HDL Particle Concentration Research Articles

1141-P: HDL Particle Concentration, Cholesterol Efflux Capacity, and All-Cause Mortality in Type 1 Diabetes

Recent evidence suggests that HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) are better predictors of coronary artery disease than HDL-C in type 1 diabetes (T1D) . We hypothesized that these novel HDL markers also predict all-cause mortality better than HDL-C in T1D. HDL-P (calibrated ion mobility analysis) and CEC (validated cell-based assay) were quantified in the first available stored sample from 550 Epidemiology of Diabetes Complications study participants with childhood onset (<17 years) T1D (baseline mean age 27.8 years and T1D duration, 19.6 years) . Vital status was assessed as of September 30, 2019. During a median follow-up of 26 years, there were 167 deaths. At analytic baseline, deceased were older, with longer T1D duration and a worse cardiovascular risk factor profile compared with survivors. In Cox proportional hazards models, after multivariable adjustments including for HDL-C, the concentration of total HDL-P (T-HDL-P, HR=0.90, 95% CI: 0.84-0.96) and that of three of the four major HDL subpopulations - extra small (XS-HDL-P, HR=0.44, 0.21-0.90) , small (S-HDL-P, HR=0.74, 0.60-0.93) and medium (M-HDL-P, HR=0.80, 0.70-0.91) particles - were associated with a lower mortality risk. Marginal protective associations were also observed for the concentration of large-sized particles (L-HDL-P, HR=0.84, 0.68-1.06) , as well as for CEC (HRs per SD was 0.86 (0.74-1.00) and 0.86 (0.73-1.01) for overall J774 and ABCA1-specific CEC, respectively) . These results remained largely unchanged by further adjustment for HDL-P (in the case of HDL-C and CEC) or APOA1 and triglyceride concentrations (for HDL-P) and were similar by sex. HDL-C was not a significant predictor of mortality in either univariate or multivariable analyses. Our findings show that higher HDL-P concentrations are negatively associated with mortality in T1D independent of other risk factors. Disclosure T.Costacou: None. R.G.Miller: Stock/Shareholder; Becton, Dickinson and Company. T.J.Orchard: None. T.Vaisar: Consultant; AstraZeneca. Funding National Institutes of Health (R01HL130153 and R01DK034818) and the Rossi Memorial Fund.

Abstract 551: HDL Particle Concentration And Incident Ischemic Stroke In Type 1 Diabetes

Recently, we showed that HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) predict coronary artery disease (CAD) better than HDL-C in people with type 1 diabetes (T1D). Cardiovascular risk factors have been shown to associate with different cardiovascular outcomes differently. We therefore investigated the association of HDL-P and CEC with ischemic stroke (IS) incidence in people with T1D. We quantified HDL-P using calibrated differential ion mobility and total and ABCA1-specific HDL CEC in 549 participants with childhood-onset (<17 years) T1D from the Epidemiology of Diabetes Complications study using the first available blood sample. The participants were free of cerebrovascular disease at baseline (mean age 27.8 years, T1D duration 19.6 years, 49% women). Stroke incidence/type was determined by self-report of physician diagnosis and confirmed by medical record review. During the follow-up (median 25 years), there were 35 (6.5%) incident IS events. Participants with IS were more likely to be older, have a longer T1D duration, have hypertension, a history of smoking, and a worse lipid, inflammatory and renal markers’ profile at baseline; HDL-C, HDL-P, and CEC did not differ between participants with and without IS. While HDL-C, total HDL-P, and CEC were not associated with IS risk, extra-small HDL-P (xsHDL-P, ~7.8nm) subspecies were strongly associated with incident IS (HR=4.49, 95% CI: 1.72-11.74), even after adjustment for IS risk factors (including smoking, diabetes duration, hypertension as well as HDL-C), in multivariable Cox proportional hazards regression analyses. When all stroke events including hemorrhagic stroke were considered the association was weaker (n=47 events, HR=2.5, 95% CI: 0.97-6.47) suggesting specificity in the association of xsHDL-P with ischemic stroke.In contrast to a strong protective association of total HDL-P and CEC against CAD in the same T1D population, these HDL metrics were not associated with IS. However, the xsHDL-P subspecies were specifically associated with increased IS risk. These striking findings require further investigation and suggest a differential association of HDL particle metrics with CAD and IS.

Abstract 193: Apolipoprotein A-I Rotamers Determine The Size And Cholesterol Efflux Capacity Of High-Density Lipoprotein

Cardiovascular disease (CVD) risk is strongly and inversely associated with plasma levels of high-density lipoprotein cholesterol (HDL-C). Recent clinical studies suggest that the association between HDL-C and CVD risk is indirect and that HDL’s cardioprotective function may be attributed to its ability to promote cholesterol efflux from macrophages. Apolipoprotein A-I (APOA1), the major protein in HDL, serves as a structural scaffold to facilitate protein binding and enzyme activation. Our previous work demonstrated that two or three molecules of APOA1 form antiparallel dimer structures (rotamers) that wrap around discoidal and spherical HDL. Human HDL contains both LL5/5 and LL5/4 rotamers. Because little is known about the impact of different rotamers on HDL function, we generated human APOA1 mutants with single cysteine mutations that produced reconstituted HDL (rHDL) locked in specific rotamer (K133C for LL5/5 and L122C for LL5/4). The LL5/5 rotamer of rHDL demonstrated four-fold higher LCAT activation efficiency than the LL5/4 rotamer. To investigate the roles of APOA1 rotamers in vivo , we used a liver-targeted adeno-associated virus (AAV) to express WT hAPOA1 and the two cysteine mutants in APOA1-deficient ( Apoa1 -/- ) mice. HDL particle concentration (HDL-P) in WT and LL5/5 mice were similar but were 250% higher (n=8; P<0.0001) than those of LL5/4 mice. Importantly, mice expressing different APOA1 rotamers had markedly different HDL size patterns: HDL in LL5/4 hAPOA1 mice consisted mainly of extra-small HDL (7.8 nm in diameter), consistent with our finding that the LL5/4 rotamer had a low efficiency in activating LCAT. HDL in WT and LL5/5 mice had the same size distribution with one major peak at 10 nm. LC-MS/MS analysis identified 48 HDL proteins. One-third of the proteins (including APOA2, APOC1, APOC3 and LCAT) differed significantly in relative abundance in the different rotamers. Importantly, on a per particle basis, HDL from LL5/4 mice demonstrated three times higher ABCA1 cholesterol efflux capacity than HDL from WT and LL5/5 mice. Our observations strongly suggest that APOA1 rotamers play distinct roles in HDL metabolism, raising the possibility that differences in APOA1 rotamer distribution alter the cardioprotective functions of HDL.

Abstract 118: Cholesteryl Ester Transfer Protein Overrides The Protective Effect Of APOA1 On Arterial APOB Lipoprotein Trapping And Atherosclerosis Progression In A Mouse Model Of Type 1 Diabetes

Despite the benefits of LDL-cholesterol-reducing medications, patients with type 1 diabetes (T1D) continue to have an increased risk of incident CVD. Preclinical and clinical observations indicate that triglyceride-rich lipoproteins (TRLs) and their remnants may contribute significantly to CVD risk in T1D. Recently, we have shown that diabetes increases levels of atherogenic TRL remnants and that improvement of remnant clearance halts atherosclerosis in a mouse model of T1D. Cholesteryl ester transfer protein (CETP), which is normally absent in mice, links metabolism of TRLs to that of HDL by mediating the transfer of cholesteryl ester from HDL to VLDL and other APOB-containing lipoproteins in exchange for triglycerides. We hypothesized that CETP impairs the atheroprotective effects of APOA1 by altering TRL and HDL metabolism in diabetes. To test this hypothesis, we developed a virally-induced T1D mouse model expressing the human APOA1 transgene ( APOA1 Tg , Ldlr –/– ). Cohorts of these mice were injected with a liver-targeted adeno-associated virus to express human CETP, and the effects on lipoproteins, plasma apolipoproteins, HDL particle concentrations (HDL-P), and atherosclerosis in the presence and absence of diabetes were determined. This mouse model exhibits an HDL profile similar to humans, with small, medium and large HDL-P, whereas wildtype ( Ldlr -/- ) littermates have only one sized HDL-P. Expression of the APOA1 transgene significantly suppressed diabetes-accelerated necrotic core expansion and accumulation of APOB and APOE in the aortic sinus (compared to wildtype Ldlr -/- mice), while CETP impaired the protective effect of APOA1 on these parameters in diabetic APOA1 Tg , Ldlr –/– mice (n= 22-30, p < 0.05). Further characterization of plasma lipoproteins and apolipoproteins by targeted mass spectrometry, FPLC and differential ion mobility analysis indicated that CETP leads to smaller TRL remnant particles, increases triglyceride content in HDL, lower levels of plasma APOA1 and reduction in large HDL-P under diabetic conditions (n= 8-10, p < 0.05). Our results are consistent with the proposal that inhibition of CETP might be cardioprotective in the setting of T1D and highlight the close links between TRL and HDL metabolism in diabetes.

The Arg82Cys Polymorphism of the Protein Nepmucin Implies a Role in HDL Metabolism.

ContextBlood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive.ObjectiveHere, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism.MethodsWe elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status.ResultsA lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P = .004) and RbG studies (P = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels.ConclusionTaken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.

Abstract P175: Combined Metabolic Health And Obesity Status Is Associated With Markers Of High-Density Lipoprotein Metabolism: Dallas Heart Study

Introduction: While high-density lipoprotein (HDL) cholesterol is a component of metabolic syndrome, an ASCVD risk factor, other markers of HDL metabolism better associate with ASCVD. However, it is unclear whether these markers better discriminate between metabolic health and obese groups. Hypothesis: We hypothesized that higher cholesterol efflux capacity (CEC) and a favorable HDL profile would be associated with metabolically healthy profiles within each weight category. Methods: Data from the second phase of the Dallas Heart Study were used to classify participants (n=2156) into four groups based on a harmonized definition of metabolic health and obesity status: Metabolically Healthy, Normal Weight (MHNW); Metabolically Unhealthy, Normal Weight (MUNW); Metabolically Healthy, Obese (MHO); Metabolically Unhealthy, Obese (MUO). MU was classified as having one or more of the following: elevated blood pressure (SBP/DBP ≥130/85 mmHg), fasting glucose (≥100 mg/dL), or fasting triglycerides (≥150 mg/dL); a history of CVD or diabetes; or any medications for these conditions. Obesity was defined as BMI ≥ 30kg/m 2 . CEC was measured using J774 macrophages, BODIPY- and radio-labeled cholesterol, and apoB-precipitated plasma. HDL particle (HDL-P) subfractions were quantified by NMR spectroscopy. Generalized linear models were used to compare paired means of CEC and HDL traits between groups controlling for age, sex, race, and smoking. Results: Small HDL-P concentration was higher in MU groups regardless of weight status. Total and medium HDL-P concentrations and radio-labeled CEC were higher in NW groups, regardless of metabolic health status. Mean HDL-P size and large HDL-P concentrations were different across all groups, with the rank order being MHNW, MUNW, MHO, MUO (Table 1). Conclusions: In conclusion, associations between HDL subfractions, CEC and metabolic/weight status are heterogeneous, highlighting the complexity of HDL physiology as it pertains to body weight and metabolic disease.

Higher Free Triiodothyronine Is Associated With Higher HDL Particle Concentration and Smaller HDL Particle Size.

ContextThyroid function status has effects on the development of atherosclerotic cardiovascular disease by affecting lipid metabolism, but associations of high-density lipoprotein (HDL) particle concentrations and subfractions with thyroid hormone levels within the reference range remain elusive.ObjectiveThe aim of the present study was to determine the associations of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels with HDL particle characteristics in euthyroid individuals.MethodsThis cross-sectional study on the associations of thyroid hormones with HDL particle concentrations, HDL subfractions, and HDL particle size included 5844 euthyroid individuals (FT3, FT4, and TSH levels within the reference range and no medication use affecting thyroid function), participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. HDL particles and subfractions were measured by nuclear magnetic resonance using an optimized version of the NMR LipoProfile Test (LP4).ResultsIn multivariable linear regression analyses, FT3 was positively associated with total HDL particle concentration (std.β = 0.14; P < 0.001) and with small (std.β = 0.13; P < 0.001) and medium-sized HDL particles (std.β = 0.05; P = 0.001). Conversely, FT3 was inversely associated with large HDL particles (std.β = −0.07; P < 0.001) and with HDL particle size (std.β = −0.08; P < 0.001). Such associations with FT4 or reciprocally with TSH were less pronounced or nonsignificant.ConclusionIn euthyroid individuals, higher FT3 is cross-sectionally associated with higher total HDL particle concentration and with lower HDL particle size. These associations may be relevant to better understand the role of HDL in thyroid function–associated atherosclerotic cardiovascular disease.

Healthy lifestyle, metabolomics and incident type 2 diabetes in a population-based cohort from Spain

BackgroundThe contribution of metabolomic factors to the association of healthy lifestyle with type 2 diabetes risk is unknown. We assessed the association of a composite measure of lifestyle with plasma metabolite profiles and incident type 2 diabetes, and whether relevant metabolites can explain the prospective association between healthy lifestyle and incident type 2 diabetes.MethodsA Healthy Lifestyle Score (HLS) (5-point scale including diet, physical activity, smoking status, alcohol consumption and BMI) was estimated in 1016 Hortega Study participants, who had targeted plasma metabolomic determinations at baseline examination in 2001–2003, and were followed-up to 2015 to ascertain incident type 2 diabetes.ResultsThe HLS was cross-sectionally associated with 32 (out of 49) plasma metabolites (2.5% false discovery rate). In the subset of 830 participants without prevalent type 2 diabetes, the rate ratio (RR) and rate difference (RD) of incident type 2 diabetes (n cases = 51) per one-point increase in HLS was, respectively, 0.69 (95% CI, 0.51, 0.93), and − 8.23 (95% CI, − 16.34, − 0.13)/10,000 person-years. In single-metabolite models, most of the HLS-related metabolites were prospectively associated with incident type 2 diabetes. In probit Bayesian Kernel Machine Regression, these prospective associations were mostly driven by medium HDL particle concentration and phenylpropionate, followed by small LDL particle concentration, which jointly accounted for ~ 50% of the HLS-related decrease in incident type 2 diabetes.ConclusionsThe HLS showed a strong inverse association with incident type 2 diabetes, which was largely explained by plasma metabolites measured years before the clinical diagnosis.

Perfil lipoproteico por espectroscopia nuclear magnética en pacientes con insuficiencia cardiaca crónica comparado con controles emparejados

Introduction and objectivesAdvanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. MethodsThis cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. ResultsThe 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P<.001) and HDL (25.7 vs 27.9μmol/L; P <.001) particle concentrations, with this last difference being mediated by a significantly lower concentration of the small subfraction of HDL (15.2 vs 18.6μmol/L; P <.001). Mean very low-density lipoprotein, LDL, and HDL particle size was significantly higher in patients with HF vs controls. All HDL-related differences from controls persisted after adjustment for New York Heart Association functional class or body mass index. We found strong negative correlations of known cardiac biomarkers (N-terminal pro-brain natriuretic peptide and interleukin-1 receptor-like 1) with total and small LDL and HDL fractions and HDL particle size. ConclusionsPatients with chronic HF significantly differ in their lipoprotein profile compared with unaffected controls. Further research is needed to better understand the pathogenic relevance of this difference.

Effects of Alirocumab on Triglyceride Metabolism: A Fat-Tolerance Test and Nuclear Magnetic Resonance Spectroscopy Study.

Background: PCSK9 antibodies strongly reduce LDL cholesterol. The effects of PCSK9 antibodies on triglyceride metabolism are less pronounced. The present study aimed to investigate in detail the effects of alirocumab on triglycerides, triglyceride-rich lipoproteins, and lipase regulators. Methods: A total of 24 patients with an indication for treatment with PCSK9 antibodies were recruited. There were two visits at the study site: the first before initiation of treatment with alirocumab and the second after 10 weeks of treatment. Fat-tolerance tests, nuclear magnetic resonance spectroscopy, and enzyme-linked immunosorbent assays were performed to analyze lipid metabolism. Results: A total of 21 participants underwent the first and second investigation. Among these, two participants only received alirocumab twice and 19 patients completed the trial per protocol. All of them had atherosclerotic vascular disease. There was no significant effect of alirocumab treatment on fasting triglycerides, post-prandial triglycerides, or lipoprotein-lipase regulating proteins. Total, large, and small LDL particle concentrations decreased, while the HDL particle concentration increased (all p < 0.001). Mean total circulating PCSK9 markedly increased in response to alirocumab treatment (p < 0.001). Whereas PCSK9 increased more than three-fold in all 19 compliant patients, it remained unchanged in those two patients with two injections only. Conclusion: Significant effects of alirocumab on triglyceride metabolism were not detectable in the ALIROCKS trial. The total circulating PCSK9 concentration might be a useful biomarker to differentiate non-adherence from non-response to PCSK9 antibodies.

Abstract 11174: Effect of APOCIII-L Rx on Lipoprotein Size and Particle Numbers Measured by NMR in Patients with Hypertriglyceridemia: Results of the AKCEA-APOCIII-L Rx Trial

Background: APOCIII-L Rx is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apoC-III and triglyceride-rich lipoproteins (TRLs). We examined the effect of APOCIII-L Rx on a variety of lipoprotein fractions measured by nuclear magnetic resonance (NMR) spectroscopy. Methods: The AKCEA-APOCIII-L Rx trial was a dose-ranging study in 114 patients with, or at risk for, ASCVD and fasting serum triglycerides 200-500 mg/dL. Patients (n=114) received AKCEA-APOCIII-L Rx (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. Comprehensive NMR LipoProfile ® analysis was performed by LipoScience/LabCorp in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. Results: Results are reported as change from baseline to PAT for the 50 mg every 4 weeks dose versus placebo. APOCIII-L Rx resulted in a significant reduction in total TRL particle (TRLP) concentration by 51% (P&lt;0.0001) with largest reductions in large-size (by 68%, P&lt;0.0001) and medium-size (by 63%, P&lt;0.0001) TRLPs. Total LDL particle (LDLP) concentration was not changed, small LDLP numerically decreased by 39% (P= 0.0713) while medium LDLP increased by 187% (P=0.0119), accompanied by an increase in average LDL size by xx 2% (p=0.0039xx). Total HDL particle (HDLP) concentration increased by 15% (P=0.0006), represented primarily by an increase in small HDL subspecies (particle diameters &lt;8.3 mm) of 32% (P=0.0008). Lower cumulative doses of APOCIII-L Rx generally reflected a dose-dependent relationship in the above parameters. Conclusion: APOCIII-L Rx results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDLP. These findings suggest an improvement in overall atherogenic risk profile.

1H-magnetic resonance spectroscopy lipoprotein profile in patients with chronic heart failure versus matched controls

Introduction and objectivesAdvanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. MethodsThis cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. ResultsThe 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P<.001) and HDL (25.7 vs 27.9μmol/L; P <.001) particle concentrations, with this last difference being mediated by a significantly lower concentration of the small subfraction of HDL (15.2 vs 18.6μmol/L; P <.001). Mean very low-density lipoprotein, LDL, and HDL particle size was significantly higher in patients with HF vs controls. All HDL-related differences from controls persisted after adjustment for New York Heart Association functional class or body mass index. We found strong negative correlations of known cardiac biomarkers (N-terminal pro-brain natriuretic peptide and interleukin-1 receptor-like 1) with total and small LDL and HDL fractions and HDL particle size. ConclusionsPatients with chronic HF significantly differ in their lipoprotein profile compared with unaffected controls. Further research is needed to better understand the pathogenic relevance of this difference.

Circulating high density lipoprotein distinguishes alcoholic hepatitis from heavy drinkers and predicts 90-day outcome: lipoproteins in alcoholic hepatitis

Alcohol-associated liver disease (ALD) and alcoholic hepatitis (AH) significantly impact the liver, an organ central to the lipid and lipoprotein metabolism. To define changes in the lipid and lipoprotein profiles in subjects with alcoholic hepatitis (AH) versus heavy drinkers with normal liver function and to determine the association of the AH-mediated lipoprotein phenotype with AH severity and outcomes. AH cases (n=196) and a heavy drinker control group (n=169) were identified in a multicenter, prospective cohort. The relationships between lipid panels and lipoprotein profiles among AH and heavy drinkers were interrogated using three common measurements: the conventional lipid panel, extended lipid panel by NMR, and NMR-based direct lipoprotein profiling. Predictive values for AH severity and mortality were determined using Harrell's C-Index. Lipid and lipoprotein profiles were significantly different in AH compared to heavy drinkers. Among them, high density lipoprotein (HDL) particle concentration exhibited the most significant reduction in AH compared to heavy drinkers (5.3 ± 3.4 vs 22.3 ± 5.4 μmol/L, p < 0.001). Within AH patients, HDL particle concentration was inversely associated with Maddrey's Discriminant Function (DF) (p < 0.001), and independently associated with mortality at both 90 and 365 days even after adjustment for DF (p=0.02, p=0.05 respectively). HDL particle concentration less than 3.5 μmol/L and total cholesterol ≤ 96 mg/dL identified AH patients with higher 90-day mortality. Lipid and lipoprotein profiles are profoundly altered in AH and can help in prognosticating disease severity and mortality.

Lipoprotein subtypes after testosterone therapy in transmasculine adolescents

Differences in lipoprotein-particle subclasses between men and women start in puberty and narrow after menopause, suggesting a role for sex steroids. In this cross-sectional cohort study, we examined lipoprotein subtype profiles in transmasculine adolescents treated with testosterone. Transmasculine adolescents (n = 17) had lipoprotein profiles that were similar to those of cisgender males (n = 33) and more atherogenic than those of cisgender females (n = 32), with higher concentrations of small low-density lipoprotein (LDL) particles (435 ± 222 nmol/L vs. 244 ± 163 nmol/L, p = 0.008) and lower concentrations of large high-density lipoprotein (HDL) particles (1.5 ± 1.3 μmol/L vs 2.7 ± 1.2 μmol/L, p = 0.003) when compared to cisgender females. Thus, testosterone appears to be a major contributor to differences in lipoprotein profiles, a surrogate for cardiovascular disease risk, between cisgender women and both transgender and cisgender men.

Good Cholesterol Gone Bad? HDL and COVID-19

The transmissible respiratory disease COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of people worldwide since its first reported outbreak in December of 2019 in Wuhan, China. Since then, multiple studies have shown an inverse correlation between the levels of high-density lipoprotein (HDL) particles and the severity of COVID-19, with low HDL levels being associated with an increased risk of severe outcomes. Some studies revealed that HDL binds to SARS-CoV-2 particles via the virus’s spike protein and, under certain conditions, such as low HDL particle concentrations, it facilitates SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2) and infection of host cells. Other studies, however, reported that HDL suppressed SARS-CoV-2 infection. In both cases, the ability of HDL to enhance or suppress virus infection appears to be dependent on the expression of the HDL receptor, namely, the Scavenger Receptor Class B type 1 (SR-B1), in the target cells. SR-B1 and HDL represent crucial mediators of cholesterol metabolism. Herein, we review the complex role of HDL and SR-B1 in SARS-CoV-2-induced disease. We also review recent advances in our understanding of HDL structure, properties, and function during SARS-CoV-2 infection and the resulting COVID-19 disease.

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.

A metabolomic index based on lipoprotein subfractions and branched chain amino acids is associated with incident hypertension

ObjectiveThe present study aims to evaluate the performance of the Diabetes Risk Index (DRI), a metabolomic index based on lipoprotein particles and branched chain amino acids, on the incidence of newly developed hypertension in a large community dwelling cohort. MethodsThe DRI was calculated by combining 6 lipoprotein parameters [sizes of very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), concentrations of large VLDL, small LDL, and large HDL particles], and the concentrations of valine and leucine. DRI scores were estimated in 4169 participants from the PREVEND prospective cohort. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident hypertension. ResultsDuring a median follow-up of 8.6 years, 924 new hypertension cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI and incident hypertension with a hazard ratio (HR) per 1 SD increase of 1.45 (95% CI 1.36,1.54; p < 0.001). After additional adjustment for traditional risk factors, the HR remained significant (HRadj 1.21, 95% CI 1.10, 1.33, p <0.001). Likewise, subjects in the top quartile of DRI presented with a higher risk of hypertension (HRadj 1.64, 95% CI 1.28, 2.10, p <0.001). Furthermore, the net reclassification improvement assessment improved after the addition of DRI to a traditional risk model (p <0.001), allowing proper reclassification of 34% of the participants. ConclusionHigher DRI scores were associated with an increased risk of incident hypertension. Such association was independent of traditional clinical risk factors for hypertension.

72-OR: HDL Particle Concentration Predicts Incident Coronary Artery Disease (CAD) in Type 1 Diabetes (T1D)

We have shown that elevated HDL cholesterol (HDL-C) levels (≥80 mg/dL) associate with increased CAD risk in women with T1D. Furthermore, HDL-C levels are not necessarily cardioprotective in nondiabetic individuals, suggesting that the cholesterol content of HDL does not accurately assess CAD risk. We thus determined whether two other HDL metrics, HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC), predicted incident CAD in a large cohort of childhood onset T1D (n=550). At baseline, mean age was 27.8 yrs, T1D duration was 19.6 yrs and 49% were women. HDL-P was assessed by calibrated ion mobility analysis and CEC was quantified with validated assays in cAMP stimulated J774 cells and in ABCA1-expressing BHK cells. CAD was defined as CAD death, myocardial infarction and/or revascularization. During a median follow-up of 26 yrs, we observed 203 incident CAD cases (36.9%). At baseline, incident cases were older, more likely to have smoked, have hypertension, longer duration of T1D, higher non-HDL-C and markers of kidney disease and inflammation. Cases were also more likely to have lower HDL-P concentrations but similar CEC to non-cases. Cox models with backward elimination were constructed for each HDL metric, allowing for potential confounding variables, including HDL-C. In separate multivariable models, higher concentrations of total HDL-P (T-HDL-P, HR=0.88, 95% CI: 0.83-0.92) and 3 major HDL subpopulations - small (S-HDL-P, HR=0.78, 0.67-0.92), medium (M-HDL-P, HR=0.79, 0.71-0.88) and large-sized (L-HDL-P, HR=0.74, 0.61-0.89) particles - associated with a lower CAD incidence whereas HDL-C did not. Higher total CEC in J774 cells also predicted lower CAD risk (HR=0.74, 0.55-0.996) after similar adjustments, but became non-significant after further adjusting for HDL-P. ABCA1-specific CEC did not predict CAD. Our results suggest that increased HDL-P levels are cardioprotective in T1D, in contrast to HDL-C and CEC which did not independently predict CAD. Disclosure T. Costacou: None. T. Vaisar: Consultant; Self; AstraZeneca. K. Bornfeldt: None. T. J. Orchard: None. J. Heinecke: None. Funding National Institutes of Health (HL130153, DK34818)

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.