Impaired High-density Lipoprotein Research Articles

ANGPTL3 as a target for treating lipid disorders in type 2 diabetes patients

Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder, and cardiovascular disease (CVD) is a significant cause of mortality and morbidity in diabetic individuals. In addition to hyperglycemia, lipid abnormalities associated with T2DM play a crucial role in the development of CVD complications. Diabetic dyslipidemia is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL) cholesterol, and impaired HDL function. Angiopoietin protein-like 3 (ANGPTL3) is a liver-derived protein that plays a crucial role in regulating plasma lipoprotein metabolism by inhibiting lipoprotein lipase and influencing lipid levels. Inhibiting ANGPTL3 has shown promising effects in promoting HDL-mediated cholesterol reverse transport and reducing the levels of TG-rich lipoproteins and LDL cholesterol. Here, we explore the potential of ANGPTL3 as a therapeutic target for lipid management in T2DM patients.

Impaired HDL antioxidant and anti-inflammatory functions are linked to increased mortality in acute heart failure patients

AimsAcute heart failure (AHF) is typified by inflammatory and oxidative stress responses, which are associated with unfavorable patient outcomes. Given the anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL), this study sought to examine the relationship between impaired HDL function and mortality in AHF patients. The complex interplay between various HDL-related biomarkers and clinical outcomes remains poorly understood. MethodsHDL subclass distribution was quantified by nuclear magnetic resonance spectroscopy. Lecithin–cholesterol acyltransferase (LCAT) activity, cholesterol ester transfer protein (CETP) activity, and paraoxonase (PON-1) activity were assessed using fluorometric assays. HDL-cholesterol efflux capacity (CEC) was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. ResultsAmong the study participants, 74 (23.5 %) out of 315 died within three months after hospitalization due to AHF. These patients exhibited lower activities of the anti-oxidant enzymes PON1 and LCAT, impaired CEC, and lower concentration of small HDL subclasses, which remained significant after accounting for potential confounding factors. Smaller HDL particles, particularly HDL3 and HDL4, exhibited a strong association with CEC, PON1 activity, and LCAT activity. ConclusionsIn patients with AHF, impaired HDL CEC, HDL antioxidant and anti-inflammatory function, and impaired HDL metabolism are associated with increased mortality. Assessment of HDL function and subclass distribution could provide valuable clinical information and help identify patients at high risk.

Impaired high-density lipoprotein function and endothelial barrier stability in severe anaphylaxis

Growing evidence demonstrates the importance of high- and low-density lipoprotein cholesterol in certain immune and allergy-mediated diseases. This study aimed to evaluate levels of high- and low-density lipoprotein cholesterol and apolipoproteins A1 and B in sera from a cohort of patients presenting with hypersensitivity reactions. We further assessed the function of high-density lipoprotein particles as well as their involvement in the molecular mechanisms of anaphylaxis. Lipid profile determination was performed in paired (acute and baseline) serum samples from 153 patients. Thirty-eight experienced a non-anaphylactic reaction and 115 had an anaphylactic reaction (88 moderate and 27 severe). Lecithin cholesterol acyl transferase activity was assessed in patient sera, and we also evaluated macrophage cholesterol efflux in response to the serum samples. Last, the effect of anaphylactic-derived high-density lipoprotein (HDL) particles on the endothelial barrier was studied. Detailed methods are provided in the Methods section in this article's Online Repository available at www.jacionline.org. Serum samples from severe anaphylactic reactions show statistically significant low levels of HDL cholesterol, low-density lipoprotein cholesterol, and apolipoproteins A1 and B, which points to their possible role as biomarkers. Specifically, HDL particles play a protective role in cardiovascular diseases. Using functional human serum cell assays, we observed impaired capacity of apolipoprotein B-depleted serum to induce macrophage cholesterol efflux in severe anaphylactic reactions. In addition, purified HDL particles from human anaphylactic sera failed to stabilize and maintain the endothelial barrier. These results encourage further research on HDL functions in severe anaphylaxis, which may lead to new diagnostic and therapeutic strategies.

Antioxidant and Anti-Inflammatory Functions of High-Density Lipoprotein in Type 1 and Type 2 Diabetes.

(1) Background: high-density lipoproteins (HDLs) exhibit antioxidant and anti-inflammatory properties that play an important role in preventing the development of atherosclerotic lesions and possibly also diabetes. In turn, both type 1 diabetes (T1D) and type 2 diabetes (T2D) are susceptible to having deleterious effects on these HDL functions. The objectives of the present review are to expound upon the antioxidant and anti-inflammatory functions of HDLs in both diabetes in the setting of atherosclerotic cardiovascular diseases and discuss the contributions of these HDL functions to the onset of diabetes. (2) Methods: this narrative review is based on the literature available from the PubMed database. (3) Results: several antioxidant functions of HDLs, such as paraoxonase-1 activity, are compromised in T2D, thereby facilitating the pro-atherogenic effects of oxidized low-density lipoproteins. In addition, HDLs exhibit diminished ability to inhibit pro-inflammatory pathways in the vessels of individuals with T2D. Although the literature is less extensive, recent evidence suggests defective antiatherogenic properties of HDL particles in T1D. Lastly, substantial evidence indicates that HDLs play a role in the onset of diabetes by modulating glucose metabolism. (4) Conclusions and perspectives: impaired HDL antioxidant and anti-inflammatory functions present intriguing targets for mitigating cardiovascular risk in individuals with diabetes. Further investigations are needed to clarify the influence of glycaemic control and nephropathy on HDL functionality in patients with T1D. Furthermore, exploring the effects on HDL functionality of novel antidiabetic drugs used in the management of T2D may provide intriguing insights for future research.

Statins influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis

ObjectivesCholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-β HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-β HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA). MethodsEvaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol. ResultsABCA1-CEC negatively correlated with ABCG1-CEC (r = −0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20–3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65–1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61–0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23–0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18–3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and < 0.001 respectively). Moreover, ABCA1-CEC (per SD) associated with greater partially/fully-calcified plaque progression (adjusted odds ratio 3.07 [95%CI 1.20–7.86]) only in patients not exposed to statins during follow-up (p-for-interaction = 0.009). ConclusionIn patients with RA, higher ABCA1-CEC may reflect a proatherogenic state, associated with enhanced cardiovascular risk. Statin use may unmask the protective impact of ABCA1-mediated cholesterol efflux on plaque formation, progression and cardiovascular risk.

Abstract 676: Novel Human Variants Of SR-B1 Impact HDL-cholesterol Clearance

The reverse cholesterol transport (RCT) pathway is the primary avenue by which our bodies lower plasma cholesterol levels. In RCT, peripheral cholesterol is transported by high density lipoproteins (HDL) to the liver for excretion. Cholesterol delivery is facilitated by a high-affinity interaction between HDL and its receptor, scavenger receptor class B member 1 (SR-B1). Recently, novel variants within the gene encoding SR-B1 were identified in a population of Icelandic people. Four missense mutations - V32M-, V111M-, V135I-, and G319V-SR-B1- were associated with elevations in plasma HDL-cholesterol. Based on these clinical phenotypes, we hypothesized that these conserved variants of SR-B1 would disrupt HDL-cholesterol transport. To assess the functions of the variants, we transiently transfected vector, wild-type, or mutant SR-B1 constructs into COS7 cells which express low endogenous SR-B1. All mutants displayed decreased DiI-HDL binding, yet only G319V-SR-B1 displayed a significant decrease in DiI lipid uptake, by 42% compared to wild-type. SR-B1 also mediates cholesterol efflux from cells into HDL. When assayed, only V32M- and G319V-SR-B1 decreased cholesterol efflux to HDL by 25 and 52%, respectively, compared to wild-type. Additionally, we demonstrated a decrease in total and cell surface expression of the G319V-SR-B1 variant compared to wild-type SR-B1, suggesting that impairments in function could be due to decreased expression. SR-B1 forms oligomers to facilitate its functions, and all variants maintained the ability to form higher order oligomers. To further characterize the SR-B1 variants, we utilized a recently-developed purification system to generate full-length SR-B1 protein and performed microscale thermophoresis to monitor changes in affinity for HDL. Paralleling our results from cellular assays, all SR-B1 variants displayed impaired HDL binding. When mapped to a homology model of full-length SR-B1, all four mutations are within the extracellular region, but the functional perturbations caused by each mutation warrants further studies. These mutants, combined with previously characterized SR-B1 variants, can be integrated as important pieces in the puzzle of cholesterol homeostasis and cardiovascular disease.

Gestational Hypertension and High-Density Lipoprotein Function: An Explorative Study in Overweight/Obese Women of the DALI Cohort.

Gestational hypertension (GHTN) is associated with an increased cardiovascular risk for mothers and their offspring later in life. High-density lipoproteins (HDL) are anti-atherogenic by promoting efflux of cholesterol from macrophages and suppression of endothelial cell activation. Functional impairment of HDL in GHTN-complicated pregnancies may affect long-term health of both mothers and offspring. We studied functional parameters of maternal and neonatal HDL in 192 obese women (pre-pregnancy BMI ≥ 29), who were at high risk for GHTN. Maternal blood samples were collected longitudinally at &lt;20 weeks, at 24-28 and 35-37 weeks of gestation. Venous cord blood was collected immediately after birth. Maternal and cord blood were used to determine functional parameters of HDL, such as HDL cholesterol efflux capacity, activity of the vaso-protective HDL-associated enzyme paraoxonase-1, and levels of the HDL-associated anti-inflammatory apolipoprotein (apo)M. In addition, we determined serum anti-oxidative capacity. Thirteen percent of the women were diagnosed with GHTN. While we found no changes in measures of HDL function in mothers with GHTN, we observed impaired HDL cholesterol efflux capacity and paraoxonase-1 activity in cord blood, while serum antioxidant capacity was increased. Of particular interest, increased maternal paraoxonase-1 activity and apoM levels in early pregnancy were associated with the risk of developing GHTN. GHTN significantly impairs HDL cholesterol efflux capacity as well as HDL PON1 activity in cord blood and could affect vascular health in offspring. Maternal paraoxonase-1 activity and apoM levels in early pregnancy associate with the risk of developing GHTN.

CSL112 Increases Plasma Cholesterol Efflux Capacity and Reduces Erythrocyte Membrane Cholesterol Content in Blood Samples from Patients with Sickle Cell Disease

Background: Lipid homeostasis is abnormal in sickle cell disease (SCD) and contributes to elevated erythrocyte cholesterol content which has been implicated in sickling. The highly oxidative environment in blood from patients with SCD alters high-density lipoprotein (HDL) composition and impairs HDL particle remodeling. Specifically, it negatively impacts on the capacity of HDL particles to mediate apolipoprotein A-I (apoA-I) exchange and protect against inflammation. Low apoA-I levels and altered composition of HDL have been well-documented at steady state, associated with high risk features of SCD, including endothelial dysfunction and risk of pulmonary hypertension. The low levels and activity of apoA-I fall even further during vaso-occlusive events in SCD. This diminished pool of apoA-I activity may mediate reduced capacity of HDL to extract cholesterol from erythrocyte membranes and increase risk of vascular dysfunction. Purpose: In this study we aimed to determine whether plasma derived apoA-I (CSL112; apolipoprotein A-I (human)) could elevate the cholesterol efflux capacity (CEC) of plasma from SCD patients and thereby reduce erythrocyte membrane cholesterol content. Methods: All SCD subjects (n=14) had confirmed HbSS genotype except one who was with HbS/β0-thalassemia, healthy control subjects (n=13) were not race-matched. CSL112 was incubated with fresh blood derived from control subjects and SCD patients for 6 hours at 37°C. The cholesterol content of ghost membranes of isolated erythrocytes was measured. HDL particle size distribution was assessed by native gel electrophoresis followed by western blotting. The ex vivo capacity of apoB-depleted plasma to efflux cholesterol was determined using [3H]cholesterol-loaded RAW264.7 macrophages. Results: CEC of SCD plasma was attenuated (75.9 ± 7.4%, n=14) compared to controls (100%, n=13), with a predominant decrease of ATP binding cassette transporter A1 (ABCA1)-dependent CEC (77.7 ± 9.2% vs 100%, respectively). Consistently, SCD plasma showed a trend towards lower levels of pre-β1 HDL (78.5 ± 6.5%) as compared to controls (100 %). Incubation with CSL112 raised plasma levels of small HDL species and pre-β1 HDL, resulting in a more than 3.5 fold increase of CEC in both patients and controls. Treatment of SCD blood with CSL112 reduced erythrocyte cholesterol content to a greater extent compared to control blood (% reduction: 12.8% ± 3.1% in SCD, 6.3% ± 5.4% in controls). Conclusion: Our data suggest that reduced levels of lipid-poor pre-β1 HDL in SCD plasma reflect impaired HDL particle remodeling and account for a decreased CEC. CSL112 may acutely generate HDL species which optimally support ABCA1-dependent cholesterol efflux and thereby improve HDL function, normalize erythrocyte membrane cholesterol content and correct the imbalance in cellular cholesterol homeostasis in SCD patients. ApoA-I as a potential therapeutic could have implications in the pathobiologic understanding and future clinical management of vaso-occlusive crisis and of chronic vascualopathy such as pulmonary hypertension.

High-density lipoprotein cholesterol efflux capacity in patients with obstructive sleep apnea and its relation with disease severity

BackgroundObstructive sleep apnea (OSA) is linked to an accelerated risk of cardiovascular disease (CVD). Some key CVD risk factors are present in patients suffering from OSA such as hypertension, inflammation, oxidative stress, and dyslipidemia. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is proposed as a reliable biomarker of HDL function and the present study aimed to quantify this biomarker in patients with OSA.MethodsATP binding cassette subfamily A member 1 (ABCA1), non-ABCA1, and total CEC were determined in 69 polysomnographic-confirmed OSA patients and 23 controls. Moreover, paraoxonase (PON) activities, high-sensitivity C-reactive protein (hsCRP), apolipoprotein B (apo B), and apolipoprotein A-I (apo A-I) circulating levels were quantified in the studied population.Results: All CEC measures were reduced in the OSA group compared to the control group. Strikingly, ABCA1 CEC was diminished in severe OSA in comparison with mild OSA. Furthermore, PON activities and apo A-I showed lower levels, while hsCRP and apo B were elevated in OSA patients compared to controls. Moreover, ABCA1 CEC showed an inverse association with hsCRP and a positive association with apo A-I, while non-ABCA1 CEC presented an association with HDL-C.ConclusionThese results suggest the presence of an impaired HDL function in OSA. In particular, ABCA1 CEC was associated with disease severity and inflammation which could be a factor increasing the risk of CVD.

Hypercholesterolemia-Induced HDL Dysfunction Can Be Reversed: The Impact of Diet and Statin Treatment in a Preclinical Animal Model.

High-density lipoproteins (HDL) undergo adverse remodeling and loss of function in the presence of comorbidities. We assessed the potential of lipid-lowering approaches (diet and rosuvastatin) to rescue hypercholesterolemia-induced HDL dysfunction. Hypercholesterolemia was induced in 32 pigs for 10 days. Then, they randomly received one of the 30-day interventions: (I) hypercholesterolemic (HC) diet; (II) HC diet + rosuvastatin; (III) normocholesterolemic (NC) diet; (IV) NC diet + rosuvastatin. We determined cholesterol efflux capacity (CEC), antioxidant potential, HDL particle number, HDL apolipoprotein content, LDL oxidation, and lipid levels. Hypercholesterolemia time-dependently impaired HDL function (−62% CEC, −11% antioxidant index (AOI); p < 0.01), increased HDL particles numbers 2.8-fold (p < 0.0001), reduced HDL-bound APOM (−23%; p < 0.0001), and increased LDL oxidation 1.7-fold (p < 0.0001). These parameters remained unchanged in animals on HC diet alone up to day 40, while AOI deteriorated up to day 25 (−30%). The switch to NC diet reversed HDL dysfunction, restored apolipoprotein M content and particle numbers, and normalized cholesterol levels at day 40. Rosuvastatin improved HDL, AOI, and apolipoprotein M content. Apolipoprotein A-I and apolipoprotein C-III remained unchanged. Lowering LDL-C levels with a low-fat diet rescues HDL CEC and antioxidant potential, while the addition of rosuvastatin enhances HDL antioxidant capacity in a pig model of hypercholesterolemia. Both strategies restore HDL-bound apolipoprotein M content.

Association between high oxidized high-density lipoprotein levels and increased pericoronary inflammation determined by coronary computed tomography angiography

BackgroundImpaired high-density lipoprotein (HDL) function is a risk factor for cardiac mortality. We aimed to investigate the association between oxidized HDL (oxHDL) and pericoronary adipose tissue (PCAT) attenuation, a novel imaging biomarker of pericoronary inflammation, by using coronary computed tomography angiography (CTA). MethodsA total of 287 outpatients with suspected coronary artery disease who had undergone both oxHDL measurement and coronary CTA were examined. PCAT attenuation values were assessed at the proximal 10–50 mm segments of the right coronary artery on coronary CTA. The presence of significant stenosis (luminal narrowing of >50 %) and high-risk plaque characteristics were also evaluated. Patients were then classified into tertiles according to their oxHDL level: low (n = 95), moderate (n = 96), and high (n = 96) groups. ResultsPCAT attenuation in the high oxHDL group was significantly higher than that in other groups after adjusting for age and apolipoprotein-A-I. Multivariate linear regression analysis revealed that oxHDL was significantly associated with PCAT attenuation in the right coronary artery (β = 3.832, p < 0.001), whereas HDL cholesterol was not. Furthermore, subgroup analyses demonstrated that the association between oxHDL and PCAT attenuation remained significant in older patients (β = 6.367, p < 0.001) and in those with hypertension (β = 4.922, p < 0.011), dyslipidemia (β = 3.264, p = 0.010), diabetes mellitus (β = 4.284, p = 0.015), and significant stenosis (β = 3.075, p = 0.021). ConclusionsHigh oxHDL levels were significantly associated with increased pericoronary inflammation, as assessed using coronary CTA. Our results may explain the association between impaired HDL function and the development of coronary atherosclerosis.

Bariatric Surgery-induced High-density Lipoprotein Functionality Enhancement Is Associated With Reduced Inflammation.

Emerging evidence suggests an association between impaired high-density lipoprotein (HDL) functionality and cardiovascular disease (CVD). HDL is essential for reverse cholesterol transport (RCT) and reduces inflammation and oxidative stress principally via paraoxonase-1 (PON1). RCT depends on HDL's capacity to accept cholesterol (cholesterol efflux capacity [CEC]) and active transport through ATP-binding cassette (ABC) A1, G1, and scavenger receptor-B1 (SR-B1). We have studied the impact of Roux-en-Y gastric bypass (RYGB) in morbidly obese subjects on RCT and HDL functionality. Biomarkers associated with increased CVD risk including tumour necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), myeloperoxidase mass (MPO), PON1 activity, and CEC in vitro were measured in 44 patients before and 6 and 12 months after RYGB. Overweight but otherwise healthy (mean body mass index [BMI] 28 kg/m2) subjects acted as controls. Twelve participants also underwent gluteal subcutaneous adipose tissue biopsies before and 6 months after RYGB for targeted gene expression (ABCA1, ABCG1, SR-B1, TNF-α) and histological analysis (adipocyte size, macrophage density, TNF-α immunostaining). Significant (P < 0.05) improvements in BMI, HDL-cholesterol, hsCRP, TNF-α, MPO mass, PON1 activity, and CEC in vitro were observed after RYGB. ABCG1 (fold-change, 2.24; P = 0.005) and ABCA1 gene expression increased significantly (fold-change, 1.34; P = 0.05). Gluteal fat adipocyte size (P < 0.0001), macrophage density (P = 0.0067), and TNF-α immunostaining (P = 0.0425) were reduced after RYBG and ABCG1 expression correlated inversely with TNF-α immunostaining (r = -0.71; P = 0.03). RYGB enhances HDL functionality in association with a reduction in adipose tissue and systemic inflammation.

Association of anti-oxidative capacity of HDL with subclinical atherosclerosis in subjects with and without non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) patients are at a substantial risk for developing cardiovascular disease (CVD). High-density lipoprotein (HDL) is well known to have protective effects against the development of atherosclerotic CVD. One of the major antiatherogenic effects of HDL is its anti-oxidative function.ObjectivesThis study investigated the association of anti-oxidative capacity of HDL with subclinical atherosclerosis in NAFLD and non-NAFLD subjects.MethodsA total of 143 subjects including 51 NAFLD and 92 control subjects were included in this case–control study. HDL oxidative index (HOI) was determined spectrophotometrically using a cell-free method in the presence of a fluorescent substrate dichlorofluorescein diacetate (DCFDA). Paraoxonase 1 (PON1) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) plasma levels were assessed in both groups.ResultsThe NAFLD patients with impaired HDL anti-oxidative function (HOI ≥ 1) had higher MDA levels, aspartate amino transferase (AST), liver stiffness (LS), and carotid intima-media thickness (cIMT) values compared to the controls. HDL oxidative index (HOI) was positively correlated with MDA levels and cIMT and negatively correlated with SOD activity.ConclusionsHigher circulating levels of MDA were associated with the impaired anti-oxidative function of HDL in NAFLD. The impaired anti-oxidative capacity of HDL might be related to NAFLD severity and subclinical atherosclerosis in NAFLD patients.

High-density lipoprotein lipid peroxidation in association with presence of coronary artery disease and atrial fibrillation in a large cross-sectional study

Abstract Background The function of high-density lipoprotein (HDL) cholesterol may play a more important role in the prevention of cardiovascular disease compared to the concentration of the HDL. Cardiovascular diseases such as coronary artery disease (CAD) and atrial fibrillation (AF) have been linked to impaired HDL function. Purpose The aim of the present study is to assess a biochemical measure of the antioxidant function of HDL and its association with presence of CAD and AF. Methods Patients admitted for elective cardiac catheterization were recruited in this cross-sectional study. Out of 1231 participants that were included in the analyses, 727 patients had confirmed CAD (CAD group), 369 patients had no CAD (no CAD group) and 129 persons were included as a control group. HDL function was measured in sera by determination of HDL-lipid peroxidation content (HDLox) assessed by a validated fluorometric cell-free biochemical assay and was normalized for the levels of HDL cholesterol (normalized HDLox/HDL-C ratio or nHDLox; no units). Results are expressed as median with interquartile range. Associations of nHDLox with presence of CAD and AF were assessed by univariate and multivariate analyses. Results Participants in the CAD group had higher levels of nHDLox (0.80, 0.61–1.03) compared to the no CAD (0.70, 0.55–0.93) and control (0.66, 0.55–1.03, no units, p&amp;lt;0.001) group. Out of 1206 participants, 233 (19%) had AF and 973 (81%) had no AF. Patients with AF have also higher nHDLox (0.82, 0.60–10.03) compared to persons without AF (0.73, 0.58–0.98, p=0.03). In univariate analysis nHDLox was associated with CAD (p&amp;lt;0.001). In multivariate analysis adjusted for age, gender, CAD, BMI and hypertension, nHDLox was a strong independent predictor of atrial fibrillation (p=0.015) but was not an independent predictor of CAD (p&amp;gt;0.05) Conclusions Reduced antioxidant function of HDL (increased HDLox measured by a biochemical assay), a metric of HDL function, is increased in patients with atherosclerosis and manifested CAD and is also associated with the presence of atrial fibrillation independent of the presence of CAD. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Medical School of Brandenburg-MHB Fontane

Longitudinal association between an overall diet quality index and latent profiles of cardiovascular risk factors: results from a population based 13-year follow up cohort study

BackgroundCardiovascular diseases (CVDs) are associated with an unhealthy lifestyle, including poor diet. Indices reflecting the overall quality of diets are more effective than single food or nutrient-based approaches in clarifying the diet disease relationship. The present study aims to use latent variable modeling to examine the longitudinal joint relationships between the latent profiles of CVDs risk factors and the diet quality index (DQI).MethodsA total of 4390 Iranian adults aged 35 and older within the framework of the Isfahan Cohort Study were included in the current secondary analysis. DQI focused on food groups, including fast foods, sweets, vegetables, fruits, fats, and proteins, based on a validated food frequency questionnaire. The score of DQI has a range between 0 (indicating healthy and high diet quality) and 2 (indicating unhealthy and low diet quality). Blood pressure (BP), anthropometric measurements, blood glucose, serum lipids, and high-sensitivity C-Reactive Protein (hs-CRP) were measured according to standard protocols in 2001, 2007, and 2013 to evaluate the profiles of CVDs risk factors. A Bayesian Multidimensional Graded Responses Linear Mixed Model was used for data analysis.ResultsAt baseline, the participants’ mean ± standard deviation age was 50.09 ± 11.21, and 49.5% of them were male. Three latent profiles of CVDs risk factors were derived: (1) Fit Pre-Metabolic Syndrome (FPMS) profile characterized by normal anthropometric indices and some impaired metabolic risk factors; (2) DysLipoproteinemia Central Obese (DLCO) profile with abdominal obesity and impaired low-density lipoprotein cholesterol as well as other normal risk factors; (3) Impaired Laboratory Inflammatory State (ILIS) profile with impaired high-density lipoprotein cholesterol and hs-CRP and other normal risk factors. In general, higher scores of the extracted latent profiles indicated more impaired function in the related risk factors. After controlling for various potential fixed and time-varying confounding variables, a significant positive longitudinal association was found between FPMS, DLCO, and ILIS profiles and DQI (β (95% CrI): 0.26 (0.03,0.51), 0.14 (0.01,0.27), and 0.24 (0.11,0.38), respectively), demonstrating that lower overall diet quality was associated with more impaired function of the related risk factors.ConclusionsMore adherence to a healthy quality diet is associated with lower levels of all emerging latent profiles of CVDs risk factors. Increasing the knowledge of the community about the importance of the quality of consumed foods may help to prevent CVDs. It is recommended that further investigations, particularly interventional studies, be conducted to confirm our results.

Abstract 14088: Pro-neurotensin/neuromedin N is Associated With Incident Metabolic Syndrome

Introduction: The tridecapeptide neurotensin increases dietary fatty acid uptake and is implicated in insulin resistance in animal models and—through plasma levels of its stable precursor pro-neurotensin/neuromedin N (pro-NT/NMN)—with human diabetes mellitus, obesity, and cardiovascular disease. We evaluated the association of pro-NT/NMN with incident metabolic syndrome (MetS). Methods: This analysis included a subcohort of 2,770 Black and White participants without prevalent MetS at baseline (2003-2007) from the REasons for Geographic And Racial Differences in Stroke study who had fasting plasma pro-NT/NMN measured by immunoassay and completed a second assessment from 2013-2016. Incident MetS was defined as ≥3 harmonized criteria at follow-up: impaired glycemic control, high systolic blood pressure, high triglycerides, low high-density lipoprotein (HDL), and increased waist circumference. Four sequential weighted logistic regression models were fitted to incident MetS overall and for each criterion separately, incorporating demographic factors, metabolic risk factors, HOMA-IR, and diet scores. Results: Over mean 9.4 (standard deviation [SD] 1.0) years follow up, 564 participants developed MetS. Median [IQR] plasma pro-NT/NMN was 160 [118-218] pmol/L. In the overall group, higher log pro-NT/NMN was associated with incidence of lower HDL (odds ratio [OR] per SD pro-NT/NMN 1.16, 95% confidence interval [CI] 1.00-1.35) and impaired glycemic control (1.25, 95% CI 1.11-1.40), but not other MetS components. Each SD higher log pro-NT/NMN was associated with a 22% increased odds of incident MetS, adjusted for demographics (Table); this was not significant when controlling for HOMA-IR in all but the White subgroup (race p -interaction 0.05). No differences by sex were observed. Conclusions: Higher neurotensin likely augments insulin resistance to increase odds of incident metabolic syndrome through impaired glycemic control and lower HDL.

Cholesterol uptake capacity: a new measure of HDL functionality as a predictor of subsequent revascularization in patients undergoing percutaneous coronary intervention

Abstract Background Recent studies have demonstrated the importance of high-density lipoprotein (HDL) functionality in the development of de novo coronary artery disease by using the cholesterol-efflux capacity, a measure of the ability of HDL to promote cholesterol removal from lipid-laden macrophages. Recently, we developed a rapid cell-free assay system to directly evaluate the capacity of HDL to accept additional cholesterol; the measurement of the cholesterol-uptake capacity (CUC) enables HDL functionality to be readily evaluated in our daily practice. However, prognostic implication of CUC measurement at the timing of percutaneous coronary intervention (PCI) remains unclear. Purpose We aimed to evaluate the association between baseline CUC and revascularization during follow-up in the patients who underwent PCI. Methods We retrospectively reviewed the patients who underwent PCI with follow-up coronary angiography (CAG) or ischemic-driven revascularization. The patients who had the frozen blood samples of which CUC were measurable at the index PCI and follow-up CAG or revascularization were enrolled. We excluded the patients under hemodialysis. Results Among a total of 703 consecutive patients who underwent PCI between Dec 2014 and Mar 2019, we finally enrolled 74 patients who underwent ischemic-driven revascularization (revascularization group) and 183 patients who underwent follow-up CAG without revascularization (non-revascularization group).There were no significant difference in baseline traditional cardiovascular risk factors between the groups. However, the presence of diabetes was significantly more frequent in the revascularization group (63.5% vs 41.0%; P=0.001) than in the non-revascularization group. CUC at the index PCI was significantly lower in the revascularization group than in the non-revascularization group (87.0±19.5 vs 93.9±19.2; P=0.004). Multivariate logistic regression analysis revealed that impaired HDL functionality assessed by decreased CUC level at the index PCI (odds ratio; 0.984, 95% confidence interval; 0.969–1.000) was independently associated with subsequent revascularization after PCI. Indeed, there was a graded inverse association between increasing tertiles of CUC levels and the incidence of revascularization during a median follow-up of 881 days (Figure). Especially in the subgroup analysis of non-diabetic patients, decreased CUC level at the index PCI was independently associated with subsequent revascularization (odds ratio; 0.947, 95% confidence interval; 0.915–0.981), while not in diabetic population. Conclusion Serum CUC level at the index procedure was associated with subsequent revascularization especially in non-diabetic patients who underwent PCI. Funding Acknowledgement Type of funding source: None

Impaired high-density lipoprotein function in patients with heart failure

Abstract Background We recently showed that a lower high-density lipoprotein cholesterol (HDL-C) concentration was one of the strongest predictors of death or heart failure (HF) hospitalisation in patients with HF. In a follow-up study, we suggested that this association could be partly explained by HDL proteome composition. However, whether the emerging concept of HDL function contributes to prognosis of HF patients has not been addressed. Methods We measured three key HDL function metrics, namely cholesterol efflux, antioxidative capacity, and anti-inflammatory capacity, at baseline and after 9 months in 446 randomly selected HF patients from BIOSTAT-CHF. Additionally, the relationship between HDL functionality and HDL proteome composition was determined in 86 patients. Results From baseline to 9 months, HDL-C concentrations did not substantially change, but HDL-mediated cholesterol efflux and anti-inflammatory capacity had decreased (both P&amp;lt;0.001). In contrast, antioxidative capacity improved during the 9 months follow-up (P&amp;lt;0.001). Higher HDL-mediated cholesterol efflux was independently associated with lower risk of mortality after adjustment for BIOSTAT risk models and log HDL-C (HR=0.81 [95% CI: 0.71–0.92], P=0.001). Other functionality parameters were not associated with outcome. Several HDL proteins correlated with HDL functionality, mainly with cholesterol efflux, and apolipoprotein A1 emerged as the main protein associated with all three functionality parameters. Conclusions HDL-mediated cholesterol efflux and anti-inflammatory capacity significantly decreased over time in patients with HF. Better baseline cholesterol efflux was prospectively associated with reduced mortality during follow-up independent of HDL-C. Combined these data indicate that HDL function measurements have the potential to provide clinical information beyond static HDL-C concentrations in HF patients. Changes in HDL functionality over time Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Commission

Impaired HDL Metabolism Links GlycA, A Novel Inflammatory Marker, with Incident Cardiovascular Events.

High-density lipoproteins (HDL) exert anti-atherosclerotic effects via reverse cholesterol transport, yet this salutary property is impaired in the setting of inflammation. GlycA, a novel integrated glycosylation marker of five acute phase reactants, is linked to cardiovascular (CV) events. We assessed the hypothesis that GlycA is associated with measures of impaired HDL function and that dysfunctional HDL may contribute to the association between GlycA and incident CV events. Baseline measurements of HDL cholesterol (HDL-C), HDL particle concentration (HDL-P), apoliprotein A1 (Apo A1), cholesterol efflux capacity, GlycA and high-sensitivity C-reactive protein (hs-CRP) were obtained from the Dallas Heart Study, a multi-ethnic cohort of 2643 adults (median 43 years old; 56% women, 50% black) without cardiovascular disease (CVD). GlycA was derived from nuclear magnetic resonance imaging. Participants were followed for first nonfatal MI, nonfatal stroke, coronary revascularization, or CV death over a median of 12.4 years (n = 197). The correlation between GlycA and hs-CRP was 0.58 (p < 0.0001). In multivariate models with HDL-C, GlycA was directly associated with HDL-P and Apo A1 and inversely associated with cholesterol efflux (standardized beta estimates: 0.08, 0.29, -0.06, respectively; all p ≤ 0.0004) GlycA was directly associated with incident CV events (adjusted hazard ratio (HR) for Q4 vs. Q1: 3.33, 95% confidence interval (CI) 1.99, 5.57). Adjustment for cholesterol efflux mildly attenuated this association (HR for Q4 vs. Q1: 3.00, 95% CI 1.75 to 5.13). In a multi-ethnic cohort, worsening inflammation, as reflected by higher GlycA levels, is associated with higher HDL-P and lower cholesterol efflux. Impaired cholesterol efflux likely explains some of the association between GlycA and incident CV events. Further studies are warranted to investigate the impact of inflammation on HDL function and CV disease.

HDL and Reverse Cholesterol Transport.

Cardiovascular disease, with atherosclerosis as the major underlying factor, remains the leading cause of death worldwide. It is well established that cholesterol ester-enriched foam cells are the hallmark of atherosclerotic plaques. Multiple lines of evidence support that enhancing foam cell cholesterol efflux by HDL (high-density lipoprotein) particles, the first step of reverse cholesterol transport (RCT), is a promising antiatherogenic strategy. Yet, excitement towards the therapeutic potential of manipulating RCT for the treatment of cardiovascular disease has faded because of the lack of the association between cardiovascular disease risk and what was typically measured in intervention trials, namely HDL cholesterol, which has an inconsistent relationship to HDL function and RCT. In this review, we will summarize some of the potential reasons for this inconsistency, update the mechanisms of RCT, and highlight conditions in which impaired HDL function or RCT contributes to vascular disease. On balance, the evidence still argues for further research to better understand how HDL functionality contributes to RCT to develop prevention and treatment strategies to reduce the risk of cardiovascular disease.