Aerobic capacity at age 34 predicts arterial stiffness in age 63, independent of classical and advanced lipid-related cardiovascular risk factors: a longitudinal cohort study

High-Density Lipoprotein Mediated Cellular Cholesterol Efflux in Acute Coronary Syndromes

A great majority of the morbidity and mortality worldwide can still be attributed to cardiovascular diseases, such as ischemic (coronary) heart disease, angina pectoris, and myocardial and cerebral infarction. Atherosclerosis, narrowing of the arteries because of arterial cholesterol deposition in macrophage foam cells, is the driving force behind the cardiovascular disease pathology. Water-soluble protein/lipid complexes called lipoproteins mediate the transport of cholesterol and other lipoid substances through the blood compartment. Relatively high levels of cholesterol associated with apolipoprotein B–containing low-density lipoprotein (LDL) particles predispose human subjects to the development of atherosclerosis and, thereby, increase the risk for cardiovascular disease.1,2 Apolipoprotein B–containing lipoproteins are, therefore, generally regarded as being proatherogenic factors. Cholesterol ester–rich high-density lipoprotein (HDL) particles use apolipoprotein A1 (apoA1) as their primary protein component. In sharp contrast to LDL, HDL is considered a potent anti-atherogenic agent. This notion is based on the fact that, in the general population, a strong inverse correlation exists between plasma levels of HDL cholesterol and the risk of cardiovascular disease.1 Of note, this inverse association seems to be independent of the level of cholesterol associated with proatherogenic LDL particles. As such, increasing plasma levels of HDL cholesterol has long been regarded a promising alternative therapy to supplement classical statin–based LDL cholesterol–lowering strategies that are able to reduce cardiovascular disease by only ≈30%.3 However, over the last decade, the enthusiasm for HDL as an interesting therapeutic target has been challenged by the HDL hypothesis critics because genetic association studies have excluded HDL cholesterol levels as determinants for cardiovascular disease risk.2,4 Furthermore, several therapeutic HDL-targeting approaches have proven insufficient to secure benefit for cardiovascular disease patients. Niacin is the most effective drug available in the clinic to raise plasma HDL cholesterol levels. Despite the fact that niacin is …

Cardiovascular disease (CVD) is the most common cause of death worldwide.1 Major CVD risk factors are hypertension, smoking, physical inactivity, abnormal glucose levels/diabetes mellitus, and dyslipidemia. Among these, dyslipidemia characterized by a low level of HDL-C (high-density lipoprotein cholesterol) is strongly and inversely correlated with CVD risk,2–4 and low HDL-C levels is part of the atherogenic dyslipidemia complex associated with diabetes mellitus.5 These observations triggered intense interest in increasing HDL-C levels for therapeutic intervention of CVD.6,7 However, several recent lines of evidence now suggest that the association between HDL-C levels and CVD status may be indirect or more complicated than previously recognized.7 Thus, human genetic studies demonstrate that genetically altered HDL-C levels do not necessarily translate to an altered risk of CVD.8–12 Phase III clinical trials of drugs that elevate HDL-C, such as niacin and CETP (cholesteryl ester transfer protein) inhibitors, also have largely failed to reduce CVD events in statin-treated subjects with established CVD.13–15 For several CETP inhibitors, improvement in CVD prevention was unsuccessful because of off-target effects (torcetrapib) or lack of efficacy (dalcetrapib and evacetrapib).14,16–18 The exception is the recent REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification), which included more subjects and was performed for longer than previous CETP inhibitor trials. The REVEAL demonstrated that the CETP inhibitor anacetrapib exhibited beneficial effects on cardiovascular outcomes on top of those of statin therapy, although the risk reduction was moderate19,20 and might have been due, at least in part, to a reduction in non-HDL-C rather than elevated HDL-C.21 Considering these cumulative observations, it remains uncertain whether increased HDL-C directly impacts atherosclerosis and the …

P3767Progressive left atrial remodeling associates with cholesterol efflux capacity of HDL in atrial fibrillation patients

Cholesterol efflux (CE) is a major athero-protective function of high density lipoproteins (HDL). HDL is a heterogeneous mixture of lipoproteins that contain apoA1, the prime protein of HDL, and may contain one or more of >200 other proteins. These other proteins cluster on subpopulations of HDL particles to form HDL subspecies. It is not entirely clear by simply measuring individual protein abundances what drives HDL function. We aimed to study the differential association of 7 HDL subspecies defined by presence or absence of a functional protein with extreme and persistent cholesterol efflux capacity (CEC). From ~3000 individuals in the multi-ethnic population-based DHS (Dallas Heart Study) cohort, people at the bottom 10% and top 90% of CEC were reassessed after 15 years resulting in 36 participants with extreme persistent high or low CEC for the present study. HDL with and without 7 individual proteins potentially relevant to HDL function were quantified using ELISA. Differences in association with CEC between HDL subspecies that contain or lack a defining protein were examined by heterogeneity test. In the low CEC group, HDL lacking apolipoprotein C3 (apoC3), complement C3, apoE (apolipoprotein E) and PLMG (plasminogen) were each associated positively with CEC while HDL subspecies containing these proteins were not positively associated with CEC. (Pearson correlation coefficient range 0.55369 to 0.66562 vs -0.08432 to -0.25198; p <0.05 for heterogeneity). In the high CEC group, no significant heterogeneity was found in association with CEC between HDL subspecies that contain or lack the same proteins. In people with extreme and persistent low CEC, HDL subspecies containing apoC3, complement C3, apoE and PLMG blunt the overall positive association between HDL and CEC. Our findings suggest that CEC of HDL in individuals with persistent and extreme low CEC is determined by the presence/absence of apoC3, complement C3, apoE and PLMG in HDL subspecies. Future studies involving manipulation of these proteins in HDL to investigate the effect on CE will provide deeper insight into functional speciation of HDL. This knowledge can be further applied to define biomarkers for altered CE in atherosclerotic cardiovascular diseases (ASCVD).

Cholesterol and lipoprotein metabolism: Early Career Committee contribution.

High-density lipoprotein cholesterol efflux capacity as a relevant predictor of atherosclerotic coronary disease.

Recent studies reported that low high-density lipoprotein (HDL)-mediated cholesterol efflux capacity rather than low HDL cholesterol (HDL-C) is strongly associated with the increased risk for coronary artery disease. It remains unclear whether exercised-based cardiac rehabilitation (CR) can increase HDL cholesterol efflux capacity. This study is a retrospective analysis of stored serum from patients with acute coronary syndrome (ACS) who participated in outpatient CR program following successful percutaneous coronary intervention. We employed a cell-based cholesterol efflux system including the incubation of (3)H-cholesterol labeled macrophages with apolipoprotein B-depleted serum at the onset or early phase of ACS and at 6-month follow-up periods in 57 male and 11 female patients with ACS. Cardiopulmonary exercise tests were performed at the beginning and end of CR program. Fifty-seven patients completed the CR program. Compared with patients who dropped out from CR program (non-CR group), CR participants showed marked amelioration in serum lipid levels, increased efflux capacity, and improved exercise capacity. Spearman's rank correlation coefficient analysis revealed that the percent increases of efflux capacity were significantly associated with the percent increases in HDL-C (ρ=0.598, p＜0.0001) and apolipoprotein A1 (ρ=0.508, p＜0.0001), whereas no association between increases in efflux capacity and increases in cardiopulmonary fitness was observed. Increases in cholesterol efflux capacity were not seen in patients who continued smoking and those who did not achieve all risk factor targets and higher exercise tolerance. CR can markedly increase both HDL-C and HDL cholesterol efflux capacity. These results suggest that CR is a very useful therapy for reverse cholesterol transport and secondary prevention.

Although plasma high-density lipoprotein (HDL) cholesterol levels correlate inversely with the incidence of cardiovascular disease,1 the causative nature of this relationship has been called into question by Mendelian randomization studies2 and several failed clinical trials involving HDL-raising drugs.3 Studies in humans have indicated that the macrophage cholesterol efflux capacity of HDL is a strong inverse predictor of subclinical atherosclerosis and cardiovascular disease and remains highly statistically significant after correction for HDL cholesterol levels,4 suggesting that HDL-C levels may be a poor surrogate for key functions of HDL mediating antiatherogenic effects. In this issue of Circulation Research , Monette et al5 measured acetylcholine-induced coronary artery vasodilation, an indicator of endothelial nitric oxide (NO) bioavailability, in subjects undergoing coronary angiography, and showed that the cholesterol efflux capacity of HDL correlated inversely with coronary endothelial dysfunction (ED), a key event in early atherogenesis. In contrast, HDL and low-density lipoprotein cholesterol levels did not correlate with coronary ED.5 However, the HDL particle concentration, as assessed by ion mobility analysis, did correlate with HDL cholesterol efflux capacity and inversely correlated with coronary ED, leading to the conclusion that both HDL cholesterol efflux capacity and HDL particle concentration might provide clinically useful information on ED and coronary risk5 and further supporting that HDL-mediated cholesterol efflux is directly related to suppression of atherogenesis in humans. Article, see p 83 Although the macrophage foam cell has recently received the lion’s share of attention in cholesterol efflux studies, this new human investigation spotlights the importance …

The objective of this study was to examine the function of high-density lipoproteins (HDL) in patients with severe carotid atherosclerosis undergoing carotid endarterectomy (CEA) and in patients with coronary artery disease (CAD). We examined clinical, biochemical and lipoprotein profiles and HDL cholesterol efflux capacity (CEC) in 155 patients undergoing CEA and compared the results with patients with an acute coronary syndrome (ACS time 0 n=26) measured within 48 hours of the event, and again at 12 weeks (ACS recovery, n=26), in patients with chronic, stable CAD (sCAD) n=27 and in healthy controls. There were 110 men (71%) and 45 women (29%) with a mean age 69±10 years in the CEA group. Mean HDL-C was 0.96±0.26 mmol/L (38±10 mg/dL). There were no significant differences in HDL-C between CEA, ACS and sCAD subjects. HDL was obtained after depletion of apo B-containing lipoproteins with PEG precipitation. Cellular efflux capacity was determined by incubating HDL in cAMP-stimulated J774 mouse peritoneal macrophages for 6 hours. Specific cholesterol efflux was obtained by subtracting total efflux from efflux in non-cAMP stimulated cells. The procedure was standardized to enable medium throughput. Coefficient of variability was approximately 5%. HDL from CEA patients differ in its ability to promote cholesterol efflux. The range of CEC observed was: min 14.7%, max 34.0% mean 22.4±0.6%; (IQR 18.9-27.3% median 22.0). We found a weak correlation between HDL-C and CEC in patients CEA (r= 0.20, P=0.012); a significant correlation was found between apo A-I and CEC (r=0.23, P=0.005). Subjects with similar HDL-C or apoA-I differed in their ability to promote cellular cholesterol efflux, suggesting that the HDL-C mass does not reflect functionality. We found similar CEC in patients with CAD and ACS recovery. Here, we report that patients with severe carotid atherosclerosis have low HDL-C and a CEC similar to that observed in CAD patients. The function of HDL to promote cellular cholesterol efflux, as determined by CEC, varied over a wide range and was only weakly correlated with HDL-C. The significant correlation between apo AI and CEC suggests that HDL particle size -and composition may also be an important determinant of the ability to promote cellular cholesterol efflux.

In the general population, high-density lipoprotein (HDL) cholesterol efflux capacity (HCEC) relates inversely to incident cardiovascular events. Previous studies have suggested that HCEC is decreased in HIV and that antiretroviral therapy (ART) initiation might improve HCEC. To evaluate HCEC in the context of ART initiation and immune activation in HIV. Baseline HCEC from 10 ART-naive HIV-infected males and 12 prospectively matched non-HIV-infected males were analyzed. In the HIV cohort, HCEC 6 months after elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) therapy was evaluated. HCEC served as the primary outcome and was measured by the ability of J774 mouse macrophages to efflux cholesterol. Our ex vivo assay used two cholesterol acceptors [apolipoprotein B (apoB)-depleted sera or purified HDL] and modulation of cellular efflux pathways using a liver X receptor (LXR) agonist. The median age was 34 years [interquartile range (IQR), 27 to 51], and baseline HDL was 46 mg/dL (IQR, 38 to 61). HCEC was significantly greater in the non-HIV-infected subjects than in the HIV-infected subjects at baseline. HCEC, assessed using apoB-depleted sera, significantly increased after ART (no LXR agonist, baseline: median, 8.1%; IQR, 7.0% to 11.9%; after ART: median, 12.9%; IQR, 10.4% to 21.1%; P = 0.006; LXR agonist, baseline, 1.3% ± 1.3%; after ART, 2.5% ± 1.0%; P = 0.02), although not to the levels in the non-HIV-infected subjects (no LXR agonist: median, 14.9%; IQR, 11.5% to 19.1%; LXR agonist: 5.8% ± 1.3%). HCEC, assessed using purified HDL, did not significantly increase after ART. The change in HCEC with ART related inversely to the change in the percentage of CD14-CD16+ (nonclassical) monocytes (ρ = -0.74, P = 0.04) and directly to the change in the percentage of CD14+CD16- (classical) monocytes (ρ = 0.72, P = 0.045). Our data suggest improvement of HCEC with E/C/F/TDF and a relationship between the ART-induced decrease in immune activation and ART-induced improvement in HCEC.

Plasma levels of high-density lipoprotein cholesterol (HDL-C) are strongly inversely associated with coronary artery disease (CAD), and high HDL-C is generally associated with reduced risk of CAD. Extremely high HDL-C with CAD is an unusual phenotype, and we hypothesized that the HDL in such individuals may have an altered composition and reduced function when compared with controls with similarly high HDL-C and no CAD. Fifty-five subjects with very high HDL-C (mean, 86 mg/dL) and onset of CAD at the age of ≈ 60 years with no known risk factors for CAD (cases) were identified through systematic recruitment. A total of 120 control subjects without CAD, matched for race, sex, and HDL-C level (controls), were identified. In all subjects, HDL composition was analyzed and HDL cholesterol efflux capacity was assessed. HDL phospholipid composition was significantly lower in cases (92 ± 37 mg/dL) than in controls (109 ± 43 mg/dL; P=0.0095). HDL cholesterol efflux capacity was significantly lower in cases (1.96 ± 0.39) than in controls (2.11 ± 0.43; P=0.04). In people with very high HDL-C, reduced HDL phospholipid content and cholesterol efflux capacity are associated with the paradoxical development of CAD.

Background: Coronary allograft vasculopathy (CAV) is an important cause of mortality after cardiac transplantation. High density lipoprotein (HDL) cholesterol efflux capacity has been inversely associated with coronary artery disease and is impaired in cardiac transplant recipients. We performed a single center case-cohort study to test the hypothesis that reduced efflux capacity is a risk factor for mortality and a second, multi-center retrospective study to test if efflux capacity is associated with CAV progression. Methods: We designed a single center case-cohort study in which we identified cardiac transplant patients who died between 2009-2012 (cases, n=34) and controls as cardiac transplant patients who were alive as of the fourth quarter of 2013 (n=57). Efflux capacity was measured by incubating apolipoprotein B-depleted serum with macrophages in a validated ex vivo system. In a second study, we utilized pre-transplant samples from the Clinical Trials in Organ Transplantation 5 (CTOT5) study to determine the association between ATP-binding-cassette (ABC) A1-dependent cholesterol efflux and CAV progression at 1 year. Results: In our single center study, the average time from transplant to study entry was well-matched between cases and controls (7.6±1.0 vs 7.7±0.8 years, respectively, p=0.48). Multivariable Cox proportional hazard ratios demonstrated that higher levels of HDL cholesterol efflux capacity were associated with survival (HR 0.61, 95% CI 0.43-0.85), even after adjustment for HDL cholesterol mass. To determine whether excess mortality observed in subjects with reduced efflux could be attributable to CAV progression, we tested the relationship between intravascular ultrasound (IVUS) progression of CAV and cholesterol efflux capacity using linear regression. ABCA1-dependent efflux and IVUS progression were significantly associated (β = -0.90, 95% CI [-1.73 - -0.07], p = 0.037, R2 = 0.37). Conclusion: Reduced efflux capacity is an important mediator of CAV progression and mortality in cardiac transplant recipients. This finding suggests that interventions to increase HDL cholesterol efflux capacity may provide clinical benefit in cardiac transplant recipients.

Association of cholesterol efflux capacity with plasmalogen levels of high-density lipoprotein: A cross-sectional study in chronic kidney disease patients

The efficiency of cholesterol efflux from cells promoted by high-density lipoproteins (HDLs) depends on HDL concentration and functional properties. The term “dysfunctional HDL” describes HDLs with impaired protective properties. Cholesterol efflux capacity (CEC) of HDL is reduced in patients with atherosclerosis, but the exact mechanisms underlying this impairment are not well characterized. Enriching HDLs with phospholipids (PLs) improves CEC. Herein, we assessed the potential of PL nanoparticles in improving HDL functionality. We lipidated HDL subfractions by incubating with PL nanoparticles containing soybean polyunsaturated phosphatidylcholine. Incubating blood plasma with PL nanoparticles resulted in the dose-dependent lipidation of all HDL subfractions. Changes in apolipoprotein A1 (apoA-1) and PL concentrations were the most prominent in the HDL2 fraction. Concentrations of PL in the HDL3 fraction and the fraction with a density > 1.21 g/mL increased by 30–50%, whereas apoA-1 levels decreased. We hypothesized that PL nanoparticles may cause HDL remodeling that can improve their functions. The CECs of lipidated HDLs were analyzed by incubating apolipoprotein B (apoB)-depleted plasma with 3H-cholesterol-labeled THP-1 macrophages. The findings revealed a two-fold increase in cholesterol efflux compared with native apoB-depleted plasma. Moreover, intravenous administration of PL nanoparticles restored lipid profiles and effectively protected blood vessels from atherosclerosis progression in cholesterol-fed rabbits compared with that of fenofibrate and atorvastatin. PL nanoparticles also protected against atherosclerosis and decreased the atherogenic index. Altogether, these results indicate that PL nanoparticles can be used to correct the lipid composition and CEC of HDLs. Data AvailabilityAdditional data can be provided upon reasonable request from the date of publication of this article within 5 years. The request should be sent to the author-correspondent at the address cd95@mail.ru.