The influence of simvastatin alone or in combination with gemfibrozil on plasma lipids and lipoproteins in patients with type III hyperlipoproteinemia

Summary Nineteen adult patients with type III hyperlipoproteinemia (HLP) and homozygosity for apolipoprotein (apo) E2 were treated with the 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase inhibitor simvastatin (20 or 40 mg per day) alone or in combination with the fibrate derivative gemfibrozil (450 mg per day) during a 30-week outpatient study. With the 20-mg dose (n = 19) the mean plasma cholesterol level decreased from 13.24±8.04 8.04 at baseline to 8.04±4.19 mmol/l (mean reduction 39.3%; P<0.05), and the mean plasma triglyceride level decreased from 13.47±19.22 to 7.84±7.71 mmol/l (–41.8%; NS); this was due to a decrease in very low density lipoprotein (VLDL) cholesterol from 8.95±8.64 to 4.94±4.24mmo1/l (–44.8%; NS), a decrease in low density lipoprotein (LDL) cholesterol from 3.54±0.93to 2.25 ± 0.59 mmol/l (–36.5%; P<0.01), and an increase in high density lipoprotein (HDL) cholesterol from 0.72±0.28 to 0.85±0.34 (+18.1%; NS). Thirteen patients were treated with 40 mg simvastatin per day. Under this regimen there was a further significant decrease in LDL cholesterol from 2.33±0.62 to 1.81±0.49 mmol/l (–22.3%; P<0.01). In six patients who remained hyperlipidemic on monotherapy combination drug therapy with simvastatin (40 mg per day) and gemfibrozil (450 mg per day) was given. Compared to simvastatin alone the addition of gemfibrozil further lowered plasma concentrations of total cholesterol by 14.9%, VLDL cholesterol by 23.5%, and triglycerides by 17.1%, although this was not statistically significant. No patient was discontinued from single or combination drug therapy, and no severe clinical or biochemical side effects were observed. The results of this study demonstrate the usefulness of simvastatin in the therapy of type III HLP and indicate that in individual patients who remain hyperlipidemic on monotherapy combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total cholesterol, VLDL cholesterol, and triglycerides. Although no patient in this investigation developed myopathy or rhabdomyolysis, combined fibrate-HMG CoA reductase inhibitor treatment should be considered only for severe forms of hyperlipidemia and for patients who do not respond sufficiently to mon-therapy of any of these drugs.Abbreviations Apo Apolipoprotein - CPK creatine phosphokinase - GGT gamma-glutamyl transpeptidase - HDL high density lipoproteins - HLP hyperlipoproteinemia - HMG CoA 3-hydroxy-3-methyl glutaryl coenzyme A - IDL intermediate density lipoproteins - LDL low density lipoproteins - TG triglycerides - VLDL very low density lipoproteins     

Treatment of patients with familial defective apolipoprotein B-100 with pravastatin and gemfibrozil: a two-period cross-over study

Thirty patients with familial defective apolipoprotein B-100 were treated in a two-period (8 weeks each) cross-over study with pravastatin and gemfibrozil. Cholesterol, LDL cholesterol, and apo B were reduced by 20–25% (P < 10^–4) by pravastatin and by 4–6% by gemfibrozil (pravastatin vs. gemfibrozil:P < 10^–4). Response to pravastatin was variable and not correlated to gender, age, or apo E genotype. Gemfibrozil lowered triglycerides by 25% (P < 10^–4) and raised HDL cholesterol by 11%. The effects of pravastatin on these two interrelated variables were significantly smaller. Both drugs increased Lp(a) significantly by about 10%. The LDL cholesterol lowering effect of pravastatin in patients with FDB is similar to that observed in patients with familial hypercholesterolemia.Abbreviations FDB familial defective apolipoprotein B-100 - LDL low density lipoprotein - VLDL very low density lipoprotein - HDL high density lipoprotein - LDL-R low density lipoprotein receptor - HMG CoA -hydroxy--methyl-glutaryl coenzyme A - FH familial hypercholesterolemia - TG triglycerides - apo B apolipoprotein B-100 - apo Al apolipoprotein Al - apo E apolipoprotein E - Lp(a) lipoprotein(a) - PCR polymerase chain reaction Correspondence to: P.S. Hansen     

Long-term experience with extracorporeal low-density lipoprotein cholesterol removal by dextran sulfate cellulose adsorption

Summary Patients with familial hypercholesterolemia have a high incidence of coronary heart disease due to diet- and drug-resistant, elevated low-density lipoprotein cholesterol (LDL-C). Five patients with familial hypercholesterolemia and diet- and drug-resistant LDL-C > 230 mg/dl were treated by LDL apheresis using dextran sulfate cellulose adsorption (Liposorber System LA-15, Kaneka). Plasma separation was by 0.5-m² polysulfone hollow fiber filter. Two columns containing 150 ml of dextran sulfate cellulose alternately adsorbed LDL and were regenerated by 4.1% saline. The five patients received a total of 360 treatments at 7-day intervals. The treated plasma volume per session was 4.1 ± 0.41. Postapheresis values compared with preapheresis were: total cholesterol, 40%; LDL-C, 28%; VLDL-C, 65%; HDL-C, 95%; triglycerides, 70%; white blood cells, 116%; platelets, 87%; C3 complement, 79%; fibrinogen, 64%; albumin, 94%. The decrease in HDL-C per treatment was not significant. The safety parameters showed only slight changes. The initial LDL of 436 ± 172 mg/dl decreased to mean pre-apheresis levels of between 150 and 100 mg/dl. The anti-atherogenic HDL increased in three and remained unchanged in two patients. Adverse events like hypotension, angina pectoris, and technical problems occurred in 11 of the 360 treatments. Long-term treatment of patients with diet- and drug-resistant familial hypercholesterolemia by extracorporeal dextran sulfate cellulose adsorption is effective and safe.Abbreviations LDL low-density lipoprotein - LDL-C lowdensity lipoprotein cholesterol - VLDL very low-density lipoprotein - HDL high-density lipoprotein - HDL-C high-density lipoprotein cholesterol - CHD coronary heart disease - FH familial hypercholesterolemia - HMG CoA hydroxy-3methyl-glutaryl coenzyme A - PTT partial thromboplastin time - IU international units - ANOVA analysis of variance     

Therapy of severe familial heterozygous hypercholesterolemia by low-density lipoprotein apheresis with immunoadsorption: effects of the addition of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to therapy

Summary To establish whether additional therapy with 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors enhances the low-density lipoprotein (LDL) cholesterol lowering effect of LDL apheresis with immunoadsorption in the treatment of patients with familial heterozygous hypercholesterolemia and coronary artery disease we studied eight patients initially on immunoadsorption therapy alone for 3 years. The adding of HMG CoA reductase inhibitors decreased pretreatment LDL cholesterol from 6.76±0.98 to 4.97±0.98 mmol/l and posttreatment LDL cholesterol from 2.33±0.80 to 1.94±0.67 mmol/l and increased pre- and posttreatment high-density lipoprotein (HDL) cholesterol by 0.08 and 0.13 mmol/l respectively. The LDL/HDL ratio was reduced from 4.0 to 2.8 (prior to any therapy the ratio was 13.4). The increase in LDL cholesterol between weekly treatments was less steep under the combined therapy. At the same time the treated plasma volume during LDL apheresis could be decreased from 5070±960 to 4370±1200 1200 ml. We conclude that in patients with severe familial heterozygous hypercholesterolemia LDL apheresis should be combined with HMG CoA reductase inhibitors.Abbreviations CoA coenzyme A - HDL high-density lipoprotein - HMG 3-hydroxy-3-methylglutaryl - LDL low-density lipoprotein Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday     

ApoB/apoA1 is an effective predictor of coronary heart disease risk in overweight and obesity

We investigated the relationship of apoB/apoA1 ratio and coronary heart disease (CHD) in persons who were overweight or obese.The subjects were divided by the body mass indexes (BMI) into the normal weight group (n=397,BMI<24 kg/m 2) and the overweight group (n=400,BMI>24 kg/m 2).Our results showed that the overweight group had higher blood pressure [(130.15±19.01) mmHg vs (123.66±18.70) mmHg] and higher levels of blood sugar [(7.09±2.89) mmol/L vs (6.21±2.59) mmol/L],triglyceride [(1.93±1.19) mmol/L vs (1.44±0.85) mmol/L],total cholesterol [(4.26±1.06) mmol/L vs (4.09±0.99) mmol/L],low-density lipoprotein cholesterol (LDL-C) [(2.56±0.75) mmol/L vs (2.39±0.72) mmol/L],and apoB [(0.83±0.27) mg/L vs (0.78±0.23) mg/L],and a higher apoB/apoA1 ratio (0.83±0.27 vs 0.75±0.25) and lower levels high-density lipoprotein cholesterol [(1.10±0.26) mmol/L vs (1.21±0.31) mmol/L] and apoA1 [(1.04±0.20) mg/L vs (1.08±0.22) mg/L] than those of the normal weight group (all P < 0.05).The prevalence of CHD in the over-weight group in the lowest LDL quartile was almost twice greater than that of the highest apoB/apoA1 quartile,compared with the subjects in the lowest apoB/apoA1 quartile.The higher apoB/apoA1 quartile was in agreement with the higher prevalence of CHD.In the overweight and obesity group,the area under ROC curve (AUC) was the highest for apoB/apoA1 (0.655).The cut-off point of apoB/apoA1 for optimal sensitivity and specificity was at 0.80,with a sensitivity of 57.19% and a specificity of 71.72%.In conclusion,apoB and apoA1 were simple clinical indicators,and the apoB/apoA1 ratio was closely related with CHD in overweight and obese patients.The apoB/apoA1 ratio may provide some useful information in the differential diagnosis.     

Clinical features of type III hyperlipoproteinemia: analysis of 64 patients

Summary The clinical and biochemical characteristics of type III hyperlipoproteinemia are described in 64 patients (35 males and 29 females). Homozygosity for apolipoprotein E2, the presence of an abnormally cholesterol-rich very low density lipoprotein fraction (-VLDL) and an elevated ratio of very low density lipoprotein cholesterol to plasma triglycerides (>0.3; normal ratio about 0.2) were the basis for the diagnosis. Mean serum cholesterol and triglyceride concentrations at the first visit in the clinic were 426 ± 221 and 719 ±996 mg/dl, respectively. The mean age at diagnosis of the disorder was 49 years in males and 53 years in females. There was a high prevalence of obesity (72%), xanthomas (42%), and atherosclerosis (39%), especially peripheral vascular disease (31%). Early and correct diagnosis of this familial lipoprotein disorder seems necessary because of the prompt and beneficial response to therapeutic interventions.Abbreviations Apo apolipoprotein - BMI body mass index - CAD coronary artery disease - HDL high-density lipoproteins - HLP hyperlipoproteinemia - HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A - LDL low-density lipoproteins - Lp(a) lipoprotein (a) - PVD peripheral vascular disease - TG triglycerides - VLDL very low density lipoproteins     

Effects of fish oil concentrate on lipoproteins and apolipoproteins in familial combined hyperlipidemia

Summary The effects of two moderate doses of long-chain n-3 fatty acids (3.0 and 4.5 g EPA + DHA per day for 4 weeks each) on serum lipids and lipoproteins of patients with familial combined hyperlipidemia (FCH) were studied in a double-blind, placebo-controlled clinical trial. In nine patients with FCH n-3 fatty acids led to a statistically significant, dose-dependent fall in very low density lipoprotein (VLDL) triglycerides (3 g/day: –42%, 4.5 g/day: –55%) VLDL cholesterol (3 g/day: –41%, 4.5 g/day: –47%), and VLDL apolipoprotein (apo) B-100 (3 g/day: –40%, 4.5 g/day: –56%). No overall change in low-density lipoprotein (LDL) cholesterol was found, as confirmed statistically. However, when analyzing the data of single patients LDL cholesterol and LDL apo B did not change in five patients but increased dose dependently (from pretreatment 4.80±0.93 mmol/l to 5.70+0.93 mmol/l LDL cholesterol after 4.5 g/day) in four. LDL and VLDL composition as indicated by cholesterol/apo B-100 and triglyceride/apo B-100 ratios did not change significantly. High-density lipoprotein (HDL) cholesterol was unchanged; the HDL cholesterol/apo A-I+apo A-II ratio increased by 19% (P<0.05) during fish oil treatment. We conclude that in FCH moderate doses of long-chain n-3 fatty acids are highly effective in lowering pathological VLDL triglycerides, VLDL cholesterol, and VLDL apo B. LDL cholesterol must, however, be monitored during treatment as it may rise substantially in some although not in all patients with this disease.Abbreviations EPA eicosapentaenoic acid - DHA docosahexaenoic acid - FCH familial combined hyperlipidemia - VLDL very low density lipoprotein - LDL low-density lipoprotein - HDL high-density lipoprotein - apo apolipoprotein Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Comparative effects of two HMG-CoA reductase inhibitors (lovastatin and pravastatin) on serum lipids and lipoproteins

The effects of the HMG-CoA reductase inhibitors lovastatin and pravastatin were studied over 4 months on serum lipids and lipoproteins in 35 patients with severe primary hypercholesterolaemia. In 17 patients 20 mg of lovastatin/day lowered the total cholesterol level by 18% (baseline 373 mg/dl) and LDL cholesterol by 20% (baseline 300 mg/dl). The corresponding data for 40 and 80 mg of lovastatin/day were respectively -23% and -29% for total cholesterol, and -30% and -36% for LDL cholesterol. Pravastatin at 20 mg/day lowered the total cholesterol in 18 patients by 20% (baseline 373 mg/dl) and LDL cholesterol by 24% (baseline 307 mg/dl). The corresponding data for 40 mg of pravastatin per day were 24% for total cholesterol and 30% for LDL cholesterol. So the effects of both HMG-CoA reductase inhibitors on total and LDL cholesterol are comparable. HDL (high-density lipoprotein) cholesterol was increased by lovastatin, whereas pravastatin showed no influence on HDL cholesterol. The reduction of serum triglycerides, VLDL triglycerides and VLDL cholesterol was more pronounced under treatment with lovastatin than under pravastatin.     

Comparative long-term experience with immunoadsorption and dextran sulfate cellulose adsorption for extracorporeal elimination of low-density lipoproteins

Two low-density lipoprotein (LDL) apheresis methods allowing a specific extracorporeal removal of atherogenic lipoproteins from plasma were compared concerning their efficacy and safety in the long-term therapy of severe familial hypercholesterolemia. Five patients were treated with immunoadsorption (IMA) at weekly intervals over 3 years each, and three patients received weekly therapy with dextran sulfate cellulose adsorption (DSA) for up to 2 years. The mean plasma volume processed per session to decrease total cholesterol to a target level of 100–150 mg/dl at the end of LDL apheresis was significantly lower in DSA than in IMA: 143% vs. 180% of the individual plasma volume. Both LDL apheresis procedures achieved a mean acute reduction of plasma LDL cholesterol by more than 70%. The average interval concentrations of plasma LDL cholesterol obtained without concomitant lipid-lowering medication were 151 ± 26 mg/dl compared to 351 ± 65 mg/dl at baseline in the IMA-treated patients and 139 ± 18 mg/dl compared to 359 ± 48 mg/dl at baseline in the DSA-treated patients. Two patients from the DSA group died after 2 years of study participation due to a stroke and a sudden cardiac death several days after the last plasma therapy. Treatment-related side effects were infrequent. Long-term therapy with IMA and DSA was associated with symptomatic improvement of coronary artery disease and mobilization of tissue cholesterol deposits. Analysis of coronary angiograms after 3 years of weekly LDL apheresis with IMA revealed in five patients nearly identical atherosclerotic lesions without definite regression or progression.Abbreviations LDL low-density lipoprotein - IMA immunoadsorption - DSA dextran sulfate cellulose adsorption - apo apolipoprotein - Lp(a) lipoprotein(a) - HDL high-density lipoprotein - ACE angiotensin-converting enzyme     

The acute effect of marathon running on plasma lipoproteins in female subjects

Summary The acute effect of running a 42.2 km marathon race on plasma lipoproteins was investigated in 12 female subjects (aged 21 to 41 years). During the race there was a significant increase (P<0.01) in the concentration of total plasma cholesterol. The mean post-race concentration of high density lipoprotein cholesterol (HDL-C) was 64.0±16.2 (SD) mg 100 ml^–1, compared with 52.1±14.0 mg 100 ml^–1 before the race, representing a significant increase (P<0.002). There was no significant difference in the concentration of very low density lipoprotein (VLDL) or low density lipoprotein (LDL) before and after the exercise. The mean concentration of the cholesteryl ester moiety of the HDL increased from 43.7±12.3 to 54.3±15.7 mg 100 ml^–1 (P<0.002), while there was no significant change in the concentration of the unesterified cholesterol, phospholipid, triacylglycerol or protein moieties of the HDL. The relative proportions of apolipoproteins A-I, A-II, C and E remained unchanged during the exercise. The changes in the concentration of each of the lipoprotein fractions observed during the marathon varied considerably between subjects. The individual increases in the concentration of HDL-C ranged from 4.1 to 28.4 mg 100 ml^–1, while both increases and decreases in individual concentrations of VLDL and LDL as well as of total plasma cholesterol were observed. These observations suggest that women undergo greater changes in HDL-C concentration than men during acute exercise, while considerable variation between individuals occurs.     

The effect of the apolipoprotein E polymorphism on lipid levels in patients with familial defective apolipoprotein B-100

Summary Serum lipid concentrations of patients with familial defective apolipoprotein B-100 (FDB) show a high interindividual variability although the underlying defect is caused by a single point mutation. On the other hand, several genetic factors modulating serum cholesterol levels are known, such as DNA polymorphisms of the apopolipoprotein B or the apolipoprotein E (apo E) gene. To assess the effect of the apo E polymorphism on serum cholesterol, lipid levels of FDB patients (n=36) were compared with those of a normolipidemic control group (n=272) according to their apo E genotype. For the FDB group mean values of low-density lipoprotein (LDL) cholesterol (mg/dl) were 225.7 ± 53.7 for E3/2 genotype (n = 3), 234.2±48.3 for E3/3 genotype (n=20), and 252.4±73.8 for E4/3 genotype (n=13). Means of triglycerides (mg/dl) were 121.0±21.2, 114.8± 60.7, and 110.0 ± 62.8 for the respective apo E genotypes. The calculated average effect of the apo E alleles on LDL cholesterol levels was –6.0% for allele e2 and +3.7% for e4 relative to the whole FDB group. The effect on triglyceride levels was +7.5% for e2 and –3.6% for e4. The control group showed a similar variation in LDL cholesterol depending on the different apo E genotypes. About 6% of the total variation in LDL cholesterol can be accounted for by the apo E locus in normolipidemic and hypercholesterolemic individuals alike.Abbreviations FDB familial defective apolipoprotein B-100 - apo apolipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein - HDL high-density lipoprotein - PCR polymerase chain reaction Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Impact of hormone replacement therapy on postprandial lipoproteins and lipoprotein(a) in normolipidemic postmenopausal women

In 43 normolipidemic postmenopausal women we studied fasting and postprandial (oral fat load with 50 g fat per square meter; blood sampling for 5 h) lipoprotein components and lipoprotein(a) levels before and with the administration of conjugated equine estrogens opposed by medrogestone (on days 11–21). Data was compared intraindividually; the second testing was performed during the last 5 days of the combined estrogen/progestogen phase of the third cycle. Fasting low-density lipoprotein (LDL) and total cholesterol concentrations decreased significantly; high-density lipoprotein (HDL) cholesterol, including subfractions HDL₂ and HDL₃, was not changed. Fasting triglyceride concentrations increased. All lipoprotein fractions measured showed a postprandial elevation with the exception of chylomicron cholesterol concentrations. There was a significant effect of hormone replacement therapy on the postprandial course of total cholesterol (decrease; P < 0.001), VLDL cholesterol (increase; P = 0.025), and the triglyceride proportion in the LDL plus HDL fraction (increase; P < 0.001). With hormone replacement therapy the postprandial curve of total triglycerides was increased only 1 h after the fat load while chylomicron triglyceride concentrations were lowered after 5 h. VLDL triglycerides were not influenced. In all patients with lipoprotein(a) levels above 10 mg/dl, this parameter decreased (about 25%). Although increasing fasting triglyceride concentrations, hormone replacement therapy does not bring about an exaggerated postprandial increase in triglycerides. Postprandial chylomicron clearance is evidently promoted. Hormone replacement therapy leads to a small increase in triglycerides in the LDL plus HDL fraction by inhibiting hepatic lipase activity. Moreover, the decrease in lipoprotein(a) levels may contribute to the antiatherosclerotic effect.Abbreviations: CEE conjugated equine estrogens - HDL high-density lipoproteins - HRT hormone replacement therapy - LDL low-density lipoproteins - TG triglycerides - VLDL very low density lipoproteins Correspondence to: U. Julius     

Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred

Plasma lipid and lipoprotein in general reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH in which 69 members were affected with type IIa hyperlipoproteinemia (HLPIIa; high plasma cholesterol) and ten with type IIb hyperlipoproteinemia (HLPIIb; high plasma cholesterol as well as plasma triglyceride). Soluble epoxide hydrolase (EPHX2, sEH) plays a role in disposition of epoxides in plasma lipoprotein particles. Intrafamilial correlation analysis of the modifier effect of Glu287Arg substitution in the EPHX2 gene was carried out among 79 LDLR mutation carriers and 81 noncarriers. In the carriers, plasma cholesterol levels were elevated among carriers of the 287Arg allele (mean±SD=358 ± 72 mg/dl) in comparison with 287Glu homozygotes (mean±SD=302 ± 72 mg/dl) (p=0.0087). Similarly, in the LDLR mutation carriers, the plasma triglyceride levels were elevated among carriers of the 287Arg allele (mean ± SD=260 ± 100 mg/dl) in comparison with 287Glu homozygotes (mean ± SD=169 ± 83 mg/dl) (p=0.020). No such gene-interactive effect was observed among noncarriers of the LDLR mutation. Half of the patients who presented with HLPIIb had inherited a defective LDLR allele as well as an EPHX2-287Arg allele, whereas the majority who presented with HLPIIa had a defective LDLR allele but not an EPHX2-287Arg allele. These results indicate a significant modification of the phenotype of FH with defective LDLR allele by EPHX2-287Arg variation in our studied kindred.     

Expression of Human Secretory Group IIA Phospholipase A2 is Associated with Reduced Concentrations of Plasma Cholesterol in Transgenic Mice

It is well known that acute and chronic inflammatory reactions are accompanied by markedly decreased concentrations of plasma total cholesterol. However, the mechanisms underlying this hypocholesterolemia are not yet completely understood. To explore the question of whether an increased serum activity of secretory group IIA phospholipase A₂ (sPLA₂) may contribute to the development of hypocholesterolemia during inflammation, the lipids and lipoprotein patterns in the plasma of transgenic mice overexpressing the human sPLA₂ gene were studied and compared with those of nontransgenic controls. The mean plasma enzyme activities determined by using [¹⁴C]-oleate labeled Escherichia coli-membranes were found to be 331 ± 262 U/l in transgenic mice while the catalytic activity in plasma of controls was below the analytical sensitivity of the assay (0.5 U/l). Compared to nontransgenic littermates, sPLA₂-transgenic mice exhibited significantly lower plasma concentrations of total cholesterol (2.53 ± 0.37 mmol/l vs. 3.49 ± 0.44 mmol/l, p < 0.0001). The reduction of total cholesterol was due to decreased HDL and LDL cholesterol levels (1.21 ± 0.10 mmol/l vs. 1.78 ± 0.37 mmol/l, and 0.28 ± 0.02 mmol/l vs. 0.69 ± 0.23 mmol/l, respectively, p < 0.05). The analysis of lipoprotein composition indicated that the LDL of transgenic mice were selectively depleted in free and esterified cholesterol, whereas HDL of the two animal groups contained comparable percentages of cholesterol. The triglycerides were significantly enriched in LDL and HDL, but tended to be less in VLDL of transgenic mice. In conclusion, the results of the study have demonstrated that the expression of sPLA₂ may influence the metabolism of lipoproteins, possibly contributing to the development of hypocholesterolemia during inflammation.     

Association of nucleotide variations in the apolipoprotein B48 receptor gene (APOB48R) with hypercholesterolemia

Factors predisposing to the phenotypic features of high total cholesterol (T-Cho) in human plasma have not been clearly defined. Here we report an association between two variations in the apolipoprotein B48 receptor gene (APOB48R) and plasma T-Cho levels among 352 adult individuals in Japan. By analyzing phenotypic associations between age- and gender-adjusted levels of plasma T-Cho, low-density lipoprotein (LDL) cholesterol (LDL-C), and high-density lipoprotein (HDL) cholesterol (HDL-C), we detected a significant correlation between genotypes of the A419P variation and adjusted T-Cho levels. Among homozygous G-allele carriers (n=265), heterozygous carriers (n=78), and homozygous minor C-allele carriers (n=9), T-Cho levels were 2.43±0.21 mg/cm³, 2.48±0.24 mg/cm³, and 2.63±0.21 mg/cm³, respectively, indicating a codominant T-Cho-elevating effect of the minor C-allele (r=0.15, P=0.007). A similar effect was detected for c.934-960/del (r=0.13, P=0.015). Linkage disequilibrium (LD) analysis detected significant LD among eight variant sites that included neighboring loci. Our results indicate that variations in APOB48R and nearby genes are among the many factors involved in hypercholesterolemia. The etiological studies should now include consideration of this novel aspect of the mechanism(s) leading to hypercholesterolemic disease.     

Dietary sodium restriction: Adverse effect on plasma lipids

Summary In order to examine the effect of dietary sodium intake on plasma lipids, 15 healthy male volunteers were given a low-salt diet (20 mmol/day) for 3 weeks, adding either placebo, sodium chloride (200 mmol/day), or a non-chloride sodium salt (sodium citrate, 200 mmol Na/day) for one week each, in a single-blind randomized crossover study.Plasma levels of total cholesterol and LDL cholesterol were significantly higher at the end of the placebo period than with either sodium chloride (by 8.7 and 11.9%, respectively) (P< 0.005) or sodium citrate (by 11.3% and 16.8%, respectively) (P< 0.005). Thus this effect was dependent on sodium but not on chloride intake. Triglyceride and HDL-cholesterol levels were not affected by the dietary regimens. We conclude that short-term dietary sodium restriction may lead to a rise in plasma total and LDL cholesterol, thereby possibly increasing the risk of atherosclerotic vascular disease. Our findings render it possible that diuretic-induced lipid disturbances may also be caused by sodium depletion.Abbreviations LDL low-density lipoprotein - HDL high-density lipoprotein - CHD coronary heart disease - Ht hematocrit - SEM standard error of mean     

Association between sympathetic activity and the atherogenic serum cholesterol fraction

Summary A possible modulating influence of nor-adrenergic activity on serum lipoproteins was assessed under placebo conditions and following 4 weeks of sympathetic neurone blockade with debrisoquine in 9 normal subjects, 11 patients with mild essential hypertension, 9 normotensive, and 9 hypertensive hemodialysis patients. Plasma nor-epinephrine (NE) did not differ significantly among groups on placebo and was consistently reduced (P<0.05–0.001) by sympathetic blockade. The latter also decreased (P<0.05–0.001) plasma total cholesterol (C) as well as low and very low density lipoprotein cholesterol (LDL + VLDL-C) in the three patient groups. In the two dialysis groups, basal levels of plasma triglycerides (Tg) were increased and high density lipoprotein cholesterol (HDL-C) was diminished (P<0.01–0.001); sympathetic blockade lowered Tg and raised HDL-C (P<0.01–0.001). In normal subjects, sympathetic blockade did not significantly modify plasma lipoproteins. In the three patient groups, significant correlations (r=0.62–0.88;P<0.05–< 0.001) existed between (a) basal plasma NE and total C or LDL + VLDL-C and (b) debrisoquineinduced changes in NE and changes in total LDL + VLDL-C. These findings suggest that in essential hypertension as well as in hemodialysis patients, the atherogenic C fraction, represented by LDL + VLDL-C, may be modulated by the nor-adrenergic activity.Supported by the Schweizerischer Nationalfonds für wissenschaftliche Forschung     

Chemistry,biochemistry, and pharmacology of HMG-CoA reductase inhibitors

Summary After an extensive searching for a microbial product that inhibits cholesterol synthesis, compactin and a series of related metabolites like monacolin K (mevinolin) have been isolated from molds as active agents. These compounds, which were structurally related to hydroxymethylglutaryl coenzyme A, were potent competitive inhibitors of hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The inhibition was reversible and the inhibitor constant Ki for compactin was around 10^–9 M. Compactin inhibited cholesterol synthesis in mammalian cells at 10^–9 M. Sterol synthesis in vivo was also reduced when compactin was given orally to rats at a dose of 50 mg/kg. Hydroxymethylglutaryl coenzyme A reductase activity of both cultured cells and rat liver was elevated when sterol synthesis was strongly inhibited by compactin. Both the growth inhibition and reductase induction could be overcome by the presence of mevalonate. A compactin-resistant cell line of mouse FM3A cells, called CR200, was developed by stepwise selection. CR200-cells had an abnormally high level of reductase activity and amplified reductase gene. Compactin was not able to lower plasma cholesterol levels in mice, rats, and hamsters. However, it was highly effective in rabbits, dogs, and monkeys; plasma cholesterol of dogs was reduced by 30%–40% at a dose of 20–50 mg/kg. The low-density lipoprotein cholesterol, which is responsible for atherosclerosis, was preferentially lowered. Compactin was also highly effective in hypercholesterolemic patients at a small dose. The results of the current studies have proved that compactin and related compounds are far more effective in lowering plasma cholesterol than any other drugs available. This work has led to the development of compactin analogues, such as lovastatin (monacolin K, mevinolin) and eptastatin (CS-514).Abbreviations HMG-CoA Hydroxymethylglutaryl coenzyme A - HDL High density lipoprotein - LDL Low density lipoprotein     

Long-term effect of lovastatin alone and in combination with cholestyramine on lipoprotein (a) level in familial hypercholesterolemic subjects

Summary We have determined the effect of lovastatin alone or in combination with cholestyramine on lipoprotein (a) [Lp(a)] levels in 59 heterozygotes for familial hypercholesterolemia (FH) treated for 33.8 (±6.1) months. The median pretrial Lp(a) value was 10.2 mg/100 ml, which is twice the median value in healthy people examined at the Institute of Medical Genetics, University of Oslo. The median Lp(a) level was insignificantly reduced by 10.3% during the first 20 weeks when the subjects were on a standardized medication of increasing doses of lovastatin and cholestyramine. The first 20 weeks were followed by usual care treatment period, and a further decrease in Lp(a) level to 16.2% (P=0.0012) was observed at the end of the study. Comparison between the 20 subjects on lovastatin monotherapy and the 31 subjects on the combined therapy of lovastatin and cholestyramine, revealed that the subjects on monotherapy had a median reduction of 20.1%, and the subjects on the combined therapy had a reduction of 15.4%. Thus, it appears that the reduction in Lp(a) level could be ascribed to lovastatin alone.Abbreviations ALAT alanine aminotransferase - ALP alkaline phosphatase - ASAT aspartate aminotransferase - CK creatine phosphokinase - FH familial hypercholesterolemia - GT glutamyl transpeptidase - HDL high density lipoprotein - HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A - LDL low density lipoprotein - Lp(a) lipoprotein (a) - apo(a) apoprotein (a)     

Lipidstatus und basale Steroidhormonspiegel nach 16 Wochen Lovastatintherapie bei primärer Hypercholesterinämie

Summary We examined the effect of a 16 week therapy with the HMG CoA reductase inhibitor lovastatin in 29 patients (mean age 43 years) with primary hypercholesterolemia. All patients had cholesterol levels above 250 mg/dl (mean 348 ±96 mg/dl) inspite of a lipid lowering diet and a therapy with conventional lipid lowering drugs during a three month screening period. After 4 weeks on placebo 20 mg lovastatin was given orally for 4 weeks. If total cholesterol exceeded 200 mg/dl the dose of lovastatin was increased monthly by 20 mg up to the maximal dose of 80mg/day. After 16 weeks lipid values changed compared with the placebo period: total-cholesterol –25%, triglycerides –8.6%, LDL-cholesterol –31%, APO B –25%, HDL-cholesterol +5.8%, APO AI +0.8%, total-cholesterol/HDL-cholesterol –25%. There was a significant improvement of lipid parameters after lovastatin therapy compared with conventional lipid lowering drugs at the end of the screening period. Lovastatin was well tolerated. A small and reversible rise of transaminases and/or creatinine kinase was observed in 6 patients. Basal levels of ACTH in the morning increased significantly during lovastatin therapy within the normal range. This observation was more frequent in females (10/12) than in males (10/ 17).

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Abkürzungen HMG Co A 3-Hydroxy-3-Methyl-Glutaryl-Coenzym A - TChol Gesamtcholesterin - LDL low density lipoprotein - HDL high density lipoprotein - TG Triglyceride - APO AI/B Apolipoprotein AI/B - ACTH Adrenocorticotropes Hormon Diese Publikation enthält Ergebnisse des Dissertationsarbeit von Frau Angela Bink.