UMLS:C0020538 - FACTA Search

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Current concepts of the pathogenesis of atherosclerosis have been reviewed, emphasizing some of the similarities of the mechanisms and events involved to those in inflammation. Figure 2 is a schematic summary of these events. Hyperlipidemia, or some component of hyperlipidemic serum, as well as other risk factors, are thought to cause endothelial injury, resulting in adhesion of platelets and/or monocytes and release of PDGF (and other growth factors), which leads to smooth muscle migration and proliferation. It is clear that endothelial injury need not be denuding, and in fact may consist of altered endothelial function (dysfunction); adhesion of monocytes, increased permeability of endothelium, and disturbances in growth control can occur without morphologically obvious endothelial injury. Hyperlipidemia, hypertension, smoking, immune injury, and other risk factors may contribute to this endothelial dysfunction in different ways and sometimes in combination. Smooth muscle cells produce large amounts of collagen, elastin, and proteoglycans and these form part of the atheromatous plaque. Hyperlipidemia contributes in a number of ways (as discussed earlier), and indeed, in the severely hypercholesterolemic patient, such as one with familial hypercholesterolemia, is alone sufficient to cause atherosclerosis in the absence of other risk factors. Foam cells of atheromatous plaques are derived both from macrophages and from smooth muscle cells; from macrophages via the beta-VLDL receptor and also possibly by way of LDL modification, recognized by the acetyl-LDL receptor (such as oxidized LDL); and from smooth muscle cells by less certain mechanisms. Extracellular lipid is derived from insudation from the lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque should be viewed as reflecting imbalance between influx and efflux, and it is possible that high-density lipoprotein is the molecule which helps clear the cholesterol from these accumulations (134). The diagram (right) also depicts the possibility that smooth muscle proliferation may occur without endothelial injury at all. There are several postulated mechanisms for such an occurrence: loss of growth control, direct smooth muscle injury (such as by LDL), and autonomous proliferation by the mechanisms suggested by Benditt. The theoretical scheme presented is based largely on in vitro work, only partly substantiated by experimental and human studies, and does not explain the precise mechanisms by which all risk factors increase the susceptibility to atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pathogenesis of atherosclerosis: atherogenesis and inflammation. 327 59

This review discusses the genetic factors in the development of arteriosclerosis and coronary heart disease (CHD). In several studies, multivariate analysis of prospective mortality/morbidity data and angiographic findings have indicated that a family history of CHD contributed to CHD risk independently of the established risk factors. In addition, ethnic groups that differ in the prevalence and incidence of CHD also markedly differ in blood groups and protein-enzymatic markers. These or other genetic differences may affect CHD rates. Data from fraternal and identical twins, the source of some early genetic CHD findings, are reviewed. Genetic disorders of lipoprotein metabolism and transport, such as familial hypercholesterolemia, as well as other monogenic disorders are discussed. The role of apoprotein E polymorphism i other monogenic disorders are discussed. The role of apoprotein E polymorphism in determining plasma LDL variability among individuals is considered. Recombinant DNA technology, molecular cloning, and the identification of restriction fragment length polymorphisms are new tools for investigators who assess DNA polymorphism. Recent advances in that domain include: DNA polymorphisms affecting blood levels of apo A-I and A-II, association of a DNA insertion on chromosome 19 with severe premature atherosclerosis, and information concerning linkage of the genes for various apolipoproteins. In addition, the evidence for a major genetic component in diabetes mellitus and research into the genetic aspects of hypertension are reviewed. The male/female ratio in pathologically and epidemiologically assessed atherosclerosis may provide clues to the role of genetics. Early structural changes in the coronary artery intima are compatible with the ethnic and gender predilection. A key question in understanding underlying mechanisms in atherosclerosis is why coronary arteries are occluded in individuals whose other arterial systems are largely unaffected. The review concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on uncovering genetically determined differences in arterial wall response to blood flow. Subpopulations with different genetic risks may be identified, in which case universal preventive strategies might be replaced with specific ones.
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PMID:Genetic aspects of arteriosclerosis. 352 20

Between March 1981 and March 1986, 200 orthotopic heart transplantations were performed at the University of Pittsburgh. Fourteen of those procedures were carried out in children 2 to 16 years of age. Two children received combined liver and heart transplants; one because of familial hypercholesterolemia with associated ischemic heart disease, and the other because of dilated cardiomyopathy associated with intrahepatic biliary atresia. Eight patients had dilated cardiomyopathy, and two had myocarditis. Two had heart transplantations for congenital heart disease: one had multiple muscular ventricular septal defects repaired in infancy and had an associated cardiomyopathy, and the other developed a cardiomyopathic ventricle from a congenital right coronary artery to right atrial fistula. Chronic immune suppression consisted 0.2 to 0.5 mg/kg/d of prednisone and 5 to 50 mg/kg/d cyclosporine, with the addition of antithymocyte globulin for unresolved moderate or severe acute rejection. There were three early postoperative deaths: one from intracranial bleeding, one from Pseudomonas mediastinitis, and one from ischemic injury to transplanted organs. Early postoperative complications included reversible renal failure, hypertension, and seizures. Late problems were related to allograft rejection and side effects of cyclosporine and corticosteroids. Significant rejection episodes occurred in all patients surviving longer than 2 weeks, with seven requiring antithymocyte globulin. Two patients died 8 months following transplantation of severe acute and chronic rejection; another patient required retransplantation for ischemic cardiomyopathy resulting from chronic rejection but subsequently died of recurring rejection 3 months after the second transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Experience with heart transplantation in children. 354 Aug 34

The degree of atherosclerotic plaques in the carotid arteries was evaluated in 85 patients with familial hypercholesterolemia and in 43 patients with familial combined hyperlipidemia by means of Duplex scan which recognizes early atherosclerosis. In patients older than 40 years carotid atherosclerosis of moderate degree was associated with coronary heart disease in 90% of cases. The extent of elevated cholesterol, age, cigarette smoking, and hypertension determined the degree of carotid atherosclerosis.
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PMID:Atherosclerosis of the carotid arteries documented by duplex scan as a predictor of coronary artery disease in familial hyperlipidemias. 355 Feb 65

The receptor-associated protein (RAP) specifically associates with gp330 and the low density lipoprotein (LDL) receptor-related protein (LRP), the two newest members of the LDL receptor gene family. Results obtained by ligand blotting, affinity chromatography, and density-gradient sedimentation demonstrate that RAP binds to both receptors with high affinity and that the binding is Ca2+ dependent. RAP also binds heparin and is identical to a mouse heparin binding protein (HBP-44) identified in a teratocarcinoma cell line (F9). While biochemical studies have shown that RAP is present on the cell surface and is an effective inhibitor of ligand binding to gp330 and LRP, immunocytochemical findings indicate that RAP is most abundant in the endoplasmic reticulum lumen and may function in receptor folding and/or trafficking. To facilitate the characterization of RAP's function(s) we have mapped its gp330 and heparin binding sites by performing direct binding studies on fusion proteins representing overlapping domains of RAP. gp330 was found to bind to two separate sites on RAP--i.e., between amino acids 85-148 and 178-248. Binding studies with radiolabeled heparin indicate that the heparin binding site is between amino acids 261 and 323, which is consistent with our previously proposed site (residues 287-306) based on the amphipathic nature of the C terminus of RAP. These data demonstrate that the gp330 and heparin binding sites and the Heymann nephritis pathogenic epitope (amino acids 1-86) demonstrated earlier are represented by distinct domains of the RAP polypeptide.
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PMID:Functional domains of the receptor-associated protein (RAP). 751 26

The effects of fluvastatin treatment on lipid profile and apolipoproteins were assessed in a group of 31 Chinese patients with hypercholesterolemia, maintained on a constant low-fat diet. Some patients had the additional cardiovascular risk factors of hypertension and non-insulin-dependent diabetes mellitus, and 6 patients had familial hypercholesterolemia. Baseline lipid levels were measured after a 4-week placebo period, and these were repeated after 4 weeks of treatment with fluvastatin 20 mg daily, and after 4 weeks of treatment with fluvastatin 40 mg daily. Total cholesterol, low density lipoprotein cholesterol, and apolipoprotein (apo) B were each reduced to the same extent with the 2 doses of fluvastatin (-20%, -26%, and -20%, respectively). Triglycerides and very low density lipoprotein cholesterol were also reduced by about 12% with the 2 doses of fluvastatin. Apo A-I was increased by 7% and high density lipoprotein cholesterol (HDL-C) was increased by 10% with the 40 mg dose. The increase in HDL-C was due to increases in both HDL2-C (18%) and HDL3-C (7%). Lipoprotein(a) levels did not show any significant change with the 2 doses of fluvastatin in this short-term study. One patient developed reversible asymptomatic elevation of liver enzymes with the higher dose of fluvastatin; otherwise the drug was well tolerated and no patients had to be withdrawn from the study.
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PMID:Effects of fluvastatin on lipid profile and apolipoproteins in Chinese patients with hypercholesterolemia. 760 89

Significant risk factors for premature coronary heart disease include: (1) family history, (2) elevated low density lipoprotein (LDL) cholesterol level > or = 160 mg/dl, l, (3) decreased high density lipoprotein (HDL) cholesterol level < 35 mg/dl, l, (4) cigarette smoking, (5) high blood pressure and (6) diabetes mellitus. All of these risk factors are common in patients with premature heart disease. Common familial lipid disorders associated with premature heart disease include familial lipoprotein(a) excess, familial dyslipidemia (elevated triglycerides and decreased HDL cholesterol), familial combined hyperlipidemia (elevations of LDL cholesterol and triglycerides, and often decreased HDL cholesterol), familial hypoapobetalipoproteinemia (elevated apolipoprotein B levels), familial hypoalphalipoproteinemia (low HDL cholesterol levels), and familial hypercholesterolemia (elevated LDL cholesterol levels). All these disorders have been characterized using age and gender specific 90th and 10th percentile values from the normal population. The diagnosis and potential management of these disorders is reviewed.
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PMID:Familial lipoprotein disorders and premature coronary artery disease. 780 28

Risk factors such as hypercholesterolemia, hypertension and smoking are already operative in children and during adolescence; it has been demonstrated that they favour the development of early atherosclerosis lesions in young adults. This fact poses the question of diagnosis and treatment of risk factors. There is still controversy whether hypercholesterolemia should be searched for by universal or by selective screening, or by no screening at all. Several professional organizations favour a selective screening strategy, i.e. determination of serum cholesterol if one parent has premature coronary heart disease (before age 55 yr) or if the family has familial hyperlipidemia, in particular familial hypercholesterolemia. This strategy is advocated here: cholesterol should be measured early, i.e. between age 6 and 8 yr. A total serum cholesterol of > 5.2 mmol/l is elevated (approx. 75th percentile) and should be further evaluated and possibly treated. The presence of familial hypercholesterolemia should be looked for in particular: such individuals can now be diagnosed with molecular genetic tools, and they are particularly prone to develop premature coronary heart disease. Treatment of hypercholesterolemia is mainly of a dietary nature, or possible with a bile acid binding resin (cholestyramine). Other drugs have not been sufficiently evaluated for efficacy and safety; they may be indicated in special cases such as patients with a very high risk. Young people with familial hypercholesterolemia should be particularly counselled to avoid other risk factors such as smoking.
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PMID:[Hypercholesterolemia in children and young adults: should screening be done?]. 787 3

Anatomopathological, biological and epidemiological studies suggest that raised cholesterol concentrations are associated with heightened risk for coronary heart disease. Preventive measures have been recommended by consensus conferences (prudent diet and cholesterol lowering drugs) for a "desirable" level of plasma total cholesterol, i.e.: 1.80 g/l before thirty years and 2 g after thirty years. The debates about the advantage of plasma cholesterol lowering have boosted many controversies after the completion of randomized primary and secondary prevention trials analyses. It was showed an increase in total mortality and a no reduction in fatal coronary events. A series of papers have tried to discourage physicians from identifying subjects with high risk. One has to continue to detect subjects with familial hypercholesterolemia and to treat them following the recommendations of consensus conferences. In the other cases, one has to attach value to HDL-cholesterol and plasma triglyceride levels, especially in patients with hyperinsulinemia, insulin resistance, hypertension and visceral obesity. As lipid oxidation products toxicity, protective diets, as the traditional mediterranean diet containing antioxidant components are important too. Relationships between lipoprotein status and hypercoagulability remains to be investigated to identify predictive factors better than cholesterol for atherothrombosis diseases in subjects at risk.
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PMID:[Cholesterol: consensus and controversies, what is the trend in 1993?]. 794 81

Total cholesterol levels, obesity index and blood pressure were measured in 6,278 school-age children living in Ibaraki Prefecture in 1991, and children with high risk for atherosclerosis were identified. The frequencies of the school-age children with hypercholesterolemia (total cholesterol > or = 200 mg/dl), obesity (obesity index > or = 40%) or hypertension were 7%, 5%, 1%, respectively. In half of the area where the children lived, lipid measurements were also obtained in the parents of hypercholesterolemic children. Twenty-nine out of ninety fathers (32%) and 22 out of 140 mothers (16%) were hypercholesterolemia (total cholesterol > or = 240 mg/dl). Among them five families of familial hypercholesterolemia were diagnosed. Seventy children with hypercholesterolemia and 81 obese children, who were screened and received health counseling, were re-examined after one year. The levels of LDL-cholesterol, triglyceride and atherogenic index were significantly decreased and HDL cholesterol level was significantly increased in the children with hypercholesterolemia. Obesity index, triglyceride level and atherogenic index were significantly decreased and HDL cholesterol level was significantly increased in the children with obesity. In addition, the frequencies of the children with dyslipidemia or liver dysfunction were significantly decreased in the obese children after one year. These data suggested that the screening system and the plans after the examinations described here were effective in reducing risk factors for atherosclerosis in children.
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PMID:[Cardiovascular risk factors among Japanese school-age children: a screening system for children with high risk for atherosclerosis in Ibaraki, Japan]. 811 Oct 84

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