-matched control individuals. All participants submitted to echo-color Doppler of carotid and femoral axis, of brachial arteries, and of the abdominal aorta. The presence and grade of atherosclerotic plaques were assessed, as well as the intima-media thickness (IMT). At least one atherosclerotic plaque was found in six cases (12.0%) versus 15 controls (30.0%); referring to the total number of plaques, 30% of them were evaluated in patients affected by decreased coagulation while 70% in subjects with normal levels of FVIII. In all the examined districts, the mean IMT was significantly lower in patients with hemophilia than in controls. Hemophilia protects against asymptomatic atherosclerosis.
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PMID:Does hemophilia protect against atherosclerosis? A case-control study. 1670 21

Haemophilia patients may develop cardiovascular diseases, suggesting that their clotting defect does not protect them completely from atherosclerosis and its complications. We aimed to evaluate cardiovascular risk factors and, for the first time, the presence of endothelial dysfunction in middle-aged haemophilia patients. We studied 40 patients with haemophilia A and B (24 with moderate-severe disease and 16 with mild disease), and 40 healthy controls. Flow-mediated dilation (FMD), carotid ultrasound (US) intima media thickness (IMT), arterial blood pressure, body mass index (BMI), cholesterol, triglycerides, glucose, insulin, lipoprotein(a) and homocysteine levels were measured, and PAI-1 and t-PA levels before and after venous occlusion (VO), and antibodies to HIV, HBV and HCV were assayed. At least one cardiovascular risk factor was detected in 87.5% of patients, and 2 or more in 47.5% of cases. At US exam, none of the patients had significant carotid stenosis or significant differences in IMT compared to controls. In contrast, all the patients had a significant FMD impairment, associated with a reduced t-PA release after VO in 70% of cases. PAI-1 levels significantly correlated with BMI, triglycerides and insulin values. Fifteen haemophilia patients with chronic viral hepatitis and/or HIV infection showed a significantly lower FMD than patients without active infection. We found an endothelial dysfunction with impaired FMD and t-PA release in our haemophilia patients, usually associated with cardiovascular risk factors. Other pathogenic mechanisms, such as chronic viral infections, are likely to be involved in this endothelial damage, however.
Haemophilia 2008 Sep
PMID:Endothelial dysfunction in haemophilia patients. 1862

Mortality due to ischemic heart disease in hemophilia patients is lower as compared to the general male population. Differences in the prevalence of cardiovascular risk factors cannot explain this finding. The hypocoagulable state of hemophilia patients might have a protective effect on thrombus formation, which precipitates infarction. It remains unclear whether the deficiency of coagulation factor VIII or IX exerts a protective effect on the development of atherosclerosis. Despite the relative protection against cardiovascular events, the incidence of ischemic cardiovascular disease in hemophilia patients is increasing, because life expectancy of these patients now approaches that of the general population. This review focuses on what is currently known about cardiovascular risk factors, atherosclerosis, arterial thrombosis and ischemic cardiovascular disease in hemophilia patients.
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PMID:Cardiovascular disease in patients with hemophilia. 1898 84

Orphan nuclear receptors have been instrumental in identifying novel signaling pathways and therapeutic targets. However, identification of ligands for these receptors has often been based on random compound screens or other biased approaches. As a result, it remains unclear in many cases if the reported ligands are the true endogenous ligands,--i.e., the ligand that is bound to the receptor in an unperturbed in vivo setting. Technical limitations have limited our ability to identify ligands based on this rigorous definition. The orphan receptor hepatocyte nuclear factor 4 alpha (HNF4alpha) is a key regulator of many metabolic pathways and linked to several diseases including diabetes, atherosclerosis, hemophilia and cancer. Here we utilize an affinity isolation/mass-spectrometry (AIMS) approach to demonstrate that HNF4alpha is selectively occupied by linoleic acid (LA, C18:2omega6) in mammalian cells and in the liver of fed mice. Receptor occupancy is dramatically reduced in the fasted state and in a receptor carrying a mutation derived from patients with Maturity Onset Diabetes of the Young 1 (MODY1). Interestingly, however, ligand occupancy does not appear to have a significant effect on HNF4alpha transcriptional activity, as evidenced by genome-wide expression profiling in cells derived from human colon. We also use AIMS to show that LA binding is reversible in intact cells, indicating that HNF4alpha could be a viable drug target. This study establishes a general method to identify true endogenous ligands for nuclear receptors (and other lipid binding proteins), independent of transcriptional function, and to track in vivo receptor occupancy under physiologically relevant conditions.
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PMID:Identification of an endogenous ligand bound to a native orphan nuclear receptor. 1944 Mar 5

This is a review of less well-known aspects of thrombophilia and hypercoagulability as they relate to thrombosis. Thrombosis is an abnormal fibrin clot that develops in circulating blood with clinical symptoms of one or more arterial and/or venous obstructions exclusively identified by imaging techniques. The terms thrombophilia and hypercoagulability are often used indiscriminately when they are in fact separate entities. Thrombophilia is an inherited or acquired clinical phenotype manifesting in selected individuals as a greater risk to develop recurrent thrombosis at a younger age than the general population, with considerable differences in the magnitude of risks among individuals in the same family with the same thrombophilic gene defect. Hypercoagulability is a laboratory phenotype whereby in vivo activation of clotting, fibrinolysis, endothelial cells and platelets is identified in vitro by specialized clotting techniques and by specific antibodies directed at biomarkers of clotting activation and damaged vasculature. Hypercoagulability may be provoked by drugs to treat bleeding in hemophilia, by sepsis, inflammation, surgery, blood stasis, atherosclerosis, and it manifests selectively in inherited and acquired thrombophilia. A chronology of the discovery of acquired and inherited thrombophilia puts in perspective the data analyzed in two representative large family studies that address whether venous and arterial thrombosis are a necessary outcome in thrombophilia, and the question, whether patients with inherited antithrombin, protein C and protein S deficiencies need to be treated after a first episode of thrombosis. The liberal use of case vignettes emphasizes a close relationship and the distinction between thrombosis, thrombophilia and hypercoagulability.
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PMID:Thrombophilia and hypercoagulability. 1979 18

The identification of defective genes associated with a number of human disorders (tyrosine hydroxylase for Parkinson's disease, aspartylglucosaminidase in lysosomal storage disease, CFTR in cystic fibrosis, and LDL receptor in familial hypercholesterolemia) has promoted the development of strategies aimed at transferring to the somatic cells of the patient or of animal models vectors carrying the corrected gene. The obstacles to overcome include targeting the specific cell type or organ (liver for Factors VIII and IX in hemophilia), enhancing entry to cells into non-lysosomal compartments, nuclear import, percentage of cells transduced with the therapeutic gene, sustained expression of the transgene in human tissues, and immunogenicity of the transduced cells expressing the recombinant or viral proteins. Improvements in each single of these steps are likely to enhance enormously the potential of gene transfer for the treatment of human diseases. A number of human diseases including HIV infections and hypertension are approached by somatic gene transfer. VEGF regulating vascular permeability, growth of endothelial cells and angiogenesis, and TGF-B implicated in wound healing and in stimulation in synthesis of extracellular matrix, are potential targets for restenosis, atherosclerosis, and cancer.
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PMID:Gene therapy to human diseases. 2154 34

Adeno-associated virus (AAV) is the most promising gene delivery vehicle for muscle-directed gene therapy. AAV's natural tropism to muscle cells, long-term persistent transgene expression, multiple serotypes, as well as its minimal immune response have made AAV vectors well suited for muscle-directed gene therapy. AAV vector-mediated gene delivery to augment muscle structural proteins, such as dystrophin and sarcoglycans, offers great hope for muscular dystrophy patients. In addition, muscle can be used as a therapeutic platform for AAV vectors to express nonmuscle secretory/regulatory pathway proteins for diabetes, atherosclerosis, hemophilia, cancer, etc. AAV vector can be delivered into both skeletal muscle and cardiac muscle by means of local, regional, and systemic administrations. Successful animal studies have led to several noteworthy clinical trials involving muscle-directed gene therapy. In this chapter, we describe the basic methodology that is currently utilized in the area of AAV-mediated muscle-directed gene therapy. These methods include vector delivery route, vector dosage, detection of transgene expression by immunostaining and western blot, determination of vector copy numbers and quantification of mRNA expression, as well as potential immune responses involved in AAV delivery. Technical details and tips leading to successful experimentation are also discussed.
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PMID:Gene therapy in skeletal muscle mediated by adeno-associated virus vectors. 2203 28

Commercial assays for determining thrombin generation in plasma are being tested in clinical conditions associated with thrombosis or bleeding. While pre-analytical conditions remain a source of inter laboratory variation, demanding for further standardization, clinical research proceeds. In patients at risk of venous thrombosis thrombin generation (TG) analysis may be utilized to detect underlying thrombophilia and this has been achieved both with addition of thrombomodulin or activated protein C, to test the contribution of the protein C system. In patients with documented venous thromboembolism, increased TG values are seen in those patients at greatest risk for recurrence, although the data are not consistent yet. In patients with arterial vascular disease, effects on TG patterns are seen that both reflect atherosclerosis (and its risk factors) and link to risk of recurrent atherothrombosis (coronary or stroke), but the data are limited. In patients with a bleeding diathesis, like hemophilia, the main importance of TG assays lies in the application for monitoring replacement therapy, either with factor concentrate or rFVIIa. An interesting application is in conjunction with thromboelastography, for monitoring peri-operative transfusion policy. Finally, TG analysis may contribute to monitoring anticoagulant drug treatment, but these and other applications would greatly benefit from whole blood, point of care applications of TG testing.
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PMID:Thrombin generation in clinical conditions. 2207 43


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