Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Abstract Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC50 of 0.96 µM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors

Inhibidores de la proproteína convertasa plasmática subtilisina kexina tipo 9 y riesgo de cataratas: revisión sistemática y metaanálisis / Plasma proprotein convertase subtilisin/kexin type 9 inhibitors and cataract risk: A systematic review and meta-analysis

Antecedentes: El marcado descenso en los niveles de C-LDL producidos por los inhibidores de la proproteína convertasa plasmática subtilisina kexina tipo 9 (iPCSK9) podría asociarse con un mayor riesgo de cataratas. Métodos: Realizamos un metaanálisis que incluyó ensayos clínicos aleatorizados y controlados con iPCSK9, solos o combinados con otros fármacos hipolipidemiantes, que reportaron nuevos casos de cataratas, buscando en PubMed/Medline, bases de datos de EMBASE y Cochrane Clinical Trials. Se utilizó un modelo de efectos fijos y se realizó una metarregresión evaluando la relación entre el C-LDL intratratamiento y el riesgo de desarrollar cataratas. Resultados: Se tomaron en cuenta 5 estudios elegibles con iPCSK9 que incluyeron 83.492 pacientes para el análisis, refiriendo 531 nuevos casos de cataratas en el grupo con iPCSK9 frente a 532 en el grupo placebo. La terapia con iPCSK9 no se asoció con un mayor riesgo de presentar cataratas (OR: 0,96; IC 95%: 0,85-1,08; p = 0,86, I2: 0%]. Asimismo, no se encontró una asociación significativa entre la diferencia de C-LDL intratratamiento entre las ramas de los estudios y el riesgo de cataratas. Conclusión. En nuestro análisis, la utilización de iPCSK9 no se asoció con un mayor riesgo de cataratas

Background: The marked decrease in LDL-C levels produced by the inhibitors of the plasma proprotein convertase subtilisin/kexin type 9 (iPCSK9) could be associated with an increased risk of cataracts. Methods: A meta-analysis was performed that included randomised clinical trials controlled with iPCSK9, alone, or in combination with other lipid-lowering drugs, which reported new cases of cataracts, by searching PubMed/Medline, databases of EMBASE and Cochrane Clinical Trials. A fixed-effect model was used, and a meta-regression was carried out evaluating the relationship between intra-treatment LDL-C and the risk of developing cataracts. Results: Five eligible studies of iPCSK9 including 83,492 patients were taken into account for the analysis, and 531 new cases of cataracts in iPCSK9 group vs. 532 in placebo group were diagnosed. The iPCSK9 therapy was not associated with an increased risk of cataracts [OR: 0.96, 95% CI: 0.85-1.08; P = .86, I2: 0%]. Likewise, no significant association was found between on-treatment LDL-C levels, differences between study arms, and new cases of cataracts. Conclusion: In this analysis, the use of iPCSK9 was not associated with an increased risk of cataracts

A comparative study of the effects of palm olein, cocoa butter and extra virgin olive oil on lipid profile, including low-density lipoprotein subfractions in young healthy Chinese people.

The aim of this study is to investigate the effects of palm olein (POL), cocoa butter (CB) and extra virgin olive oil (EVOO) on the lipid profile and low-density lipoprotein subfractions in a young, healthy Chinese population. After screening, 72 subjects were randomly assigned to three groups, and an 18-week randomized crossover trial was conducted. The first phase was a 2-week run-in period, followed by three phases of the 4-week experimental periods with a 2-week washout period between experimental periods. Three groups of subjects alternately consumed a Chinese diet enriched with the different test oils. The various indices of subjects were collected before and after each experimental period. Sixty-seven subjects completed the study, and there were no significant differences in conventional indices amongst the three groups at the beginning of the three experimental periods (p > .05). Each test oil accounted for approximately 40% of total fat intake and approximately 11.3% of the total energy supply. After controlling for dietary interventions, only the serum triglyceride level of the POL-Diet was significantly lower than that of the EVOO-Diet (p = .034), and most indices did not significantly differ amongst the three test oil diets (p > .05). POL, CB and EVOO have almost identical effects on serum lipids.

Low-density lipoprotein-associated variables and the severity of coronary artery disease: an untreated Chinese cohort study.

BACKGROUND AND AIMS: Elevated low-density lipoprotein cholesterol (LDL-C) is causal risk for coronary artery disease (CAD) and LDL-associated variables including LDL-C, apolipoprotein B (apoB), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein a [Lp(a)], small dense LDL (sd-LDL), and oxidized LDL (ox-LDL) have been widely used for predicting the risk of CAD. This study was aimed to compare the values of six LDL-related variables for predicting the severity of CAD using untreated patients undergoing coronary angiography (CAG). METHODS: A group of 1977 individuals were consecutively enrolled and divided into CAD (n = 1151) and non-CAD groups (n = 826) according to the results of CAG. LDL-C, apoB, non-HDL-C, Lp(a), sd-LDL and ox-LDL were measured, respectively. The numbers of stenotic arteries and Gensini Scores (GS) were used to calculate the severity of CAD and the associations of six variables with the severity of CAD and predicting value of these parameters were simultaneously examined. RESULTS: CAD patients had significantly higher concentrations of LDL-related variables than non-CAD ones (all p < 0.05). Importantly, all variables rose with the increase in the severity of CAD. The predicting value of CAD manifested as sd-LDL > ox-LDL > apoB > non-HDL-C > LDL-C > Lp(a) [area under curve (AUC): sd-LDL 0.641; ox-LDL 0.640; apoB 0.611; non-HDL-C 0.587; LDL-C 0.583; Lp(a) 0.554; respectively]. In multivariate logistic analysis, all variables showed as independent risk factors for the severity of CAD [odds ratio (OR): ox-LDL > sd-LDL > apoB > non-HDL-C > LDL-C > Lp(a)]. CONCLUSIONS: All of LDL-related variables could be useful marker for predicting the severity of CAD but sd-LDL and ox-LDL appeared to litter better. Further study may be needed to validate our results.

The effects of exercise on the lipoprotein subclass profile: A meta-analysis of 10 interventions.

OBJECTIVE: The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. METHODS: Nuclear magnetic resonance spectroscopy was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P, respectively) before and after an exercise intervention in 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group. RESULTS: Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL-P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant increases in the concentration of large LDL-P and large HDL-P and mean LDL-P size. These changes remained significant in meta-analysis with adjustment for age, sex, race, baseline body mass index, and baseline trait value. CONCLUSIONS: Despite differences in exercise programs and study populations, regular exercise produced putatively beneficial changes in the lipoprotein subclass profile across 10 exercise interventions. Further research is needed to examine how exercise-induced changes in lipoprotein subclasses may be associated with (concomitant changes in) cardiovascular disease risk.

A systematic approach to obtain validated partial least square models for predicting lipoprotein subclasses from serum NMR spectra.

A systematic approach is described for building validated PLS models that predict cholesterol and triglyceride concentrations in lipoprotein subclasses in fasting serum from a normolipidemic, healthy population. The PLS models were built on diffusion-edited (1)H NMR spectra and calibrated on HPLC-derived lipoprotein subclasses. The PLS models were validated using an independent test set. In addition to total VLDL, LDL, and HDL lipoproteins, statistically significant PLS models were obtained for 13 subclasses, including 5 VLDLs (particle size 64-31.3 nm), 4 LDLs (particle size 28.6-20.7 nm) and 4 HDLs (particle size 13.5-9.8 nm). The best models were obtained for triglycerides in VLDL (0.82 < Q(2) <0.92) and HDL (0.69 < Q(2) <0.79) subclasses and for cholesterol in HDL subclasses (0.68 < Q(2) <0.96). Larger variations in the model performance were observed for triglycerides in LDL subclasses and cholesterol in VLDL and LDL subclasses. The potential of the NMR-PLS model was assessed by comparing the LPD of 52 subjects before and after a 4-week treatment with dietary supplements that were hypothesized to change blood lipids. The supplements induced significant (p < 0.001) changes on multiple subclasses, all of which clearly exceeded the prediction errors.

Distribution of low-density lipoprotein and high-density lipoprotein subclasses in patients with sarcoidosis.

CONTEXT: Systemic inflammatory diseases are associated with proatherogenic lipoprotein profile, but there is a lack of information regarding overall distributions of lipoprotein subclasses in sarcoidosis. OBJECTIVE: To investigate whether patients with sarcoidosis have altered distributions of plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. DESIGN: Seventy-seven patients with biopsy-proven sarcoidosis (29 with acute and 48 with chronic sarcoidosis) treated with corticosteroids and 77 age- and sex-matched controls were included in the study. Low-density lipoprotein and HDL subclasses were determined by gradient gel electrophoresis, while inflammatory markers and lipid parameters were measured by standard laboratory methods. RESULTS: Compared to controls, patients had fewer LDL I subclasses (P < .001), but more LDL II and III (P < .001) subclasses. This pattern was evident in both acute and chronic disease groups. Patients also had smaller HDL size (P < .001) and higher proportions of HDL 2a (P = .006) and 3a particles (P = .004). Patients with chronic sarcoidosis had smaller LDL size than those with acute disease (P = .02) and higher proportions of HDL 3a subclasses (P = .04) than controls. In acute sarcoidosis, relative proportions of LDL and HDL particles were associated with levels of inflammatory markers, whereas in chronic disease an association with concentrations of serum lipid parameters was found. CONCLUSIONS: The obtained results demonstrate adverse lipoprotein subfraction profile in sarcoidosis with sustained alterations during disease course. Evaluation of LDL and HDL particles may be helpful in identifying patients with higher cardiovascular risk, at least for prolonged corticosteroid therapy due to chronic disease course.

Serum low density lipoprotein subclasses in asthma.

BACKGROUND: The levels of serum low-density lipoproteins (LDL) have been implicated in the inflammatory cascade in a murine model of asthma. Recent findings suggest that LDL may modulate the inflammatory state of the asthmatic airways in humans. OBJECTIVE: We explored whether LDL subclasses are associated with the occurrence and severity of asthma. METHODS: 24 asthmatics (M/F: 11/13) and 24 healthy individuals, with normal BMI and absence of metabolic syndrome, matched for age and gender. Serum concentrations of LDL subclasses were distributed as seven bands (LDL-1 and -2 defined as large, least pro-inflammatory LDL, and LDL-3 to -7 defined as small, most pro-inflammatory LDL), using the LipoPrint(©) System (Quantimetrix Corporation, Redondo Beach, CA, USA). RESULTS: LDL-1 was similar in the two groups (56 ± 16% vs. 53 ± 11, p = NS), while LDL-2 was significantly lower in asthmatics as compared to controls (35 ± 8% vs. 43 ± 10%, p = 0.0074). LDL-3 levels were two-fold higher in the asthmatics, but the difference did not reach the statistical significance (8 ± 7.3% vs. 4 ± 3%, p = NS). Smaller subclasses LDL-4 to LDL-7 were undetectable in controls. In asthmatics, LDL-1 was positively associated with VC% predicted (r = +0.572, p = 0.0035) and FEV1% predicted (r = +0.492, p = 0.0146). LDL-3 was inversely correlated with both VC% predicted (r = -0.535, p = 0.0071) and FEV1% predicted (r = -0.465, p = 0.0222). CONCLUSIONS: The findings of this pilot study suggest a role of LDL in asthma, and advocate for larger studies to confirm the association between asthma and dyslipidemia.

Heterogeneous properties of intermediate- and low-density lipoprotein subpopulations.

OBJECTIVE: Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) consist of heterogeneous particles whose subpopulations may have different atherogenic characteristics. This study investigated the associations between these subpopulations and other lipids, lipoproteins and atherosclerosis-related markers. DESIGN AND METHODS: A total of 416 subjects (124 males and 292 females, mean age: 50.8 years) were enrolled in this study. Using polyacrylamide gel electrophoresis, serum lipoproteins were separated according to their specific electrophoretic mobility based on particle size. The IDL particles were separated into three midbands (MID-A to C), and the LDL particles were separated into seven subfractions (LDL1 to 7). RESULTS: MID-B, MID-C, LDL2 and LDL3 to 6 (as a small LDL fraction) were significantly and positively correlated with very LDL (VLDL), while MID-A and LDL1 were significantly and inversely correlated with VLDL. MID-A and LDL1 were significantly and positively correlated with high-density lipoprotein (HDL). The correlation patterns between MID-A or LDL1 and triglycerides, apolipoprotein A-I, glucose, the insulin resistance index, creatinine and the mean LDL particle size had similar trends to those between HDL and these parameters. CONCLUSIONS: The respective subpopulations of IDL and LDL particles can vary in their ability to predict cardiovascular disease risks. These variations may partially explain why quantitative assessments using LDL-cholesterol concentrations, as typically performed in conventional practice, are not perfect predictors of cardiovascular disease. Further studies are required to determine the clinical relevance of analyzing the IDL and LDL subpopulations.

Lipoprotein subfractions by ion mobility in lean and obese children.

OBJECTIVE: To establish normative data for lipoprotein subfractions using a novel ion mobility assay in healthy lean children and to compare their data with those of obese children preselected with normal glucose, blood pressure, and relatively normal lipids. STUDY DESIGN: Fasting blood samples in 162 children aged 7.0-18.9 years (75 lean [body mass index: 18.6 ± 6.6 kg/m(2)] and 87 obese [body mass index: 31.7 ± 5.4 kg/m(2)]) were analyzed. Correlation of lipoprotein subfractions with anthropometric and laboratory markers was performed. Principal component analysis was used to avoid using correlated variables. RESULTS: Normative data for lipid subfractions were obtained in healthy children. Lean children had higher high-density lipoprotein (HDL)-large (76%), HDL-small (13%), and HDL-total (27%) compared with obese (P < .01), and lower low-density lipoprotein (LDL)-medium (-30%, P < .01) and medium + small (-21%, P = .02) as well as LDL-total (-13%, P = .035). In both groups, the LDL component was higher in males and pubertal children (P < .01). Prepubertal children had a higher HDL component than pubertal ones (P < .004). Adjusting for sex and pubertal status LDL component was positively, and HDL component negatively, correlated with obesity (P < .004). CONCLUSIONS: Despite relatively normal triglycerides and cholesterol measured with standard assays at screening, ion mobility analysis showed significant differences in lipid and apolipoprotein subfractions between lean and obese children, even those prepubertal. Long-term, prospective follow-up may better characterize the predictability of lipid subfractions for future cardiovascular disease risk in children.

Associations between small dense LDL, HDL subfractions (HDL2, HDL3) and risk of atherosclerosis in Japanese-Americans.

AIM: Small dense low-density lipoprotein (sdLDL) has been suggested to be more atherogenic than large buoyant LDL. High-density lipoprotein (HDL) consists of two major subfractions (HDL2, HDL3), and just as controversy remains regarding which of the two is the more powerful negative risk factor for atherosclerosis, associations between sdLDL and these HDL subfractions are unclear. METHODS: We measured sdLDL cholesterol (sdLDL-C), HDL2 cholesterol (HDL2-C) and HDL3 cholesterol (HDL3-C) by a newly developed method in 481 Japanese-Americans who were not using lipid-lowering medication, and examined the associations of these cholesterol concentrations with variables related to atherosclerosis. RESULTS: In multivariate analysis, sdLDL-C was positively correlated with the body mass index (BMI), fasting glucose and insulin, 2-h glucose, HOMA-IR, high sensitivity C-reactive protein (hsCRP), and carotid artery intima-media thickness (IMT) after adjustment for age and sex. In particular, sdLDL-C was positively correlated with IMT, even after adjustment for sex, age, smoking status, hypertension, diabetes mellitus and hsCRP. HDL2-C was more closely inversely correlated than total HDL-C with BMI, fasting glucose and insulin, 2-h glucose, HOMA-IR, and hsCRP, whereas HDL3-C was not correlated with these factors. Additionally, HDL2-C was more closely correlated than total HDL-C or HDL3-C with sdLDL-C, LDL-C, triglycerides (TG), and apolipoprotein B (apoB). CONCLUSIONS: SdLDL-C was closely associated with insulin resistance and glucose tolerance, lending credence to its potential as a useful risk marker in assessing carotid artery IMT and the present degree of atherosclerosis in Japanese-Americans. The findings also suggest that subjects with higher HDL2-C levels were better protected from atherosclerosis.

Comparability of two different polyacrylamide gel electrophoresis methods for the classification of LDL pattern type.

BACKGROUND: The measurement of small dense low-density lipoprotein (sdLDL) particles is relevant when assessing cardiovascular risk. However, there is as yet no referenced method for the determination of LDL subfractions or a standardized comparison of the methods currently available. Therefore, the aim of this study was to compare the pattern of LDL particles measured by polyacrylamide tube gel electrophoresis (PTGE) and polyacrylamide gradient gel electrophoresis (PGGE) and to correlate the results with triglyceride concentration. MATERIALS AND METHODS: Serum samples were collected from 177 patients. Lipid profile and LDL particle size were assessed using PTGE and PGGE. RESULTS: Pearson correlation and kappa index revealed a very good agreement between the methods. There was 81.3% concordance for classification of sdLDL particles and 97.2% concordance for classification of large LDL when PTGE and PGGE were compared. LDL size correlated with triglyceride in subjects with triglyceride levels >116 mg/dl, pointing to a high CAD risk, as reflected by their higher prevalence of pattern B. CONCLUSIONS: PTGE correlates favourably and is in very good agreement with PGGE. The determination of LDL particle size may be an appropriate analytical procedure to estimate CAD risk in patients with high triglyceride levels.

"European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses.

Aim of the present Consensus Statement is to provide a comprehensive and up to-date document on the pathophysiology, atherogenicity and clinical significance of low density liproproteins (LDL) subclasses. We sub-divided our statement in 2 sections. section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drug and lifestyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions.

Association between moderately oxidized low-density lipoprotein and high-density lipoprotein particle subclass distribution in hemodialyzed and post-renal transplant patients.

Disturbances in the metabolism of lipoprotein profiles and oxidative stress in hemodialyzed (HD) and post-renal transplant (Tx) patients are proatherogenic, but elevated concentrations of plasma high-density lipoprotein (HDL) reduce the risk of cardiovascular disease. We investigated the concentrations of lipid, lipoprotein, HDL particle, oxidized low-density lipoprotein (ox-LDL) and anti-ox-LDL, and paraoxonase-1 (PON-1) activity in HD (n=33) and Tx (n=71) patients who were non-smokers without active inflammatory disease, liver disease, diabetes, or malignancy. HD patients had moderate hypertriglyceridemia, normocholesterolemia, low HDL-C, apolipoprotein A-I (apoA-I) and HDL particle concentrations as well as PON-1 activity, and increased ox-LDL and anti-ox-LDL levels. Tx patients had hypertriglyceridemia, hypercholesterolemia, moderately decreased HDL-C and HDL particle concentrations and PON-1 activity, and moderately increased ox-LDL and anti-ox-LDL levels as compared to the reference, but ox-LDL and anti-ox-LDL levels and PON-1 activity were more disturbed in HD patients. However, in both patient groups, lipid and lipoprotein ratios (total cholesterol (TC)/HDL-C, LDL-C/HDL-C, triglyceride (TG)/HDL-C, HDL-C/non-HDL-C, apoA-I/apoB, HDL-C/apoA-I, TG/HDL) were atherogenic. The Spearman's rank coefficient test showed that the concentration of ox-LDL correlated positively with HDL particle level (R=0.363, P=0.004), and negatively with TC (R=-0.306, P=0.012), LDL-C (R=-0.283, P=0.020), and non-HDL-C (R=-0.263, P=0.030) levels in Tx patients. Multiple stepwise forward regression analysis in Tx patients demonstrated that ox-LDL concentration, as an independent variable, was associated significantly positively with HDL particle level. The results indicated that ox-LDL and decreased PON-1 activity in Tx patients may give rise to more mildly-oxidized HDLs, which are less stable, easily undergo metabolic remodeling, generate a greater number of smaller pre-ß-HDL particles, and thus accelerate reverse cholesterol transport, which may be beneficial for Tx patients. Further studies are necessary to confirm this.

LDL-containing immune complexes in the DCCT/EDIC cohort: associations with lipoprotein subclasses.

Immune complexes containing modified LDL (LDL-IC) and NMR-determined Total LDL particle concentrations are significantly associated with intima-media thickness (IMT). We analyzed the associations between concentrations of NMR-determined lipoprotein subclasses and LDL-IC in the DCCT/EDIC cohort. LDL-IC concentrations in women and men of the DCCT/EDIC cohort did not differ significantly and were positively associated with Total LDL particle concentrations in men and women (r=0.34, r=0.32, respectively; P<.01) and with Small LDL concentration (r=0.22, r=0.13, respectively; P<.01). In women, Large LDL concentrations were also associated with LDL-IC (r=0.20, P<.01) while in men, the association was more modest (r=0.11, P<.05). Thus, both Small and Large LDL are associated with LDL-IC formation. Based on the results from statistical mediation analyses, we concluded that plasma concentrations of LDL-IC may provide a physiological link between the statistically significant association of Total LDL particle concentration with carotid artery IMT in subjects with Type 1 diabetes. Furthermore, after adjusting for conventional risk factors, there was a decrease in LDL-IC concentration even in the presence of high Total LDL particle concentrations in those women with high concentrations of Large HDL, but the association was not evident in men. This suggests that the associations between Large HDL and Total LDL particle concentrations, and their associations with LDL-IC levels, differ by gender and suggest that LDL-IC partially mediate the contribution of Total LDL particle concentration to increased carotid IMT in diabetic men.

Estimation of the low-density lipoprotein (LDL) subclass phenotype using a direct, automated assay of small dense LDL-cholesterol without sample pretreatment.

BACKGROUND: A new method (sLDL-EX "SEIKEN") is commercially available for the direct quantification of small dense LDL-cholesterol (sd-LDL) on automated chemistry analyzers, without manual sample pretreatment. We evaluated the performance of this direct assay to estimate the small dense LDL subclass phenotype ("non-A"), defined by polyacrylamide gel tube electrophoresis. METHODS: Fasting serum samples from 189 healthy subjects (age 18-75y, 96 females) were collected. The direct sd-LDL assay (from Randox Laboratories) was applied on a Roche Modular P analyzer. The Quantimetrix Lipoprint(TM) LDL System was used to define LDL subclass phenotypes (A and non-A). ROC curve analysis was performed for sd-LDL and other lipids and apolipoproteins (apo) with respect to phenotype non-A. RESULTS: sd-LDL concentrations (40.4+/-18.6mg/dl) in the total group correlated (P<0.0001) with apoB (r=0.831), apoB/A-I ratio (r=0.757), non-HDL-cholesterol (r=0.821), triglycerides (r=0.439), and LDL-cholesterol (r=0.641). Higher sd-LDL concentrations (P<0.0001) were measured in subjects with LDL phenotype non-A (53.6+/-17.0mg/dl, n=92) than in those with phenotype A (27.9+/-8.9mg/dl, n=97). In logistic regression analysis, sd-LDL and apoA-I were independently associated with LDL subclass phenotype non-A. Highest areas under ROC curves were obtained for sd-LDL (0.943), triglycerides (0.833), triglyceride/HDL-cholesterol (0.838) and apoB/A-I ratio (0.826) to predict phenotype non-A. The sd-LDL cut-off point for optimal sensitivity (87.9%) and specificity (92.8%) was >38.5mg/dl. CONCLUSIONS: The direct, homogeneous sd-LDL method is easily applicable on an automated chemistry analyzer and shows acceptable performance to estimate the electrophoretic LDL subclass phenotype.

Lipoprotein subfractions and cardiovascular disease risk.

PURPOSE OF REVIEW: Subfractions of LDL and HDL defined by differences in particle size and density have been associated to varying degrees with risk of cardiovascular disease (CVD). Assessment of these relationships has been clouded by lack of standardization among the various analytic methodologies as well as the strong correlations of the subfractions with each other and with standard lipid and lipoprotein risk markers. This review summarizes the properties of the major LDL and HDL particle subclasses, and recent evidence linking their measurement with risk of atherosclerosis and CVD. RECENT FINDINGS: Several recent studies have shown independent relationships of levels of LDL and HDL-size subclasses to risk of both coronary artery and cerebrovascular disease. However, the two largest studies, employing nuclear magnetic resonance and ion mobility, respectively, did not find evidence that these measurements improved risk assessment compared with standard lipoprotein assays. In the latter study, principal component analysis was used to group multiple subfraction measurements into three distinct and statistically independent clusters that were related both to cardiovascular outcomes and to genotypes that may reflect underlying metabolic determinants. SUMMARY: Although there is as yet inconclusive evidence as to the extent to which LDL and HDL subfraction measurements improve clinical assessment of CVD risk beyond standard lipid risk markers, recent studies suggest that more refined analyses of lipoprotein subspecies may lead to further improvements in CVD risk evaluation and particularly in identification of appropriate targets for therapeutic intervention in individual patients.

Effects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndrome.

BACKGROUND: The purpose of this study was to determine whether a preparation of controlled-release alpha lipoic acid (CRLA) influences features of the polycystic ovary syndrome (PCOS). METHODS: We administered CRLA 600 mg twice daily for 16 weeks to six lean, nondiabetic patients with PCOS. Insulin sensitivity was measured by the euglycemic, hyperinsulinemic clamp. Plasma lipids were measured by vertical ultracentrifugation. Oxidative stress markers were measured in serum. RESULTS: At the end of 16 weeks of CRLA treatment, there was a 13.5% improvement in insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp (p < .03). There was also a lowering of triglyceride levels (p < .04) and a shift in the distribution of low-density lipoprotein (LDL) particles toward the larger, more buoyant LDL subclass fraction. Two of the subjects who were not on oral contraception had an increased number of menstrual cycles. Controlled-release alpha lipoic acid treatment, however, was neither associated with an increase in plasma antioxidant capacity nor with a reduction in plasma lipid oxidation products. CONCLUSIONS: These data suggest that the CRLA has positive effects on the PCOS phenotype. The effects of CRLA, however, may have been exerted through a mechanism not involving changes in oxidative stress.