Large HDL Particle Concentration Research Articles

The Effect of Carbohydrate Restriction on Lipids, Lipoproteins, and Nuclear Magnetic Resonance-Based Metabolites: CALIBER, a Randomised Parallel Trial.

Low-carbohydrate high-fat (LCHF) diets can be just as effective as high-carbohydrate, lower-fat (HCLF) diets for improving cardiovascular disease risk markers. Few studies have compared the effects of the UK HCLF dietary guidelines with an LCHF diet on lipids and lipoprotein metabolism using high-throughput NMR spectroscopy. This study aimed to explore the effect of an ad libitum 8-week LCHF diet compared to an HCLF diet on lipids and lipoprotein metabolism and CVD risk factors. For 8 weeks, n = 16 adults were randomly assigned to follow either an LCHF (n = 8, <50 g CHO p/day) or an HCLF diet (n = 8). Fasted blood samples at weeks 0, 4, and 8 were collected and analysed for lipids, lipoprotein subclasses, and energy-related metabolism markers via NMR spectroscopy. The LCHF diet increased (p < 0.05) very small VLDL, IDL, and large HDL cholesterol levels, whereas the HCLF diet increased (p < 0.05) IDL and large LDL cholesterol levels. Following the LCHF diet alone, triglycerides in VLDL and HDL lipoproteins significantly (p < 0.05) decreased, and HDL phospholipids significantly (p < 0.05) increased. Furthermore, the LCHF diet significantly (p < 0.05) increased the large and small HDL particle concentrations compared to the HCLF diet. In conclusion, the LCHF diet may reduce CVD risk factors by reducing triglyceride-rich lipoproteins and improving HDL functionality.

Fatty fish consumption reduces lipophilic index in erythrocyte membranes and serum phospholipids

Background and aimsLipophilic index (LI) has been introduced to assess the overall fatty acid lipophilicity and as a simple estimate of membrane fluidity. However, little is known on effect of diet on LI. We tested if Camelina sativa oil (CSO) high in ALA, fatty fish (FF) or lean fish (LF) affect LI as compared to control diet and, secondarily, if the LI is associated with HDL lipids and functionality and LDL lipidome. Methods and resultsWe used data from two randomized clinical trials. The AlfaFish intervention lasted 12 weeks and 79 subjects with impaired glucose tolerance were randomized to FF, LF, CSO or control group. In the Fish trial, 33 subjects with myocardial infarction or unstable ischemic heart attack were randomized to FF, LF or control group for 8 weeks. LI was calculated from erythrocyte membrane fatty acids in AlfaFish and from serum phospholipids in Fish trial. HDL lipids were measured using high-throughput proton nuclear magnetic resonance spectroscopy. There was a significant decrease in LI in the FF group in the AlfaFish (fold change 0.98 ± 0.03) and in the Fish trial (0.95 ± 0.04) and the decrease differed from that of control group in both trials and from CSO group in the AlfaFish study. There were no significant changes in LI in LF or CSO groups. The mean diameter of HDL particles and concentration of large HDL particles were inversely associated with LI. ConclusionFF consumption decreased LI indicating better membrane fluidity in subjects with impaired glucose tolerance or coronary heart disease.

Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.

Abstract P139: Diet-induced Shifts In HDL Profiles Are Associated With Changes In Immune Parameters

Introduction: Preclinical and population-based studies have demonstrated immunomodulatory and anti-inflammatory properties of HDL; however, it is unclear whether diet-induced changes in HDL profiles can directly impact markers of immune inflammation. Hypothesis: We hypothesized that daily consumption of different egg-based diets, which have been shown to differentially impact serum lipids and lipoprotein profiles, would induce changes in HDL parameters that correspond to shifts in clinical and molecular immune markers. Methods: Healthy men and women (18-35y, BMI &lt; 30kg/m 2 or &lt; 30% body fat for men and &lt; 40% body fat for women, n = 26) participated in a 16-week randomized, crossover intervention trial (NCT03577223), in which they consumed an egg-free diet for 4 weeks, followed by a 4-week diet containing either 3 whole eggs or 3 egg whites per day. Participants then followed a 4-week egg-free diet washout period, before switching to the alternative whole egg or egg white diet treatment. Fasting lipoprotein profiles, complete blood cell counts, and gene expression in peripheral blood mononuclear cells (PBMCs) was measured at the end of each diet period. Results: While no changes in total HDL particles, average HDL particle diameter, or the concentration of small (7.4-8.0 nm) or medium (8.1-9.5 nm) HDL particles was observed, the concentration of large HDL particles (10.8nm) was increased by whole egg intake as compared to intake of egg whites. A trend toward increased apolipoprotein A1 during the whole egg diet period as compared to the egg-free diet period was additionally observed. In line with our hypothesis, changes in large HDL concentrations between whole egg vs. egg white periods were inversely correlated with total white blood cell counts and absolute lymphocyte counts. CD8A mRNA expression in PBMCs was inversely correlated with concentrations of total and large HDL particles. Importantly, while serum choline and betaine were increased by whole egg intake compared to the other diet periods, no differences in pro-atherogenic and inflammatory trimethylamine-N-oxide (TMAO) between diet periods was observed. Conclusion: These findings suggest that diet-induced changes in HDL profiles are directly associated with changes in immune parameters.

Event-free FH patients >65 years of age are characterized by higher concentration of large HDL particles

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Cholesterol-lowering therapy (statins) reduces CHD risk, but have only been available for the last 25 years, thus, elderly (>65 years) FH patients have been untreated several decades of their life. Surprisingly, some of these have never experienced any CHD event, raising the question whether they present CHD-resistant characteristics. To our knowledge, there are no reports of comprehensive metabolite profiling in these individuals. Therefore, we aimed to characterize metabolic differences between elderly FH subjects with and without CHD.

Abstract P105: Associations Of Subclasses, Content And Function Metrics Of High-density Lipoprotein With Carotid Intima-media Thickness In Women Transitioning Through Menopause Swan Hdl And Swan Heart Studies

Objective: Higher levels of high-density lipoprotein cholesterol (HDL-C) may not always be cardio-protective in midlife women. Novel metrics of HDL including nuclear magnetic resonance (NMR) spectroscopy subclasses (large, medium and small HDL particles (HDL-P), and size), HDL content of phospholipids (HDL-PL) and triglycerides (HDL-Tg), and HDL function as measured by cholesterol efflux capacity (HDL-CEC) show strong associations with cardiovascular disease (CVD) risk beyond HDL-C. Women experience increases in carotid Intima-media thickness (cIMT), a subclinical measure of atherosclerosis, over the menopause transition. Associations of novel metrics of HDL with cIMT have not been well characterized in midlife women. Our objective was to assess the associations of HDL subclasses, HDL-PL, HDL-Tg, and HDL-CEC with cIMT and to determine whether these associations vary by age at menopause. Design: We assessed 303 women (at baseline: age 51.0 ± 2.8 years; 67.8% White and 32.2% Black; 56.6% Pre-/Early perimenopausal) who had HDL metrics and cIMT measured once (N=37 [12%]) or twice (N=266 [88%]) over the menopause transition. Age at menopause was observed prospectively among 73% of women (defined as no menses for 12 consecutive months) and imputed among the rest. Linear mixed effect models were used to individually assess the association of each HDL metric with cIMT, and to test whether the association varied by age at menopause (&lt;50, 50-53, &gt;53 years old). Final models were adjusted for race, education, and time varying: age, systolic blood pressure, body mass index, menopausal status, triglycerides, low density lipoprotein cholesterol and HDL-C. Results: In unadjusted analyses, higher concentrations of large HDL-P, medium HDL-P, HDL-PL, and HDL-CEC, and larger HDL size, and lower concentrations of small HDL-P were associated with lower cIMT; all p &lt;0.05. In final models, only associations of medium HDL-P (p=0.008) and HDL-PL (p=0.005) with cIMT remained statistically significant. Age at menopause modified associations of HDL-Tg with cIMT in both unadjusted and final models (p=0.05 for both); in the final model, per 1 SD unit increase in HDL-Tg, women with age at menopause &gt;53 had thicker cIMT(β(SE): 6.72(6.27) μm) than those with age at menopause &lt;50 (β(SE): -17.88(8.48) μm), p for comparison=0.01. Conclusions: In midlife women, higher concentrations of medium HDL-P and greater content of HDL phospholipids were associated with thinner cIMT beyond traditional CVD risk factors including HDL-C. Associations of HDL triglycerides content with thicker cIMT was more pronounced in women who reached menopause at older ages. Findings support utilizing other metrics of HDL rather than HDL-C to better characterize CVD risk in midlife women.

HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: a cross-sectional study.

The prevalence of atherosclerosis is increased in type 1 diabetes despite normal-to-high HDL-cholesterol levels. The cholesterol efflux capacity (CEC) of HDL is a better predictor of cardiovascular events than static HDL-cholesterol. This cross-sectional study addressed the hypothesis that impaired HDL function contributes to enhanced CVD risk within type 1 diabetes. We compared HDL particle size and concentration (by NMR), total CEC, ATP-binding cassette subfamily A, member 1 (ABCA1)-dependent CEC and ABCA1-independent CEC (by determining [3H]cholesterol efflux from J774-macrophages to ApoB-depleted serum), and carotid intima-media thickness (CIMT) in 100 individuals with type 1 diabetes (37.6 ± 1.2years; BMI 26.9 ± 0.5kg/m2) and 100 non-diabetic participants (37.7 ± 1.1years; 27.1 ± 0.5kg/m2). Compared with non-diabetic participants, total HDL particle concentration was lower (mean ± SD 31.01 ± 8.66 vs 34.33 ± 8.04μmol/l [mean difference (MD) -3.32μmol/l]) in participants with type 1 diabetes. However, large HDL particle concentration was greater (9.36 ± 3.98 vs 6.99 ± 4.05μmol/l [MD +2.37μmol/l]), resulting in increased mean HDL particle size (9.82 ± 0.57 vs 9.44 ± 0.56nm [MD +0.38nm]) (p < 0.05 for all). Total CEC (14.57 ± 2.47%CEC/4h vs 12.26 ± 3.81%CEC/4h [MD +2.31%CEC/4h]) was greater in participants with type 1 diabetes relative to non-diabetic participants. Increased HDL particle size was independently associated with increased total CEC; however, following adjustment for this in multivariable analysis, CEC remained greater in participants with type 1 diabetes. Both components of CEC, ABCA1-dependent (6.10 ± 2.41%CEC/4h vs 5.22 ± 2.57%CEC/4h [MD +0.88%CEC/4h]) and ABCA1-independent (8.47 ± 1.79% CEC/4h vs 7.05 ± 1.76% CEC/4h [MD +1.42% CEC/4h]) CEC, were greater in type 1 diabetes but the increase in ABCA1-dependent CEC was less marked and not statistically significant in multivariable analysis. CIMT was increased in participants with type 1 diabetes but in multivariable analysis it was only associated negatively with age and BMI. HDL particle size but not HDL-cholesterol level is independently associated with enhanced total CEC. HDL particle size is greater in individuals with type 1 diabetes but even after adjusting for this, total and ABCA1-independent CEC are enhanced in type 1 diabetes. Further studies are needed to understand the mechanisms underlying these effects, and whether they help attenuate progression of atherosclerosis in this high-risk group. Graphical abstract.

Increased ABCA1 (ATP-Binding Cassette Transporter A1)-Specific Cholesterol Efflux Capacity in Schizophrenia.

Patients with schizophrenia have increased long-term mortality attributable to cardiovascular disease and commonly demonstrate features of mixed dyslipidemia with low HDL-C (high-density lipoprotein cholesterol). The removal of cholesterol from cells by HDL via specific ATP-binding cholesterol transporters is a major functional property of HDL, and its measurement as cholesterol efflux capacity (CEC) can predict cardiovascular risk. Whether HDL function is impaired in patients with schizophrenia is unknown. Approach and Results: We measured basal and ABCA1 (ATP-binding cassette transporter A1)- and ABCG1 (ATP-binding cassette transporter G1)-dependent CEC, comparing patients with schizophrenia with age- and sex-matched healthy controls, and related our findings to nuclear magnetic resonance analysis of lipoprotein subclasses. Total plasma cholesterol and LDL-C (low-density lipoprotein cholesterol) were comparable between healthy controls (n=51) and patients (n=120), but patients with schizophrenia had increased total plasma triglyceride, low HDL-C and apo (apolipoprotein) A-I concentrations. Nuclear magnetic resonance analysis indicated a marked (15-fold) increase in large triglyceride-rich lipoprotein particle concentration, increased small dense LDL particles, and fewer large HDL particles. Despite lower HDL-C concentration, basal CEC was 13.7±1.6% higher, ABCA1-specific efflux was 35.9±1.6% higher, and ABCG1 efflux not different, in patients versus controls. In patients with schizophrenia, ABCA1-specific efflux correlated with the abundance of small 7.8 nm HDL particles but not with serum plasminogen or triglyceride levels. Patients with schizophrenia have increased concentrations of atherogenic apoB-containing lipoproteins, decreased concentrations of large HDL particles, but enhanced ABCA1-mediated CEC. In this population, preventative strategies should focus on reducing atherogenic lipoproteins rather than increasing CEC.

Abstract P401: Associations Between High-density Lipoprotein Subclasses and Coronary Artery Calcification Vary by Menopausal Stage. The Study of Women's Health Across the Nation Hdl Ancillary Study

Objective: Higher levels of high-density lipoproteins cholesterol (HDL-C) may not always be cardio-protective in midlife women. Nuclear magnetic resonance (NMR) spectroscopy HDL subclasses have shown strong associations with CVD risk beyond HDL-C. Preliminary work suggests significant declines in large HDL particles (HDL-P) and overall HDL size, but increases in small HDL-P during the perimenopause stage. Our objective was to assess whether associations between NMR HDL subclasses and risk of coronary artery calcification (CAC) vary by menopausal stage. Design: We assessed 283 women (at baseline : age 51.4 ± 3.0 years; 56.6% Pre-/Early peri-, 8.8% late peri-, 34.6% post-menopausal) who had NMR HDL subclasses and CAC Agatston score measured once (N=48 [17%]) or twice (N=235 [83%]) around menopause. CAC presence was defined as CAC&gt;0. Effect modifications of menopausal stage on associations between HDL subclasses and CAC presence overtime were tested using generalized estimating equation for binary outcome. Final models were adjusted for study site, race and time varying: age, body mass index, physical activity, alcohol consumption, insulin resistance, triglycerides and low-density lipoprotein cholesterol. Results: In final models, menopausal stage modified the associations of small HDL-P (p=.009), large HDL-P (p=.05) and overall HDL size (p=.007) with CAC presence ( Table ). Higher concentration of small HDL-P, lower concentration of large HDL-P, and smaller overall HDL size significantly associated with greater risk of CAC presence during the late-peri stage compared to pre-/early peri-menopausal stage ( Table) . Conclusions: Changes in HDL subclasses during the menopause transition may increase the likelihood of measurable CAC developing in women, particularly during the later peri-menopausal stage. Characterizing associations of HDL composition and function metrics with CVD risk over the menopause transition is critical to better understand the relationship of HDL to coronary disease in midlife women.

Haptoglobin Phenotype Modulates Lipoprotein-Associated Risk for Preeclampsia in Women With Type 1 Diabetes.

The incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease. To investigate whether Hp phenotype is associated with PE in type 1 diabetes mellitus (T1DM) and/or modulates lipoprotein-associated risks. Multicenter prospective study of T1DM pregnancy. Pregnant women with T1DM (normal albuminuria, normotensive at enrolment, n = 47) studied at three visits, all preceding PE onset: 12.3 ± 1.9, 21.8 ± 1.5, and 31.5 ± 1.6 weeks' gestation (mean ± SD). Hp phenotype and lipoprotein profiles in women with (n = 23) vs without (n = 24) subsequent PE. Hp phenotype did not predict PE, but lipoprotein associations with subsequent PE were confined to women with Hp 2-2, in whom the following associations with PE were observed: increased low-density lipoprotein (LDL) cholesterol, LDL particle concentration, apolipoprotein B (APOB), triacylglycerol/high-density lipoprotein (HDL) cholesterol ratio, and APOB/apolipoprotein AI (APOA1) ratio; decreased HDL cholesterol, APOA1, large HDL particle concentration, and peripheral lipoprotein lipolysis (all P < 0.05). In women with one or two Hp-1 alleles, no such associations were observed. In women with T1DM, although Hp phenotype did not predict PE risk, lipoprotein-related risks for PE were limited to those with the Hp 2-2 phenotype. Hp phenotype may modulate PE risk in diabetes.

MENOPAUSAL STAGE INFLUENCES LIPOPROTEIN SUBCLASS PROFILE IN HABITUALLY ACTIVE WOMEN

Menopause is associated with increased cardiovascular disease risk, in part due to worsening cholesterol profile with advancing menopausal stage. The effect of menopausal stage on lipoprotein cholesterol, lipoprotein particle size and number in active midlife women has not been evaluated.PURPOSETo evaluate differences in lipoprotein subclass concentrations between highly‐fit, habitually active women at distinct menopausal stages.METHODSWomen (40–65 yr) were healthy habitually active highly‐fit pre‐, peri‐, and postmenopausal women (PRE, n = 10, VO2peak = 47.0 ± 2.4 ml/kg/min, PERI, n = 12, VO2peak = 49.1 ± 2.4 ml/kg/min, and POST, n = 13, VO2peak = 43.8 ± 1.8 ml/kg/min). Menopausal stage was defined using the STRAW+10 criteria. Particle subclass concentrations and mean particle sizes (were measured using nuclear magnetic resonance spectroscopy (LabCorp). Calculated lipids (total triglyceride, total VLDL and chylomicron triglyceride, and total HDL cholesterol) were also analyzed. Blood samples for lipoprotein particle analysis were collected during days 1–6 of the menstrual cycle for PRE. ANOVAs with Holm‐Sidak post hoc testing were used to determine differences between groups for each lipid outcome. Nonparametric tests were employed if assumptions were not met. Data are presented as mean ± SEM.RESULTSThere was a significant effect of menopause stage on total HDL cholesterol (p = 0.010) with greater HDL cholesterol in POST (88.5 ± 2.2 mg/dl) vs. PRE (72.2 ± 5.7 mg/dl, p = 0.032) and total HDL particle concentration (p = 0.010) with significantly greater total HDL particle concentration in POST (40.2 ± 1.1 μmol/L) compared with PRE (34.9 ± 1.5 μmol/L, p = 0.023) and POST compared with PERI (PERI, 35.5 ± 1.3 μmol/L, p = 0.033). There was a trend for an effect of menopausal status on large HDL particle concentration (p = 0.072) with progressively greater large HDL particle concentration with each advancing stage (PRE 12.1 ± 1.1 μmol/L, PERI, 14.0 ± 1.2 μmol/L, POST, 15.5 ± 0.6 μmol/L). There was no significant effect of menopausal stage on medium or small HDL particle concentration or HDL size (all p&gt;0.05). There was an effect of menopausal stage on large LDL particle concentration (p = 0.039) with greater concentration of large LDL particles in PRE (479 ± 52.6 nmol/L) vs. POST (663 ± 47.5 nmol/L, p = 0.034) but no effect of menopausal stage on small LDL, IDL, or total LDL particle concentration, or LDL size (all p&gt;0.05). There was no effect of menopausal status on any VLDL &amp; chylomicron particle concentration or VLDL size (all p&gt;0.05).CONCLUSIONThese data indicate that in healthy, highly fit women, advancing menopausal stage does not have a negative effect on many lipoprotein particle concentrations. Habitual physical activity may eliminate or potentially reverse some of the negative consequences of menopause on lipids.Support or Funding InformationFunding Sources: American College of Sports Medicine Foundation Doctoral Student Research Grant (Serviente), National Institute on Aging Grant T32‐AG049676 (Pennsylvania State University), University of Massachusetts Amherst Provost's Undergraduate Research Fellowship (Chalvin).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Paradox of hypercholesterolaemia in highly trained, keto-adapted athletes

ObjectiveA growing number of ultra-endurance athletes have switched to a very low-carbohydrate/high-fat eating pattern. We compared markers of cholesterol and the lipoprotein profile in a group of elite ultra-runners consuming...

Abstract 176: Preoperative Small HDL Particle Concentration is Associated with Paraoxonase-1 activity and the Risk of Acute Kidney Injury After Cardiac Surgery

Acute kidney injury (AKI) after cardiac surgery occurs in up to 30% of patients and predicts death. We have reported that a higher preoperative HDL particle concentration is independently associated with a decreased risk of AKI after cardiac surgery. HDL has known anti-oxidant properties that may attenuate AKI. We hypothesized that HDL particle size is associated with paraoxonase-1 (PON-1) activity and with the risk of AKI after cardiac surgery. We selected 90 patients who developed mild, moderate, severe, or no AKI from a prospective trial of perioperative atorvastatin to prevent post-cardiac surgery AKI. PON-1 paraoxonase activity was measured in apoB-depleted serum with fluorescent substrate 7-diethylphospho-6,8-dixuor-4-methylumbelliferyl. HDL particle size was assessed using the NMR Lipoprofile test. Linear regression was used to assess the association between preoperative small, medium, and large HDL particle concentrations and PON-1 activity. We assessed the association between HDL particle levels and the maximum serum creatinine change from baseline in the first 48 postoperative hours using two-component latent variable mixture models adjusted for AKI risk factors. A higher preoperative small HDL particle concentration was associated with a higher preoperative PON-1 activity (p=0.003, Figure 1A). Medium and large HDL particle concentrations were not associated with PON-1 activity. Small HDL particle concentration was found to be independently associated with postoperative serum creatinine change (p=0.02, Figure 1B), while medium and large HDL particle concentrations were not. Conclusions: A higher preoperative small HDL particle concentration was associated with a higher PON-1 activity and a decreased risk of AKI after cardiac surgery. Future work will characterize HDL throughout the surgical course to identify the mechanism underlying the protective association between HDL and AKI.

Abstract 383: HDL Particles, Cell-Cholesterol Efflux, and CHD Risk: the Preβ-1 Paradox

Objective: The cell-cholesterol efflux capacity (CEC) of high-density lipoprotein (HDL) is inversely associated with coronary heart disease (CHD) risk. ATP-binding cassette transporter-A1 (ABCA1) plays a crucial role in cholesterol efflux from macrophages to preβ-1-HDL. We tested the hypothesis that CHD patients have functionally abnormal preβ-1-HDL. Approach and Results: We measured HDL CEC via the ABCA1 and the scavenger receptor class B type-I (SR-BI) pathways, HDL anti-oxidative capacity, apolipoprotein A-I-containing HDL particles, and inflammatory- and oxidative-stress markers in 64 CHD cases and 64 gender-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preβ-1-particles in both cases (R 2 =0.541) and controls (R 2 =0.350). Cases had almost twice the levels of preβ-1-HDL than controls, but the functionality of their preβ-1 particles (preβ-1-concentration-normalized ABCA1-dependent efflux capacity) was significantly lower (-39%). There were significant positive correlations between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1 + α-2) HDL particles in both cases (R 2 =0.828) and controls (R 2 =0.671). Cases had significantly lower (-11%) levels of large HDL particles, but the functionality of their particles (large-HDL-concentration-normalized SR-BI-dependent efflux capacity) was significantly higher (+27%) compared to controls. High plasma levels of inflammatory and oxidative stress markers were not associated with the functionality of HDL particles. High plasma levels of triglycerides were associated with increased HDL particle functionality. HDL anti-oxidative capacity was significantly lower (-15%) in cases than in controls. There were no significant correlations between HDL anti-oxidative capacity and the concentrations of inflammatory- and oxidative-stress markers or HDL CEC. Conclusions: HDL CEC is significantly influenced by both the concentration and the functionality of specific HDL particles. CHD patients have higher than normal preβ-1 concentration with decreased functionality and lower than normal large-HDL particle concentration with enhanced functionality.

Greater circulating concentrations of large HDL particles associate with more favorable HDL functionality in young adults

Greater circulating concentrations of large HDL particles associate with more favorable HDL functionality in young adults

Influence of HDL particles on cell-cholesterol efflux under various pathological conditions

It has been reported that low cell-cholesterol efflux capacity (CEC) of HDL is an independent risk factor for CVD. To better understand CEC regulation, we measured ABCA1- and scavenger receptor class B type I (SR-BI)-dependent cell-cholesterol efflux, HDL anti-oxidative capacity, HDL particles, lipids, and inflammatory- and oxidative-stress markers in 122 subjects with elevated plasma levels of triglyceride (TG), serum amyloid A (SAA), fibrinogen, myeloperoxidase (MPO), or β-sitosterol and in 146 controls. In controls, there were strong positive correlations between ABCA1-dependent cholesterol efflux and small preβ-1 concentrations (R2 = 0.317) and SR-BI-dependent cholesterol efflux and large (α-1 + α-2) HDL particle concentrations (R2 = 0.774). In high-TG patients, both the concentration and the functionality (preβ-1 concentration-normalized ABCA1 efflux) of preβ-1 particles were significantly elevated compared with controls; however, though the concentration of large particles was significantly decreased, their functionality (large HDL concentration-normalized SR-BI efflux) was significantly elevated. High levels of SAA or MPO were not associated with decreased functionality of either the small (preβ-1) or the large (α-1 + α-2) HDL particles. HDL anti-oxidative capacity was negatively influenced by high plasma β-sitosterol levels, but not by the concentrations of HDL particles, TG, SAA, fibrinogen, or MPO. Our data demonstrate that under certain conditions CEC is influenced not only by quantitative (concentration), but also by qualitative (functional) properties of HDL particles.

HDL efflux capacity, HDL particle size, and high-risk carotid atherosclerosis in a cohort of asymptomatic older adults: the Chicago Healthy Aging Study

HDL efflux capacity and HDL particle size are associated with atherosclerotic CVD (ASCVD) events in middle-aged individuals; however, it is unclear whether these associations are present in older adults. We sampled 402 Chicago Healthy Aging Study participants who underwent a dedicated carotid MRI assessment for lipid-rich necrotic core (LRNC) plaque. We measured HDL particle size, HDL particle number, and LDL particle number with NMR spectroscopy, as well as HDL efflux capacity. We quantified the associations between HDL particle size and HDL efflux using adjusted linear regression models. We quantified associations between the presence of LRNC and HDL and LDL particle number, HDL particle size, and HDL efflux capacity using adjusted logistic regression models. HDL efflux capacity was directly associated with large (β = 0.037, P < 0.001) and medium (β = 0.0065, P = 0.002) HDL particle concentration and inversely associated with small (β = -0.0049, P = 0.018) HDL particle concentration in multivariable adjusted models. HDL efflux capacity and HDL particle number were inversely associated with prevalent LRNC plaque in unadjusted models (odds ratio: 0.5; 95% confidence interval: 0.26, 0.96), but not after multivariable adjustment. HDL particle size was not associated with prevalent LRNC. HDL particle size was significantly associated with HDL efflux capacity, suggesting that differences in HDL efflux capacity may be due to structural differences in HDL particles. Future research is needed to determine whether HDL efflux is a marker of ASCVD risk in older populations.

Ethnic differences in serum lipids and lipoproteins in overweight/obese African-American and white American women with pre-diabetes: significance of NMR-derived lipoprotein particle concentrations and sizes

ObjectiveAfrican-American women (AAW) suffer disproportionately from higher rates of cardiovascular disease (CVD) mortality compared with white American women (WAW), despite favorable lipid and lipoprotein profile. Therefore, we used nuclear magnetic...

Abstract P101: Menopause and its Related Endogenous Sex Hormone Alterations are Associated with Changes in Function and Subclasses of High-density Lipoprotein in Women at Midlife

Objective: Growing evidence challenges the cardioprotective effects of high-density lipoprotein-cholesterol (HDL-C) in postmenopausal women. HDL particle size and concentration are heterogeneous and HDL-C only measures the cholesterol content of all HDL particles. Therefore, HDL-C does not necessarily reflect HDL subclasses or functionality, which may be more important in predicting CVD risk. Our main objective was to characterize HDL subclasses and functional alterations over menopause and to evaluate their associations with changes in estradiol (E2) and follicle stimulating hormone (FSH), cardinal hormonal markers of menopause. Methods: Participants were drawn from the Study of Women’s Health Across the Nation (SWAN) at the Pittsburgh site. The women had stored blood specimens at two time points; one before and one after they reached menopause. HDL particle concentration and size using calibrated ion mobility analyses and HDL cholesterol efflux capacity (HDL-CEC) with radiolabeled J774 macrophages were measured at the two time points. None of the study participants were on lipid lowering medications or hormone therapy. Results: The study included 50 women (66% White and 34% Black), who were 47 (45, 49) years old (median (Q1, Q3)) and were either pre- (38%) or early peri-menopause (62%) at the first time point. At the second time point, all participants were postmenopausal with a median (Q1, Q3) time since their final menstrual period of 2.14 (1.55, 3.41) years. After menopause, women had significantly higher concentrations of total and large HDL particles, and smaller sizes of medium and small HDL particles (all P&lt;0.05), independent of race and change in age. HDL-CEC was significantly higher after menopause. Independent of age and race, larger declines in E2 were correlated with a more atherogenic changes (smaller increases in large HDL particles and larger increases in small HDL particles concentrations, P&lt;0.05). Additionally, greater rises in FSH were correlated with bigger reductions in sizes of large and medium HDL particles (P&lt;0.05). Conclusions: Within a median of 2.14 years of menopause, an improvement in HDL-CEC and significant alterations in HDL particle subclasses were observed. Whether patterns of these alterations change further in late postmenopause and how they relate to atherosclerotic risk are not known. The reported changes in HDL metrics over menopause warrant further evaluation of their potential risk on CVD after menopause.

Abstract 17913: Inhibition of CETP by Dalcetrapib Results in a Modest Increase in Cholesterol Efflux Capacity Associated With an Increase in Large HDL Particles, but Does Not Impact Carotid Intima-Media Thickness in a dal-PLAQUE-2 Substudy

Inhibition of cholesteryl ester transfer protein (CETP) is an approach aiming at raising HDL-cholesterol levels and reducing cardiovascular risk. The dal-PLAQUE-2 phase III study recruited 988 subjects with stable coronary artery disease. Its primary objective was to evaluate the effect of dalcetrapib on the progression of carotid atherosclerotic disease measured by intima-media thickness after one year of therapy. As dalcetrapib showed a neutral effect on cardiovascular risk in the dal-OUTCOMES study, our objective was to evaluate its effect on cIMT and markers of HDL mass, lipoprotein subclass distribution and HDL function. All subjects from dal-PLAQUE-2 who had provided serum samples at baseline and one year were included in our substudy of 193 subjects on placebo and 186 subjects on dalcetrapib. Comparisons between groups at one year were made by ANCOVA after adjustment for baseline levels. No significant differences between groups for all variables considered were observed at baseline. Dalcetrapib reduced CETP activity as measured by a fluorescent method by 30% after 1 year (p&lt;0.001), which resulted in increases in HDL-cholesterol and apoA-I levels by 32% and 11%, respectively (both p&lt;0.001). Dalcetrapib markedly increased the concentration of large HDL particles measured by NMR profiling (+59%, p&lt;0.001), at the expense of small HDL particles (-9.5%, p&lt;0.001). Cholesterol efflux capacity of serum was measured from J774 macrophages under basal conditions and after cAMP stimulation. Dalcetrapib increased basal and stimulated efflux by 7.1% and 5.5% (both p&lt;0.001), but was without effect on the ABCA1-dependent component (p=0.26). Despite these effects, dalcetrapib had no impact on mean and maximal cIMT (p=0.98 and p=0.85). While the change in cIMT was inversely correlated with basal cholesterol efflux in the placebo group (Spearman r=-0.163, p&lt;0.05), such a relationship was not found in the dalcetrapib group. Moreover, the change in total HDL particles concentration was inversely correlated with change in cIMT (r=0.181, p&lt;0.05) in the placebo arm only. In conclusion, dalcetrapib raised HDL-C and larger HDL, but this had minimal effects on cholesterol efflux capacity of patients’ serum and had a neutral effect on carotid artery plaque burden.