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)

Familial hypercholesterolemia (FH) is characterized by an autosomal codominant inheritance, an abnormality in low-density lipoprotein (LDL) receptor function, elevated plasma cholesterol levels and premature atherosclerosis. Sixteen patients with homozygous FH were studied to correlate the extent of their atherosclerotic disease with their lipid levels and receptor function. The age range at initial presentation was 3 to 38 years (mean 12), and at the last examination, 6 to 43 years (mean 20). The mean pretreatment total plasma cholesterol concentration for all patients was 729 +/- 58 mg/dl (+/- standard error of the mean), and the mean LDL cholesterol level was 672 +/- 58 mg/dl (normal 60 to 176). High-density lipoprotein cholesterol was 28 +/- 3 mg/dl (normal 30 to 74). In the 7 patients with FH who had symptoms of myocardial ischemia (Group I), the mean pretreatment LDL cholesterol value (817 +/- 62 mg/dl) was higher than that of the 9 asymptomatic patients (Group II) (560 +/- 74 mg/dl). In Group I, 5 of 7 patients had left or right coronary ostial narrowing and 3 had significant left ventricular outflow obstruction. Most coronary arterial narrowing occurred in the right coronary and left anterior descending arteries and the least amount in the left circumflex coronary artery. A femoral bruit was the physical finding that correlated best with the Group I population; brother:sister pairs revealed a milder clinical course for the female. Seven of the 16 patients have survived into their third decade without symptoms. Comparison of these persons with those in whom angina developed reveals a marked heterogeneity in their clinical course, which appears to be associated with receptor negative/defective status.
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PMID:Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. 633 Nov 47

There is conflicting evidence on the relationship between increased low density lipoprotein (LDL) concentration in Type II hyperlipoproteinemia and premature development of peripheral atherosclerosis of the lower limbs. We evaluated the early signs of iliac artery involvement in patients with asymptomatic Type II hyperlipoproteinemia. Of these, 23 were Type IIA, 12 were Type IIB. Thirty-five consecutive patients, ages 40 to 60 years, with asymptomatic Type II hyperlipoproteinemia (LDL cholesterol greater than or equal to 3.80 mmol/liter, 147 mg/dl) and 54 normocholesterolemic controls (plasma cholesterol less than 5.70 mmol/liter, 220.6 mg/dl) from a random sample of clinically healthy, 50-year-old men had a noninvasive examination to detect common and external iliac artery stenosis. Both Type II patients and the controls were examined by the echo-Doppler technique (Duplex Scanner III-ATL Mark V) with spectral analysis of the Doppler signals. This method is sensitive not only to severe stenosis or occlusion but also to non-flow-reducing stenosis (less than 50% narrowing of the lumen diameter) and to minor wall irregularities (1%-15% stenosis). In Type II patients, 19 of 70 limbs (27%) were abnormal as compared to 6 of 108 limbs (6%) in the controls (p less than 0.001). The premature development of an obliterating disease of the iliac arteries was demonstrated in persons asymptomatic for Type II hyperlipoproteinemia.
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PMID:Premature development of iliac artery stenosis in asymptomatic type II hyperlipoproteinemia. 639 45

Atherosclerosis and its consequences account for most morbidity and mortality in Western countries. Atherosclerosis develops over a period of decades and has a complex pathogenesis. It is a disease of the intima and primarily involves four cell types, i.e. endothelial and vascular smooth muscle cells, monocytes and platelets. In recent years, elucidation of the cellular and molecular mechanisms of these cells, and their alterations by cardiovascular risk factors and in atherosclerosis, has markedly expanded knowledge of this disease. In particular, it became clear that endothelial cells play a crucial role in the regulation of platelet function and coagulation, as well as vascular tone and structure. Interestingly, endothelial dysfunction occurs early on in the presence of cardiovascular risk factors such as hyperlipidemia, hypertension and diabetes. This could lead to adhesion of circulating platelets and monocytes, increased accumulation of lipids in the subintima, increased contraction, migration and proliferation of vascular smooth muscle cells. The fact that atherosclerosis develops only in some but not in other parts of the circulation, however, has rarely been considered. With the development of molecular biology it has now become possible to clone differentially expressed genes in vessels with or without atherosclerosis; this in turn makes it possible to characterize better the molecular and cellular mechanisms of the disease. The search for such candidate genes could form the basis for future genetic interventions. This therapeutic approach is likely to assume clinical importance, particularly in monogenetic diseases (i.e. familial hypercholesteremia), while its use in complex polygenetic diseases such as atherosclerosis is more difficult. Restenosis, however, may be accessible to gene therapy earlier on as it is accessible to local gene transfection.
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PMID:[Molecular medicine and gene therapy as exemplified with arteriosclerosis and restenosis]. 750 10

Familial hypercholesterolemia carries a markedly increased risk of coronary artery disease. Reduction of plasma low density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors plus resins or fibrates. The current, 60-week, open-label investigation involved 22 patients whose plasma LDL-C had not reached the target level for prevention of coronary artery disease in 3 previous studies using fluvastatin alone and in combination with other cholesterol-lowering medications. At the beginning of the current study, patients were stabilized on fluvastatin monotherapy at 40 mg/day. After 6 weeks, the daily treatment changed to a combination of fluvastatin 40 mg/day in the evening and bezafibrate 400 mg/day in the morning. After a further 6 weeks, a lunchtime dose of cholestyramine 8 g/day was added, to form triple cholesterol-lowering therapy. Efficacy was determined by plasma lipid/lipoprotein analysis. Baseline levels were assessed after 4 weeks of placebo treatment, prior to active treatment, in the first fluvastatin study. Safety analyses included liver and renal function tests, creatine phosphokinase levels and blood counts. Compliance was determined by counting the fluvastatin capsules, bezafibrate tablets, and cholestyramine sachets returned by the patients at each visit. The triple-drug combination used in this study was more effective than the double therapy and resulted in stabilization of the LDL-C:high density lipoprotein cholesterol (HDL-C) ratio, at a reduction from baseline ranging from -40.4 to -52.5%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Efficacy and safety of triple therapy (fluvastatin-bezafibrate-cholestyramine) for severe familial hypercholesterolemia. 760 7

The aim was to identify genetic determinants for the development of hyperlipidemia and/or atherosclerosis. The present set of studies demonstrates for the first time the clinical expression (phenotype) of a newly discovered monogenic disorder named Familial Defective Apolipoprotein B-100 (FDB). FDB is caused by a G to A mutation in the binding protein (apolipoprotein B-100) for the cholesterol-rich low density lipoprotein (LDL), such that the affinity of LDL to the LDL receptor is severely reduced. In all 135 individuals with FDB from 56 families and 8 different countries, including Denmark, are described. On average, the effect of the FDB mutation was to increase plasma and LDL cholesterol in both men and women by about 3 mmol/l; at age 55 the average plasma cholesterol of men and women with FDB was 9.4 mmol/l and 8.9 mmol/l, respectively. A sharp rise in frequency of coronary artery disease as a function of age in both FDB males and females was comparable to that found in Familial Hypercholesterolemia (FH). At the age of 60, about 70% of both men and women with FDB had coronary artery disease; at the same age approximately 40% had tendon xanthomas, and 35% had arcus corneae, irrespective of gender. Surprisingly, the frequencies of arcus corneae were not strikingly higher than those found in the general population sample from the Copenhagen City Heart Study. Only few patients with FDB had xanthelasmas. Finally, the frequency of this mutation was estimated at 1/500-1/700 in the general population, which is equivalent to that of clinical FH. All in all the results suggest FDB to be a severe genetic disorder with early penetrance, associated with substantial elevations in plasma and LDL cholesterol and with an increased frequency of premature coronary artery disease and of tendon xanthomas. For comparison, a number of common polymorphisms in the 5'-flanking region of the insulin gene, in the apoB gene and in the apoAI-CIII-AIV gene cluster, associated with minor effects on hyperlipidemia and/or cardiovascular disease are also examined.
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PMID:Rare and common mutations in hyperlipidemia and atherosclerosis. With special reference to familial defective apolipoprotein B-100. 765 81

The development of advanced coronary atherosclerosis was studied in the FHC swine. This model exhibits spontaneous elevations in plasma cholesterol, LDL, and apo B while fed a low-cholesterol, low-fat diet. Hypercholesterolemic animals bearing the apo B genotypes Lpb2/3, 3/3, 3/5, 5/5 and 3/8 developed stenotic coronary lesions containing necrotic cores, fibrous caps, calcification, neovascularization, hemorrhage, and fissuring. Myocardial infarction and myocardial ischemia were also observed. The complicated atherosclerotic plaques observed in this swine model closely resemble advanced coronary artery disease (CAD) found in humans. While coronary atherosclerosis was not observed in the absence of hypercholesterolemia, neither the apo B genotype nor the level of hypercholesterolemia was found to predict the extent of lesion formation. Similar to the case in humans, the familial dyslipidemia associated with the development of CAD in the FHC swine appears to be polygenic.
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PMID:Familial hypercholesterolemia associated with coronary atherosclerosis in swine bearing different alleles for apolipoprotein B. 769 72

Familial hypercholesterolemia (FH) is the genetic lipid disorder with a higher risk to develop coronary heart disease (CHD). In the heterozygous patients there are, however, variability in the atherosclerosis age of onset and severity. In recent years, it has been reported elevated levels of Lp(a) in FH, and it is proposed that this lipoprotein contributes to the development of CHD in these patients. This study evaluates the relationship between Lp(a) levels and the presence of CHD in FH. We included 38 patients with heterozygous FH with or without CHD (13 and 25 respectively), and a control group. In comparison to the control group, FH patients had significant elevated levels of Lp(a) (median 8.1 vs 16 mg/dL), and a greater prevalence of hyper Lp(a) (with a cut-off level of 30 mg/dL) (11.4 vs 25.7%). FH patients with CHD had higher levels of Lp(a) than those without CHD (22.8 vs 14.4 mg/dL). A significative negative correlation between age of onset of CHD and Lp(a) levels was found in females. CHD in FH was associated with male gender, older age, higher prevalence of hypertension, higher waist/hip ratios, higher levels of triglycerides and prevalence of hypertriglyceridemia. Our findings suggest that Lp(a) may play a role as an additional risk factor to develop atherosclerosis in FH.
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PMID:[Lipoprotein(a) in heterozygote familial hypercholesterolemia]. 772 91

Familial hypercholesterolemia (FH) is a disorder of LDL receptor abnormalities, and the resultant high-LDL-cholesterolemia produces atherosclerosis. More than 150 different mutations in the LDL receptor gene have been reported in the world. Seven variants of the LDL receptor gene have been identified in our laboratory. These seven mutants in 85 patients from 31 families accounted for only 15.5% of the FH cases. LDL receptor gene abnormalities are highly heterogenous in Japan, and the variation of the LDL receptor mutant may determine the severity of hypercholesterolemia and coronary heart disease in FH. A serum HDL above 60 mg/dl is a negative risk factor for coronary atherosclerosis. We found that familial hyperalphalipoproteinemia can be produced by CETP deficiency due to a CETP gene. Two common mutants of the CETP gene produce a CETP deficiency and resultant antiatherogenic lipoprotein pattern (i.e. hyper-HDL-cholesterolemia and hypo-LDL-cholesterolemia), and the frequency of the mutant allele is more than 1 in 10 subjects in Japan. Finally, we found unique patients with double heterozygotes of FH and CETP deficiency. We found 16 double heterozygotes of the LDL receptor gene and CETP gene. Four of the 16 patients showed myocardial infarction and 4 showed angina pectoris. These findings suggest that the atherogenicity of hyper-LDL-cholesterolemia in FH is more powerful than antiatherogenicity of hyper-HDL-cholesterolemia in CETP deficiency.
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PMID:[Molecular genetics of cholesterol transport and cholesterol reverse transport disorders (familial hypercholesterolemia and CETP deficiency), and coronary heart disease]. 773 14

In order to the reduce the LDL level of Familial hypercholesterolemia (FH), direct LDL removal techniques have been used in several laboratories. In Japan, selective LDL-apheresis by dextran sulfate cellulose column have been developed and is used in treatment of homo- and heterozygous FH patients. In this paper, I reviewed the effectiveness of LDL-apheresis treatment in FH patients with many evidences of regression of atherosclerosis and discussed the potential role of this technique in the future treatment for coronary heart disease. No significant side effect for long term treatment is not experienced.
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PMID:[LDL apheresis in the treatment of hyperlipoproteinemia]. 785 26

Several experimental trials are under way to correct the deficiency of LDL receptor function known as Familial Hypercholesterolemia (FH) that develops devastating atherosclerosis leading to premature fatal coronary occlusion. Recently, a 28-year-old FH homozygous woman has received ex vivo autologous liver transplantation after transduction with retroviral vector expressing functional LDL receptors. The outcome is partially successful but is still controversial because of an argument that the apparent small decrease in the total plasma cholesterol level is not necessarily caused by the correction of the LDL receptor expression. In addition to retrovirus, adenovirus vector and non-viral methods are being employed as potential tools for FH gene therapy.
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PMID:[Perspective of gene therapy in hyperlipoproteinemia]. 785 27


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