Familial combined hyperlipidemia and insulin resistance.
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Apolipoproteins B↗
Biomedical subjects
J Frohlich
Publications and source records attributed to J Frohlich.
Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels.
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Anticholesteremic Agents↗
Conformal boundary conditions and three-dimensional topological field theory
We present a general construction of all correlation functions of a two-dimensional rational conformal field theory, for an arbitrary number of bulk and boundary fields and arbitrary topologies. The correlators are expressed in terms of Wilson graphs in a certain three-manifold, the connecting manifold. The amplitudes constructed this way can be shown to be modular invariant and to obey the correct factorization rules.
Journal Article↗
Chemical precipitation of apolipoprotein B-containing lipoproteins facilitates determination of LDL particle size.
OBJECTIVES: To simplify the determination of low-density lipoprotein (LDL) particle size by eliminating the need for ultracentrifugation. DESIGN AND METHODS: We compared LDL particle size determination by gradient gel electrophoresis using two different methods for separation of LDL: (a) by ultracentrifugation with a density between 1.019 and 1.063 g/mL, and (b) by precipitation of the apolipoprotein B-containing lipoproteins from plasma. LDL particle size was determined for 41 individuals using both methods. RESULTS: The correlation between these two methods was r = 0.98; peak particle diameter (nm) was reproducible with a coefficient of variation of 1. 3% for LDL separated by ultracentrifugation and 1.4% for LDL prepared by precipitation. The intra-assay variation within a single gel was 0.2%. CONCLUSION: Elimination of the need for ultracentrifugation or lipid staining significantly reduces the cost and simplifies the procedure of LDL particle sizing. As a result, larger patient populations can be more readily screened for the determination of LDL particle size.
Adult↗
Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.
We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.
ATP Binding Cassette Transporter 1↗
A randomized placebo-controlled double-blind trial of lipid-lowering strategies in patients with renal insufficiency: diet modification with or without fenofibrate.
BACKGROUND: Renal insufficiency is characterized by lipoprotein abnormalities including elevated triglyceride levels. PATIENTS AND METHODS: The safety and efficacy of micronized fenofibrate as a treatment for dyslipidemia in patients with progressive renal insufficiency was evaluated in a randomized, placebo-controlled double-blind study comparing fenofibrate and dietary modification to dietary modification alone. Patients were evaluated following a 3-month pre-randomization period of dietary counseling. Twenty-eight patients with moderate renal insufficiency and triglyceride levels 2.3 mmol/l or LDL/HDL ratio 5 were randomized to placebo (n = 12) or fenofibrate (n = 16) therapy. Treatment and dietary counseling continued for 6 months. RESULTS: Ten of 16 patients (63%) treated with fenofibrate achieved a 30% reduction in triglyceride levels or LDL/HDL ratio reduction < 5 compared to 2 of 17% in the placebo group (p = 0.015). Triglyceride levels were significantly reduced in the fenofibrate group (-31%) versus placebo (+1.3%, p = 0.003). In compliant patients (n = 25) there was also a significantly greater increase in HDL cholesterol levels in the fenofibrate group (+19.9%) compared to placebo (-4.7%, p = 0.001). Changes in measured creatinine clearance were not significantly different between the groups and there were no serious adverse effects of treatment. CONCLUSION: Fenofibrate therapy combined with dietary modification effectively reduced triglyceride levels in renal insufficiency patients without serious adverse effects.
Adult↗
Effect of labeling of plasma lipoproteins with [(3)H]cholesterol on values of esterification rate of cholesterol in apolipoprotein B-depleted plasma.
The fractional esterification rate of cholesterol in apolipoprotein B (apoB)-depleted plasma (FER(HDL)) is a good indicator of particle size distribution in high density lipoprotein (HDL) and low density lipoprotein (LDL). However, there has been a discrepancy in the absolute values of FER(HDL) published by different laboratories. Because the main difference between the methods was in the labeling of lipoproteins with [(3)H]cholesterol we investigated the effect of using Corning immunoplates and paper discs as carriers of the labeled unesterified cholesterol. We found that Corning plates trap some (3)H-labeled free cholesterol, which is released during incubation at 37 degrees C. This means that this additional (3)H-labeled free cholesterol is exposed to lecithin: cholesterol acyltransferase (LCAT) for a shorter time and artificially decreases FER(HDL). Using paper discs discarded before incubation as carriers of the (3)H-labeled free cholesterol results in complete labeling of HDL and thus yields higher values of FER(HDL).
Apolipoproteins B↗
[The new atherogenic plasma index reflects the triglyceride and HDL-cholesterol ratio, the lipoprotein particle size and the cholesterol esterification rate: changes during lipanor therapy].
The new atherogenic plasma index (AIP) is a logarithmic transformation of the ratio of the molar triglyceride (TG) concentration and high density lipoprotein cholesterol (HDL-C). AIP correlates closely with the size of LDL particles (r = 0.8) and esterification rate of plasma cholesterol devoid of apo B lipoproteins (FERHDL), r = 0.9 which are considered at present the most sensitive indicators of the atherogenic plasma profile. AIP was recommended by the authors, based on analysis of results of 11 previous studies (1156 subjects) where FERHDL and plasma lipid parameters were investigated in different groups of people who differed as to the atherogenic risk. The AIP index was moreover used for evaluation of a clinical study comprising 609 patients with hyperlipidaemia, who were treated for three months with ciprofibrate (Lipanor). The mean AIP values of non-risk groups (plasma from umbilical blood, children, healthy women etc.) equalled zero or were lower, while with an increasing atherogenic risk (men, women after the menopause) AIP reached positive values, incl. high positive values in risk groups (plasma of diabetic subjects, patients with HLP, patients with positive angiography, myocardial infarction etc.). In all groups women had lower AIP values as compared with males. In patients after Lipanor therapy the AIP declined (from 0.58 +/- 0.17 to 0.33_0.18 in men, from 0.50 +/- 0.18 to 0.21 +/- 0.19 in women). If we consider AIP values from negative ones to 0.15 as "safe" from the aspect of atherogenicity, before Lipanor treatment these "safe" levels were recorded in 1.5% men and in 5.2% women and after treatment in 32% men and 48% women. The results indicate, that AIP which reflects the plasma lipoprotein profile quantifies the relations between TG and HDL-C and thus can be an objective indicator of the atherogenic risk and effectiveness of treatment and it is useful because it can be assessed in any surgery.
Adult↗
Dyslipidaemia and coagulation defects of insulin resistance.
Among the traditional risk factors, dyslipidaemia and coagulation disorders play an important role in increasing the risk of coronary heart disease (CHD) in patients with type 2 diabetes. The lipid abnormalities of patients with insulin resistance and type 2 diabetes include increased triglycerides, lower high density lipoprotein (HDL)-cholesterol and the predominance of small dense low density lipoprotein (LDL)-particles. The composition of HDL particles is different from healthy controls and the concentration of the larger, more anti-atherogenic particles is decreased in patients with insulin resistance and type 2 diabetes. Subgroup analyses of several large studies have shown that lowering LDL-cholesterol with statin treatment decreased cardiovascular events in patients with type 2 diabetes. In other studies, gemfibrozil decreased cardiovascular events in a subgroup of patients with diabetes, although the decreases were not always statistically significant. Platelets from patients with diabetes are more sensitive to several aggregating agents, have increased numbers of glycoprotein receptors and a lower activity of guanylate cyclase. These factors may contribute to the documented hyperreactivity of platelets in patients with type 2 diabetes. Other factors in patients with type 2 diabetes include alterations in serum fibrinogen, PAI-1, tissue-type plasminogen activator (tPa) and factors V, II and VII, which have all been linked to the risk of myocardial infarction. Increased D-dimer, von Willebrand factor (vWf) antigen, A-II anti-plasmin and decreased anti-thrombin III were also reported in patients with type 2 diabetes. This pro-thrombotic risk profile of the circulating blood in type 2 diabetes patients, together with the lipid abnormalities, contributes to the increased risk of vascular events in this population.
Blood Coagulation Disorders↗
Hormones, genes and the structure of sexual arousal.
Despite the inherent difficulty of connecting individual genes with integrated mammalian behaviors, it has been determined that a series of genes are turned on by estrogenic hormones acting in forebrain. Their products are, in turn, facilitatory for female reproductive behaviors such as lordosis. The causal routes by which two genes contribute to the control of lordosis behavior, the classical estrogen receptor gene (ER-alpha) and a thyroid hormone (TH) receptor gene (TR-beta), have been delineated. Beyond the mechanisms underlying the expression of concrete, specific natural behaviors, lies the question of sexual motivation. Required as an intervening variable to explain fluctuations in natural behaviors in the face of constant stimuli, motivational states have both general and specific features. Most theoretical and experimental approaches toward the general aspects of motivation have depended heavily on concepts of 'arousal.' Sexual arousal is likely to depend both on very general, broadly distributed neuronal influences and on specific affiliative and sexual tendencies. Is 'general arousal' a monolithic, undifferentiated process? In no way can a review at this time settle such issues, but the reasons behind six new experimental approaches to these questions are described.
Animals↗
Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I.
A randomized, blinded, multicenter clinical trial was performed comparing low- and high-dose simvastatin (40 and 80 mg) with comparable doses of atorvastatin (20 and 40 mg) for effects on plasma concentrations of lipoproteins and apolipoprotein A-I over 12 weeks in 842 patients with elevated low-density lipoprotein cholesterol. The 2 agents reduced low-density lipoprotein cholesterol and triglycerides to a comparable degree, but simvastatin raised high-density lipoprotein cholesterol and apolipoprotein A-I more than atorvastatin, suggesting differences in metabolic effects of the 2 agents on plasma lipids and lipoproteins.
Anticholesteremic Agents↗
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.
Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).
ATP Binding Cassette Transporter 1↗
Homocyst(e)ine and vascular access complications in haemodialysis patients: insights into a complex metabolic relationship.
BACKGROUND: As elevated total homocyst(e)ine (tHcy) is associated with increased risk of vascular thrombosis, we hypothesized that the elevated levels of tHcy seen in patients on haemodialysis may be associated with an increased risk of thrombosis of native arteriovenous fistulae (vascular access failure). Our study was designed to investigate the relationship between tHcy and vascular access failure. The relationship between tHcy and mortality was explored as a secondary analysis. METHODS: The study comprised a cross-sectional analysis of 96 haemodialysis patients at a single university-affiliated hospital and a subsequent 9-month prospective follow-up of 88 of the 96 patients. RESULTS: Levels of tHcy (median 30 micromol/l) were elevated. In the initial cross-sectional sample, there was an inverse relationship between tHcy and history of vascular access failure which was not observed in the prospective study. Variables influencing the risk of vascular access failure in the prospective study included history of previous vascular access failure (RR=2.93, P=0.03), use of antiplatelet agents (RR=0.13, P=0.01), increased urea reduction ratio (RR=0.55 for a 5% increase, P=0.01) and increased weight (RR=0.61 for a 10 kg increase, P=0.02). Secondary analysis showed an unexpected inverse relationship between tHcy and mortality (RR=0.033 for 1 log increase in tHcy, P=0.006), such that the lower levels of tHcy were associated with an increased risk of death in short-term follow-up. CONCLUSION: We did not demonstrate a relationship between tHcy and risk of vascular access failure. Patients with the lowest levels of tHcy appeared to be at increased risk of death in this short-term follow-up. The relationship of tHcy to vascular access complications and death in haemodialysis patients appears complex and requires further study.
Adult↗
Detection of early atherosclerosis with B mode carotid ultrasonography: assessment of a new quantitative approach.
PURPOSE: To examine the relation between carotid artery (CA) intima-media thickness (IMT) assessed by B mode ultrasonography (US), presence of plaques and major risk factors in a population without known vascular disease. Alternative methods of quantifying US results and implications for starting lipid-lowering therapy were also explored. DESIGN: Prospective study. SETTING: Specialized lipid clinic. PATIENTS: One hundred and sixty patients with hyperlipidemia but without symptomatic coronary or peripheral vascular disease were examined by US, of whom 92 patients with normal blood pressure who were not receiving lipid-lowering treatment were included in the analysis. INTERVENTIONS: B mode US of the CA was performed. Measurements were made of the IMT of the right and left common CA, and the average IMT (AIMT) was calculated. The number of plaques (PN) in the CA and its bifurcations was counted, and the average total thickness (ATT), the total area (TA), and average plaque thickness (APT) were calculated. RESULTS: Stepwise regression analysis showed that age, the ratio of total cholesterol to high-density-lipoprotein cholesterol, weight and smoking significantly predicted ATT, APT and PN. By contrast, age, weight and apo B levels predicted AIMT. Detection of patients with CA abnormalities was improved by incorporating plaque dimensions: AIMT had a 63% sensitivity in detecting CA abnormalities, whereas TA had a sensitivity of 72%. CONCLUSION: Indices of CA atherosclerosis that integrate the contribution of plaque to overall atheroma burden are related to known risk factors and are more sensitive than AIMT for detection of abnormalities.
Adolescent↗
Lipids and cardiovascular diseases.
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Cardiovascular Diseases↗
Understanding the mechanism of LCAT reaction may help to explain the high predictive value of LDL/HDL cholesterol ratio.
Traditionally, lecithin:cholesterol acyltransferase (LCAT) role in the reverse cholesterol transport (RCT) has been considered "antiatherogenic" as the cholesterol esterification is the prerequisite for the formation of mature high density lipoprotein (HDL) particles and may create a gradient necessary for the flow of unesterified cholesterol (UC) from tissues to plasma. However, newer data suggest that a higher esterification rate is not necessarily protective. Here we review the available data on the role of LCAT in RCT and propose that the LCAT-mediated esterification of plasma cholesterol promotes RCT only in the presence of sufficient concentrations of HDL2 while this reaction may be atherogenic in the presence of high concentration of plasma low density lipoprotein (LDL) cholesterol Thus, the "protective" or potentially "atherogenic" role of LCAT depends on the quality of HDL and concentration of LDL. This hypothesis is consistent with the known high predictive value of LDL/HDL cholesterol ratio.
Animals↗
Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDL-Atherosclerosis Treatment Study Design.
Evidence supports the idea that substantial benefits may derive from treatments that increase high density lipoprotein (HDL) cholesterol (HDL-C), apolipoprotein (apo) A-I, HDL2 (or 2b) or the size of HDL particles with, or without, apo A-II. HDL3 appears to be neutral in terms of coronary artery disease risk, and apo A-II appears to be adverse. Because HDL particles serve as antioxidants in vitro, the hypothesis that low HDL-C reflects an antioxidant deficiency state appears tenable. Based on these observations, a three-year angiographic study was proposed and received funding. Enrollment began in January 1995 and was completed in January 1997.
Adult↗
Rationale for and outline of the recommendations of the Working Group on Hypercholesterolemia and Other Dyslipidemias: interim report. Dyslipidemia Working Group of Health Canada.
A panel consisting of lipidologists, epidemiologists, cardiologists, internists, general practitioners, and public health and government representatives used the evidence-based approach to examine the rationale for a draft of recommendations for medical management of lipid disorders. The proposed recommendations deal with assessment of cardiovascular risk based on history, physical examination and laboratory findings; assessment of the fasting lipid profile; diagnosis and treatment of secondary risk factors; calculation of the 10-year risk of a cardiac event; initiation of lifestyle modifications in patients in whom low density lipoprotein cholesterol (LDL-C), total:high density lipoprotein cholesterol (HDL-C) ratio or triglycerides exceeds target values based on a patient's risk category; follow-up; treatment with drugs; and choices of drugs. In contrast to previous recommendations, there are new, considerably lower, cholesterol level targets for secondary prevention, with a less important emphasis on total cholesterol value than on LDL-C or total:HDL-C ratio and triglyceride levels, and an emphasis on determining the likelihood of a cardiac event by evaluating all relevant risk factors and sharpening the focus on nondrug treatment, which should result in treating a greater percentage of at-risk patients.
Anticholesteremic Agents↗