High-density Lipoprotein Subclasses Research Articles

A new risk factor for coronary artery disease can be detected by an ApoA1 mAb-based assay

BackgroundThis study aimed to find coronary artery disease (CAD) related apolipoprotein A1 (ApoA1) monoclonal antibody (mAb) and to evaluate the diagnostic value of the assay based on it. MethodsPatients with CAD diagnosed by coronary angiography (disease group, n = 180) and healthy subjects (control group, n = 199) were recruited. The correlation between methods and CAD were evaluated by Spearman’s rank correlation coefficients. Receiver operating characteristic (ROC) curve analysis was used to evaluate the auxiliary diagnostic value of methods for CAD. Odds ratios (ORs) of the test results in CAD were estimated using logistic regression analysis. ResultsMeasurements from an ApoA1 mAb were found significantly positively correlated with CAD (r = 0.243, P < 0.01), unlike the measurements from the ApoA1 pAb were negatively correlated with CAD (r = -0.341, P < 0.001). The areas under the ROC curve of the ApoA1 mAb and pAb measurements were 0.704 and 0.563, respectively, in patients with normal HDL-C levels. ApoA1 values from the mAb assay had a significant positive impact on CAD risk. ConclusionAn ApoA1 mAb-based assay can distinguish a high-density lipoprotein (HDL) subclass positively related to CAD, which can be used to improve and reappraise CAD risk assessment.

Total Outflow of High-Density Lipoprotein–Cholesteryl Esters from Plasma Is Decreased in a Model of 3/4 Renal Mass Reduction

(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins.

Abstract 14972: Association Between CEC Measured by Immobilized Liposome-Bound Gel Beads Method and the Size of Lipid-Rich Coronary Artery Plaque

Introduction/Background: High-density lipoprotein (HDL) exerts cholesterol efflux capacity (CEC), and it ameliorates cardiovascular disease (CVD). CEC had been expected as a surrogate biomarker in addition to HDL cholesterol (HDL-C), which has been found not always to reflect the CVD risk. However, the procedures of the conventional CEC assays were too complex to be introduced into clinical practice because of cell-based assay. Given this situation, we invented novel cell-free CEC assay named immobilized liposome-bound gel beads (ILG) method. ILG method utilizes liposomes which contain fluorescence labeled cholesterol instead of lipid loaded foam cells, and has advantage of simplicity of procedure and accuracy. Reserch Question/Hypothesis: Does ILG method show some associations between CEC and HDL subclass, and also reflect the condition of coronary artery plaque? Goals/Aim: We aim to demonstrate CEC by ILG method has clinical significance for assessment of the CVD risk. Methods/Approach: Patients who underwent diagnostic catheterization or percutaneous coronary intervention were enrolled, and 61 patients were examined through CEC analysis by ILG method and assessment of coronary artery plaque by optical coherence tomography (OCT) imaging. Large lipid-rich plaque was defined as a lipid plaque with a lipid arc ≥180°and lipid length ≥5 mm. Serum HDL subclass was analyzed by enzymatic assay (Denka). We defined the ratio apolipoprotein E(apoE)-containing HDL-C to HDL-C as %apoE, and we also calculated the value of HDL 3 -C/HDL 2 -C, and classified HDL 3 - or HDL 2 -rich group. Results/Data: HDL-C was positively associated with %apoE, and CEC of apoE-rich patients was higher than that of apoE-poor patients. This correlation was maintained after classified based on size of HDL. CEC and %apoE in patients with large lipid-rich plaque were significantly lower than in those in without. In contrast, there was no significant difference in HDL-C and LDL-C. Conclusion: In present study, ILG method showed that apoE has some influence on CEC, and CEC was inversely correlated with size of lipid-rich plaque. These results implied that ILG method, suitable CEC assay for clinical site, might be useful to assess the CVD risk.

Low levels of small HDL particles predict but do not influence risk of sepsis

BackgroundLow levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling.MethodsIn the UK Biobank, ~ 270,000 individuals have data on HDL subclasses derived from nuclear magnetic resonance analysis. We estimated the association of particle count of total HDL and HDL subclasses (small, medium, large, and extra-large HDL) with sepsis, sepsis-related death, and critical care admission in a Cox regression model. We subsequently utilised genetic data from UK Biobank and FinnGen to perform Mendelian randomisation (MR) of each HDL subclass and sepsis to test for a causal relationship. Finally, we explored the role of IL-6 signalling as a potential causal driver of changes in HDL subclasses.ResultsIn observational analyses, higher particle count of small HDL was associated with protection from sepsis (Hazard ratio, HR 0.80; 95% CI 0.74–0.86, p = 4 × 10–9 comparing Quartile 4, highest quartile of HDL to Quartile 1, lowest quartile of HDL), sepsis-related death (HR 0.80; 95% CI 0.74–0.86, p = 2 × 10–4), and critical care admission with sepsis (HR 0.72 95% CI 0.60–0.85, p = 2 × 10–4). Parallel associations with other HDL subclasses were likely driven by changes in the small HDL compartment. MR analyses did not strongly support causality of small HDL particle count on sepsis incidence (Odds ratio, OR 0.98; 95% CI 0.89–1.07, p = 0.6) or death (OR 0.94, 95% CI 0.75–1.17, p = 0.56), although the estimate on critical care admission with sepsis supported protection (OR 0.73, 95% CI 0.57–0.95, p = 0.02). Bidirectional MR analyses suggested that increased IL-6 signalling was associated with reductions in both small (beta on small HDL particle count − 0.16, 95% CI − 0.10 to − 0.21 per natural log change in SD-scaled CRP, p = 9 × 10–8).and total HDL particle count (beta − 0.13, 95% CI − 0.09 to − 0.17, p = 7 × 10–10), but that the reverse effect of HDL on IL-6 signalling was largely null.ConclusionsLow number of small HDL particles are associated with increased hazard of sepsis, sepsis-related death, and sepsis-related critical care admission. However, genetic analyses did not strongly support this as causal. Instead, we demonstrate that increased IL-6 signalling, which is known to alter infection risk, could confound associations with reduced HDL particle count, and suggest this may explain part of the observed association between (small) HDL particle count and sepsis.

FRI181 Increased LDL Particle And Apolipoprotein B Concentrations In Patients With Nonfunctioning And Cortisol Secreting Adrenal Adenomas

Abstract Disclosure: R. Sandooja: None. A. Kittithaworn: None. P. Dogra: None. D. Gruppen: None. E. Atkinson: None. S. Achenbach: None. K. Yu: None. M. Connelly: None. V. Simha: None. R.P. Dullaart: None. I. Bancos: None. INTRODUCTION: Based on the spectrum of cortisol excess, adrenal adenomas are classified as adenomas with Cushing syndrome (CS), adenomas with mild autonomous cortisol secretion (MACS), and non-functioning adenomas (NFA). Patients with adrenal adenomas demonstrate a high prevalence of cardiovascular morbidity and mortality proportional to the degree of hypercortisolism. Evidence on whether dyslipidemia is a contributing cardiovascular risk factor in patients with NFA and MACS is discrepant. We aimed to characterize (apo) lipoprotein abnormalities across the spectrum of cortisol excess in patients with adenomas as compared to referent subjects. METHODS: Study Design: Single center cross sectional study between 01/2015 - 05/2021.Patients: Adults with NFA, MACS, or CS were consecutively enrolled. MACS was diagnosed based on post-dexamethasone cortisol &amp;gt;1.8 mcg/dL. Referent subjects were recruited from local population of patients with available abdominal imaging and no adrenal disorders. All subjects provided fasting ethylenediaminetetraacetic acid (EDTA) venous samples. Measurements: Nuclear magnetic resonance (NMR) spectroscopy measurements included total cholesterol (TC), low-density lipoprotein (LDL) and LDL particle concentrations, high-density lipoprotein (HDL) subclasses, apolipoprotein B (apo B), triglycerides (TG) and TG-rich lipoprotein concentrations. RESULTS: Participants included 101 patients with CS (median age 44 years, IQR 31-58, 85% women), 158 patients with MACS (median age 62 years, IQR 51-70, 62% women), 166 patients with NFA (median age 60 years, IQR 53--66, 63% women) and 136 referent subjects (median age 68 years, IQR 57-77, 52% women). Patients had higher BMI (32 vs 27 kg/m2), higher prevalence of hypertension (72% vs 46%) and diabetes mellitus (27% vs 9%) as compared to reference subjects. Statin therapy was used in 32% of patients and referent subjects. After adjusting for age, sex, BMI, smoking, diabetes, hypertension, and statin therapy, as compared to referent subjects, we found inconsistent increase in TC, LDL cholesterol and TG across CS, MACS and NFA and no consistent differences in LDL size, HDL variables, TG and TG-rich lipoproteins. However, when compared to referent subjects, LDL particle concentrations- CS(OR 1.78, 95% CI 1.33-2.39), MACS (OR 1.31, 95% CI 1.03-1.67), and NFA (OR 1.43, 95% CI 1.12-1.82) and Apo B levels were higher in all patient categories: CS (OR 2.26, 95% CI 1.57-3.24), MACS (OR 1.36 95% CI 1.00-1.85 ), and NFA (OR 1.54 95% CI 1.13-2.09). These differences were particularly evident in patients not on statin therapy. CONCLUSIONS: We found that LDL particle and Apo B concentrations were elevated in all patient groups, including those with MACS and NFA. In comparison to conventional lipid measurements, LDL particle and Apo B may serve as a better biomarker of the future cardiovascular risk in patients with adrenal adenomas. Presentation: Friday, June 16, 2023

Metabolomic Profiling of Cholesterol Efflux Capacity in a Multiethnic Population: Insights From MESA.

Impaired cholesterol efflux capacity (CEC) is a novel lipid metabolism trait associated with atherosclerotic cardiovascular disease. Mechanisms underlying CEC variation are unknown. We evaluated associations of circulating metabolites with CEC to advance understanding of metabolic pathways involved in cholesterol efflux regulation. Participants enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) who underwent nuclear magnetic resonance metabolome profiling and CEC measurement (N=3543) at baseline were included. Metabolite associations with CEC were evaluated using standard linear regression analyses. Repeated ElasticNet and multilayer perceptron regression were used to assess metabolite profile predictive performance for CEC. Features important for CEC prediction were identified using Shapley Additive Explanations values. Greater CEC was significantly associated with metabolite clusters composed of the largest-sized particle subclasses of VLDL (very-low-density lipoprotein) and HDL (high-density lipoprotein), as well as their constituent apo A1, apo A2, phospholipid, and cholesterol components (β=0.072-0.081; P<0.001). Metabolite profiles had poor accuracy for predicting in vitro CEC in linear and nonlinear analyses (R2<0.02; Spearman ρ<0.18). The most important feature for CEC prediction was race, with Black participants having significantly lower CEC compared with other races. We identified independent associations among CEC, the largest-sized particle subclasses of VLDL and HDL, and their constituent apolipoproteins and lipids. A large proportion of variation in CEC remained unexplained by metabolites and traditional clinical risk factors, supporting further investigation into genomic, proteomic, and phospholipidomic determinants of CEC.

Proteomic and functional analysis of HDL subclasses in humans and rats: a proof-of-concept study

BackgroundThe previous study investigated whether the functions of small, medium, and large high density lipoprotein (S/M/L-HDL) are correlated with protein changes in mice. Herein, the proteomic and functional analyses of high density lipoprotein (HDL) subclasses were performed in humans and rats.MethodsAfter purifying S/M/L-HDL subclasses from healthy humans (n = 6) and rats (n = 3) using fast protein liquid chromatography (FPLC) with calcium silica hydrate (CSH) resin, the proteomic analysis by mass spectrometry was conducted, as well as the capacities of cholesterol efflux and antioxidation was measured.ResultsOf the 120 and 106 HDL proteins identified, 85 and 68 proteins were significantly changed in concentration among the S/M/L-HDL subclasses in humans and rats, respectively. Interestingly, it was found that the relatively abundant proteins in the small HDL (S-HDL) and large HDL (L-HDL) subclasses did not overlap, both in humans and in rats. Next, by searching for the biological functions of the relatively abundant proteins in the HDL subclasses via Gene Ontology, it was displayed that the relatively abundant proteins involved in lipid metabolism and antioxidation were enriched more in the medium HDL (M-HDL) subclass than in the S/L-HDL subclasses in humans, whereas in rats, the relatively abundant proteins associated with lipid metabolism and anti-oxidation were enriched in M/L-HDL and S/M-HDL, respectively. Finally, it was confirmed that M-HDL and L-HDL had the highest cholesterol efflux capacity among the three HDL subclasses in humans and rats, respectively; moreover, M-HDL exhibited higher antioxidative capacity than S-HDL in both humans and rats.ConclusionsThe S-HDL and L-HDL subclasses are likely to have different proteomic components during HDL maturation, and results from the proteomics-based comparison of the HDL subclasses may explain the associated differences in function.

Measurement of cholesterol levels of lipoprotein subclasses in human serum using anion-exchange high-performance liquid chromatography with a linear concentration gradient of sodium perchlorate.

Relationships between the subclasses of high-density lipoprotein (HDL) or low-density lipoprotein (LDL) and the risk of atherosclerotic cardiovascular disease have been studied, and using various methods, such as ultracentrifugation, electrophoresis, and nuclear magnetic resonance, for analysing lipoprotein subclasses. We established a method for HDL and LDL subclasses using anion-exchange high-performance liquid chromatography (AEX-HPLC) with a linear concentration gradient of sodium perchlorate (NaClO4). In the AEX-HPLC, the subclasses of HDL and LDL were separated, and detected using a post-column reactor with an enzymatic cholesterol reagent, that contained cholesterol esterase, cholesterol oxidase, and peroxidase as major ingredients. LDL subclasses were divided based on the absolute value of first-derivative chromatogram. Three HDL subclasses, HDL-P1, HDL-P2, and HDL-P3, and three LDL subclasses, LDL-P1, LDL-P2, and LDL-P3, were separated by AEX-HPLC, and detected in order. The major components of HDL-P2 and HDL-P3 were HDL3 and HDL2, respectively. The linearity was determined for each lipoprotein subclass. The coefficients of variation of cholesterol concentration of the subclasses for within-day assay (n = 10) and between-day assay (n = 10) ranged between 3.08-8.94% and 4.52-9.97%, respectively. Cholesterol levels in HDL-P1 of diabetic patients were positively correlated with oxidized LDL levels (r = 0.409, p = 0.002). Moreover, cholesterol levels in LDL-P2 and LDL-P3 were positively correlated with oxidized LDL levels (r = 0.393, p = 0.004 and r = 0.561, p < 0.001, respectively). AEX-HPLC may be highly suitable as an assay to clinically assess lipoprotein subclasses.

Hepatic Cdkal1 deletion regulates HDL catabolism and promotes reverse cholesterol transport

Background and aimsAssociations between CDKAL1 variants and cholesterol efflux capacity (CEC) have been reported. This study aimed to investigate the effects of Cdkal1 deficiency on high-density lipoprotein (HDL) metabolism, atherosclerosis, and related pathways. MethodsLipid and glucose metabolic profiles, CEC, and in vivo reverse cholesterol transport (RCT) were compared in liver-specific Alb-Cre:Cdkal1fl/fl and Cdkal1fl/fl mice. Aortic atherosclerosis was compared in Apoe−/−Alb-Cre:Cdkal1fl/fl and Apoe−/− mice fed high-fat diets. HDL subclasses and mediators of HDL metabolism from Alb-Cre:Cdkal1fl/fl mice were examined. ResultsHDL-cholesterol level tended to be higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.050). Glucose and other lipid profiles were similar in the two groups of mice, irrespective of diet. The mean CEC was 27% higher (p = 0.007) in the Alb-Cre:Cdkal1fl/fl mice, as were the radioactivities of bile acids (mean difference 17%; p = 0.035) and cholesterol (mean difference 42%; p = 0.036) from faeces. The radioactivity tendency was largely similar in mice fed a high-fat diet. Atherosclerotic lesion area tended to be smaller in the Apoe−/−Alb-Cre:Cdkal1fl/fl mice than in the Apoe−/− mice (p = 0.067). Cholesterol concentrations in large HDLs were higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.024), whereas in small HDLs, they were lower (p = 0.024). Endothelial lipase (mean difference 39%; p = 0.002) and hepatic lipase expression levels (mean difference 34%; p < 0.001) were reduced in the Alb-Cre:Cdkal1fl/fl mice, whereas SR-B1 expression was elevated (mean difference 35%; p = 0.007). ConclusionsThe promotion of CEC and RCT in Alb-Cre:Cdkal1fl/fl mice verified the effect of CDKAL1 seen in human genetic data. These phenotypes were related to regulation of HDL catabolism. This study suggests that CDKAL1 and associated molecules could be targets for improving RCT and vascular pathology.

Altered high-density lipoprotein composition is associated with risk for complications in type 2 diabetes mellitus in South Asian descendants: A cross-sectional, case-control study on lipoprotein subclass profiling.

Composition of high-density lipoproteins (HDL) is emerging as an important determinant in the development of microvascular complications in type 2 diabetes mellitus (T2DM). Dutch South Asian (DSA) individuals with T2DM display an increased risk of microvascular complications compared with Dutch white Caucasian (DwC) individuals with T2DM. In this study, we aimed to investigate whether changes in HDL composition associate with increased microvascular risk in this ethnic group and lead to new lipoprotein biomarkers. Using 1 H nuclear magnetic resonance spectroscopy and Bruker IVDr Lipoprotein Subclass Analysis (B.I.LISA) software, plasma lipoprotein changes were determined in 51 healthy individuals (30 DwC, 21 DSA) and 92 individuals with T2DM (45 DwC, 47 DSA) in a cross-sectional, case-control study. Differential HDL subfractions were investigated using multinomial logistic regression analyses, adjusting for possible confounders including BMI and diabetes duration. We identified HDL compositional differences between healthy and diabetic individuals in both ethnic groups. Specifically, levels of apolipoprotein A2 and HDL-4 subfractions were lower in DSA compared with DwC with T2DM. Apolipoprotein A2 and HDL-4 subfractions also negatively correlated with waist circumference, waist-to-hip ratio, haemoglobin A1c, glucose levels and disease duration in DSA with T2DM, and associated with increased incidence of microvascular complications. While HDL composition differed between controls and T2DM in both ethnic groups, the lower levels of lipid content in the smallest HDL subclass (HDL-4) in DSA with T2DM appeared to be more clinically relevant, with higher odds of having diabetes-related pan-microvascular complications such as retinopathy and neuropathy. These typical differences in HDL could be used as ethnicity-specific T2DM biomarkers.

Preeclampsia Affects Lipid Metabolism and HDL Function in Mothers and Their Offspring.

Preeclampsia (PE) is linked to an overall increased cardiovascular risk for both the mother and child. Functional impairment of high-density lipoproteins (HDL) may contribute to the excess cardiovascular risk associated with PE. In this study, we investigated the effects of PE on maternal and neonatal lipid metabolism, and the parameters of HDL composition and function. The study cohort included 32 normotensive pregnant women, 18 women diagnosed with early-onset PE, and 14 women with late-onset PE. In mothers, early- and late-onset PE was associated with atherogenic dyslipidemia, characterized by high plasma triglycerides and low HDL-cholesterol levels. We observed a shift from large HDL to smaller HDL subclasses in early-onset PE, which was associated with an increased plasma antioxidant capacity in mothers. PE was further associated with markedly increased levels of HDL-associated apolipoprotein (apo) C-II in mothers, and linked to the triglyceride content of HDL. In neonates of early-onset PE, total cholesterol levels were increased, whereas HDL cholesterol efflux capacity was markedly reduced in neonates from late-onset PE. In conclusion, early- and late-onset PE profoundly affect maternal lipid metabolism, potentially contributing to disease manifestation and increased cardiovascular risk later in life. PE is also associated with changes in neonatal HDL composition and function, demonstrating that complications of pregnancy affect neonatal lipoprotein metabolism.

Associations between Endothelial Lipase, High-Density Lipoprotein, and Endothelial Function Differ in Healthy Volunteers and Metabolic Syndrome Patients.

Metabolic syndrome (MS) is characterized by endothelial- and high-density lipoprotein (HDL) dysfunction and increased endothelial lipase (EL) serum levels. We examined the associations between EL serum levels, HDL (serum levels, lipid content, and function), and endothelial function in healthy volunteers (HV) and MS patients. Flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), serum levels of HDL subclasses (measured by nuclear magnetic resonance (NMR) spectroscopy), and EL serum levels differed significantly between HV and MS patients. The serum levels of triglycerides in large HDL particles were significantly positively correlated with FMD and NMD in HV, but not in MS patients. Cholesterol (C) and phospholipid (PL) contents of large HDL particles, calculated as HDL1-C/HDL1-apoA-I and HDL1-PL/HDL1-apoA-I, respectively, were significantly negatively correlated with FMD in HV, but not in MS patients. Cholesterol efflux capacity and arylesterase activity of HDL, as well as EL, were correlated with neither FMD nor NMD. EL was significantly negatively correlated with HDL-PL/HDL-apoA-I in HV, but not in MS patients, and with serum levels of small dense HDL containing apolipoprotein A-II in MS patients, but not in HV. We conclude that MS modulates the association between HDL and endothelial function, as well as between EL and HDL. HDL cholesterol efflux capacity and arylesterase activity, as well as EL serum levels, are not associated with endothelial function in HV or MS patients.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank

ObjectiveHigh-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility.Research design and methodsHDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value.ResultsOver median (IQR) 5.2 (5.0–5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model.ConclusionSmall HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

Doxorubicin-induced cardiotoxicity is associated with a change in high density lipoprotein subclasses in a mouse breast cancer model

Doxorubicin-induced cardiotoxicity is associated with a change in high density lipoprotein subclasses in a mouse breast cancer model

Association of High-Density Lipoprotein Subclasses Levels with Sleep Duration and Other Lifestyles in Middle-Aged and Elderly Women: Cross-Sectional Study.

Objective: We aimed at investigating the association of high-density lipoprotein subclasses (HDL2-C and HDL3-C) levels with sleep duration, in comparison to other lifestyles in middle-aged and elderly women. Materials and Methods: A total of 69 women aged older than 40 who underwent "Anti-aging Health Checkups" were enrolled in the study. The analyses were conducted for all the subjects using personal data regarding clinical characteristics and lifestyle. Sleep duration was categorized into two groups of less than or more than 6 hrs. First, an analysis was performed to assess the correlation of two major HDL subclasses with various factors. Next, a multiple regression analysis was conducted to identify the association for each HDL2-C and HDL3-C with lifestyles such as sleep duration, daily breakfast, dinner time, habitual exercise, and drinking. Moreover, we examined the associations between HDL2-C and sleep duration combined with other lifestyle factors such as dinner time, daily breakfast, habitual exercise, and drinking. Results: In comparison to lifestyles, sleep duration had a strong association with only HDL2-C after adjustment for confounders. The "less 6 hrs sleep" group in combination with the "no exercise habit" or the "routine drinking habit" significantly decreased HDL2-C levels more than the assumed reference group. Regarding breakfast, there is a significant association between the "less than 6 hrs sleep with no daily breakfast" and the "more than 6 hrs sleep with daily breakfast." Conclusion: The results of this study may suggest that sufficient sleep might be significant for maintaining appropriate HDL2-C levels in middle-aged and elderly women under the condition that lifestyle might change during the ongoing COVID-19 pandemic.

Associations of HDL subclasses and lipid content with complement proteins over the menopause transition: The SWAN HDL ancillary study: HDL and complement proteins in women

The menopause transition (MT) could trigger low-grade chronic inflammation which may modify high-density lipoproteins (HDL) and lead to additional inflammatory responses contributing to atherosclerosis development. To test whether complement proteins C3 and C4 increase around the final menstrual period (FMP), and whether changes in HDL subclasses and lipid content associate with C3 and C4 levels over time in midlife women. The study included 471 women (at baseline: age 50.2(2.7) years; 87.3% pre or peri-menopausal) who had nuclear magnetic resonance spectroscopy HDL subclasses, lipid content, and C3 and C4 measured up to 5 times over the MT. Adjusted annual changes in C3 and C4 varied by time segments relative to FMP with significant increases, steeper for C3, only observed within 1 year before to 2 years after the FMP. Greater decreases in large HDL particles (HDL-P), HDL size, and HDL-phospholipids, and greater increases in small HDL-P and HDL-Triglycerides were associated with higher C3 and C4 over time, although associations with C4 were weaker than those with C3. Complement proteins C3 and C4 significantly rise around menopause with C3 showing the steepest rise. Changes in HDL subclasses, overall size, and lipid content, over the MT may play a role in modulating inflammation responses known to be related to atherosclerosis. These results raise the possibility that novel therapeutic agents focusing on HDL might contribute to CVD protection by modulating inflammation.

Lipoprotein subfractions and subclinical vascular health in middle aged women: does menopause status matter?

During midlife, women experience changes in lipoprotein profiles and deterioration in vascular health measures. We analyzed the associations of groups of lipoprotein subfractions as determined by principal component analysis (PCA) with subclinical vascular health measures in midlife women and tested if these associations were modified by menopause status. PCA was used to generate principal components (PCs) from 12 lipoprotein subfractions quantified among 545 midlife women. The associations of the identified PCs and concurrent vascular health measures were assessed using linear or logistic regressions among participants with carotid intima-media thickness (cIMT; n = 259), coronary artery calcium (n = 249), or aortic calcium (n = 248) scores. PCA generated four PCs representing groups of (1) small, medium, and large very low-density lipoproteins subclasses-very low-density lipoprotein PC; (2) very small, small, and medium low-density lipoprotein (LDL) subclasses-small-medium LDL-PC; (3) large and small high-density lipoproteins subclasses and midzone particles-high-density lipoprotein PC; and (4) large LDL and small intermediate-density lipoproteins-large LDL-PC. Small-medium LDL-PC was positively associated with cIMT, coronary artery calcium, and aortic calcium in unadjusted but not in adjusted models. Menopause status modified the positive association of the small-medium LDL-PC with cIMT (interaction P = 0.02) such that this association was stronger after versus before menopause ( P = 0.01). Carotid intimal medial thickening is positively and independently associated with small- and medium-sized LDL particles after menopause. Monitoring levels of specific lipoprotein fractions may have value in identifying midlife women at risk for developing atherosclerotic vascular disease.

ANGPTL3 Is Involved in the Post-prandial Response in Triglyceride-Rich Lipoproteins and HDL Components in Patients With Coronary Artery Disease.

It is well-established that there exists an inverse relationship between high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels in the plasma. However, information is lacking on the impact of post-prandial triglyceride-rich lipoproteins (TRLs) on the structure of HDL subclasses in patients with coronary artery disease (CAD). In this study, the data of 49 patients with CAD were analyzed to evaluate dynamic alterations in post-prandial lipid profiles using nuclear magnetic resonance-based methods. An enzyme-linked immunosorbent assay was used to quantify the serum angiopoietin-like protein 3 (ANGPTL3). After glucose supplementation, the expression of hepatic ANGPTL3 was evaluated both in vitro and in vivo. Compared to fasting levels, the post-prandial serum TG level of all participants was considerably increased. Although post-prandial total cholesterol in HDL (HDL-C) remained unchanged, free cholesterol in HDL particles (HDL-FC) was significantly reduced after a meal. Furthermore, the post-prandial decrease in the HDL-FC level corresponded to the increase in remnant cholesterol (RC), indicating the possible exchange of free cholesterol between HDL and TRLs after a meal. Moreover, CAD patients with exaggerated TG response to diet, defined as TG increase >30%, tend to have a greater post-prandial increase of RC and decrease of HDL-FC compared to those with TG increase ≤30%. Mechanistically, the fasting and post-prandial serum ANGPTL3 levels were significantly lower in those with TG increase ≤30% than those with TG increase >30%, suggesting that ANGPTL3, the key lipolysis regulator, may be responsible for the different post-prandial responses of TG, RC, and HDL-FC.

Review of Laboratory Methods to Determine HDL and LDL Subclasses and Their Clinical Importance

Given the high prevalence of cardiovascular disease, accurate identification of methods for assessing lipoprotein subclasses, mainly low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions, can play an essential role in predicting the incidence of cardiovascular disease such as heart attack. LDL and HDL subclasses differ in size, surface charge, lipid and protein compositions, and biological role. There is no “gold standard” method for measuring the LDL and HDL subclasses or standardizing the different methods used to measure their subfractions. Over the past decades, various techniques have been introduced to evaluate and measure subclasses of these two lipoproteins, each with its own advantages and disadvantages. Development of laboratory methods that accurately HDL and LDL function must be developed and validated to high-throughput for clinical usage. In this review study, we tried to examine different methods of evaluating various subclasses of LDL and HDL by mentioning the strengths and weaknesses of each.

Anorexia Nervosa Is Associated with a Shift to Pro-Atherogenic Low-Density Lipoprotein Subclasses.

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors.