Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoprotein(a) [Lp(a)] represents an LDL-like particle to which the Lp(a)-specific apolipoprotein(a) is linked via a disulfide bridge. It has gained considerable interest as a genetically determined risk factor for atherosclerotic vascular disease. Several studies have described a correlation between elevated Lp(a) plasma levels and coronary heart disease, stroke, and peripheral atherosclerosis. In healthy individuals, Lp(a) plasma concentrations are almost exclusively controlled by the apo(a) gene locus on chromosome 6q2.6-q2.7. More than 30 alleles at this highly polymorphic gene locus determine a size polymorphism of apo(a). There exists an inverse correlation between the size (molecular weight) of apo(a) isoforms and Lp(a) plasma concentrations. The standardization of Lp(a) quantification is still an unresolved task due to the large particle size of Lp(a), the presence of two different apoproteins [apoB and apo(a)], and the large size polymorphism of apo(a) and its homology with plasminogen. A working group sponsored by the IFCC is currently establishing a stable reference standard for Lp(a) as well as a reference method for quantitative analysis. Aside from genetic reasons, abnormal Lp(a) plasma concentrations are observed as secondary to various diseases. Lp(a) plasma levels are elevated over controls in patients with nephrotic syndrome and patients with end-stage renal disease. Following renal transplantation, Lp(a) concentrations decrease to values observed in controls matched for apo(a) type. Controversial data on Lp(a) in diabetes mellitus result mainly from insufficient sample sizes of numerous studies. Large studies and those including apo(a) phenotype analysis came to the conclusion that Lp(a) levels are not or only moderately elevated in insulin-dependent patients. In noninsulin-dependent diabetics, Lp(a) is not elevated. Conflicting data also exist from studies in patients with familial hypercholesterolemia. Several case-control studies reported elevated Lp(a) levels in those patients, suggesting a role of the LDL-receptor pathway for degradation of Lp(a). However, recent turnover studies rejected that concept. Moreover, family studies also revealed data arguing against an influence of the LDL receptor for Lp(a) concentrations. Several rare diseases or disorders, such as LCAT- and LPL-deficiency as well as liver diseases, are associated with low plasma levels or lack of Lp(a).
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PMID:Lipoprotein(a) in health and disease. 898 7

The current recommendations for childhood cholesterol screening include screening children in whom 1) a parent/grandparent has premature heart or vascular disease or died suddenly; 2) a parent has an abnormal lipid profile; 3) the family history is unobtainable. Over a 3-year period, 256 children referred for hypercholesterolemia were evaluated for heritable hyperlipidemia. We reviewed their family histories and obtained lipoprotein profiles of all of their immediate family members. Of these families, 89 parents had unsuspected hypercholesterolemia of whom 38, whose average age was 36 years, died of a myocardial infarction. In addition, 83 children with no family history of premature coronary artery disease or hypercholesterolemia, were diagnosed with inherited hyperlipidemia (25 with hetrozygous familial hypercholesterolemia, and 58 with familial combined hyperlipidemia). Thus, many adults have no awareness of hyperlipidemia prior to a fatal heart attack, nor of their children as having hyperlipidemia, and a large percentage of children with inherited hyperlipidemia would not have been diagnosed if all of their immediate family members (parents and siblings) had not been screened for a complete lipid profile. These results suggest that in addition to screening, all family members of hypercholesterolemic children, pediatricians and family practitioners should urge parents who may be unaware of their cholesterol levels or have no knowledge of their family history to undergo cholesterol screening in order to comply with NCEP guidelines calling for serum cholesterol measurements in all adults above the age of twenty.
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PMID:Pediatric cholesterol screening: missed opportunities. 939 39

Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disorder characterized by high serum low-density lipoprotein (LDL)-cholesterol concentrations, xanthoma formation, and premature atherosclerosis. Homozygous individuals die of vascular disease as children or young adults; heterozygous persons are at high risk for premature cardiovascular death. Mutations in the LDL-receptor gene are responsible for FH. We studied 49 members of a consanguineous Syrian kindred containing 6 homozygous individuals from the same pedigree. Half of the homozygotes had giant xanthomas, while half did not, even though their LDL-cholesterol concentrations were elevated to similar degrees (> 14 mmol/l). Heterozygous FH individuals from this family were also clearly distinguishable with respect to xanthoma size. We performed DNA analysis and were successful in identifying a hitherto not described mutation in this family's LDL receptor. DNA sequence analysis of the LDL-receptor gene revealed a T to C substitution at nucleotide 1,999 in codon 646 of exon 14. We next conducted a segregation analysis, which suggests that a susceptibility gene may explain the formation of giant xanthomas in this family. We raise the hypothesis that the appearance of giant xanthomas in this FH family is controlled by a second gene acting in an autosomal-dominant or recessive fashion. Elucidation of this 'xanthoma' gene may shed additional light on LDL-cholesterol deposition.
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PMID:A xanthomatosis-susceptibility gene may exist in a Syrian family with familial hypercholesterolemia. 941 89

Recent developments in ultrasound technology enable the noninvasive measurement of structural and functional vessel wall changes. Until now, the effect of homocysteine on the arterial wall has remained unclear: reports on intima-media thickness (IMT) yield conflicting results, whereas data on vessel wall stiffness are lacking. Because several cardiovascular risk factors result in an increased IMT or stiffness, different groups at risk for atherosclerotic disease, with special emphasis on hyperhomocysteinemia, were studied. Nineteen patients homozygous and 14 subjects heterozygous for cystathionine beta-synthase (CBS) deficiency, 21 patients with familial hypercholesterolemia (FH), 15 patients with essential hypertension, 20 smokers, and 28 control subjects were studied. The IMT values (both right and left) of the common carotid artery (CCA), bulb (BUL), internal carotid artery (ICA), and common femoral artery (CFA) were measured in millimeters by high-resolution ultrasound (Biosound). The distensibility (DC, in 10(-3). kPa-1) and compliance (CC in mm2. kPa-1) coefficients of the CCA (right and left) and CFA (right) were determined by a wall track system (Pie Medical). The mean IMT of the posterior wall in the CCA was 0.70+/-0.09 mm in healthy controls. For patients with vascular disease, FH, and hypertension and in smokers, the mean CCA IMT was larger, whereas no major differences in IMT were observed in patients either homozygous or heterozygous for CBS deficiency. The DC and CC in the right CCA were 23.5+/-6.9 (10(-3). kPa-1) and 0.9+/-0.3 (mm2. kPa-1) in healthy subjects, slightly lower in patients homozygous for CBS deficiency, and clearly lower in patients with vascular disease, FH, and hypertension. No positive correlation was found between plasma homocysteine level and either IMT, CC, or DC. Because smoking was a confounder in each risk group, a stepwise regression analysis was carried out to assess the contribution of each risk factor on IMT and arterial wall stiffness. Age explained most of the variation in IMT of the CCA (coefficient of determination R2 of 0.34), whereas R2 values for serum low density lipoprotein cholesterol, smoking (pack-years), and systolic blood pressure were 0.08, 0.07, and 0.06, respectively. Homocysteine did not contribute to variation in IMT in both the CCA and CFA. Age and smoking contributed to the variation in IMT in the CFA. The variation in DC and CC in the right CCA and right CFA could in part be explained by age, low density lipoprotein cholesterol, and blood pressure. Plasma homocysteine concentration explained only a small proportion of the variation in DC in the CCA (R2=0.02) and in CC in the CFA (R2=0.04). In this study, no relationship was found between homocysteine level and the thickness of the arterial wall, with only a marginal influence on stiffness.
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PMID:Carotid and femoral artery wall thickness and stiffness in patients at risk for cardiovascular disease, with special emphasis on hyperhomocysteinemia. 984 90

Patients with hypercholesterolemia without vascular disease have an impaired endothelium-dependent (nitric oxide-mediated) vasodilation in coronary and peripheral vascular beds. This study was designed to establish whether hypercholesterolemia (and its reduction) affects also the microcirculation vasomotion during postischemic hyperemia in both calf and forearm. Thirteen male patients, aged 36.2+/-8.5 years, mean +/-SD, with heterozygous familial hypercholesterolemia and 10 male control subjects, aged 32.2+/-3.6 years free from vascular lesions were studied. Plasma lipids, hematologic parameters, and limb vasoreactivity were evaluated while the patients were treated only with diet and during therapy with simvastatin. Calf and forearm blood flows were determined by venous occlusion strain gauge plethysmography at rest, during reactive hyperemia, and after sublingual isosorbide dinitrate administration. Calf resting flow rate of the hypercholesterolemic patients during and without treatment was similar to that of the controls. Calf resting vascular resistance was greater in the untreated hypercholesterolemic subjects than in the normal controls, but during treatment this difference was abolished. Peak flow during reactive hyperemia and flow debt repayment were lower in the untreated hypercholesterolemic subjects as compared to the controls, but they were normalized following hypocholesterolemic therapy. No differences were observed in forearm blood flow measurements between hypercholesterolemic subjects (without and during therapy) and control subjects. The blood flow and vascular resistance after isosorbide dinitrate were modified in a similar manner in the hypercholesterolemic (without and during therapy) and control subjects at both calf and forearm. Hypercholesterolemia does not affect vasodilation in the forearm as determined by postocclusive reactive hyperemia, while in the calf hypercholesterolemia is associated with higher resting vascular resistance, lower peak flow during reactive hyperemia, and lower flow debt repayment. These abnormalities are corrected by the hypocholesterolemic treatment.
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PMID:Calf and forearm blood flow in hypercholesterolemic patients. 1077 1

Lectin-like oxidized LDL receptor (LOX)-1 is a type II membrane protein that belongs to the C-type lectin family of molecules, which can act as a cell-surface endocytosis receptor for atherogenic oxidized LDL. LOX-1 can support binding, internalization and proteolytic degradation of oxidized LDL, but not of significant amounts of acetylated LDL, which is a well-known high-affinity ligand for class A scavenger receptors and scavenger receptor expressed by endothelial cells (SR-EC). LOX-1 is initially synthesized as a 40-kDa precursor protein with N-linked high mannose-type carbohydrate, which is further glycosylated and processed into a 50-kDa mature form. LOX-1 expression is not constitutive, but can be induced by proinflammatory stimuli, such as tumour necrosis factor-alpha, transforming growth factor-beta and bacterial endotoxin, as well as angiotensin II, oxidized LDL itself and fluid shear stress. In addition, LOX-1 expression is detectable in cultured macrophages and activated vascular smooth muscle cells. In vivo, endothelial cells that cover early atherosclerotic lesions, and intimal macrophages and smooth muscle cells in advanced atherosclerotic plaques can express LOX-1. Cell-surface LOX-1 can be cleaved through some protease activities that are associated with the plasma membrane, and released into the culture media. Purification of soluble LOX-1 and the N-terminal amino-acid sequencing identified the two cleavage sites (Arg86-Ser87 and Lys89-Ser90), both of which are located in the membrane proximal extracellular domain of LOX-1. Measurement of soluble LOX-1 in vivo may provide a novel diagnostic tool for the evaluation and prediction of atherosclerosis and vascular disease.
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PMID:Roles of lectin-like oxidized LDL receptor-1 and its soluble forms in atherogenesis. 1150 27

The advent of treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors has meant that, with a combination of diet and drug therapy, adequate control of serum cholesterol concentrations can be achieved in most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy to lower their cholesterol levels. In recent years, low-density lipoprotein (LDL) apheresis has emerged as an effective method of treatment in these patients. The criteria for commencement of LDL apheresis are LDL cholesterol levels of 500 mg/dL or higher for homozygous FH patients, 300 mg/dL or higher for heterozygous FH patients in whom medical therapy has failed, and 200 mg/dL or higher for heterozygous FH patients with documented coronary disease and in whom medical therapy has failed. In addition to cholesterol lowering in patients with FH, other indications for LDL apheresis are emerging. These include its use in the treatment of graft vascular disease in patients receiving cardiac transplants as well as in the treatment of certain glomerulonephritides. This review examines the role of LDL apheresis in the management of lipid disorders and the evidence available to support its use in clinical practice.
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PMID:Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia. 1160 88

Linkage of the lipoprotein lipase (LPL) gene to blood pressure levels has been reported. The LPL S447X single nucleotide polymorphism (cSNP) has been associated with decreased triglycerides (TG), increased high density lipoprotein cholesterol, and a decreased risk of coronary artery disease (CAD), which may occur independently of its beneficial lipid changes. To investigate the relationship between LPL S447X cSNP and these parameters, we studied a cohort of individuals with familial hypercholesterolemia in whom blood pressures and information regarding the use of blood pressure lowering medications were available. Carriers of the S447X variant had decreased TG (1.21+/-0.47 vs. 1.52+/-0.67, p<0.001) and a trend towards decreased vascular disease (12.7 vs. 19.5%) compared to non-carriers. More interestingly, however, carriers of this cSNP had decreased diastolic blood pressure compared to non-carriers (78+/-10 vs. 82+/-11, p=0.002), evident in both men and women, youths and adults, with similar trends for systolic blood pressure. Furthermore, the decrease in blood pressure appeared independent of the decrease in TG (p=0.02), suggesting that the LPL protein may have a direct influence on the vascular wall. This suggests an additional mechanism whereby this variant may have protective effects, independent of changes in plasma lipid levels.
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PMID:The LPL S447X cSNP is associated with decreased blood pressure and plasma triglycerides, and reduced risk of coronary artery disease. 1168 75

To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia (FH) on regular LDL apheresis, we prospectively studied the rheological variables fibrinogen, plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit and platelet aggregation in 12 patients (two homozygous, ten heterozygous) before and during treatment with atorvastatin. Baseline values of red cell aggregation and whole blood viscosity were increased in FH patients on regular LDL apheresis compared with healthy controls (P<0.05), whereas fibrinogen, plasma viscosity and hematocrit were similar in the two groups. Treatment with atorvastatin reduced red cell aggregation (P<0.01), whole blood viscosity (P<0.01), plasma viscosity (P<0.01) and platelet aggregation (P<0.05), but caused a slight increase in plasma fibrinogen (by 5%; P<0.01). Our findings suggest that atorvastatin improves blood rheology in patients with FH on regular LDL-apheresis. This improvement in blood flow properties may contribute to the well-known beneficial effects of atorvastatin on cardiovascular risk in patients with severe hyperlipidemia and atherosclerotic vascular disease.
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PMID:Atorvastatin improves blood rheology in patients with familial hypercholesterolemia (FH) on long-term LDL apheresis treatment. 1173 Aug 33

A female patient born in 1950 underwent plasma exchange and concomitant drug therapy for 20 yr due to homozygous familial hypercholesterolemia. Plasma exchange reduced total cholesterol levels from 25-30 mmol/L (967-1160 mg/dL) before treatment to 9.5 mmol/L (363 mg/dL) with regression of xanthomas and no side effects of long-term treatment. Due to end-stage calcific left ventricular outflow tract obstruction not amenable to standard valve reconstructive surgery, a combined heart-liver transplantation was successfully performed in 1996. She is without symptoms and living a normal life 4 yr after transplantation. Total cholesterol value is normal (4.7 mmol/L [182 mg/dL]) using a moderate dose of statins. Selective coronary angiography is without signs of graft vascular disease and the liver function is normal.
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PMID:Plasma exchange and heart-liver transplantation in a patient with homozygous familial hypercholesterolemia. 1173 22


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