Lipoprotein Cholesterol Subfractions Research Articles

The role of small dense LDL-C/large buoyant LDL-C ratio as an independent risk factor in patients with type 2 diabetes mellitus and metabolic syndrome

Dyslipidemia plays a key role in metabolic syndrome (MS), intricately linked to type 2 diabetes mellitus (T2DM). This study aimed to investigate the differences in low-density lipoprotein cholesterol (LDL-C) subfraction levels between T2DM and T2DM with MS, and identify the risk factors associated with the disease. A total of 246 individuals diagnosed with T2DM, including 144 T2DM patients with MS, and 147 healthy subjects were recruited. All participants underwent a comprehensive clinical evaluation. Lipoprotein subfraction analysis was performed using the Lipoprint LDL system. Multivariate logistic regression analysis revealed that several lipid markers, including triglyceride (TG), LDL-C, large buoyant LDL-C (lbLDL-C), small dense LDL-C (sdLDL-C), LDLC2-5, and sdLDL-C/lbLDL-C ratio, were identified as independent risk factors for T2DM. Additionally, TG, sdLDL-C, LDLC-4, LDLC-5, and sdLDL-C/lbLDL-C ratio were found to be independent risk factors for T2DM with MS. Furthermore, the results of the receiver operating characteristic (ROC) curves demonstrated that sdLDL-C, LDLC-4, LDLC-3, and sdLDL-C/lbLDL-C ratio exhibited excellent predictive performance for the risk of T2DM (AUC >0.9). The sdLDL-C/lbLDL-C ratio emerges as a shared independent risk factor for T2DM and MS complications. Furthermore, sdLDL-C/lbLDL-C ratio, along with LDL-4 and LDL-3, exhibits noteworthy predictive capabilities for T2DM.

Association of sdLDL-C With Incident Carotid Plaques With Stable and Vulnerable Morphology: A Prospective Cohort Study.

Small dense low-density lipoprotein cholesterol (sdLDL-C) particles are more atherogenic than large and intermediate low-density lipoprotein cholesterol (LDL-C) subfractions. We sought to investigate the association of sdLDL-C and the sdLDL-C/LDL-C ratio with incident carotid plaques with stable and vulnerable morphology in rural China. This community-based cohort study used data from the RICAS study (Rose Asymptomatic Intracranial Artery Stenosis), which enrolled 887 participants (aged ≥40 years) who were living in Kongcun Town, Pingyin County, Shandong, and free of carotid plaques and had no history of clinical stroke or transient ischemic attack at baseline (2017). Incident carotid plaques and their vulnerability were detected by carotid ultrasound at follow-up (2021). Multivariable logistic regression models were used to explore the association of sdLDL-C or sdLDL-C/LDL-C ratio with incident carotid plaques while adjusting for demographic factors, vascular risk factors, and follow-up time. Of the 887 participants (mean age [SD], 53.89 [8.67%] years; 54.34% women), 179 (20.18%) were detected with incident carotid plaques during an average follow-up of 3.94 years (SD=0.14). Higher sdLDL-C or sdLDL-C/LDL-C ratio, but not LDL-C, was significantly associated with an increased risk of incident carotid plaques. The upper tertile of sdLDL-C (versus lower tertile) was associated with the multivariate-adjusted odds ratio of 2.48 (95% CI, 1.00-6.15; P=0.049; P for linear trend=0.046) for carotid plaques with vulnerable morphology (n=41), and the association remained significant in participants with normal LDL-C (<130 mg/dL; n=693; upper versus lower tertile: odds ratio, 3.38 [95% CI, 1.15-9.90]; P=0.027; P for linear trend=0.025). Moreover, the sdLDL-C/LDL-C ratio was associated with a higher odds ratio of incident carotid plaques in participants without diabetes (P for interaction=0.014). Higher sdLDL-C was associated with an increased risk of incident carotid plaques, especially carotid plaques with vulnerable morphology, even in participants with normal LDL-C. This suggests the potential of sdLDL-C as a therapeutic target for stroke prevention. URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1800017197.

Genetically predicted small dense low-density lipoprotein cholesterol and ischemic stroke subtype: multivariable Mendelian randomization study.

Small dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design. We identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis. In univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117-1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106-1.597, P = 0.002). Findings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.

High-density lipoprotein cholesterol subfraction HDL2 is associated with improved endothelial function in systemic lupus erythematosus

ObjectivePatients with systemic lupus erythematosus (SLE) have increased risk of premature atherosclerosis but the exact mechanisms remains unclear. Flow-mediated dilatation (FMD) is an established non-invasive assessment of vascular endothelial function....

Supplementation with a β-glucan tablet has no effect on hyperlipidemia: a randomized, placebo-controlled clinical trial

BackgroundClinical evidence has suggested that the oat-soluble fiber β-glucan might have lipid-lowering effects. ObjectivesThe present clinical trial was conducted to evaluate the efficacy and safety of high-medium molecular weight β-glucan on serum low-density lipoprotein (LDL) cholesterol and other lipid subfractions in subjects with hyperlipidemia. MethodsA randomized double-blinded trial was performed to assess the efficacy and safety of β-glucan supplementation in reducing lipid levels. Subjects with LDL cholesterol levels of >3.37 mmol/L when treated or not with a statin were randomly assigned to receive 1 of 3 daily doses of a tableted formulation of β-glucan (1.5, 3, or 6 g) or placebo. The primary efficacy end point was the change from baseline to 12 wk in LDL cholesterol. Secondary end points of lipid subfractions and safety were also assessed. ResultsA total of 263 subjects were enrolled; 66 subjects were assigned to each of the 3 β-glucan groups, and 65 subjects were assigned to the placebo group. The mean change from baseline to 12 wk in serum LDL cholesterol level was 0.08, 0.11, and −0.04 mmol/L in the 3 β-glucan groups (P = 0.23, 0.18, and 0.72 compared with the placebo group, respectively) and −0.10 mmol/L in the placebo group. The changes in total cholesterol, small LDL cholesterol subclass particle concentration, non–high-density lipoprotein cholesterol, apolipoprotein B, very low–density lipoprotein cholesterol, and high-sensitivity C-reactive protein were also not significant in the β-glucan groups when compared with the placebo group. Gastrointestinal adverse events were reported in 23.4%, 34.8%, and 66.7% of patients in the β-glucan groups and in 36.9% of patients in the placebo group (P < 0.0001 for the overall comparison across the 4 groups). ConclusionsIn subjects with LDL cholesterol levels of >3.37 mmol/L, a tablet formulation of β-glucan was not effective in reducing LDL cholesterol concentration or other lipid subfractions when compared with a placebo.This trial was registered at clinicaltrials.gov as NCT03857256.

Associations of perfluoroalkyl substances (PFAS) with lipid and lipoprotein profiles

BackgroundPerfluoroalkyl substances (PFAS) are man-made chemicals with unique properties that are widely distributed in humans and the environment. Recent studies suggest that PFAS are involved in cholesterol metabolism, however, the mechanisms underlying the associations are poorly understood.ObjectiveWe aimed to evaluate associations of plasma PFAS with detailed lipid and lipoprotein subfractions in an adult population of men and women.MethodsWe measured concentrations of cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein subclasses, as well as fatty acid and different phospholipid measures, using serum proton nuclear magnetic resonance (1H-NMR), and four plasma PFAS using liquid chromatography-mass spectrometry (UHPLC-MS/MS). Measurements were available for 493 participants (all aged 50 years, 50% female). Multivariable linear regression was used to estimate the association of four PFAS with 43 different 1H-NMR measures, with adjustment for body mass index (BMI), smoking, education, and physical activity.ResultsWe found that perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), but not perfluorohexanesulfonate (PFHxS), concentrations were consistently positively associated with concentrations of cholesterol in lipoprotein subfractions, apolipoproteins, as well as composite fatty acid- and phospholipid profiles. The most consistent associations were found for the relationship of PFAS with total cholesterol in intermediate-density lipoprotein (IDL), across all low-density lipoprotein (LDL) subfractions and small high-density lipoprotein (HDL). Moreover, we found weak to null evidence for an association of any of the measured 13 triglyceride lipoprotein subfractions with PFAS.ConclusionsOur results suggest that plasma PFAS concentrations are associated with cholesterol in small HDL, IDL and all LDL subfractions, as well as apolipoproteins and composite fatty acid and phospholipid profiles but to a lesser extent with triglycerides in lipoproteins. Our findings draw attention to the need for more detailed measurements of lipids across various lipoprotein subfractions and subclasses in assessing the role of PFAS in lipid metabolism.ImpactBy performing an in-depth characterization of circulating cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein, fatty acid, and phospholipid concentrations, this study has expanded upon the limited literature available on the associations of plasma PFAS concentrations beyond clinical routine laboratory testing for lipids.

Development of Machine Learning Tools for Predicting Coronary Artery Disease in the Chinese Population.

Coronary artery disease (CAD) is one of the major cardiovascular diseases and the leading cause of death globally. Blood lipid profile is associated with CAD early risk. Therefore, we aim to establish machine learning models utilizing blood lipid profile to predict CAD risk. In this study, 193 non-CAD controls and 2001 newly-diagnosed CAD patients (1647 CAD patients who received lipid-lowering therapy and 354 who did not) were recruited. Clinical data and the result of routine blood lipids tests were collected. Moreover, low-density lipoprotein cholesterol (LDL-C) subfractions (LDLC-1 to LDLC-7) were classified and quantified using the Lipoprint system. Six predictive models (k-nearest neighbor classifier (KNN), logistic regression (LR), support vector machine (SVM), decision tree (DT), multilayer perceptron (MLP), and extreme gradient boosting (XGBoost)) were established and evaluated by the confusion matrix, area under the receiver operating characteristic (ROC) curve (AUC), recall (sensitivity), accuracy, precision, and F1 score. The selected features were analyzed and ranked. While predicting the CAD development risk of the CAD patients without lipid-lowering therapy in the test set, all models obtained AUC values above 0.94, and the accuracy, precision, recall, and F1 score were above 0.84, 0.85, 0.92, and 0.88, respectively. While predicting the CAD development risk of all CAD patients in the test set, all models obtained AUC values above 0.91, and the accuracy, precision, recall, and F1 score were above 0.87, 0.94, 0.87, and 0.92, respectively. Importantly, small dense LDL-C (sdLDL-C) and LDLC-4 play pivotal roles in predicting CAD risk. In the present study, machine learning tools combining both clinical data and blood lipid profile showed excellent overall predictive power. It suggests that machine learning tools are suitable for predicting the risk of CAD development in the near future.

Abstract 11198: Role of Different Lipid Parameters and Lipoproteins on Coronary Microvascular Dysfunction in the Young

Aim: Young with coronary microvascular dysfunction (CMD) have increased cardiovascular morbidity. Particularly, Asian patients with CMD are considerably younger than their Western peers. Blood lipids are traditionally considered risk factors for myocardial infarction (MI) of the elderly. However, little is known about CMD in the young. The purpose of our study was to test the associations between lipids and lipoprotein particles and CMD in the young. Methods: A cross-sectional study was conducted from 2014 to 2020, 1868 young participants were included. CMD was defined as angina but no obstructive coronary disease. All participants had baseline laboratory testing. Lipid parameters, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), small dense low density lipoprotein cholesterol (sd LDL-C), high-density lipoprotein (HDL), non-HDL, TC/HDL ratio, TG/HDL ratio and LDL/HDL ratio were measured. Both low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) subfractions were measured using the Quantimetrix Lipoprint System. Logistic regression analysis was performed to determine associated factors for CMD. Results: Very low-, intermediate-, small dense-, and low- density lipoprotein particles were positively associated with CMD. HDL particles were inversely associated with CMD apart from small HDL. Cholesterol in large HDL was inversely associated with CMD (odds ratio [OR] = 0.75), whereas cholesterol in small HDL was not (OR = 1.08). TG within all lipoproteins, including most HDL particles, were positively associated with CMD. In multiple logistic regression analyses, non-HDL [OR = 1.56 (1.16-1.87)], sd LDL-C [OR = 1.80 (1.21-2.27)], TC [OR = 1.41 (1.25-1.93)], TC/HDL [OR = 1.26 (1.15-1.68)] were significantly associated with CMD. Conclusions: Lipids and lipoproteins showed similar associations with CMD. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with CMD. Non-HDL, sd LDL-C, TC, and TC/HDL were significantly associated with CMD than others. This result should be considered in future clinical lipid-lowering trials and a routine screening for CMD in the young.

Association of High-Density Lipoprotein Cholesterol Subfractions with Insulin Resistance in Nigerians with Type 2 Diabetes Mellitus

Background: There are conflicting reports on the relationship of each of the two subfractions of high-density lipoprotein cholesterol (HDL-C) with insulin resistance in patients with type 2 diabetes mellitus (T2DM). Information on the relationship between HDL-C subfractions and insulin resistance in Nigerian patients with T2DM is not available in the literature. Aim: The aim of this article is to determine the association between subfractions of HDL-C and insulin resistance in Nigerian patients with T2DM. Materials and Methods: Patients with T2DM who were being managed by the Endocrinology, Diabetes, and Metabolism unit of the Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nnewi, South-East Nigeria were recruited for this study, whereas individuals with normal glucose tolerance (NGT) were recruited from Nnewi town. The study was carried out within a 5-month period. History was taken and physical examination was done on study participants. Fasting venous samples were collected for plasma glucose, plasma total HDL-C, plasma HDL-C phenotypes, serum C-peptide, serum creatinine, and serum alanine transferase estimation. Homeostasis Model Assessment for Insulin Resistance (HOMA2-IRC-peptide) score was determined using plasma glucose and serum C-peptide concentrations. Data were analyzed using appropriate statistical software. Results: A total of 616 participants consisting of 400 participants with T2DM and 216 participants with NGT were recruited for the study. Difference in age, sex, and blood pressure was not statistically significant between participants with T2DM and those with NGT. There were statistically significant differences in body mass index, fasting plasma glucose, C-peptide, HOMA-IR, total HDL-C, and HDL-C subfractions between subjects with T2DM and those with NGT. There was a significant negative correlation between HOMA-IR score and each of HDL2-C (r s= −0.513, P &lt; 0.01), HDL3-C (r s= −0.471, P &lt; 0.01), and HDL2-C/HDL3-C ratio (r s= −0.416, P &lt; 0.01) in subjects with T2DM. Total HDL-C (odds ratio (OR)=3, P = 0.02), HDL2-C (OR=3.87, P = 0.01), and HDL3-C (OR=2.54, P = 0.02) were significant predictors of insulin resistance in individuals with T2DM after univariate and multivariate logistic regressions. Conclusion: This study showed a negative correlation between insulin resistance and each of the HDL-C subfractions in Nigerian patients with T2DM with HDL2-C having the strongest correlation with HOMA-IR score.

Low-Density Lipoprotein Cholesterol 4: The Notable Risk Factor of Coronary Artery Disease Development

Background: Coronary artery disease (CAD) is the leading cause of death worldwide, which has a long asymptomatic period of atherosclerosis. Thus, it is crucial to develop efficient strategies or biomarkers to assess the risk of CAD in asymptomatic individuals.Methods: A total of 356 consecutive CAD patients and 164 non-CAD controls diagnosed using coronary angiography were recruited. Blood lipids, other baseline characteristics, and clinical information were investigated in this study. In addition, low-density lipoprotein cholesterol (LDL-C) subfractions were classified and quantified using the Lipoprint system. Based on these data, we performed comprehensive analyses to investigate the risk factors for CAD development and to predict CAD risk.Results: Triglyceride, LDLC-3, LDLC-4, LDLC-5, LDLC-6, and total small and dense LDL-C were significantly higher in the CAD patients than those in the controls, whereas LDLC-1 and high-density lipoprotein cholesterol (HDL-C) had significantly lower levels in the CAD patients. Logistic regression analysis identified male [odds ratio (OR) = 2.875, P < 0.001], older age (OR = 1.018, P = 0.025), BMI (OR = 1.157, P < 0.001), smoking (OR = 4.554, P < 0.001), drinking (OR = 2.128, P < 0.016), hypertension (OR = 4.453, P < 0.001), and diabetes mellitus (OR = 8.776, P < 0.001) as clinical risk factors for CAD development. Among blood lipids, LDLC-3 (OR = 1.565, P < 0.001), LDLC-4 (OR = 3.566, P < 0.001), and LDLC-5 (OR = 6.866, P < 0.001) were identified as risk factors. To predict CAD risk, six machine learning models were constructed. The XGboost model showed the highest AUC score (0.945121), which could distinguish CAD patients from the controls with a high accuracy. LDLC-4 played the most important role in model construction.Conclusions: The established models showed good performance for CAD risk prediction, which can help screen high-risk CAD patients in asymptomatic population, so that further examination and prevention treatment might be taken before any sudden or serious event.

Clinical-epidemiological analysis of HDL2 and HDL3 subfractions in adults from Maracaibo city, Venezuela.

To carry out a clinical-epidemiological analysis of high-density lipoprotein cholesterol subfractions (HDL-C) in adults from Maracaibo, Venezuela. A descriptive and cross-sectional study of the database from the Metbolic Syndrome Prevalence in Maracaibo Study was carried out. HDL3 and HDL2 serum concentration, as well as the HDL2/HDL3 ratio, were determined in 359 individuals of both sexes, over 18 years of age. Values obtained were evaluated according to sociodemographic, clinical and biochemical characteristics. Mean population age was 39.4 ± 15.2 years, and 51.5% were female. Differences in HDL-C subfraction levels were only observed in those subjects with low HDL-C levels. Women with hypertriglyceridemia showed significantly lower serum HDL3 and HDL2 concentrations than those with normal triglycerides (p=0.033), as well as a lower HDL3 level and HDL2 / HDL3 ratio in those with higher levels of ultra-sensitive C-reactive protein (us-CRP) (p<0.001). A significantly lower concentration of HDL2 was observed in men with some degree of hypertension (p=0.031), insulin resistance (p=0.050) and metabolic syndrome (p=0.003); while those with elevated us-CRP showed a lower concentration of HDL3 (p=0.011). HDL-C subfractions show varying clinical-epidemiological behavior in adults from Maracaibo. Lower serum levels are observed in men, differences only in those with low HDL-C; and no predominance of any subclass was observed according to sociodemographic, clinical and biochemical characteristics.

2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD)

It has been demonstrated that diabetic dyslipidaemia is the chief bridge between diabetes and incremental risk of cardiovascular disease in patients with diabetes. However, the characteristics of lipoprotein subfractions distribution in patients with type 2 diabetes (T2D) have not been fully investigated. The aim of present study was to evaluate the distributions of lipoprotein subfractions in T2D patients.A total of 920 patients, who have not received lipid-lowering drug treatment previously, were consecutively enrolled in this study. Based on the evidence of diabetes, patients were divided into T2D group (n=204) and non-T2D group (n=716). Both low- and high-density lipoprotein cholesterol (LDL- and HDL-C) subfractions were analysed using the Quantimetrix Lipoprint System. The distributions of lipoprotein subfractions were evaluated in patients with and without T2D.Compared with non-T2D individuals, the T2D group manifested significantly lower large HDL-C concentration/HDL subfraction percentage, smaller mean LDL particle size but higher small HDL-C and LDL-C concentrations as well as small HDL and LDL subfraction percentages. Moreover, the data indicated that the small HDL-C/ LDL-C concentrations, the small and large HDL subfraction percentages along with the mean LDL particle size were independently related to the existence of T2D (95% CI=1.009–1.067, p=0.009; 95% CI=0.938-0.983, p=0.001; 95% CI=1.023–1.135, p=0.005; 95% CI= 1.005–1.048, p=0.014; 95% CI=0.940-0.999, p=0.040; respectively) assessed by logistic regression analysis.The present study indicated that the changes of lipid profile in patients with T2D are characterised by abnormal distributions of lipoprotein subfractions apart from clinically atherogenic dyslipidaemia.

Diabetes alters the association between high-density lipoprotein subfractions and carotid intima-media thickness: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

High-density lipoprotein cholesterol comprises a group of heterogeneous subfractions that might have differential effects on atherosclerosis. Moreover, prior investigations suggest that the presence of diabetes (T2D) modifies the impact of some subfractions on atherosclerosis. In this study, we aimed to evaluate the association between high-density lipoprotein cholesterol subfractions and carotid intima-media thickness in the baseline assessment of the Brazilian Longitudinal Study of Adult Health participants from the São Paulo investigation centre. We evaluated 3930 individuals between 35 and 74 years without previous cardiovascular disease not using lipid-lowering drugs. High-density lipoprotein cholesterol subfractions (HDL2-C and HDL3-C) were measured by vertical ultracentrifugation (vertical auto profile). The relationship between each high-density lipoprotein cholesterol subfraction and carotid intima-media thickness was analysed by multiple linear regression models. Total high-density lipoprotein cholesterol, as well as HDL2-C and HDL3-C, was negatively associated with carotid intima-media thickness after adjustment for demographic data (all p < 0.001) and traditional risk factors (all p < 0.05). When stratified by T2D status, the HDL2-C/HDL3-C ratio showed a negative association with carotid intima-media thickness in participants with T2D ( p = 0.032), even after fully controlling for confounding variables, including total high-density lipoprotein cholesterol. HDL2-C, HDL3-C and HDL2/HDL3-C ratio are inversely associated with carotid intima-media thickness after adjustment for traditional risk factors. Association of the HDL2-C/HDL3-C ratio is modified by the presence of diabetes, being more pronounced in diabetic individuals.

Relationship between lipoprotein subfraction cholesterol and residual risk for cardiovascular outcomes: A post hoc analysis of the AIM-HIGH trial

The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial failed to demonstrate incremental clinical benefit of extended-release niacin (ERN) in 3414 statin-treated patients with established cardiovascular (CV) disease who had low baseline levels of high-density lipoprotein cholesterol (HDL-C) as compared to placebo. A previous secondary analysis suggested that ERN provided outcome benefits in ERN-treated patients with high triglycerides (TGs; >200mg/dL) and very low HDL-C (<32mg/dL) at baseline. The current analysis sought to ascertain how changes in TG-enriched lipoproteins and HDL subfractions impact residual risk in the comparator treatment arms. We evaluated the relationship between niacin treatment, lipoproteins and their subfractions, and CV outcomes in a non-prespecified, post hoc analysis of the AIM-HIGH trial. Lipoprotein subfraction analysis was performed with zonal ultracentrifugation in 2457 AIM-HIGH participants at baseline and 1year of treatment. Hazard ratios were estimated using Cox proportional hazards models for relationships between lipoproteins and the composite primary endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Analyses were performed for the entire cohort and in participants with TGs > 200mg/dL and HDL-C < 32mg/dL. Apoprotein B-containing lipoproteins and their subfractions decreased significantly in both treatment arms but decreased more with ERN treatment. HDL-C and its subfractions increased significantly in both treatment groups, but more so in patients treated with ERN. For the entire study population, neither apoB- nor apoA1-containing lipoprotein subfractions predicted risk at baseline or at 1year of follow-up. In the high TG and low HDL-C subgroup treated with placebo, changes at 1year in HDL2-C, total cholesterol/HDL2-C, and non-HDL-C/HDL2-C may be associated with increased CV events, whereas in the ERN treatment arm, changes at 1year in very low-density lipoprotein cholesterol and very low-density lipoprotein subfractions, total remnant lipoproteins, and various risk ratios may be associated with increased CV events, while HDL2-C may be associated with reduced risk. We provide hypothesis-generating findings that ERN may confer benefit in patients with coronary heart disease who have high TGs and low HDL by reducing serum levels of remnant lipoprotein cholesterol and increasing HDL2-C.

Impact of Smoking Status on Lipoprotein Subfractions: Data from an Untreated Chinese Cohort

ObjectiveCigarette smoking is one of the established risk factors of atherosclerotic cardiovascular disease, however, its impact on lipids is not completely understood, especially in the Chinese population. Therefore, this study evaluated the impact of smoking status (non, former, and current smoking) on the distribution of lipoprotein subfractions in untreated patients with angina-like chest pain. MethodsA total of 877 patients were consecutively enrolled and divided into nonsmoking (n = 518), former smoking (n = 103), and current smoking (n = 256) groups. Both low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) subfractions were measured using the Quantimetrix Lipoprint System. The distributions of lipoprotein subfractions were evaluated among the groups. ResultsCompared with nonsmoking subjects, the current smoking group had significantly lower large/medium HDL-C (both P < 0.001) concentration and large HDL subfraction percentage but higher small HDL-C and medium LDL-C concentrations as well as medium LDL subfraction percentage. Importantly, former smoking subjects showed elevated levels of large HDL-C concentration, large HDL particle percentage, and mean LDL particle size and attenuation in small HDL/LDL percentages and small LDL-C concentration, but these levels did not reach the optimal status compared with those of the non-smoking group (data not shown). ConclusionSmoking has an adverse impact on the lipoprotein subfractions, presented as lower large HDL particles besides higher small HDL and medium LDL particles, whereas smoking cessation could reverse these change to a certain degree.

Greater remnant lipoprotein cholesterol reduction with pitavastatin compared with pravastatin in HIV-infected patients.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in those with HIV. An emerging CVD risk factor is triglyceride-rich remnant lipoprotein cholesterol (RLP-C: the sum of intermediate-density lipoprotein and very low-density lipoprotein cholesterol). The effects of statin therapy on lipoprotein subfractions, including RLP-C, in HIV dyslipidemia are unknown. This is a post hoc analysis of the randomized INTREPID trial (NCT 01301066) comparing pitavastatin 4 mg daily vs. pravastatin 40 mg daily in study participants with HIV. We measured apolipoproteins AI and B and lipoprotein cholesterol subfractions separated by density gradient ultracentrifugation at baseline and 12 weeks. We compared changes in atherogenic subfractions over 12 weeks in INTREPID participants using analysis of covariance. Lipoprotein subfraction data were available for 213 study participants (pitavastatin n = 104, pravastatin n = 109). Baseline characteristics were similar between treatment groups. Reductions in RLP-C were significantly greater in the pitavastatin group compared with pravastatin group (-11.6 mg/dl vs. -8.5 mg/dl; P = 0.01). Similarly, ratios of risk [apolipoproteins B/apolipoproteins AI, total cholesterol/high-density lipoprotein cholesterol (HDL-C)] showed greater reductions with pitavastatin (P < 0.05). There were no differences in changes in HDL-C, HDL-C subfractions or lipoprotein(a) cholesterol levels. In patients with HIV, pitavastatin 4 mg/dl lowered both RLP-C and established apolipoprotein and lipid risk ratios more so than pravastatin 40 mg/dl. The impact of RLP-C reduction on CVD in HIV dyslipidemic patients merits further study.

High-Density Lipoprotein Cholesterol Subfractions in Collegiate Female Volleyball Players

Much of the published data on the lipid profiles of athletes are based on studies of endurance athletes. Data on female volleyball players are rare. The purpose of this study was thus to examine serum high-density-lipoprotein cholesterol (HDL-C) subfractions in collegiate female volleyball players. Twenty-six female collegiate volleyball players were compared with 26 age- and body mass index-matched control subjects. Dietary information was obtained with a food frequency questionnaire. The subjects were all nonsmokers and were not taking any drug known to affect lipid and lipoprotein metabolism. The volleyball players showed significantly higher mean HDL2-C than the control group. There were no significant differences in HDL-C and HDL3-C between the 2 groups. The results indicate that favorable lipid and lipoprotein profiles could be obtained by vigorous volleyball training and significantly higher HDL2-C could be obtained without observing significant differences in HDL-C and HDL3-C.

Pitavastatin 4 mg Provides Significantly Greater Reduction in Remnant Lipoprotein Cholesterol Compared With Pravastatin 40 mg: Results from the Short-term Phase IV PREVAIL US Trial in Patients With Primary Hyperlipidemia or Mixed Dyslipidemia

PurposeRemnants are partially hydrolyzed, triglyceride-rich lipoproteins that are implicated in atherosclerosis. We assessed the adequacy of pitavastatin 4 mg and pravastatin 40 mg in reducing atherogenic lipid parameters beyond LDL-C, in particular remnant lipoprotein cholesterol (RLP-C). MethodsFrom the Phase IV, multicenter, randomized, double-blind PREVAIL US (A Study of Pitavastatin 4 mg Vs. Pravastatin 40 mg in Patients With Primary Hyperlipidemia or Mixed Dyslipidemia) trial, we examined lipoprotein cholesterol subfractions using Vertical Auto Profile testing and apolipoproteins B and A-I at baseline and 12 weeks. Participants with primary hyperlipidemia or mixed dyslipidemia had LDL-C levels of 130 to 220 mg/dL and triglyceride levels ≤400 mg/dL. In this post hoc analysis, changes in lipid parameters were compared by using ANCOVA. FindingsLipoprotein subfraction data were available in 312 patients (pitavastatin, n = 157; pravastatin, n = 155). Pitavastatin promoted a greater reduction in RLP-C than pravastatin (–13.6 [8.7] vs –9.3 [9.5] mg/dL). Furthermore, the pitavastatin group reported greater reductions in both components of RLP-C (both, P < 0.001): intermediate-density lipoprotein cholesterol (–9.5 [6.3] vs –6.4 [6.6] mg/dL) and very low-density lipoprotein cholesterol subfraction 3 (–4.1 [3.5] vs –2.9 [3.8] mg/dL). There were also greater reductions in the major ratios of risk (apolipoprotein B/apolipoprotein A-I and total cholesterol/HDL-C) (both, P < 0.001). There were no significant changes in HDL-C, its subfractions, or natural log lipoprotein(a)-cholesterol. The mean age was 58.8 ± 8.9 years in the pitavastatin group and 57.0 ± 10.2 years in the pravastatin group. ImplicationsCompared with pravastatin 40 mg daily, pitavastatin 4 mg provided superior reductions in atherogenic lipid parameters beyond LDL-C, including RLP-C. Future studies are needed investigate the clinical implications of lowering directly measured RLP-C as the principal target. ClinicalTrials.gov identifier: NCT01256476.

Remnant Lipoprotein Cholesterol and Mortality After Acute Myocardial Infarction: Further Evidence for a Hypercholesterolemia Paradox From the TRIUMPH Registry.

Remnants are partially hydrolyzed, triglyceride-rich lipoproteins that, like other apolipoprotein B-containing lipoproteins, are atherogenic. Prior observational studies suggest paradoxically better outcomes in hypercholesterolemic patients who sustain an acute myocardial infarction (AMI), one of several known recurrent risk paradoxes. To date, the association of directly measured remnant lipoprotein cholesterol (RLP-C) with survival after an AMI has not been examined. Higher RLP-C levels may be paradoxically associated with lower mortality. We examined 2465 AMI survivors in a prospective, 24-center US study of AMI outcomes. Lipoprotein cholesterol subfractions were directly measured by ultracentrifugation. RLP-C was defined as intermediate-density lipoprotein cholesterol (IDL-C) + very-low-density lipoprotein cholesterol subfraction 3 (VLDL3 -C). Given a linear relationship between RLP-C and mortality, we examined RLP-C by tertiles and continuously. Cox regression hazard ratios (HRs) were adjusted for the Global Registry of Acute Coronary Events (GRACE) score and 23 other covariates. Participants were age 58 ± 12 years (mean ± SD), and 68% were men. After 2 years of follow-up, 226 (9%) participants died. The mortality proportion was 12.4% in the lowest tertile of RLP-C (0-15 mg/dL), 8.5% in the middle tertile (16-23 mg/dL), and 6.8% in the highest tertile (24-120 mg/dL; P < 0.001). A 1-SD increase in RLP-C (11 mg/dL) predicted a 24% lower adjusted risk of 2-year mortality (HR: 0.76, 95% confidence interval [CI]: 0.64-0.91). Similar results were found for a 1-SD increase in IDL-C (HR per 8 mg/dL: 0.80, 95% CI: 0.67-0.96), VLDL3 -C (HR per 4 mg/dL: 0.74, 95% CI: 0.61-0.89), and very-low-density lipoprotein cholesterol (VLDL-C; HR per 8 mg/dL: 0.69, 95% CI: 0.55-0.85). Higher RLP-C levels were associated with lower mortality 2 years after AMI despite rigorous adjustment for known confounders. Unknown protective factors or a lead-time bias likely explains the paradox.

Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: The Very Large Database of Lipids-4 (VLDL-4) study.

High levels of the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio are associated with obesity, metabolic syndrome, and insulin resistance. We evaluated variability in the remaining lipid profile, especially remnant lipoprotein particle cholesterol (RLP-C) and its components (very low-density lipoprotein cholesterol subfraction 3 and intermediate-density lipoprotein cholesterol), with variability in the TG/HDL-C ratio in a very large study cohort representative of the general U.S. We examined data from 1,350,908 US individuals who were clinically referred for lipoprotein cholesterol ultracentrifugation (Atherotech, Birmingham, AL) from 2009 to 2011. Demographic information other than age and sex was not available. Changes to the remaining lipid profile across percentiles of the TG/HDL-C ratio were quantified, as well as by three TG/HDL-C cut-off points previously proposed in the literature: 2.5 (male) and 2 (female), 3.75 (male) and 3 (female), and 3.5 (male and female). The mean age of our study population was 58.7 years, and 48% were men. The median TG/HDL-C ratio was 2.2. Across increasing TG/HDL-C ratios, we found steadily increasing levels of RLP-C, non-HDL-C and LDL density. Among the lipid parameters studied, RLP-C and LDL density had the highest relative increase when comparing individuals with elevated TG/HDL-C levels to those with lower TG/HDL-C levels using established cut-off points. Approximately 47% of TG/HDL-C ratio variance was attributable to RLP-C. In the present analysis, a higher TG/HDL-C ratio was associated with an increasingly atherogenic lipid phenotype, characterized by higher RLP-C along with higher non-HDL-C and LDL density.