摘要:

The genetic basis of familial combined hyperlipidemia (FCHL) has eluded investigators for 20 years, despite the apparent segregation of FCHL as an autosomal dominant disorder affecting 1% to 2% of individuals. Etiologic heterogeneity and additive effects of traits controlled by other genetic loci have been suggested. Two traits have been implicated in FCHL. The first is the predominance of a small, dense low-density lipoprotein (LDL), LDL subclass phenotype B, which segregates as a mendelian trait. The second is a mendelian locus with large effects on apolipoprotein (apo) B levels that is defined by complex segregation analysis (predicted apoB level genotype). This study shows that these factors appear to be separate genetic effects, both of which aid in the prediction of FCHL in four large pedigrees. The results suggest that FCHL may be best predicted by a threshold model in which apoB level genotype and LDL subclass phenotype each act to increase the risk of FCHL. Heterogeneity in the transmission of apoB levels among families is suggested, supporting the etiologic heterogeneity of FCHL. These results emphasize the advantages inherent in the study of large pedigrees when disease heterogeneity is suspected.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We identified the first insertion mutation that specifies an apolipoprotein (apo)B truncation, apoB-70., in a father and son with hypobetalipoproteinemia (total and lowdensity lipoprotein [LDL] cholesterol <5th percentile, plasma apoB levels approximately one third of normal). The mutation is due to insertion of an adenine (A) into a 7-A repeat between cDNA position 9754 and 9760 of the apoB gene, resulting in a frame shift of 13 new amino acids and a termination codon at amino acid residue 3197. The DNA mutation cosegregated with the apoB truncation and hypobetalipoproteinemia in the kindred. The two apoB-70.5/apoB-100 heterozygotes also are apoE2 homozygotes by genotyping; β-very-low-density lipoprotein (VLDL) was present, and VLDL cholesterol/triglyceride ratios were increased (0.29) in the plasmas of both. Density gradient ultracentrifugation and gel filtration chromatography profiles showed increased amounts of particles in the VLDL and intermediate-density lipoprotein density and size ranges and relatively smaller peaks of LDL than in controls. Two populations of LDL were present. ApoB-70.5 was primarily associated with LDL particles of higher density and of smaller size than the LDL particles containing apoB-100. ApoB-48-containing particles were present in the VLDL of fasting plasmas of both subjects, and the postprandial levels of chylomicrons and remnants as measured by the vitamin A fat tolerance test were increased. In conclusion, both subjects heterozygous for apoB-70.5 and homozygous for apoE2 showed the classic characteristics of dysbetalipoproteinemia superimposed onto the hypolipoproteinemic state.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with familial dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Argl58→Cys) homozygosity (the E2-158 variant, n=6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n=6), or apoE2(Lysl46→»Gln) heterozygosity (the E2-146 variant, n=6), with average plasma cholesterol concentrations of 8. 9±1.34 mmol/L, 9.29±1.55 mmol/L, and 8.46 ±1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90±0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70±0.26, 1.50±0.26, 1.05±0.36, and 0.47±0.14 mmol/L, respectively), LDL cholesterol concentration (1.83+0.50, 3.09±0.32, 3.79±0.76, and 3.77±0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98 ± 0.28, 0.48+0.04, 0.28 ± 0.09, and 0.12 ± 0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin: cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We used the single-strand conformational polymorphism method to screen 311 patients with familial hypercholesterolemia from London lipid clinics and Southampton and South West Hampshire health district for mutations in the 3′ part of exon 4 of the low-density lipoprotein (LDL) receptor gene. This part of the gene codes for repeat 5 of the binding domain of the LDL receptor, which is known to be critical for the receptor-mediated removal of both triglyceride-rich lipoprotein remnants and LDL. Six previously described mutations were identified in 29 apparently unrelated individuals (9.3%), with the mutations all lying within a 50-bp fragment of the gene. Three of the mutations are null alleles producing no protein, and the other three lead to production of a defective protein. The effect of the different gene mutations on lipid levels was examined, after the data were combined with information on previously reported mutations in this patient group. Mean LDL cholesterol levels were highest in those individuals with a mutation creating a null allele (9.54 mmol/L) and were similar to levels in those individuals with a mutation affecting repeat 5 that resulted in the production of a defective protein (9.37 mmol/L). In this sample, previously identified patients with a defective protein mutation outside repeat 5 had lower mean levels of LDL cholesterol (7.78 mmol/L), which were similar to levels seen in patients in whom the specific mutation had not been identified (7.31 mmol/L). Overall, these differences were highly statistically significant (P< .001). These data reinforce the observations of other researchers that specific mutations in the LDL receptor gene are associated with different effects on plasma lipids and indicate that the phenotype is influenced by the genotype.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We explored the concept that transesophageal echocardiography can be used as a tool to detect, characterize, and study plaque morphology in the descending thoracic aorta. The pattern of atherosclerotic plaques in the descending thoracic aorta in familial hypercholesterolemic (FH) patients was evaluated. Additionally, evolution of plaque characteristics as a result of therapy was analyzed. In a randomized prospective protocol, eight FH patients (five men and three women, aged 23 to 65 years [mean±SD, 42±14 years]) receiving standard therapy (n=3; baseline low-density lipoprotein [LDL] cholesterol, 222+71 mg/dL, mean±SD) or LDL apheresis (n=5; baseline LDL cholesterol, 262±51 mg/dL) were studied. Baseline and follow-up (mean, 12 months) transesophageal echocardiog aphic studies were performed. Measurements obtained were atherosclerotic plaque area (PA), aortic wall area (WA), total arterial area (TAA), and plaqueto-wall area ratio (PWR). LDL cholesterol decreased in both groups. The greatest severity of plaque was detected at 30 to 35 cm from the incisors (approximately 15 to 20 cm from the O 1994 American Heart Association, Inc. aortic arch). The smallest plaques were present at the arch and more distal descending aorta. In the control group, TAA, PA, and PWR did not change significantly (P= NS versus baseline). In the LDL-apheresis group, TAA increased (P< .05 versus baseline), PA decreased in three of five patients (f=NS versus baseline), and PWR fell (P< .05 versus baseline). When represented in absolute percentages, the changes between baseline and follow-up among the control group were TAA +4%, PA +32%, and PWR +24%; among the LDL apheresistreated group, they were TAA +38%, PA −24%, and PWR −46%. These preliminary data suggest that transesophageal echocardiography is a useful tool to study atherosclerosis evolution in the descending thoracic aorta. In this preliminary study, LDL apheresis was associated with greater plaque regression than standard therapy.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The relation between lipoprotein(a) [Lp(a)] as an independent risk factor for coronary atherosclerosis and the severity and extension of angiographically detectable coronary atherosclerotic lesions has not been systematically evaluated. In 118 male patients (54.3±7.4 years) with suspected coronary artery disease and without a history of myocardial infarction undergoing coronary angiography, the relation between plasma Lp(a) levels and other lipoproteins and the severity and extension of coronary lesions was studied. The coronary angiograms were evaluated in a blinded manner according to three scores: vessel score (0 to 3 points for 0 to 3 vessels with stenoses $70%), stenosis score (0 to 32 points; number and severity of coronary stenoses or lesions), and extent score (0 to 100 points; length-extension of all coronary lesions in relation to the total coronary vessel length). The score values obtained were analyzed for correlations with age and levels of total cholesterol (6.08 ± 1.26 mmol/L; mean ± SD), high-density lipoprotein cholesterol (1.04 ± 0.33 mmol/L), low density lipoprotein cholesterol (4.18 ± 1.15 mmol/L), triglycerides (1.88 ± 1.37 mmol/L), and Lp(a) in plasma (19.5 ± 22.6 mg/dL). Bivariate correlation analysis resulted in positive correlations between Lp(a) and vessel score (p< .01), stenosis score (p< .01), and extent score (p< .05). With multivariate analyses, besides Lp(a) plasma level (nl), only patient age showed a significant correlation to all three scores used, whereas none of the lipid parameters correlated significantly with all three scores.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The plasma level of factor VII activity was a risk factor for the development of ischemic heart disease (IHD) in a prospective epidemiological study of hemostatic factors. We have previously reported significant correlations between factor VII clotting activity or antigen and lipid fractions in a group of 132 young men (<30 years old) at low risk for IHD and concluded that control of the plasma factor VII level may be linked to lipid metabolism in normal male physiology. Because factor VII is one of four vitamin K-dependent procoagulant proteins, we hypothesized that plasma levels of all these proteins would be similarly controlled in normal physiology. In an extension of this study, we have measured two additional vitamin K-dependent clotting factors (prothrombin [factor II] and factor X activity), as well as factor VII activity and antigen and fasting serum lipid fractions in healthy young men and women (<30 years old) at low risk for IHD. In the women, we found significant positive correlations of factor VII antigen with total or HDL cholesterol and of prothrombin or factor X with total or LDL cholesterol. In the men, factor VII activity or antigen correlated with total cholesterol, triglycerides, HDL cholesterol, or LDL cholesterol; prothrombin or factor X correlated with total cholesterol, triglycerides, or LDL cholesterol. In contrast, we found no significant correlations of fibrinogen with any of the lipid fractions in our groups of men or women. Our data support the hypothesis that control of the levels of the vitamin K-dependent procoagulant proteins is linked to lipid metabolism in the normal physiology of both men and women.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We evaluated 106 subjects with and 109 subjects without a history of ischemic stroke. All were attending a metabolic ward. The two groups were compared for major risk factors for ischemic events. A positive family history for ischemic complications of atherosclerosis was more common in subjects with a history of stroke than in those without; moreover, plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (TPA) were higher in patients with documented previous events. A strong positive significant correlation was found between TPA and PAI-1 levels, and an interaction between age and TPA was observed when the sample was stratified according to ages being above or below 70 years. When the patient population was analyzed according to the number of ischemic events, it was found that 62 of the 106 subjects with a history of stroke had experienced more than one ischemic event. Under these conditions, the levels of TPA and PAI-1 still correlated with the occurrence of previous ischemic episodes. As in the whole patient sample, TPA was the strongest discriminator. We conclude that in subjects attending a metabolic ward, TPA and PAI-1 levels consistently help identify subjects with a history of cerebral ischemic episodes and that TPA is the strongest discriminator.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The purposes of this study were to compare fibrinofytic responses to moderate intensity exercise in physically active and inactive men and during morning and evening exercise. Fourteen physically inactive men (mean age, 34.7±4.0 years) and 12 regularly active men (34.8±4.0 years) performed two exercise sessions, morning and evening, at 50% of maximal oxygen consumption. Tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1) activity were measured before and after exercise. Data were analyzed using a three-way ANOVA with repeated measures. TPA activity increased with exercise in both groups, although the active group demonstrated greater increases than the inactive group. Postexercise TPA activity was greater with evening than morning exercise. The inactive group exhibited greater PAI-1 activity than the active group. PAI-1 activity was higher during the morning than evening but did not change with exercise for either group. We conclude that moderate intensity exercise increases TPA activity in physically active and inactive men, with greater increases seen in active men, particularly during evening exercise. Moderate intensity exercise does not appear to affect PAI-1 activity. The lower PAI-1 activity in active men may be one mechanism whereby regular physical activity lowers the risk for coronary artery disease.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Study subjects (6 women and 5 men) over the age of 40 years with fasting low-density lipoprotein cholesterol concentrations >130 mg/dL were studied during three 5-week diet phases and one 10-week phase: baseline (36% fat: 13% saturated fatty acids [SFA], 12% monounsaturated fatty acids [MUFA], 8% polyunsaturated fatty acids [PUFA], and 128 mg cholesterol/1000 kcal); reduced fat (29% fat: 7% SFA, 9% MUFA H% PUFA, and 85 mg cholesterol/1000 kcal); and two low fat (15% fat: 5% SFA 5% MUFA 3% PUFA and 73 mg cholesterol/1000 kcal). Body weight was maintained during the first three 5-week phases (baseline, reduced fat, and low fat [energy]) and decreased during the last 10-week phase when the low-fat diet was provided such that the subjects determined, in part, their caloric intake (low fat [J, energy]). Mean body weight declined by 0.62 ±0.47 kg/wk during the first 5 weeks and 0.43 ±0.43 kg/wk during the second 5 weeks of the 10-week low-fat (], energy) period. Relative to the baseline diet, plasma cholesterol concentrations decreased from 226±33 to 195±19 (−13%), 208±22 (−7%), and 190±19 (−15%) mg/dL when the subjects consumed the reduced-fat, low-fat (energy), and low-fat (j energy) diets, respectively. Low-density lipoprotein cholesterol concentrations decreased from 158±28 to 128±16 (−18%), 134±17 (−14%), and 119±15 (−23%) mg/dL when the subjects consumed the reduced-fat, low-fat (→ energy), and low-fat (j. energy) diets, respectively. High-density lipoprotein cholesterol concentrations decreased from 48±11 to 42±9 (−10%), 35±7 (−25%), and 38±8 (−18%) mg/dL when the subjects consumed the reduced-fat, low-fat (→ energy), and low-fat (j energy) diets, respectively. Triglyceride concentrations increased from 110±32 to 115±31 (8%), 188±76 (75%), and 130±32 (22%) mg/dL when the subjects consumed the reduced-fat, low-fat (→ energy), and low-fat (J, energy) diets, respectively. Maximal changes in plasma h'pid concentrations were observed after the first 5 weeks of the low-fat (J. energy) diet phase despite continued weight loss throughout the entire 10-week diet period. These data suggest that very-low-fat diets (15% of calories) beneficially affect plasma lipid profiles relative to the baseline (36% of calories) or reduced-fat (29% of calories) diets only when accompanied by weight loss.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID