Impaired Cholesterol Efflux Capacity Research Articles

Defective biological activities of high-density lipoprotein identify patients at highest risk of recurrent cardiovascular event.

Low cholesterol efflux capacity and elevated levels of Interleukin-1ß (IL-1ß) are both associated with residual cardiovascular risk in patients with acute myocardial infarction (MI) and may be used as new biomarkers to identify patients at higher cardiovascular risk. We evaluated potential synergetic effect of cholesterol efflux capacity and IL-1ß on recurrent major adverse cardiovascular events (MACE) at one-year in 2012 patients with acute ST- segment elevation MI who underwent primary percutaneous coronary intervention. In addition, we evaluated the contribution to residual risk of HDL biological functions from 20 patients of the two extreme subgroups, focusing on cholesterol efflux capacity and anti-inflammatory properties. Patients with MACE during the first year after the MI had significantly lower serum cholesterol efflux capacity as compared to those without recurrent events and higher level of IL-1ß, both associations were confirmed after multivariate analysis. We found an inverse relationship between CEC and circulating levels of the inflammatory markers IL-1ß, defining a very high risk (Low CEC/High IL-1ß) and a low risk (High CEC/Low IL-1ß) group of patients. Patients combining Low CEC/High IL-1ß exhibited the highest risk of recurrent MACE at one year showing an additive prognostic value of these biomarkers, regardless of all the other clinical or biological factors. In this very high-risk subgroup, patients exhibited reduced HDL-efflux capacity and defective ABCA1 and SR-BI with enhanced pro-inflammatory activity as a potential explanation for our clinical findings. Impaired cholesterol efflux capacity and elevated IL-1β synergistically increase the residual cardiovascular risk in MI patients, which could be explained by reduced HDL-efflux capacity and enhanced HDL pro-inflammatory activity.

Impaired high-density lipoprotein-associated cholesterol efflux capacity predicts coronary rapid plaque progression

Abstract Background Rapid progression of coronary atherosclerotic plaques is recognized as a surrogate endpoint of cardiac ischemic events. Low high-density lipoprotein (HDL)-associated cholesterol efflux capacity (CEC) has been associated with atherosclerotic cardiovascular disease independent of HDL cholesterol (HDL-C) level. In this study, we aim to investigate the predictive role of CEC in rapid plaque progression (RPP). Methods We consecutively enrolled patients with stable angina from January 2017 to August 2019 in our hospital who underwent elective coronary angiography with at least one untreated coronary lesion. A follow-up angiography was performed at around 12 months. Afterwards, these patients were followed-up for every 3 months to June 2021. The primary endpoint was RPP during the 12-month angiography follow-up. The second endpoint was defined as a composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unplanned coronary revascularization. Fluorescence-labeled cholesterol and J774 macrophages were used to measure CEC of ApoB-depleted serum samples. Results A total of 430 patients with 586 coronary lesions were included in the final analysis. During a mean follow-up of 12.7 ± 2.0 months, 120 lesions (20.5%) in 80 patients (18.6%) exhibited RPP. CEC, rather than HDL-C, was inversely associated with the extent of plaque progression (net luminal loss from the lowest to highest CEC quartile: 0.22±0.42 vs. 0.20±0.41 vs. 0.13±0.36 vs. 0.11±0.34 mm, P = 0.035). In multivariate analysis, baseline CEC was inversely associated with RPP independent of conventional risk and protective factors including HDL-C or apolipoprotein A-I. Subgroup analysis demonstrated that the association between CEC and RPP was more prominent in patients with high (≥4.02 mmol/L) than low (<4.02 mmol/L) total cholesterol. Finally, although patients with RPP had higher risk of the composite endpoint than those without RPP (P=0.012), no significant difference was observed between patients in different quartiles of CEC (P=0.720). Conclusions HDL-associated CEC is inversely associated with RPP in patients with coronary artery disease. HDL function assessment behaves as a better diagnostic biomarker than HDL-C for predicting RPP.

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

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

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.

Abstract 11756: Tracking High-Density Lipoprotein Functionality in Diabetic and Non-Diabetic Patients With Toe Amputations

Introduction: High-density lipoprotein cholesterol (HDL-c) levels have an established inverse association with cardiovascular event risk. More recently, the focus has shifted to HDL functionality as an improved metric of its predictive value and is impaired in patients with coronary arterial disease. HDL-c levels have been reported to inversely associate with the risk of amputation in patients with diabetic foot ulcers (DFUs), but whether HDL functionality is predictive of wound closure success is currently unknown. Methods: Eighteen diabetic and eight non-diabetic patients with toe/s amputations had blood collected at: (1) the time of surgery, (2) four weeks and (3) six months post-amputation. Wound areas were tracked until closure by 3D camera. Blood was collected from 20 healthy age and gender-matched participants. From blood, HDL was isolated and its functionality tested via (1) cholesterol efflux from macrophages, and (2) anti-inflammatory and (3) pro-angiogenic effects in endothelial cells. Results: Wound closure was faster in non-diabetic than diabetic amputation patients at four weeks (186.6%, P =0.12). Diabetic HDL promoted less cholesterol efflux at four-weeks (37.8%, P &lt;0.05) and six-months (45.6%, P &lt;0.01) post-amputation, compared to non-diabetic HDL. Incubation of non-diabetic HDL with endothelial cells caused greater reductions in inflammatory markers RELA (51.4%, P &lt;0.01), CCL5 (46.9%, P &lt;0.01), CCL2 (15.3%, P &lt;0.05) and ICAM-1 (33.1%, P &lt;0.05) than non-diabetic HDL. Non-diabetic HDL elicited greater endothelial cell angiogenesis with increased Matrigel tubule number at four weeks post amputation (46.15%, P &lt;0.05), compared to diabetic HDL. There were significant correlations between the rate of wound closure and HDL-c levels (R 2 = +0.62, P &lt;0.05), CCL2 (R = -0.64, P &lt;0.05) and ICAM-1 (R = -0.71, P &lt;0.05). Conclusion: In toe amputation patients, HDL-c levels and inflammatory HDL functionality markers associate with the rate of wound closure. HDL from diabetic patients had impaired cholesterol efflux capacity, reduced anti-inflammatory effects and was less able to promote angiogenesis, compared to non-diabetic HDL.

Early time-restricted feeding improves high-density lipoprotein amount and function in nonhuman primates, without effects on body composition.

Time-restricted feeding (TRF), whereby caloric intake is limited to a <12-hour window, is a potential regimen to ameliorate metabolic syndrome and cardiovascular disease (CVD) risk co-occurring with aging and with obesity. Early TRF (eTRF; early morning feeding followed by overnight fasting) times calorie consumption with hepatic circadian gene expression rhythms. Brief TRF trials demonstrate that high-density lipoprotein (HDL) cholesterol increases similar to diet/exercise interventions, which may impart beneficial CVD effects. Using a nonhuman primate (NHP) model, the efficacy of eTRF to raise HDL and increase plasma cholesterol efflux capacity (CEC) (primarily mediated by cholesterol efflux to HDL particles, a process that is inversely associated with CVD risk) was examined. Adult (8-16 years old, n=25) and geriatric (≥17 years old) NHPs were randomized to ad libitum feeding or eTRF for 12 months, and relevant body composition, glycemic control, and plasma HDL cholesterol levels and CEC were measured. Impaired CEC was found in geriatric NHPs. eTRF induced larger-sized HDL particles, increased HDL apolipoprotein A-1 content, lowered triglyceride concentrations, and increased plasma CEC (primarily to HDL particles) in both adult and geriatric NHPs without changes in glycemic control or body composition. A beneficial effect of eTRF on increasing HDL CEC in NHPs was demonstrated.

Normal HDL Cholesterol Efflux and Anti-Inflammatory Capacities in Type 2 Diabetes Despite Lipidomic Abnormalities.

ObjectiveTo assess whether, in type 2 diabetes (T2D) patients, lipidomic abnormalities in high-density lipoprotein (HDL) are associated with impaired cholesterol efflux capacity and anti-inflammatory effect, 2 pro-atherogenic abnormalities.Design and MethodsThis is a secondary analysis of the Lira-NAFLD study, including 20 T2D patients at T0 and 25 control subjects. Using liquid chromatography/tandem mass spectrometry, we quantified 110 species of the main HDL phospholipids and sphingolipids. Cholesterol efflux capacity was measured on THP-1 macrophages. The anti-inflammatory effect of HDL was measured as their ability to inhibit the tumor necrosis factor α (TNFα)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on human vascular endothelial cells (HUVECs).ResultsThe cholesterol-to-triglyceride ratio was decreased in HDL from T2D patients compared with controls (-46%, P = 0.00008). As expressed relative to apolipoprotein AI, the amounts of phosphatidylcholines, sphingomyelins, and sphingosine-1-phosphate were similar in HDL from T2D patients and controls. Phosphatidylethanolamine-based plasmalogens and ceramides (Cer) were, respectively, 27% (P = 0.038) and 24% (P = 0.053) lower in HDL from T2D patients than in HDL from controls, whereas phosphatidylethanolamines were 41% higher (P = 0.026). Cholesterol efflux capacity of apoB-depleted plasma was similar in T2D patients and controls (36.2 ± 4.3 vs 35.5 ± 2.8%, P = 0.59). The ability of HDL to inhibit the TNFα-induced expression of both VCAM-1 and ICAM-1 at the surface of HUVECs was similar in T2D patients and controls (-70.6 ± 16.5 vs -63.5 ± 18.7%, P = 0.14; and -62.1 ± 13.2 vs -54.7 ± 17.7%, P = 0.16, respectively).ConclusionDespite lipidomic abnormalities, the cholesterol efflux and anti-inflammatory capacities of HDL are preserved in T2D patients.

HDL particle morphology in Alzheimer’s disease patients compared to healthy human subjects and chemically modified HDL

AbstractBackgroundIn various chronic diseases including Alzheimer’s disease, a common clinical manifestation is defective high‐density lipoprotein (HDL) status. Published evidence suggests that HDL particles from Alzheimer’s patients are functionally deficient, as measured by impaired cholesterol efflux capacity. However, the structural and compositional alterations of HDL particles that contribute to this loss of function in Alzheimer’s disease are currently not well understood.MethodIn this study, we investigated the morphological characteristics of HDL particles from 7 patients confirmed with Alzheimer’s disease and 3 age‐matched healthy subjects using transmission electron microscopy. We also analyzed how oxidation, glycation, deglycosylation, and acidification alter the morphology of HDL isolated from healthy human subjects and compared these chemically treated HDL with HDL from Alzheimer’s patients and controls.ResultDistinct treatment‐specific variation patterns of HDL particles, including particle size change, aggregation, and disintegration, were observed. Most prominently, HDL incubated at a pH of 5.5 for 18 hours had an increased average HDL particle diameter from 10.65 ± 2.22 nm to 13.08 ± 2.77 nm (P&lt;0.001). In addition, both glycation and oxidation treatment caused HDL to form aggregates. HDL isolated from patients with Alzheimer’s disease and age‐matched, cognitively normal subjects displayed aggregate structures that resembled those of chemically glycated and oxidized HDL. These aggregated HDL structures were found in both patients and controls.ConclusionFurther studies with larger sample sizes are needed to better characterize the morphological, structural, and compositional alterations that cause the loss of HDL function in patients with Alzheimer’s disease.

Cholesterol efflux capacity and its association with prevalent metabolic syndrome in a multi-ethnic population (Dallas Heart Study)

Metabolic syndrome (MetS) is characterized by adiposity and atherogenic dyslipidemia consisting of elevated triglyceride and decreased high density lipoprotein cholesterol (HDL-C) levels however, cholesterol concentration alone does not reflect HDL functionality. Cholesterol efflux capacity (CEC) captures a key anti-atherosclerotic function of HDL; studies linking CEC to MetS have yielded inconsistent findings and lacked racial/ethnic diversity. The aim of this study was to evaluate the association between CEC and MetS in a large multi-ethnic population utilizing two different CEC assays interrogating overlapping but distinct reverse cholesterol transport pathways. A cross-sectional study was performed using the Dallas Heart Study cohort and cholesterol efflux was measured with radiolabeled and fluorescent cholesterol assays. The relationship between CEC and MetS was assessed using multivariable regression analyses. A total of 2241 participants were included (mean age was 50 years; 38% men and 53% Blacks). CEC was independently and inversely associated with MetS irrespective of efflux assay (CEC-radiolabeled, adjusted OR 0·71 [95% CI 0·65–0·80]. CEC-fluorescent, adjusted OR 0·85 [95% CI 0·77–0·94]). Both CEC measures were inversely associated with waist circumference and directly associated with HDL-C but not with other MetS components. There was an interaction by sex but not by race such that the inverse associations between CEC and MetS were somewhat attenuated in men (OR 0·86, 95%CI 0·74–1·01). In this large multi-ethnic cohort, impaired CEC is linked to MetS irrespective of efflux assay and race/ethnicity but less so among men. Future studies are needed to assess whether CEC mediates the atherosclerotic cardiovascular disease risk of MetS.

Impaired HDL cholesterol efflux capacity in subjects with metabolically- but not genetically- driven non-alcoholic fatty liver disease (NAFLD)

Impaired HDL cholesterol efflux capacity in subjects with metabolically- but not genetically- driven non-alcoholic fatty liver disease (NAFLD)

Impaired cholesterol efflux capacity in patients with Helicobacter pylori infection and its relation with inflammation

BackgroundGut microorganisms are associated with atherosclerosis and related cardiovascular disease. Helicobacter pylori (H. pylori) infection is associated with dyslipidemia and inflammation contributing to the progression of atherosclerosis. ObjectiveSeveral studies have reported reduced HDL-C levels in H. pylori infected patients, but HDL cholesterol efflux capacity (CEC) as the most important function of HDL has not been evaluated yet. MethodsThis cross-sectional study was conducted with 44 biopsy confirmed H. pylori patients and 43 controls. ABCA1-mediated, non-ABCA1 and total CEC were measured in ApoB-depleted serum and levels of ApoA-I, ApoB and hsCRP were estimated using ELISA technique. ResultsTotal and ABCA1 mediated-CEC were reduced in patients compared to controls, independent of age, sex, body mass index and HDL-C (p < 0.001), while non-ABCA1 CEC indicated no significant change between the groups. In addition, patients showed lower serum levels of ApoA-I but increased levels of hsCRP when compared to controls. Total CEC and ABCA1-mediated CEC positively correlated with ApoA-I and HDL-C, furthermore, ABCA1-mediated CEC as well as ApoA-I inversely correlated with hsCRP. ConclusionThe results of the present study indicate reduced CECs in H. pylori infected patients, especially ABCA1-mediated CEC which is associated with decreased ApoA-I and increased inflammation.

Prolonged bedrest reduces plasma high-density lipoprotein levels linked to markedly suppressed cholesterol efflux capacity

Recent observations strongly connect high-density lipoproteins (HDL) function and levels with coronary heart disease outcomes and risk for infections and sepsis. To date, our knowledge of factors determining this connection is still very limited. The immobility associated with prolonged bedrest is detrimental to health, affecting several systems, including the cardiovascular, pulmonary, gastrointestinal, musculoskeletal and urinary. Effects of prolonged bedrest on the composition and functional properties of HDL remain elusive. We evaluated metrics of HDL composition and function in healthy male volunteers participating in a randomized, crossover head-down bedrest study. We observed that HDL cholesterol efflux capacity was profoundly decreased during bedrest, mediated by a bedrest associated reduction in plasma levels of HDL-cholesterol and major apolipoproteins (apo) apoA-I and apoA-II. Paraoxonase activity, plasma anti-oxidative capacity and the activities of lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein were not affected. No change was observed in the content of HDL-associated serum amyloid A, a sensitive marker of inflammation. Resistive vibration exercise countermeasure during bedrest did not correct impaired cholesterol efflux capacity and only tended to increase arylesterase activity of HDL-associated paraoxonase. In conclusion, prolonged bedrest reduces plasma HDL levels linked to markedly suppressed HDL cholesterol efflux capacity. Resistive vibration exercise during bedrest did not correct HDL levels and impaired cholesterol efflux capacity.

No benefit of HDL mimetic CER-001 on carotid atherosclerosis in patients with genetically determined very low HDL levels

Background and aimsInfusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol. MethodsIn this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18F-FDG PET/CT to quantify arterial wall inflammation. ResultsA total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm2, p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks. ConclusionIn patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo.

Cardiac apoptosis caused by elevated cholesterol level in experimental autoimmune myocarditis

It has been reported that cholesterol-lowing agents can ameliorate severity of myocarditis. However, the beneficial effect of the agents has been claimed to be independent of cholesterol reduction as there is no significant change in the plasma cholesterol level in myocarditis. In the present study, using experimental autoimmune myocarditis (EAM) rats as an animal model, we demonstrated that EAM induced elevation of cholesterol level and impaired cholesterol efflux capacity in the cardiac tissue. Moreover, serum high-density lipoprotein (HDL) content was reduced and HDL function associated protein Paraoxonase 1 (PON1) activity was decreased. Besides, the major structural protein within HDL, Apolipoprotein A1 (ApoA1) expression in the cardiac tissues was significantly reduced while the level of serum ApoA1 was not significantly altered. Importantly, cholesterol depleting agent methyl-β-cyclodextrin (MβCD) alleviated the development of EAM, as monitored by decreased ratio of heart weight to body weight (HW/BW), decreased infiltration of inflammatory cells and collagen deposition, improved cardiac function, reduced expression of apoptosis-related protein Bax, Fas, FasL and caspase-3 and increased level of anti-apoptotic protein Bcl-2. These results suggest that reduction of cholesterol level in cardiac tissue could suppress EAM-induced cardiac apoptosis through both intrinsic and extrinsic apoptotic pathways.

Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity.

Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from Apoe−/− macrophages. Direct modification of HDL with MDA increased apoAI crosslinking and reduced the cholesterol efflux capacity. MDA modification of HDL reduced its anti-inflammatory function compared to native HDL. MDA-HDL also had impaired ability to increase PON1 activity. Importantly, HDL from subjects with familial hypercholesterolemia (FH-HDL) versus controls had increased MDA-apoAI adducts, and PON1 activity was also impaired in FH. Consistently, FH-HDL induced a pro-inflammatory response in Apoe−/− macrophages and had an impaired ability to promote cholesterol efflux. Interestingly, reactive dicarbonyl scavengers, including 2-hydroxybenzylamine (2-HOBA) and pentyl-pyridoxamine (PPM), effectively abolished MPO-mediated apoAI crosslinking, MDA adduct formation, and improved cholesterol efflux capacity. Treatment of hypercholesterolemic mice with reactive dicarbonyl scavengers reduced MDA-HDL adduct formation and increased HDL cholesterol efflux capacity, supporting the therapeutic potential of reactive carbonyl scavenging for improving HDL function.

Association of hemoglobin A1C with circulating metabolites in Dutch with European, African Surinamese and Ghanaian background

BackgroundThe prevalence of type 2 diabetes mellitus (T2DM) varies significantly across ethnic groups. A better understanding of the mechanisms underlying the variation in different ethnic groups may help to elucidate the pathophysiology of T2DM. The present work aims to generate a hypothesis regarding “why do subjects with African background have excess burden of T2DM?”.MethodsIn the current study, we performed metabolite profiling of plasma samples derived from 773 subjects of three ethnic groups (Dutch with European, Ghanaian and African Surinamese background). We performed Bayesian lognormal regression analyses to assess associations between HbA1c and circulating metabolites.ResultsHere we show that subjects with African Surinamese and Ghanaian background had similar associations of HbA1c with circulating amino acids and triglyceride-rich lipoproteins as subjects with European background. In contrast, subjects with Ghanaian and African Surinamese background had different associations of HbA1c with acetoacetate, small LDL particle and small HDL particle concentrations, compared to the subjects with European background.ConclusionsOn the basis of the observations, we hypothesize that the excess burden of T2DM in subjects with African background may be due to impaired cholesterol efflux capacity or abnormal cholesterol uptake.

Vitamin E supplementation improves high-densitiy lipoprotein and endothelial functions in end-stage kidney disease patients undergoing hemodialysis .

Patients with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) have been shown to be at increased risk for cardiovascular disease (CVD). Decreased high-density lipoprotein cholesterol (HDL-C) and impaired cholesterol efflux capacity (CEC) have been reported in such patients, and effects of vitamin E supplementation on HDL functions are poorly understood. Therefore, the present study aimed to investigate effects of vitamin E supplementation on HDL and endothelial functions in ESKD patients undergoing HD. We also assessed the influence of diabetes and haptoglobin (Hp) phenotype on the effects of vitamin E. Vitamin E (300mg daily) was supplemented for 12weeks, followed by a 10-week washout phase in 40 ESKD patients undergoing HD (20 diabetic and 20 nondiabetic patients). HDL functions, including CEC, antioxidant capacity, and anti-inflammatory activity, were investigated. In diabetic patients, endothelial function, as represented by flow-mediated vasodilatation (FMD), was also assessed. The findings were compared according to diabetic condition or Hp phenotype. Vitamin E significantly increased CEC, whereas antioxidant capacity and anti-inflammatory activity remained unchanged. Further, the improvement in CEC was maintained after the 10-week washout phase. Endothelial function was significantly improved in diabetic patients. Subanalyses based on diabetes or Hp phenotype revealed that neither diabetes nor Hp phenotype influenced the effects of vitamin E. In ESKD patients undergoing hemodialysis, vitamin E supplementation significantly improved the HDL function of CEC and, in diabetic patients, endothelial function. These effects were independent of Hp phenotype. .

Elastic aortic wrap reduced aortic stiffness by partially alleviating the impairment of cholesterol efflux capacity in pigs.

Metabolic syndrome patients exhibit impaired cholesterol efflux capacity. Previous studies have shown a positive association between aortic stiffness and metabolic syndrome. However, it is unknown whether cholesterol efflux capacity participates in the process of aortic stiffness. This study sought to determine the effect of metabolic syndrome on aortic stiffening, and to investigate the effectiveness of aortic wraps on aortic compliance and the underlying mechanisms. In a swine model of metabolic syndrome, we compared the cholesterol efflux capacity and aortic compliance responding to diet modifications and aortic wrap applications. Metabolic syndrome induced by high cholesterol diet significantly decreased cholesterol efflux capacity and aortic compliance. Elastic aortic wrap application increased aortic compliance and partially restored cholesterol efflux capacity via ATP binding cassette transporter A1 (ABCA1) pathway. Cholesterol efflux plays a role in aortic stiffening. Elastic aortic wrap application could be a potential treatment for aortic stiffness related to metabolic syndrome.

Impaired HDL cholesterol efflux capacity in patients with non-alcoholic fatty liver disease is associated with subclinical atherosclerosis

Non-alcoholic fatty liver disease (NAFLD) is associated with a substantial increased risk of atherosclerotic cardiovascular disease (ASCVD), which is partly related to dyslipidemia and low HDL-C level. The cardioprotective activity of HDL in the body is closely connected to its role in promoting cholesterol efflux, which is determined by cholesterol efflux capacity (CEC). Hitherto, the role of HDL, as defined by CEC has not been assessed in NAFLD patients. In this research study, we present the results of a study of cAMP-treated J774 CEC and THP-1 macrophage CEC in ApoB-depleted plasma of 55 newly diagnosed NAFLD patients and 30 controls. Circulating levels of ApoA-I, ApoB, preβ-HDL, plasma activity of CETP, PLTP, LCAT and carotid intima-media thickness (cIMT) were estimated. cAMP-treated J774 and THP-1 macrophage CEC were found to be significantly lower in NAFLD patients compared to controls (P < 0.001 and P = 0.003, respectively). In addition, it was discovered that both ApoA-I and preβ1-HDL were significantly lower in NAFLD patients (P < 0.001). Furthermore, cAMP-treated J774 CEC showed independent negative correlation with cIMT, as well as the presence of atherosclerotic plaque in NAFLD patients. In conclusion, our findings showed that HDL CEC was suppressed in NAFLD patients, and impaired cAMP-treated J774 CEC was an independent risk factor for subclinical atherosclerosis in NAFLD patients, suggesting that impaired HDL functions as an independent risk factor for atherosclerosis in NAFLD.

Abstract MP046: Visceral Adipose Tissue but Not Subcutaneous Adipose Tissue Associates With Cholesterol Efflux Capacity in Psoriasis

Background: Psoriasis (PSO), a chronic inflammatory disease associated with increased cardiovascular (CV) risk, provides an ideal model to study inflammatory atherogenesis in vivo. PSO is associated with impaired cholesterol efflux capacity (CEC) and increased cardiometabolic dysfunction including adipose tissue dysregulation. Recently, visceral adiposity (VAT) was shown to be associated with increased CV events. However, neither VAT nor subcutaneous adiposity (SAT) have been shown to be associated with CEC. Hypothesis: Increased VAT by CT is associated with a decrease in CEC independent of CV risk factors. Methods: Consecutively recruited PSO patients (N=76) underwent CT scans to measure abdominal adiposity. VAT and SAT volume was quantified from the level vertebral level T10 to pubic symphysis. CEC was quantified using a cell-based ex vivo assay measuring the ability of apoB-depleted plasma to mobilize cholesterol from lipid-laden macrophages. The relationship of VAT and SAT with CEC was analyzed using multivariable regression models (STATA 12). Results: The cohort had a low CV risk by FRS [median (IQR): 4.0 (2.0-7.0)], mild to moderate PSO [median (IQR): 5.2 (3.0-8.5)], overweight to obese with a mean BMI of 30, 40% were on statin treatment, and 40% were on systemic/biologic therapy for PSO. In unadjusted models VAT was inversely associated with CEC (beta = -0.41, p &lt;0.001) while SAT was not significantly associated (beta = -0.12, p = 0.32). In fully adjusted models VAT retained inverse association with CEC (beta = -0.35, p = 0.04) while SAT remained insignificant (beta coefficient = 0.15, p-value = 0.43) (Table 1). Conclusions: VAT inversely associated with CEC while SAT showed no significant relationship suggesting that VAT may directly drive inflammatory HDL dysfunction while SAT may not. However, larger studies are needed to confirm these findings.