[HMG-CoA reductase inhibitors].
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Clinical Trials as Topic↗
Biomedical subjects
D Seidel
Publications and source records attributed to D Seidel.
Aggressive lowering of fibrinogen and cholesterol in the prevention of graft vessel disease after heart transplantation.
BACKGROUND: A combined treatment of statins and extracorporeal H.E.L.P.-apheresis (Heparin-mediated Extracorporeal LDL/fibrinogen Precipitation) has already been shown to be beneficial for coronary artery disease (CAD). Presumably high levels of LDL cholesterol, Lp(a), and fibrinogen also increase the risk for graft vessel disease (GVD). Therefore, we studied whether this concept can be applied in GVD, based on the hypothesis that GVD is an accelerated form of CAD. METHODS AND RESULTS: For comparison of statin treatment alone with the combined treatment, two matched groups of 10 cardiac transplant recipients were studied during a mean period of 3.6+/-1.0 years. Both groups were comparable in clinical characteristics, immunosuppressive medication, baseline plasma Lp(a), and high fibrinogen levels. Group I had normal LDL-C levels (3.36+/-0.60 mmol/L). Simvastatin alone was administered in this group to counteract the LDL-increasing effect of the immunosuppressive medication. Group II had marked hypercholesterolemia (LDL-C, 6.07+/-1.89 mmol/L), which was treated, in addition to simvastatin, with H.E.L.P.-apheresis weekly. GVD was assessed by coronary angiography. Simvastatin alone kept LDL-C levels within baseline limits but could not prevent GVD in 7 of 10 patients. In contrast, the combined treatment prevented GVD in 9 of 10 patients (P=.006) by simultaneous and drastic reduction of 48% LDL-C (P=.006), 35% fibrinogen (P=.002), and 47% Lp(a) (P=.006) below baseline. Both treatments were well tolerated and did not affect prevention of graft rejection and infections. CONCLUSIONS: A strategy of early, drastic lowering of fibrinogen, LDL-C, and Lp(a) helps to prevent GVD.
Adult↗
Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial.
BACKGROUND: Accelerated graft vessel disease (GVD) represents the most serious long-term complication of heart transplantation. A possible cause underlying this progressive coronary vascular disease is believed to be post-transplantation hypercholesterolemia. METHODS AND RESULTS: In a 4-year prospective randomized study with heart transplant recipients, the efficacy of primary antihypercholesterolemic therapy with simvastatin was compared with that of general dietary therapy. The aim of the treatment was to maintain post-transplantation LDL-cholesterol levels at <120 mg/dL. Seventy-two heart transplant recipients receiving standard triple immunosuppression were randomly assigned to an active-treatment group (low-cholesterol diet and simvastatin, n=35) or a control group (general dietary measures, n=37). In the course of 4 years after transplantation, the simvastatin group had significantly lower LDL-cholesterol concentrations than the control group (mean+/-SD, 115+/-14 versus 156+/-17 mg/dL,P=.002), a significantly better long-term survival (88.6% versus 70.3%,P=.05), and a lower incidence of GVD in the coronary angiographic findings (16.6% versus 42.3%,P=.045). The incidence of graft rejections did not differ between the two groups, although there was a tendency toward a lower number of serious rejections in the simvastatin group (2.8% versus 13.5%, P=.1). Intracoronary ultrasound performed after 4 years in a subgroup of 27 patients (simvastatin, 10; control, 17) showed less intimal thickening in patients with LDL-cholesterol levels of <110 mg/dL (170+/-84 versus 370+/-171 microm, P=.04) and a lower intimal index (13.8+/-7.1% versus 27.9+/-12.1%,P=.04). CONCLUSIONS: In comparison with dietary measures alone, the combination of a low-cholesterol diet and simvastatin after heart transplantation led to a significant reduction in cholesterol levels, a significantly higher long-term survival rate, and a lower incidence of GVD.
Adult↗
Ten-year follow-up results from the Goettingen Risk, Incidence and Prevalence Study (GRIPS). I. Risk factors for myocardial infarction in a cohort of 5790 men.
Besides the accepted major risk factors for myocardial infarction (MI), cholesterol, hypertension and smoking, several other variables such as lipoproteins, apolipoproteins, fibrinogen and family history of MI, have been considered, but their usefulness as predictors of MI is controversially discussed. The Göttingen Risk Incidence and Prevalence Study (GRIPS) aimed to evaluate the independent impact of the latter in comparison to the established risk factors. GRIPS is a prospective cohort study, which included 5790 men, aged 40-59.9 years, without cardiovascular disease at baseline. Multivariate logistic regression models for the estimation of the MI risk based on the 10-year follow-up data from 97.4% of the study participants established LDL cholesterol as the strongest predictor of MI. It was followed by family history of MI, Lp(a), age, smoking, systolic blood pressure, HDL cholesterol (inversely related) and plasma glucose (P < 0.001). Apolipoprotein B as well as the ratios total/HDL cholesterol, LDL/HDL cholesterol and Apo B/AI were less effective predictors than LDL cholesterol and did not contribute independently to the estimation of MI risk. Similarly apoprotein AI was a weaker predictor of MI risk then HDL cholesterol. GRIPS is the first prospective cohort study which clearly justifies the key role of LDL cholesterol in preventive strategies. However, the data also give strong support for the additional consideration of other risk factors for a valid estimation of the MI risk for an individual subject.
Blood Glucose↗
Transforming growth factor-beta1 induces activation of Ras, Raf-1, MEK and MAPK in rat hepatic stellate cells.
The transdifferentiation of hepatic stellate cells into myofibroblast-like cells and the proliferation of the transdifferentiated cells are controlled by TGF-beta1. Little is known about the intracellular signal transducers of TGF-beta1. In this paper we show that in cultured hepatic stellate cells TGF-beta1 induces activation of Ras, Raf-1, MEK and MAPK p42 and p44. The activation of MAPK depends on the activation of MEK. Our data exclude that the observed effects are mediated by a bFGF or PDGF autocrine loop.
Animals↗
Expression of vascular cell adhesion molecule-1 (VCAM-1) in the aortae of hypercholesterolemic rabbits with high (HAR) and low (LAR) atherosclerotic response.
Recently we have described two strains of rabbits, one with a low (LAR) the other with a high (HAR) atherosclerotic response to dietary hypercholesterolemia. After feeding a cholesterol diet for 12 weeks, HAR rabbits developed atherosclerotic lesions throughout the entire aortic arch and thoracic aorta. In contrast, the lesions in LAR rabbits were mainly confined to the aortic arch. Presently we studied the cellular composition and expression of vascular cell adhesion molecule-1 (VCAM-1) in aortic lesions and in the uninvolved aorta of cholesterol fed HAR and LAR rabbits. Plasma cholesterol levels were 1106 +/- 160 and 1152 +/- 232 mg/dl in HAR and LAR rabbits, respectively, and the distribution of cholesterol among the lipoprotein fractions was similar after 16 weeks of 0.5% cholesterol feeding. In analogy to our previous findings, in the HAR rabbits more than 70% of the aorta (aortic arch and thoracic aorta) was covered with lesions, whereas in the LAR rabbits the lesions were seen in the aortic arch only and covered less than 20% of the total aortic surface. The cellular composition of aortic lesions was defined using specific antibodies to macrophages, smooth muscle cells, T lymphocytes and Ia expressing cells. All these cellular elements were represented in lesions derived from both strains of rabbits. We also examined the expression of VCAM-1 in the aorta of HAR and LAR rabbits after cholesterol feeding. In the aortic arch, a positive reaction for VCAM-1 was found in lesions from both strains of rabbits. The staining was seen in the endothelium and within the lesion, mainly at its base. In the thoracic aorta of HAR rabbits, VCAM-1 expression was found in all lesions examined. In the thoracic aorta of LAR rabbits, VCAM-1 expression was seen in an occasional very small lesion found at the ostium of an intercostal artery. These results show that the VCAM-1 gene is expressed in the LAR rabbits, but its induction is perhaps attenuated.
Animals↗
Chronic work stress is associated with atherogenic lipids and elevated fibrinogen in middle-aged men.
OBJECTIVES: To examine the association between a model of chronic work stress (high efforts in combination with low rewards) and two risk factors of coronary heart disease, low-density-lipoprotein (LDL)-cholesterol and fibrinogen. DESIGN: A cross-sectional study in a group of 179 healthy middle-aged (48.5 +/- 4.5) male middle managers. SETTING: A large car-producing enterprise in Germany. RESULTS: After adjustment for relevant covariates, logistic regression analysis showed independent effects of a composite measure of high effort and low reward at work on the prevalence of elevated (upper tertile, i.e. > or = 160 mg dL-1) LDL-cholesterol (prevalence odds ratio (POR) = 3.57; 95% confidence intervals (CI): 1.24-10.20) and on elevated (upper quintile, i.e. > or = 420 mg dL-1) plasma fibrinogen (POR = 6.71 (CI: 1.57-28.76). Apart from this core measure, cigarette smoking, overweight and alcohol consumption were the covariates with the relatively strongest contributions to the multivariate model. CONCLUSIONS: Results give preliminary evidence on an independent association of chronic work stress with atherogenic lipids and with elevated fibrinogen in an occupationally homogeneous group of healthy middle-aged men.
Adult↗
Increased oxidation of LDL in patients with coronary artery disease is independent from dietary vitamins E and C.
There is increasing experimental evidence that oxidation of LDL plays a major role in the pathogenesis of coronary artery disease (CAD). However, results from clinical studies on LDL oxidation and CAD are not consistent. In most studies only single plasma factors of LDL oxidation have been determined. We studied 207 patients who underwent coronary angiography. They were divided into subjects with CAD (n = 137) and those without CAD (n = 70). We determined the susceptibility of LDL to in vitro oxidation (lag phase), potential prooxidative and antioxidative plasma factors (plasma vitamin E, LDL vitamin E, ascorbate, iron, copper, ferritin, and ceruloplasmin), and markers of in vivo LDL oxidation (autoantibodies to malondialdehyde-modified LDL, oxidized LDL, and thiobarbituric acid-reactive substances), plasma lipids and lipoproteins, smoking habits, and other coronary risk factors in both groups. The lag phase was significantly shorter in patients with CAD than in patients without CAD (101 +/- 38.6 versus 119 +/- 40.6 minutes, P < .01). There was no correlation between the lag phase and the other oxidation parameters or the coronary risk factors. In multivariate regression analyses the lag phase remained significant in all tested models. Our data suggest that a short lag phase of LDL oxidation might be an independent risk factor of CAD.
Aged↗
The acid lipase gene family: three enzymes, one highly conserved gene structure.
Human gastric lipase (HGL; triacylglycerol lipase; EC 3.1.1.3) plays an important role in the digestion of dietary triglycerides in the gastrointestinal tract, especially in patients suffering from pancreatic lipase deficiencies. The enzyme is secreted by the fundic mucosa of the stomach and hydrolyzes the ester bonds of triglycerides under acidic pH conditions, while cholesteryl esters are not attacked. The 379-amino acid protein is highly homologous to two other acidic lipases, rat lingual lipase (RLL; triacylglycerol lipase; EC 3.1.1.3) and human lysosomal acid lipase (HLAL; cholesteryl esterase; EC 3.1.1.13). To determine whether this remarkable similarity is also present at the genomic level, we have elucidated the respective gene structures by screening three bacteriophage lambda libraries and by polymerase chain reaction-based intron amplification. The genes encoding HGL, RLL, and HLAL are composed of 10 exons interrupted by nine introns and span about 14 kb, 18.7 kb, and 38.8 kb of genomic DNA, respectively. The HGL and RLL gene organizations are identical, suggesting that RLL is the rat gastric lipase expressed in the serous von Ebner glands of the tongue. The positions of the HLAL intervening sequences are also absolutely conserved, except for the location of intron 1. Our results support the concept that HLAL and HGL/RLL are members of a gene family of lipases that most likely have evolved by duplication of an ancestral gene and subsequently assumed distinct roles in neutral lipid metabolism due to sequence divergence and different expression patterns.
Animals↗
Human lysosomal acid lipase/cholesteryl ester hydrolase and human gastric lipase: identification of the catalytically active serine, aspartic acid, and histidine residues.
Human lysosomal acid lipase/cholesteryl ester hydrolase (HLAL), human gastric lipase (HGL), and rat lingual lipase (RLL) constitute a family of mammalian lipases characterized by an acidic pH optimum. HGL and RLL are secreted by the chief cells of the stomach and by the serous von Ebner's glands of the tongue, respectively, and hydrolyze dietary longchain triglycerides in the gastrointestinal tract. HLAL, in contrast, catalyzes the intralysosomal degradation of both triglycerides and cholesteryl esters in virtually all cells except erythrocytes. All three enzymes are proposed to be serine esterases with a catalytic Ser-Asp-His triad similar to other lipases, despite their sensitivity towards sulfhydryl modifying reagents. To investigate the role of conserved serine, aspartic acid, and histidine residues in HLAL and HGL, we constructed 24 mutant lipases with single amino acid substitutions using the site-directed mutagenesis approach. Our combined data strongly support the conclusion that Ser153, Asp324, and His355 are components of the catalytic triad of HLAL and HGL. Structural integrity of the conserved His-Gly dipeptide of lipases also appears to be important for neutral lipid hydrolysis, as replacement of His65 by glutamine abolished HLAL and HGL enzymic activity. Substitution of HLAL residues Asp93, Asp130, and Asp328 with glycine, in contrast, had a more pronounced impact on cholesteryl oleate hydrolysis than on triglyceride hydrolysis. These results provide new insights into the structural basis of HLAL and HGL function.
Animals↗
A multicentre evaluation of the CA 15-3 assay, CA 19-9 assay and CA 125 II assay on the Bayer Immuno 1 System.
The analytical performance of the tumour markers CA 15-3 assay, CA 19-9 assay and Ca 125 II assay on the Bayer Immuno I System was studied according to a revised version of the ECCLS guidelines (Haeckel R. In: Evaluation methods in laboratory medicine, Weinheim, VCH Verlag 1993:47-69) in a multicentre evaluation involving five laboratories. Determination of the 3 analytes generated more than 6000 data. On the Bayer Immuno I System, the imprecisions of the CA 15-3 assay, CA 19-9 assay and CA 125 II assay were better than those found for comparison methods. The median recovery over all five laboratories of system assigned values in control sera was within the 1-s range for the three tumour marker assays. No deviation of linearity could be detected experimentally for all assays. Results for patients' samples showed acceptable agreement between the Bayer Immuno 1 system and several different comparison methods in most cases. One exception was the CA 15-3 assay in comparison with the MCA assay from Roche Diagnostic Systems, where the large difference in values is due to the use of different antibodies and calibrators in the two assays. No carry-over effects could be detected. The selective Bayer Immuno 1 system is fully automated; its practicability was rated as high.
Antigens, Tumor-Associated, Carbohydrate↗
Human lysosomal acid lipase/cholesteryl ester hydrolase and human gastric lipase: site-directed mutagenesis of Cys227 and Cys236 results in substrate-dependent reduction of enzymatic activity.
Chemical modification studies and site-directed mutagenesis experiments have provided evidence that human lysosomal acid lipase/cholesteryl ester hydrolase (HLAL), human gastric lipase (HGL), and rat lingual lipase (RLL) are serine esterases. Loss of HLAL and HGL activity was also observed in the presence of sulfhydryl-reactive substances, suggesting that cysteines are likewise essential for substrate hydrolysis. To study the functional role of the HLAL and HGL cysteine residues, we replaced these amino acids with alanine by site-directed mutagenesis. Substitutions at positions 227 and 236, alone or together, drastically reduced hydrolytic activity in a substrate-dependent manner while the other mutants were not affected to any great extent. HLAL(Cys227-->Ala), HLAL(Cys236-->Ala), and HLAL(Cys227-->Ala, Cys236-->Ala) were essentially inactive against cholesteryl oleate, but retained about 23-39%, 28-37%, and 13-17% of catalytic activity for both triolein and tributyrin, respectively. The data obtained with the corresponding HGL mutants confirmed the importance of residues 227 and 236 in maintaining enzymatic activity towards long- and short-chain triglycerides. In order to assess the contribution of the eight amino acids delimited by Cys227 and Cys236 to lipolysis, we generated HLAL replacement mutants containing the corresponding residues 228-235 of HGL or RLL. Both HLAL chimeras were catalytically active towards all three substrates analyzed, indicating that these amino acids do not determine HLAL substrate specificity. Deletion of the eight-amino acid alpha-helix as well as disruption of its hydrophobic surface, in contrast, abolished enzymatic activity. Our studies suggest that Cys227, Cys236, and the amphipathic helix formed by residues 228-235 are essential for HLAL- and HGL-mediated neutral lipid catabolism.
Amino Acid Sequence↗
In memoriam Professor Dr. Dr.h.c.mult. Gotthard Schettler.
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Arteriosclerosis↗
Determination of LDL- and scavenger-receptor activity in adherent and non-adherent cultured cells with a new single-step fluorometric assay.
Lipoproteins labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) are widely used to visualize LDL-and scavenger-receptor activity in cultured cells. The purpose of this study was to evaluate a new single-step fluorometric assay with high sensitivity for the quantitative determination of the LDL- or scavenger-receptor activity in adherent and non-adherent cells. We used an aqueous solution of 1 g/l SDS dissolved in 0.1 M NaOH to lyse the cells after incubation with DiI-LDL or DiI-acetylated LDL. This allows for the first time the determination of fluorescence intensity and cell protein in the same sample without prior lipid extraction of the fluorochrome. Fluorescence of the cell lysates was determined in microtiter plates with excitation-emission set at 520 and 580 nm, respectively. This rapid method demonstrates high specificity for determining the LDL- and scavenger-receptor activity in cultured cells (e.g., human skin fibroblasts from patients with and without familial hypercholesterolemia; human U-937 monocyte and murine P388 D1 macrophage cell lines). The validity of our fluorescence assay is demonstrated by comparison of cellular uptake and metabolism of lipoproteins labeled with both, DiI and 125iodine. The rapidity and accuracy of this assay allows its routine application for studying receptor-mediated lipoprotein uptake in various cell types.
Animals↗
Considerations about plasma fibrinogen concentration and the cardiovascular risk: combined evidence from the GRIPS and ECAT studies. Goettingen Risk Incidence and Prevalence Study. European Concerted Action on Thrombosis and Disabilities.
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Adult↗
The T-cell receptor beta chain CDR3 region of BV8S1/BJ1S5 transcripts in type 1 diabetes.
We recently described the T-cell receptor (TCR) beta chain CDR3 motif S-SDRLG-NQPQH (BV8S1-BJ1S5) in an islet-specific T-cell clone (K2.12) from a type 1 diabetic patient (AS). A similar motif (RLGNQ) was also reported in a T-cell clone of non-obese diabetic (NOD) mice by others. In order to determine the frequency of our motif in selected and unselected T-cell populations, we cloned and sequenced the CDR3 region of BV8S1-BJ1S5 transcripts. These transcripts were derived from unstimulated peripheral blood T lymphocytes from two type 1 diabetic patients (AS and FS) and their non-diabetic sibling (WS), as well as from an islet-specific T-cell line of one of the patients. In addition, we compared the structure and composition of the CDR3 region in BV8S1-BJ1S5 transcripts from peripheral blood T cells between the patients and their non-diabetic sibling (>50 sequences each). We found that 30% of the islet-specific T-cell line cDNA clones expressed the entire sequence-motif, whereas it was absent in the clones of unstimulated peripheral blood T cells from both patients and their non-diabetic sibling. The average length of the CDR3 region was shorter in the patients (mean AS 9.9, FS 9.9, versus WS 10.7, p = 0.0037) and the number of inserted nucleotides in N nucleotide addition at the DJ-junction lower (mean AS 3.5, FS 3. 2, versus WS 5.2, P = <10(-4)) as compared with their non-diabetic sibling. Moreover, the pattern of amino acid usage in the CDR3 region was dissimilar at positions 5 and 6, where polar amino acids predominated in both diabetic siblings. In contrast, basic amino acids are preferentially used at position 5 in the clones of the non-diabetic sibling. These data provide information on the general structure of the TCR(BV8S1-BJ1S5) CDR3 region in type 1 diabetes and may indicate differences in the amino and nucleic acid composition of the TCR beta chain CDR3 region between two type 1 diabetic patients and their non-diabetic sibling.
Adult↗
Study of causes underlying the low atherosclerotic response to dietary hypercholesterolemia in a selected strain of rabbits.
We have recently characterized a strain of rabbits that shows a low atherosclerotic response (LAR) to dietary hypercholesterolemia in contrast to the usual high atherosclerotic response (HAR) of rabbits [1]. Presently, we have focused on three well established and important stages of atherogenesis, i.e., monocyte adhesion to endothelium, cell mediated peroxidative modification of lipoproteins and induction of a receptor that recognizes modified low density lipoprotein (LDL). The results obtained show that (1) beta-very low density lipoprotein (beta-VLDL) from LAR and HAR rabbits enhanced monocyte adhesion to endothelial cells to the same extent; (2) Cell mediated peroxidation of LDL and beta-VLDL, tested by loss of alpha-tocopherol and formation of thiobarbituric acid reacting substances (TBARS), was compared using macrophages, fibroblasts and smooth muscle cells (SMC) of LAR and HAR rabbits and no significant differences were found; (3) Induction of scavenger receptor by phorbol ester (phorbol 12-myristate 13-acetate (PMA)) and platelet-derived growth factor-BB (PDGF-BB) was determined in SMC or fibroblasts from LAR and HAR rabbits using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-acetylated LDL (DiL-acLDL). We found a significantly higher uptake of DiI-acLDL in SMC and fibroblasts derived from HAR rabbits as compared with cells from LAR rabbits. Similar results were also obtained with [125I]-acLDL in fibroblasts from LAR and HAR rabbits with respect to cellular lipoprotein degradation after PMA pretreatment. Even though the attenuated atherosclerotic response to hypercholesterolemia of LAR rabbits may have multiple underlying causes, the most prominent so far is an apparent difference in inducibility of scavenger receptor in SMC and fibroblasts.
Animals↗
Hyperlipoprotein(a)aemia in nephrotic syndrome.
The nephrotic syndrome is frequently associated with hyperlipidaemia and hyperfibrinogenaemia, leading to an increased coronary and thrombotic risk, which may be enhanced by high lipoprotein (a) [Lp(a)] concentrations. We followed the quantitative and qualitative pattern of plasma lipoproteins over 18 months in a patient with nephrotic syndrome suffering from premature coronary artery disease and with elevated level of Lp(a) (470 mg dL-1). Analysis of kinetic parameters after heparin-induced extracorporeal plasma apheresis revealed a reduced fractional catabolic rate for both low-density lipoprotein (LDL) and Lp(a). After improvement of the nephrotic syndrome, Lp(a) decreased to 169 mg dL-1 and LDL concentrations were normalized. The decrease of Lp(a) was associated with an increase in plasma albumin concentrations. Analysis of apo(a) isoforms in the patient showed the presence of isoform S2 (alleles 10 and 19). Consequently, the authors' present strategy is to normalize the elevated Lp(a) and fibrinogen levels. For this purpose heparin-mediated extracorporeal LDL precipitation (HELP) apheresis is a promising regimen, helping to reduce the thrombotic risk and prevent coronary and graft atherosclerosis as well as the progression of glomerulosclerosis in our patient.
Adult↗