[Clinical importance of HDL cholesterol]. / Klinische Bedeutung des HDL-Cholesterins.

BACKROUND: Each year 16-17 million determinations of high-density lipoprotein cholesterol (HDL-C) are conducted and interpreted in Germany. Recently acquired data have led to a fundamental reassessment of the clinical significance of HDL-C. METHOD: This review article is based on a selective literature search. RESULTS: Low HDL­C levels usually indicate an increased cardiovascular risk, particularly in primary prevention but the epidemiological relationship between HDL­C and the risk is complex. The HDL plays a role in the back transport and excretion of cholesterol; however, the biological functions of HDL are dependent on the protein and lipid composition, which is not reflected by the HDL­C concentration. If the composition of HDL is pathologically altered it can also exert negative vascular effects. CONCLUSION: Compared with low-density lipoprotein cholesterol (LDL-C), HDL­C is of secondary importance for cardiovascular risk stratification and the calculation of the LDL-C:HDL­C ratio is not useful for all patients. Low HDL­C levels should prompt a search for additional metabolic and inflammatory pathologies. An increase in HDL­C through lifestyle changes (e.g. smoking cessation and physical exercise) has positive effects and is recommended; however, HDL­C is currently not a valid target for drug therapy.

Plasma cholesteryl ester transfer protein concentrations predict cardiovascular events in patients with coronary artery disease treated with pravastatin.

OBJECTIVE: The B1B1 variant of the cholesteryl ester transfer protein (CETP) TaqIB polymorphism and high plasma CETP concentrations are associated with favourable angiographic outcomes in pravastatin-treated patients suffering from coronary artery disease (CAD). The purpose of the present study was to test whether CETP TaqIB genotypes and/or plasma CETP concentrations at baseline also predict clinical end-points in patients with CAD. DESIGN: Prospective longitudinal observational study. SETTING: Primary care doctors (n=88) and hospitals (n=7) in Austria. SUBJECTS: A total of 1620 men and women with preexisting CAD were recruited and plasma lipids were determined at study entry. 1389 hypercholesterolaemic patients were included and 1002 patients completed the follow-up. INTERVENTIONS: In all patients treatment with pravastatin was started and patients were followed up for 2 years. MAIN OUTCOME MEASURES: Cardiovascular events. RESULTS: One hundred patients suffered at least one cardiovascular event. We observed significantly more events in patients within the lowest compared with the highest quartile of plasma CETP concentrations (odds ratio 3.20, CI95 1.65-6.23; P=0.001, adjusted for known risk factors of CAD). No significantly different numbers of cardiovascular events were found between CETP TaqIB genotypes. CONCLUSIONS: Plasma CETP concentrations, but not CETP TaqIB genotypes, predict cardiovascular events in patients with CAD treated with pravastatin. Despite higher LDL cholesterol concentrations, high plasma CETP concentrations at baseline are associated with fewer cardiovascular events compared with low plasma CETP concentrations in CAD patients treated with pravastatin.

Hepatic lipase polymorphism and increased risk of peripheral arterial disease.

BACKGROUND: Hepatic lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. We hypothesized single nucleotide polymorphisms in the promoter region of the hepatic lipase gene to be associated with an increased risk for peripheral arterial disease (PAD). METHODS: A total of 241 patients with PAD and 241 controls matched for sex and age (+/-2 years) were genotyped cross-sectionally for the --250 single nucleotide polymorphism in the hepatic lipase promoter. RESULTS. The frequency for the -250 A allele in patients with PAD was 0.203, whereas it was 0.147 in the controls (P=0.022). Hepatic lipase promoter polymorphism distribution remained significantly different between cases and controls after multivariate logistic regression analysis (P=0.021). The odds ratio of the -250 A hepatic lipase allele for the PAD was 1.69 (95% confidence interval of 1.08-2.64), when adjusted for current smoking, arterial hypertension, cholesterol, triglycerides, HbA(1C), total homocysteine and high sensitivity C-reactive protein. CONCLUSION: Previous data in patients with ischaemic heart disease have suggested a pro-atherogenic role of low hepatic lipase levels. Our results extend these data to the vascular territory of the lower limbs, such that hepatic lipase promoter variation represents a genetic risk factor of PAD.

Tracing surfactant transformation from cellular release to insertion into an air-liquid interface.

Pulmonary surfactant is secreted by alveolar type II cells as lipid-rich, densely packed lamellar body-like particles (LBPs). The particulate nature of released LBPs might be the result of structural and/or thermodynamic forces. Thus mechanisms must exist that promote their transformation into functional units. To further define these mechanisms, we developed methods to follow LBPs from their release by cultured cells to insertion in an air-liquid interface. When released, LBPs underwent structural transformation, but did not disperse, and typically preserved a spherical appearance for days. Nevertheless, they were able to modify surface tension and exhibited high surface activity when measured with a capillary surfactometer. When LBPs inserted in an air-liquid interface were analyzed by fluorescence imaging microscopy, they showed remarkable structural transformations. These events were instantaneous but came to a halt when the interface was already occupied by previously transformed material or when surface tension was already low. These results suggest that the driving force for LBP transformation is determined by cohesive and tensile forces acting on these particles. They further suggest that transformation of LBPs is a self-regulated interfacial process that most likely does not require structural intermediates or enzymatic activation.

Molecular characterization of rabbit scavenger receptor class B types I and II: portal to central vein gradient of expression in the liver.

To further elucidate the role of scavenger receptor class B type I (SR-BI) in reverse cholesterol transport and in atherogenesis, we performed studies in the rabbit, an animal model displaying a lipoprotein profile similar to that of human, expressing cholesteryl ester transfer protein in plasma and having been demonstrated to be susceptible to atherosclerosis. In this report, we describe for the first time the isolation and characterization of rabbit cDNA fragments encoding SR-BI and scavenger receptor class B type II (SR-BII). Development of an isoform-specific Taqman Real Time PCR system and generation of isoform-specific polyclonal antibodies allowed us to measure SR-BI and SR-BII expression in various rabbit organs on mRNA and protein levels, respectively. We found the highest expression of SR-BI in adrenal gland, liver, and proximal intestine; lesser expression was found in appendix and spleen. Immunohistochemical staining of frozen sections showed SR-BI expression in the cortex but not in the medulla of adrenal gland. An increasing portal to central vein gradient of expression was found within the hepatic lobule. As shown in this report, identification and characterization of SR-BI expression in the rabbit affords a powerful tool to elucidate the role of SR-BI in cholesterol homeostasis and atherogenesis in human.

Relationship between cholesteryl ester transfer protein and atherogenic lipoprotein profile in morbidly obese women.

OBJECTIVE: Obesity is associated with increased morbidity and mortality from atherosclerotic disease. Lipid abnormalities contribute to the increased relative risk in obese subjects. Cholesteryl ester transfer protein (CETP) mass is increased in these patients and might mediate the atherogenic lipoprotein pattern observed in obesity. METHODS AND RESULTS: Twenty-one morbidly obese, middle-aged, female subjects participated in this prospective study. Subjects were examined before and 1 year after surgical treatment. Fat mass was determined by body impedance analysis; CETP mass, by ELISA; CETP activity, by exogenous substrate assay; and LDL particle diameter, by gradient gel electrophoresis. Mean weight loss after 1 year was 28.7 kg; mean fat mass loss was 22.6 kg. Mean CETP mass decreased from 1.81 to 1.32 microg/mL (P=0.008); mean CETP activity decreased from 244 to 184 nmol x mL(-1) x h(-1) (P=0.004); and in parallel, the mean diameter of LDL particles increased (256.8 to 258.4 A, P=0.04). CONCLUSIONS: We conclude that weight loss is associated with a pronounced decrease in CETP mass and activity and a consistent increase in LDL particle diameter. After 1 year of this prospective study in morbidly obese subjects undergoing weight loss by surgical treatment, it has been determined that some features of the atherogenic lipoprotein profile can be reversed.

Influence of leptin and insulin on lipid transfer proteins in human hepatoma cell line, HepG2.

AIM: Phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) are key enzymes in lipoprotein metabolism facilitating the transfer and exchange of cholesteryl esters, triglycerides and phospholipids between lipoproteins. In the study presented here, we investigated the influence of two hormones-the adipocyte-derived hormone leptin as well as insulin on the hepatic secretion of both, PLTP and CETP. METHODS: PLTP activity and CETP concentration-measured by exogenous substrate assay and enzyme-linked immunosorbent assay-were determined in supernatant of human hepatoma cell line HepG2 after single or combined exposure to leptin and insulin at physiological and supraphysiological concentrations, respectively. Messenger-RNA of PLTP and CETP was quantified by Northern blot analysis. RESULTS: Leptin suppressed PLTP activity and CETP-concentration by up to 33% and 23%, respectively. Insulin also suppressed PLTP activity by up to 11% and CETP-concentration by up to 16%. In combination, the two hormones had additive suppressive effects for both, PLTP activity and CETP-concentration. Northern blot analysis showed no difference in m-RNA levels after exposure to leptin or insulin. CONCLUSIONS: Leptin and insulin, both known to increase with body fat mass, suppress production of PLTP and CETP in HepG2 cells. When extrapolated to the in vivo situation, this suppressive effect may constitute a mechanism counteracting the potentially harmful action of lipid transfer proteins, particularly reduction of HDL-cholesterol, in conditions frequently associated with increased plasma triglyceride levels such as obesity and insulin resistance.

Pronounced postprandial lipemia impairs endothelium-dependent dilation of the brachial artery in men.

OBJECTIVE: Pronounced postprandial lipemia has been established as a risk factor for cardiovascular disease, but reports regarding its effect on endothelial function have been controversial. In the present study the influence of a standardized fatty meal with its ensuing postprandial lipemia of highly varying magnitude on endothelium-dependent dilation (EDD) was investigated. METHODS: In 17 healthy, normolipidemic men EDD of the brachial artery was quantified in two series of three measurements each. In both series initial measurements were performed at 08:00 h after an overnight fast followed by measurements at 12:00 and 16:00 h, in the first series with continued fasting and in the second following the ingestion of a standardized fatty test meal 4 and 8 h postprandially. RESULTS: Measurements of EDD in the fasting state revealed the recently appreciated diurnal variation with higher values in noon and afternoon hours compared with morning values (2.5+/-1.6% at 08:00, 7.5+/-2.7% at 12:00, and 7.0+/-2.1% at 16:00 h, P<0.001 by analysis of variance). Postprandial EDD values measured at 12:00 h were, at the average, lower than fasting EDD values measured at 12:00 h and correlated inversely with the magnitude of postprandial triglyceridemia (r=-0.81, P<0.001). In multivariate analysis, higher postprandial lipemia was associated with impaired postprandial EDD (P<0.001) independent of fasting triglycerides, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, insulin, age and body mass index. CONCLUSION: We conclude that pronounced postprandial lipemia is associated with transient impairment of endothelial function. Our findings support the notion that impaired triglyceride metabolic capacity plays an important role in atherogenesis.

Flow-mediated, endothelium-dependent vasodilatation is impaired in male body builders taking anabolic-androgenic steroids.

Self-administration of anabolic-androgenic steroids to increase muscular strength and lean body mass has been used widely among athletes. Flow mediated dilatation (FMD) determined by ultrasound of the brachial artery is accepted as both an in vivo index of endothelial function and an indicator for future atherosclerosis. FMD was calculated in 20 male non-smoking body builders in different phases of their training cycle and in six male non-smoking control athletes. Ultrasound studies of the brachial artery were performed according to the protocol of Celermajer et al. Of the entire training cycle, work-out phase was training phase without actual intake of anabolic-androgenic steroids over 8 weeks; build-up phase included actual intake of anabolic-androgenic steroids; and competition phase consisted of 8 weeks post intake of anabolic-androgenic steroids. Baseline characteristics did not differ between body builder groups except for a higher weight in competition phase body builders. Hormonal analysis revealed suppressed luteinizing hormone and follicle stimulating hormone levels in build-up phase body builders. The lipid profiles showed a marked reduction of HDL-C in build-up phase body builders. FMD was reduced in body builders of all phases when compared to control athletes (work-out phase: 2.5+/-2.7%; build-up phase: 2.1+/-3.0%; competition phase: 0.4+/-2.9% vs. 10.9+/-4.4%, P<0.05 by pairwise comparison using Scheffe's test for work-out phase, build-up phase and competition phase vs. control athletes). The glyceryl trinitrate-induced vasodilatation was diminished, though not statistically significantly, in body builders when compared with control athletes. The differences in FMD persisted after adjustment for vessel size. Our data indicate that intake of anabolic-androgenic steroids is associated with both an atherogenic blood lipid profile and endothelial dysfunction and thus may pose an increased risk of atherosclerosis.

Lipoprotein profile and cholesteryl ester transfer protein in neonates.

Undernourishment in utero appears to be associated with persisting changes in the metabolic, endocrine, and immune functions. In this study, we determined the influence of birth weight on the lipoprotein profile and cholesteryl ester transfer protein (CETP), which promotes a proatherogenic lipoprotein profile in plasma by determining the chemical, physical, and biologic properties of the respective lipoprotein particles. Triglyceride (TG) concentrations were highest and high-density lipoprotein (HDL)(2)-cholesterol levels were lowest in small for gestational age (SGA) neonates. CETP-mass was determined by enzyme-linked immunosorbent assay (ELISA) and CETP-activity by using exogenous lipoproteins. Cholesteryl ester transfer was determined as transfer of radiolabeled cholesteryl esters (CE) from HDL to apolipoprotein B-containing lipoproteins. CETP mass was lowest and cholesteryl ester transfer was highest in SGA neonates. CETP-activity did not differ among the neonates. Our results suggest that increased and decreased nourishment in utero affects the lipoprotein profile and CETP in neonates. High TG and low HDL(2) levels in SGA neonates might result from increased cholesteryl ester transfer and, may in part, explain the increased risk of coronary heart disease (CHD) of small for gestational age neonates in later life.

7 detecting cholesteryl ester transfer protein in plasma.

Transport of triglycerides (TGs) and cholesteryl esters (CEs) in plasma can be viewed as taking place via two major groups of lipoproteins, the TG-rich lipoproteins (chylomicrons and VLDL), on one hand, and the cholesterol-rich lipoproteins (LDL and HDL), on the other. The metabolism of these groups is linked by exchange processes, catalyzed mainly by a plasma glycoprotein referred to as lipid transfer protein I (LTP-I) (1) or cholesteryl ester transfer protein (CETP) (2-5).

Pancreas transplantation modulates reverse cholesterol transport.

Hyperinsulinemia secondary to insulin resistance in type-II diabetes or in the metabolic syndrome is associated with the "atherogenetic lipoprotein phenotype": high triglycerides, small, dense low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol. In contrast, hyperinsulinemia in pancreas-kidney transplant recipients (PKT-R), secondary to systemic venous drainage of the heteropically implanted pancreas graft, leads to high lipoprotein lipase (LPL) activity and a presumably antiatherogenic lipoprotein profile with very attenuated postprandial lipemia, high HDL cholesterol, and a preponderance of large-sized HDL (HDL(2)) and large buoyant LDL particles. We interpret these findings to suggest that in PKT-R, peripheral hyperinsulinemia upregulates LPL activity in peripheral tissues, which induces rapid clearance of chylomicron triglycerides from plasma and, thus, attenuates postprandial lipemia. Low postprandial lipemia allows little net cholesteryl ester transfer from HDL to triglyceride-rich lipoproteins, keeping the levels of the antiatherogenic lipoprotein HDL high and potentially increasing, thereby reverse cholesterol transport. The type of lipoprotein metabolism and pattern present in PKT-R is associated with a low cardiovascular risk in the general population; it cannot be excluded, however, that hyperinsulinemia as found in PKT-R may contribute to atherosclerosis by effects unrelated to lipoprotein metabolism.

Cholesteryl ester transfer protein gene expression is not specifically regulated by CCAAT/enhancer-binding protein in HepG2-cells.

Cholesteryl ester transfer protein (CETP) mediates the exchange of neutral lipids among plasma lipoproteins and is expressed predominantly in liver and intestine. In band shift assays employing nuclear extracts of HepG2 cells we identified C/EBPbeta as the predominant C/EBP isoform involved in binding to the C/EBP consensus sequence within the 5' upstream region of the CETP gene. This was demonstrated by supershift experiments using antibodies specific for C/EBPalpha, C/EBPbeta and C/EBPdelta and an oligonucleotide containing a single point mutation (CAAT-->CTAT) in this site. Expression of a CETP promoter-fragment/luciferase construct in transiently transfected HepG2 and CaCo-2 cells and enhancement of promoter activity by co-transfection with human C/EBPalpha in HepG2 cells could be influenced neither by the mutation in the consensus sequence nor by elimination of this site together with a second potential binding site for C/EBP. Furthermore, transfection of HepG2 with human C/EBPalpha did not influence the synthesis of CETP by these cells. Our results indicate that the expression of C/EBP in HepG2 cells is not able (1) to influence specifically the expression of a transfected CETP promoter dependent reporter through binding to C/EBP sites in the promoter region and (2) to significantly enhance expression of the endogenous CETP gene.

[Leptin--an interim evaluation]. / Leptin--eine Zwischenbilanz.

The discovery of leptin, the product of the obese (ob)-gene, has broadened the horizons of research on energy balance. This hormone, produced and secreted by adipose tissue and some placental cells, finds its way to the hypothalamus, where it binds to the leptin receptors and signals satiety through the neuroendocrine axis. The fact that adipose tissue is not merely a storage depot, but also an important endocrine tissue, has revived the interest in the "lipostatic" theory of body fat regulation and has initiated many research efforts in the field of obesity, anorexia nervosa, bulimia, reproduction and haematology.

Deficiency of cholesteryl ester transfer protein. Description of the molecular defect and the dissociation of cholesteryl ester and triglyceride transport in plasma.

A patient is described who exhibited, despite excessively high postprandial triglyceride levels, high levels of HDL cholesterol. Measurement of CETP activity and mass in the patient's plasma showed values of less than 5% and 2%, respectively, of a normolipidemic plasma pool. The CETP cDNA of the patient exhibited a mutation (T-->G), turning codon 57 (TAT) of exon 2 into a stop codon (TAG) and abolishing a, XcmI restriction site. Digestion of directly amplified CETP cDNA from the patient with XcmI indicated the exclusive presence of CETP cDNA containing the mutation. Analysis of the corresponding region of the CETP gene indicated the patient to be heterozygous for the nonsense mutation at codon 57, a finding that can only be explained by the presence of a null allele in addition to the allele with the nonsense mutation. The combination of TG intolerance of uncertain cause, together with CETP deficiency due to a novel mutation, produced the paradoxical constellation--high levels of HDL cholesterol (172 mg/dL) associated with a high post-prandial lipemia of 1460 mg triglycerides/dL.8 hours--and provided further insight into the role of CETP as mediator between pools of triglycerides and cholesteryl esters in plasma.

Relationship of plasma cholesteryl ester transfer protein to HDL cholesterol. Studies in normotriglyceridemia and moderate hypertriglyceridemia.

To evaluate the independent effect of cholesteryl ester transfer protein (CETP) on HDL concentrations in humans, we measured lipids, lipoproteins, postprandial lipemia after an oral fat load, CETP mass, and the activities of CETP, lipoprotein lipase (LPL), and hepatic lipase in 16 healthy, normotriglyceridemic men and in 23 men with moderate, primary hypertriglyceridemia on an American Heart Association Step I diet. Fasting triglycerides and postprandial lipemia were increased and HDL cholesterol (HDL-C) was decreased in hypertriglyceridemic men compared with control subjects (P < .001). In the normotriglyceridemic group, CETP mass (P < .001) and activity (P < .005) were directly related to LPL activity After statistical adjustment for this close association, no significant relationship of CETP to HDL-C independent of LPL activity could be demonstrated in the normotriglyceridemic subjects. In contrast, CETP was unrelated to LPL activity in the hypertriglyceridemic subjects, but CETP concentrations showed a close inverse relationship to HDL-C (r = -.504, P = .014). Structural equation modeling of the association structures between HDL and fasting and postprandial triglycerides, endothelial lipases, and CETP in both groups indicated that the overall regression models for the two groups differed (P < .05). Specifically, the associations between CETP mass and activity and HDL-C differed between both groups (both P < .01). We conclude that high-normal CETP levels lower HDL-C in nonsmoking, nonobese men with moderate, primary hypertriglyceridemia on a hypolipidemic diet, but not in healthy, normotriglyceridemic men on an unrestricted diet. Thus, variation in CETP plasma concentrations may contribute to the high-triglyceride, low-HDL phenotype.

Effects of pancreas transplantation on distribution and composition of plasma lipoproteins.

In type I (insulin-dependent) diabetic patients, peripheral hyperinsulinemia due to subcutaneous insulin treatment is associated with increased high-density lipoprotein (HDL) cholesterol, and also with an altered surface composition of HDL. Pancreas grafts also release insulin into the systemic rather than into the portal venous system, giving rise to pronounced peripheral hyperinsulinemia. We hypothesized that if peripheral hyperinsulinemia is responsible for high HDL cholesterol and/or altered surface composition of HDL in diabetic subjects, similar changes in the lipid profile should be present in pancreas-kidney transplant recipients (PKT-R). Using zonal ultracentrifugation, we isolated HDL2, HDL3, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) from fasting plasma of 14 type I diabetic PKT-R, eight nondiabetic kidney transplant recipients (KT-R), and 14 healthy control subjects and determined the level and composition of the above lipoproteins. HDL2 cholesterol was increased in PKT-R as compared with KT-R and healthy controls (both P < .05), whereas HDL3 cholesterol was unchanged. However, an altered lipoprotein surface composition was evident in PKT-R: HDL2, HDL3, and LDL were enriched in unesterified cholesterol ([UC] PKT-R v KT-R, P=.13, P < .005, and P < .05, respectively; PKT-R v controls, all P < .005); HDL2 was enriched in phospholipids; and LDL was depleted of phospholipid. KT-R, in contrast, showed no changes in lipoprotein surface composition but a substantial triglyceride enrichment of HDL2 as compared with PKT-R and healthy controls (both P < .05). LDL size as determined by gradient gel electrophoresis was increased in PKT-R compared with controls (P < .005). The plasma concentration of cholesteryl ester (CE) transfer protein (CETP), involved also in phospholipid transfer, was increased in both transplant groups compared with healthy controls (both P < .05). Insulin concentrations in fasting plasma were directly related to CETP levels and to the weight-percentage of UC in HDL3, and inversely to the weight-percentage of phospholipids in LDL (all P < .05). We explain the increase in HDL2 cholesterol and LDL size in PKT-R by their high lipoprotein lipase (LPL) activity conferring an excellent capacity to clear chylomicron triglycerides. Effective handling of postprandial triglycerides, high HDL2 cholesterol, and predominance of LDL pattern A, respectively, are established indicators of a low risk of atherosclerosis. However, it is presently unclear what effects the compositional changes on the surface of HDL and LDL may have on cardiovascular risk in clinically stable PKT-R.

Treatment of primary mixed hyperlipidemia with etophylline clofibrate: effects on lipoprotein-modifying enzymes, postprandial lipoprotein metabolism, and lipoprotein distribution and composition.

In 17 patients with primary mixed hyperlipidemia we studied levels and composition of lipoproteins in fasting plasma, lipoprotein-modifying enzymes, and postprandial lipoprotein metabolism after an oral fat-tolerance test supplemented with vitamin A before, and 12 weeks after treatment with etophylline clofibrate. With treatment, fasting plasma cholesterol, triglycerides, and the levels of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) decreased significantly; high density lipoprotein (HDL) cholesterol increased significantly. Treatment caused also an increase in the protein content of IDL, a decrease in the triglyceride content of LDL, and an increase in the size of LDL as assessed by gradient gel electrophoresis. Concentrations of triglycerides, chylomicrons, and chylomicron remnants after an oral fat load supplemented with vitamin A decreased by 33%, 30% and 6%, respectively (P < 0.005; P < 0.01; and P < 0.05). The activity of lipoprotein lipase and hepatic lipase in postheparin plasma increased by 51% and 45%, respectively (P < 0.01; P < 0.05). We found a decrease in the mass concentration of cholesteryl ester transfer protein (P < 0.05). Stepwise multiple regression analysis showed that the triglyceride content of LDL is determined primarily by fasting triglycerides (r = + 0.53, P < 0.05;baseline) and cholesteryl ester transfer protein (r = + 0.49, P < 0.05; 12 weeks); in contrast, the triglyceride content of HDL3 is determined exclusively by accumulation of postprandial triglycerides (r = + 0.67; P < 0.05; baseline) and postprandial chylomicrons (r = +0.87; P < 0.005; 12 weeks). We conclude that hypolipidemic treatment with etophylline clofibrate favorably affects the cardiovascular risk factor profile in primary mixed hyperlipidemia.

Relationship of high-density lipoprotein subfractions and cholesteryl ester transfer protein in plasma to carotid artery wall thickness.

High plasma concentrations of high-density lipoprotein (HDL) cholesterol are a powerful indicator of low vascular risk. By decreasing HDL cholesterol, cholesteryl ester transfer protein (CETP) could perhaps constitute an atherogenic protein. We measured HDL cholesterol and HDL subfractions and quantified CETP mass in fasting plasma in 21 asymptomatic probands, and related these variables to the mean intima media thickness of the extracranial carotid arteries. HDL2 cholesterol, the less dense HDL subfraction, was inversely related to carotid wall thickness (r = -0.378; P < 0.05), and CETP was directly related to carotid wall thickness (r = 0.436; P < 0.05). In plasma CETP is associated mostly with the HDL3 subfraction. We therefore calculated from our measurements the relative CETP content of HDL3, i.e., CETP/HDL3 cholesterol. This ratio was correlated with carotid wall thickness stronger than any other variable measured (r = 0.718, P < 0.001). We conclude that variation in HDL subfractions and CETP may be more closely associated with carotid intima media thickness than the accepted strong risk factor of HDL cholesterol.