High-density lipoprotein cholesterol efflux capacity and cardiovascular risk in autoimmune and non-autoimmune diseases

High-density lipoprotein cholesterol efflux capacity and cardiovascular risk in autoimmune and non-autoimmune diseases

Journal Pre-proof High-density lipoprotein cholesterol efflux capacity and cardiovascular risk in autoimmune and non-autoimmune diseases Anouar Hafia...

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Journal Pre-proof High-density lipoprotein cholesterol efflux capacity and cardiovascular risk in autoimmune and non-autoimmune diseases

Anouar Hafiane, Elda Favari, Stella S. Daskalopoulou, Nicolas Vuilleumier, Miguel A. Frias PII:

S0026-0495(20)30005-6

DOI:

https://doi.org/10.1016/j.metabol.2020.154141

Reference:

YMETA 154141

To appear in:

Metabolism

Received date:

30 October 2019

Accepted date:

5 January 2020

Please cite this article as: A. Hafiane, E. Favari, S.S. Daskalopoulou, et al., High-density lipoprotein cholesterol efflux capacity and cardiovascular risk in autoimmune and nonautoimmune diseases, Metabolism(2020), https://doi.org/10.1016/j.metabol.2020.154141

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© 2020 Published by Elsevier.

Journal Pre-proof High-density lipoprotein cholesterol efflux capacity and cardiovascular risk in autoimmune and non-autoimmune diseases Anouar Hafiane1 MSc, PhD, Elda Favari2 PhD, Stella S. Daskalopoulou3 MD, MSc, PhD, Nicolas Vuilleumier4,5 MD, Miguel A. Frias4,5 PhD

Authors Affiliations:

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Corresponding Author:

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1. Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University. 1001 Decarie Blvd, Bloc E01. 3370H Montréal, Qc, H4A 3J1. E-mail: [email protected] 2. Department of Food and Drug University of Parma, Parco Area delle Scienze, 27/A, 43124 Parma, Italy. E-mail: [email protected] 3. Department of Medicine, Division of Internal Medicine McGill University, Research Institute of the McGill University Health Centre. 1001 Decarie Blvd, EM1.2230. Montreal, Quebec, Canada H4A 3J1. Montreal, Canada. Email: [email protected] 4. Division of Laboratory Medicine, Diagnostic Department, Geneva University Hospitals, 1211 Geneva, Switzerland. E-mail: [email protected] 5. Division of Laboratory Medicine, Department of Medical Specialties, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland. E-mail: [email protected]

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Anouar Hafiane, MSc, PhD. Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University. 1001 Decarie Blvd, Bloc E01. 3370H Montréal, Qc, H4A 3J1. E-mail: [email protected] Elda Favari, PhD. Department of Food and Drug, University of Parma, Parco Area delle Scienze, 27/A, 43124 Parma, Italy. E-mail: [email protected]

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Journal Pre-proof Abstract Functional assessment of cholesterol efflux capacity (CEC) to high-density lipoprotein (HDL) is an emerging tool for evaluating morbidity and mortality associated with cardiovascular disease (CVD). By promoting macrophage reverse cholesterol transport (RCT), HDLmediated CEC is believed to play an important role in atherosclerotic lesion progression in the vessel wall. Furthermore, recent evidence indicates that the typical inverse associations between various forms of CEC and CV events may be strongly modulated by environmental systemic factors and traditional CV risk factors, in addition to autoimmune diseases. These

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factors influence the complex and dynamic composition of HDL particles, which in turn positively or negatively affect HDL-CEC. Herein, we review recent findings connecting HDL-CEC to traditional CV risk factors and cardiometabolic conditions (non-autoimmune diseases) as well as autoimmune diseases, with a specific focus on how these factors may

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influence the associations between HDL-CEC and CVD risk.

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Keywords: High-density lipoprotein (HDL), HDL-cholesterol, HDL function, Cardiovascular risk, Cholesterol efflux capacity, Autoimmune disease, cardiovascular disease (CVD).

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Journal Pre-proof Introduction Cardiovascular disease (CVD) remains the leading cause of death worldwide both in developed and in developing countries.1 Numerous epidemiological studies have established an inverse association between serum high-density lipoprotein cholesterol (HDL-C) concentrations and CVD risk, specifying that low HDL-C concentrations is an independent risk factor of CVD in different populations.2 However, the results of epidemiological studies are not in line with those of most genetic studies, most notably Mendelian randomization studies, indicating that genetic polymorphisms associated with lower HDL-C values are not related to increased CVD risk.3 Traditionally, the risk of cardiovascular (CV) events,

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including ischemic heart disease (IHD) or stroke, is calculated based on prediction scores (i.e. Framingham, European Systematic Coronary Risk Evaluation (SCORE), Prospective Cardiovascular Munster (PROCAM), ASSIGN – SCORE, QRISK1 or 2). These scores

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combine several clinical and biological parameters, including smoking, age, sex, dyslipidaemia, hypertension, cholesterol (total cholesterol and/or HDL-C) and diabetes into a

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10-year risk classes of developing fatal or non-fatal CVD.4 Due to the relative sensitivity and specificity of these risk stratification tools, for most individuals deemed at moderate risk, the

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identification of other biomarkers that could improve this predictive performance remains an unmet clinical need. Furthermore, recent interventional studies have challenged the concept

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that elevated concentrations of HDL-C could reduce CVD risk.5 As such, there has been a major shift in focus toward the functionality of HDL particles, as opposed to the sole

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quantification of cholesterol mass within the HDL fraction.6 HDL particles are composed of a heterogeneous population of particles varying in size between 7 and 20 nm in diameter and

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can be isolated by ultracentrifugation at a density range 1.063–1.21 g/mL. On top of their numerous pleiotropic effects, HDL particles exert their atheroprotective properties through cholesterol removal from macrophages in atherosclerotic plaques (Figure 1).6 This process is mediated through the ATP-binding cassette (ABC) A1 and ABCG1 transporters that simultaneously facilitate HDL biogenesis and reverse cholesterol transport (RCT).7 Recent studies have investigated the effect of changes in HDL function on pathophysiological conditions, including CVD, with the aim of identifying reliable biomarkers and targets for the prevention and treatment of CVD. Reviews on HDL function, particularly HDL cholesterol efflux capacity (HDL-CEC), in both autoimmune and non-autoimmune diseases are limited. In this review, we highlight the different forms of HDL-mediated CEC as key features of HDL functionality and delineate their relationships with traditional CV risk factors and CV risk in autoimmune diseases and cardiometabolic conditions. 3

Journal Pre-proof I. HDL function in CVD I. 1 Moving from HDL-C hypothesis to HDL functionality The long-lasting discrepancy between epidemiological studies and Mendelian randomization genetic studies has weakened the hypothesis that low HDL-C concentrations is a causal factor of CVD.8 Most of the interventions aiming at increasing HDL-C levels have failed to improve CV patient outcomes.5 Consequently, there has been a major shift of focus from HDL-C quantification to the functionality of HDL particles.6 As further discussed below, investigations of the various aspects of HDL functionality have revealed a high level of complexity. This includes the presence of various CV risk factors and inflammatory-related

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systemic conditions, such as autoimmune diseases as well as other factors that could blunt the associations between HDL functions and CVD risk (Table 1).9 In physiological states, HDL exerts various pleiotropic beneficial effects and protects against atherosclerosis through

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multiple mechanisms (Figure 1).6,10 Among these properties, the ability of HDL to promote RCT through HDL-CEC has been the most extensively studied and will therefore be focus of

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this review.

I. 2 HDL role in cholesterol efflux

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Cholesterol efflux process is mediated by four different pathways that can mainly be distinguished by the transporters involved and the acceptor particle subclasses (Table 2). The

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major rate limiting step of RCT occurs via the interaction between the ABCA1 and apoA-I complexes that produces preβ migrating HDL or very-small HDL particles based on a

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mechanism termed HDL biogenesis. In turn, nascent will become mature HDL particles by undergoing further lipidation via ABCG1. This is essential for de novo biogenesis of HDL

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particles in the intimal layer of the arterial wall.11 However, the specific and relative contributions of these four pathways to the net efflux of cholesterol from macrophages are still an area to be explored in greater depth. Nevertheless, previous studies have indicated that in normocholesterolemic conditions, aqueous diffusion accounts for up to 80% of total macrophage efflux, whereas ABCA1-mediated efflux is the predominant pathway representing up to 60% of total macrophage cholesterol efflux in the presence of an intracellular cholesterol load.12 The inability of macrophages to efficiently efflux the remaining of excess cholesterol results not only in foam cell formation, but also in the generation and local recruitment of pro-inflammatory cells, providing a milieu favouring the initiation of plaque progression.13 Impaired HDL-CEC is a significant determinant of reduced HDL function that in addition contributes to the pathogenesis and risk of CVD. Based on the concept previously proposed by Glomest et al. the concentration of cholesterol accumulated 4

Journal Pre-proof in HDL particles has been considered as a biomarker for evaluating the efficiency of RCT.14 At present, measuring HDL-CEC is still not part of the guidelines for patient routine lipid profile assessment. II. HDL composition and cholesterol efflux capacity II. 1 HDL composition HDL particles are highly heterogeneous in composition, and the methods of their measurement are increasingly complex.6 These particles comprise the highest protein:lipid ratio amongst all the lipoprotein categories (i.e. chylomicrons, VLDL, LDL), where apoA-I accounts for approximately 70% of the protein mass.15 More than 80 other proteins have been

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associated with HDL particles,16 22 of which have been linked to cholesterol and lipoprotein metabolism, whereas 23 are related to acute phase-response proteins.17 HDL particles also contain 150 different lipid molecules as well as microRNAs.18,19 Under chronic metabolic

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disturbance or stress, HDL components undergo structural modifications, such as nonenzymatic glycation, oxidation, or carbamylation (Figure 2). These modifications impair

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HDL’s atheroprotective capacity.20 Differences in HDL function, as measured by CEC, could be explained by differences in the composition and physicochemical properties within the

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circulating HDL particles.21 Indeed, CEC to HDL3 subpopulations (350 kDa) has been found to be most efficient when compared with more mature larger spherical HDL particles (HDL2)

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of 175 kDa.22 HDL3 species have also been associated with greater antioxidant and antiapoptotic activities than HDL2 particles that contain apoCIII, which is associated with a

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higher CVD risk.23 However, the clinical usefulness of measuring HDL subpopulations for the prediction of CVD risk remains debatable. Mechanisms altering ABCA1-CEC in patients

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with coronary heart disease (CHD) could be linked to changes in specific components of HDL particles, such as triglycerides (TG), serum amyloid A (SAA), and sphingosine-1-phosphate (S1P) content.which could also influence other HDL’s pleiotropic protective functions (Figure 2).24 Another possibility is that apoA-I conformational variability within HDL particles could affect its interaction with ABCA1.25 In addition, defects in preβ-1 particles maturation into larger HDL particles, and conformational changes of apoA-I within HDL particles may underlie a loss of HDL function in CVD settings.25-27 HDL composition changes attributed to impaired HDL functionality are discussed below in greater detail. II. 2 Triglycerides and CEC In certain metabolic diseases such as diabetes, metabolic syndrome and obesity, HDL (Figure 2),28 modifying the conformational

particles are loaded with an excess of TG

stability of the lipoprotein and affecting its lipid removal function.4 HDL enrichment and 5

Journal Pre-proof depletion in TG and phospholipids respectively both impair the ability of HDL to promote CEC.19 In addition, enrichment in TG destabilises the HDL particles and leads to increased clearance, reducing the amount of circulating apoA-I, and thereby reducing the levels of cholesterol acceptors.29 A recent omega-3 clinical trial showed a clinically favorable profile for reducing TG with potentially promising effects in CVD.30 Omega-3 polyunsaturated fatty acids may beneficially affect RCT, mainly by favorably influencing HDL remodeling and by promoting hepatobiliary sterol excretion.31 However, omega-3 may not significantly affect the ABCA1-CEC within atherosclerotic plaque macrophages. Further studies are needed to clarify this mechanism.

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II. 3 Serum amyloid A and CEC

HDL possesses the ability to scavenge pro-inflammatory factors such as SAA. SAA is an acute phase response protein that can bind to and accumulate on the HDL particle. However,

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this action induces the displacement of apoA-I from HDL particles, leading to a loss of HDLatheroprotective function.32 In fact, several studies have demonstrated a positive association

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between high SAA-HDL levels and CV mortality. 33 Along these lines, Zimetti and colleagues demonstrated that in 59 patients with acute phase reaction, total HDL-CEC was impaired in

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comparison to controls (-18%) with an inverse relationship between SAA-HDL and ABCG1mediated CEC. They highlighted reductions in HDL-CEC by aqueous diffusion, SR-BI, and

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by ABCG1 transport, but not by ABCA1 in acute phase response.34 Importantly, we have previously demonstrated that impairment of HDL-CEC through ABCA1 occurs within 72h of

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myocardial infarction (MI), independently of changes in plasma HDL-C and apoA-I levels.35 In another study, such impairment was associated with increased SAA and Lp-PLA2

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plasmatic levels.36 Interestingly, SAA has been shown in vitro to alter the vascular protective functions of HDL, including CEC, which may contribute in part to the inverse association of HDL-C with CV outcomes.37

II.4 A novel role of sphingosine-1-phosphate in CEC S1P is a chemotactic lipid carried by approximately two thirds of HDL particles in plasma.38 This sphingolipid is a new potential player in the functionality of HDL. S1P has various roles in regulating the immune response and has been demonstrated to have anti-atherogenic properties.38 S1P is generated intracellularly via sphingosine kinase activity, which adds a phosphate group to sphingosine. It can be transported to the extracellular environment, where it binds to the protein-rich HDL3 subtype via apolipoprotein M (apoM).39 Reduced S1P content in HDL particle (HDL-S1P) may result in the impairment of several HDL-S1Pdependent atheroprotective functions. Notably, HDL-S1P content is inversely associated with 6

Journal Pre-proof coronary artery disease (CAD),24 and therefore may be an independent predictor of the severity of CAD specifically in patients undergoing elective percutaneous coronary intervention.40 The impact of S1P on CEC had not been investigated until very recently. Vaidya and colleagues demonstrated that sphingosine kinase 2 activity is induced by the LXR agonist 22(R)-hydroxycholesterol and is required for the stimulation of ABCA1-CEC to apoA-I (apoA-I/ABCA1-CEC).41 Increased S1P levels in HDL particles might point at differences in HDL functionality other than CEC. Other mechanisms may interfere with the relationship between HDL-S1P and HDL-CEC in macrophages. III. HDL function in non-autoimmune diseases

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III. 1 HDL ABCA1-CEC and cardiovascular risk prediction in human studies Several clinical studies have evaluated the association between atherogenesis or CV events and HDL-CEC (Table 1). The first study, published in 2002, used skin fibroblasts from

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individuals with ABCA1 mutations and controls to evaluate the association of ABCA1-CEC using HDL as the acceptor (HDL/ABCA1-CEC) within atherosclerotic lesions.42 An inverse

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correlation between HDL/ABCA1-CEC and arterial-wall thickness was noted, suggesting that increasing efflux could inhibit progression of atherosclerosis prior to the manifestation of

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symptomatic CVD.43 In accordance with these findings, ABCA1-CEC in apoB depleted serum conditions within patients with incident CHD was significantly, inversely associated

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with incident CAD events.44 This was independent of established CV risk factors, even after adjustment for HDL-C and apoA-I levels.44 These results were reinforced by the study of

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Rohatgi and colleagues that showed a 67% reduction in CV risk in participants with the highest vs the lowest quartile of ABCA1-CEC.45 Interestingly, coronary artery calcium

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(CAC) score, C-reactive protein (CRP) and lipoprotein (a) levels were not significantly different across ABCA1-CEC quartiles.45 In a separate study, ABCA1-CEC was shown to improve arteriosclerotic cardiovascular disease (ASCVD) prediction among patients with high CAC score and elevated CRP.46 Meta-analysis studies highlighted that either ABCA1CEC or ABCG1-CEC were significantly associated with a reduced risk of CV events, indicating that CV risk decreased by 39% for each CEC unit increase.47 In addition, Shea and colleagues investigated ABCA1-CEC and ABCG1-CEC in patients with IHD and stroke.48 For IHD, higher ABCA1-CEC and ABCG1-CEC levels were negatively associated with CVD and unexpectedly, positively associated with carotid atherosclerotic plaque progression (Table 1).48 Nevertheless, no association was found with stroke events.48 Paradoxically, Lucero and colleagues showed that ABCA1-CEC was higher in patients with metabolic syndrome (MetS) compared to healthy controls that did not exhibit a difference in ABCG17

Journal Pre-proof CEC.49 In addition, Li and colleagues found that enhanced ABCA1-CEC at the time of cardiac catheterization was positively associated with prospective acute events (MI, stroke, or death).50 While the reason for this paradox is presently unknown, possible explanations include an overriding effect of either CV risk factors, or the presence of other systemic factors or diseases.67 In summary, human studies do not uniformly agree to a consistent inverse association between HDL-CEC and CV risk. In obese patients and those with MetS, a direct positive association between different forms of HDL-CEC and IHD/CAD risk could exist, adding further complexity to the straightforward interpretation of HDL-CEC. These findings emphasize the need for a better understanding of the determinants of HDL-CEC, including the

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impact of traditional CV risk factors on HDL function, which will be reviewed in the following sections.

III. 2 HDL-CEC in primary prevention and association with traditional CV risk factors

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The association of HDL-CEC with traditional CV risk factors has been poorly investigated. In the following sections we will review the existing evidence indicating that these factors do not

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affect HDL-CEC in a same way.

III. 2. 1 Smoking and HDL-CEC

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Cigarette smoking is associated with increased atherogenesis and can interfere with lipid metabolism.51 The direct impact of smoking on HDL functionality, including HDL-CEC, is

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poorly documented. Previous evidence from small studies is somewhat controversial. In a recent study examining the direct impact of smoking on HDL/ABCA1-CEC and ABCG1-

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CEC, 24 subjects were evaluated (16 non-smokers and 8 chronic smokers) before and after 2h of acute smoking (8 cigarettes).52 Surprisingly, HDL-CEC at baseline was significantly higher

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in chronic smokers than in non-smokers (29.1 ± 6.3% versus 18.7 ± 6.2%, p < 0.05), and not affected in acute smokers.52 In contrast, a previous study analyzing 39 healthy middle-aged women (21 non-smokers and 18 smokers), found that ABCA1-CEC was significantly higher in non-smokers than in smokers (14.22 ± 1.75% vs. 13.17 ± 1.33%; p < 0.05).53 Other findings include in vitro evidence which suggests that HDL/ABCA1-CEC is remarkably reduced when plasma HDL particles are subjected to cigarette smoke compared to control conditions, and this is accompanied by an increase in lipid peroxidation in HDL particles.54 More recently, Chen and colleagues measured HDL/ABCA1-CEC in smokers with CAD (n = 28) and healthy smokers (smokers without CAD, n = 30), who were divided into smoking cessation

and

continuous

smoking

groups,

respectively.55

Three

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after smoking cessation, HDL/ABCA1-CEC had not improved in CAD smokers in comparison to healthy smokers.55 In a previous study involving subjects with CAD smokers 8

Journal Pre-proof (n=28) and non-CAD smokers (n=35) vs non-smokers (n=17), ABCA1 expression level and HDL/ABCA1-CEC were reduced in macrophages from non-CAD and CAD smokers compared to non-smokers at baseline.56 After 3 months of smoking cessation, ABCA1 expression and function were improved in CAD smokers.56 However, ABCG1 expression and function did not change after smoking cessation. ABCG1-CEC might not be implicated in tobacco-induced changes in macrophage cholesterol metabolism. It is also noteworthy that increased ABCA1-CEC independently of HDL-C or apoA-I levels or HDL subfractions is one of the suggested mechanisms by which smoking cessation improves the risk of CVD.57 However, further studies are required to determine whether smoking really impacts the

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various forms of HDL-CEC functions. III. 2. 2 Age and HDL-CEC

It is well established that aging is associated with an increased risk of CVD and impairs many

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of the beneficial effects of apoA-I and HDL (Table 3). Age itself may be a critical determinant of HDL-CEC function.58 A positive correlation exists between aging and HDL2

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particle concentration, while aging is negatively correlated with HDL3 particle concentration.59 The associations between ABCA1-CEC and ABCG1-CEC and aging remain

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elusive.44 A small study of healthy elderly subjects (over 80 years old, n=59) reported no association between HDL-CEC and atherosclerotic burden, as measured by CAC score or

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markers of vulnerable atherosclerotic plaques.60 Interestingly, the ABCA1-CEC measured in the serum of these patients was significantly higher than those from middle age patients. This

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result may suggest that in healthy individuals reaching older age, ABCA1-CEC is significantly higher relative to younger healthy individuals. In contrast, other evidence

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exhibits an impairment of ABCA1-CEC and ABCG1-CEC in aging mice and humans.61 This appears to be consistent with a previous report that HDL functionality is decreased due to oxidation with aging.62 Several factors predispose HDL to oxidation, including fatty acid composition content, hydroperoxide levels, apoA‐I/A‐II protein content, HDL particle size, and the HDL2/HDL3 subfractions ratio.63 Changes in HDL function associated with aging are summarized in Table 3. Whether HDL-CEC is causative or simply a marker of healthy longevity needs to be further investigated.

III. 2. 3 Gender and HDL-CEC Women have significantly higher concentrations of total HDL particles as well increased HDL3 and HDL2 compared to men.64 Catalano and colleagues reported a significant increase (+14%; p < 0.03) in serum-CEC in women via the SR-BI-dependent pathway, whereas men 9

Journal Pre-proof were shown to have an increased CEC via ABCA1 (+31%; p < 0.001) compared to women , as well as a significant increase in HDL2 particles (+20%; p < 0.04).65 However, another study found no difference in HDL/ABCA1-CEC and ABCG1-CEC between healthy men and healthy pre- or post-menopausal women.66 After menopause, HDL2 particle concentration decreases, while HDL3 increases.67 Whether HDL sub-particles influence HDL-CEC remains elusive. In a longitudinal study, women were studied pre- and post-menopause (over 2 years follow-up), and both HDL particle concentration and ABCA1-CEC were found to increase post-menopause.68 Although the effects of menopause on HDL-CEC are still not well understood, these preliminary results indicate that menopause could be an important factor

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impacting HDL-CEC in a sex-specific manner but remains an area that requires further investigation.

III. 2. 4 Obesity, metabolic syndrome and HDL-CEC

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Obesity, defined by a body mass index (BMI) over 30 kg/m2, is closely linked to CVD.69 When it comes to ABCA1-CEC, several studies reported contradictory results between HDL-

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CEC and BMI and CV risk reporting either a negative association,44 or a lack of association.70 These studies did not observe a direct association of BMI with ABCA1-CEC.70 In addition,

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obesity is directly associated with a decrease in ABCA1 and ABCG1 gene expression.71 Interestingly, bariatric surgery improves HDL-CEC via increased activity of the SR-BI and

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ABCG1 pathways.72 In contrast, weight loss achieved by caloric restriction or dietary changes failed to improve HDL-CEC through ABCA1 and ABCG1 in THP-1 cells,73 or in BHK cells

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expressing ABCA1, ABCG1, or SR-BI transporters.74 The reasons for such differences remain elusive. Gall and colleagues investigated serum-CEC from patients with MetS

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displaying atherogenic dyslipidaemia during primary prevention.75 By using diluted serum as a cellular cholesterol acceptor, total-CEC was reduced progressively by 4% to 11% (p < 0.0001) with an increasing number of criteria for MetS.75 This study indicated that serumCEC via SR-BI and ABCG1 was significantly associated with established MetS independently of age, low density lipoprotein cholesterol (LDL-C), smoking status, and alcohol consumption.75 Therefore, whether decreased CEC could serve as a surrogate marker for increased CVD risk in obese individuals is still controversial and should be elucidated through larger prospective studies. III. 2. 5 Hypertension and HDL-CEC In general, human studies have demonstrated no association between blood pressure and HDL-CEC.44,48 In a more focused study, the direct impact of blood pressure on CEC was studied in women with preeclampsia. In this context, Mistry and colleagues investigated 10

Journal Pre-proof ABCA1-CEC in maternal and fetal plasma from women with preeclampsia and normotensive controls (n = 17). They reported that maternal and fetal total HDL-mediated CEC were both increased (by 10-20%) in the presence of preeclampsia, whereas ABCA1-CEC was decreased (by 20-35%; p < 0.05).76 Whether these changes can be attributed to the placental ABCA1 downregulation observed in preeclampsia is still unknown.77 The sterol 27-hydroxylase CYP27A1 activity around fetal vessels may partially compensate for ABCA1 downregulation by activating the LXR-ABCA1 pathway.76 This mechanism supports the notion of dysregulated fetal cholesterol uptake in preeclamptic cases, suggesting disturbed cholesterol uptake in the affected fetuses. Taken together, these results indicate that aside from

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preeclampsia, hypertension is not associated with substantial changes in HDL-CEC. III.2.6 Familial hypercholesterolemia and HDL-CEC

Familial hypercholesterolemia (FH) is a genetic disorder caused by a mutation in one of the

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following genes: LDL receptor (LDLr) (>95%), apoB (2-11%) or proprotein convertase subtilisin kexin 9 (PCSK9) (less than 1%).13 Homozygous patients display very high LDL-C

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levels and an increased risk of CV events in the first decades of life. HDL-ABCA1-CEC was independently and inversely associated with the presence of arteriosclerotic cardiovascular

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disease ASCVD in heterozygous FH.78 In conjunction with the accumulation of LDL particles in the plasma, the lipid transfer step of HDL metabolism is also disturbed in FH. Indeed, the

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lipid transfer step of unesterified cholesterol to HDL is diminished in these subjects which could be related to some alterations in the RCT steps.79 HDL isolated from FH patients

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without CHD has been shown to have increased ABCA1-CEC compared to that of their nonFH siblings.80 This may be explained by differences in composition of HDL such as

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cholesterol, S1P and apoM levels. Higher S1P and apoM content of HDL in asymptomatic FH patients may play a role in their apparent protection from premature CHD irrespective of the LDL‐receptor locus activity that modulates the composition of HDL.80 These findings strengthen the concept that assessment of HDL function may provide more information about HDL-mediated atheroprotection in patients with FH. III.2.7 Hyperglycaemia High concentration of circulating glucose is defined as hyperglycaemia. Hyperglycaemiainduced advanced glycation end products (AGEs) contribute to the generation of proteins and lipids, oxidative stress, and low-grade inflammation. In general, accumulation of AGEs in the vessel wall induces endothelium damage and decreases NO activity. These processes contribute to the progression of diabetic complications such as retinopathy, nephropathy and 11

Journal Pre-proof CVD. Chronic hyperglycaemia leads to abnormalities in lipoprotein metabolism and modifies the structural and functional lipidome and proteome of the HDL particle that can potentially promote HDL dysfunctionality (Figure 2).81 Epidemiological and pathophysiological studies suggest that hyperglycaemia may be largely responsible for CVD.38 The vast majority of cases of diabetes mellitus (DM) fall into the following two broad etiopathogenetic categories; type 2 diabetes (T2DM), which is more prevalent in the general population, and type 1 diabetes mellitus (T1DM). These two types are further discussed below within the context of HDL-CEC and changes in HDL particles.

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III.2.7.1 Type 2 diabetes mellitus Patients with T2DM exhibit methylglyoxal modifications (glycation) of their HDL particles that cause conformational changes, decreasing HDL stability and plasma half-life (Figure

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2).82 Increased plasma HDL clearance may reflect greater shedding of HDL components (protein and lipid), yielding smaller HDL particles that are more easily catabolized by the

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liver and kidneys.83 Nuclear magnetic resonance spectroscopic analysis of the HDL fractions showed that most (59%) of the HDL particles were small in patients with moderately

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controlled T2DM and no CVD.84 In this study, despite the greater abundance of small HDL particles, there was no correlation between the concentration of small HDL particles and

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HDL-CEC (Table 1). More recently, measuring the rate of HDL/apoA-I exchange by electron paramagnetic resonance has been reported as a major contributor of residual risk of CVD in

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T2DM patients.27 Other studies have shown reduced HDL-CEC from cultured adipose cells obtained from subjects with T2DM expressing ABCA1/ABCG1 when compared to cells

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obtained from non-diabetic controls.85 Furthermore, Isoda and colleagues showed that glycation of albumin impaired HDL-CEC and decreased the expression of ABCG1 but not ABCA1 in macrophages, and in an LXR-independent manner.86 This resulted in a significant reduction of CEC mediated by HDL2 and HDL3 but not by apoA-I. This process induces intracellular lipid accumulation in macrophages and possibly contributes to atherosclerosis. Plasma from overweight subjects with insulin resistance exhibited greater in vitro ABCA1CEC and ABCG1-CEC compared with their normal weight counterparts.87 In summary, T2DM exacerbates CVD at least in part through impairment of macrophage cholesterol efflux and levels of the cholesterol transporters ABCA1 and ABCG1.88 Hence, exploring HDL functions, even in the presence of normal HDL-C levels, might provide additional insight into the underlying pathophysiology associated with CV risk assessment in patients with diabetes. III.2.8 Chronic kidney disease (CKD) and HDL-CEC 12

Journal Pre-proof III.2.8.1 HDL-CEC and CVD in CKD The European Society of Cardiology guidelines consider low renal function and albuminuria as important CV risk factors.89 These risk factors were integrated in the Systematic Coronary Risk Evaluation (SCORE) algorithm to evaluate the 10-year risk of CV mortality based on traditional risk factors and renal function within the following categories: 10% as very high risk, 5-10% as high risk, 1-5% as moderate risk, and <1% as low risk. According to these guidelines, patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and diabetes plus albuminuria are considered at very high risk for CVD, and those with eGFR 30-59 mL/min/1.73 m2 at high risk.90

Compelling evidence suggests that HDL

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particles from CKD patients may have impaired ABCA1-CEC, without however, increased risk of CV events. Annema and colleagues reported that although ABCA1-CEC to apoBdepleted plasma did not differ between surviving and deceased renal transplant recipients

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(RTR), lower ABCA1-CEC was associated with incident graft failure in RTR without higher

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overall or CV-related mortality 91 (Table 1). In accordance with these findings, other studies showed no evidence of an association between ABCA1-CEC and incidence of CV events in

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patients with CKD.92 It is possible that CVD risk in CKD patients is not related to atherosclerosis burden but rather with atherothrombotic events.93 Alternatively, this may be

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related to arteriosclerotic changes of the smaller vessels with thickening of the medial arterial layer, resulting in cardiac fibrosis and heart failure 94. In CKD, HDL molecules from patients with CKD lose their anti-atherogenic properties (as summarized in Table 4), suggesting that

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HDL molecules could become “dysfunctional”. HDL not only loses its vasoprotective

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properties, but it also seems to become a noxious particle that induces endothelial dysfunction and inflammation through toll-like receptor signalling.95 This was confirmed in end-stage renal disease (stages 3 and 4), where modifications in HDL proteome and lipidome lead to altered function.96 In summary, as opposed to what has been regularly reported in other conditions associated with high CV risk, the frequently altered composition of HDL particles observed in renal disease does not seem to be associated with a loss of HDL-CEC (Table 1). The reasons for such differences remain elusive, and more extensive studies are required addressing different CKD stages and different forms of HDL-CEC. IV. HDL function in autoimmune diseases Various animal studies conducted in different models have suggested a link between cellular cholesterol accumulation and autoimmunity.97 Studies on cholesterol homeostasis in immune cells derived from mice lacking LDL-receptor or apoA-I fed with atherogenic diet have 13

Journal Pre-proof shown that an activation of T cells in the skin draining lymph nodes led to the development of an autoimmune phenotype.98 Furthermore, the classical apoE knock-out mice model is characterized by high circulating cholesterol levels together with significant production of various autoantibodies,99 further linking disruption of cholesterol homeostasis with autoimmunity. Previous evidence suggests a relationship between dyslipidaemia and several autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).100,101 In patients with both acute and chronic inflammation, HDL particles undergo post-translational modifications giving rise to a pro-inflammatory molecule (Figure 2).21 The identification of CV biomarkers that could improve CV risk stratification in the presence of

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autoimmune disease remains an unfulfilled clinical necessity. This is because most of the standard CV risk scores currently available are suboptimal and do not capture true CV risk in these patients.102 As such, some features of HDL-CEC could represent useful option in

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evaluating autoimmune disease. Furthermore, Maden and colleagues have recently examined the relationship between HDL-C and the risk of developing an autoimmune disease in two

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population-based cohort studies, and demonstrated that low HDL-C (<1.0 mmol/L or 39 mg/dL) levels were associated with a higher risk of autoimmune disease (odds ratio,

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1.84; p < 0.001).103 Numerous studies have noted important

HDL loss-of-function

mechanisms in different autoimmune diseases (Table 1). In the following section we will give

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evidence that HDL-CEC is impaired in the major autoimmune disease, T1DM. IV. 1 Type 1 diabetes mellitus (T1DM)

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T1DM is characterized by an absolute deficiency of insulin secretion that results from cellular-mediated autoimmune β-cell destruction of the pancreas. This form of diabetes can

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often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. In T1DM, increased CV risk is widely recognized as a complication due to multiple risk factors, such as HbA1c, blood pressure, lipids and smoking.104 However, subjects with T1DM, despite their higher incidence of CVD, seem to have a reduced atherogenic fasting lipid profile compared to subjects without diabetes.81 In subjects with T1DM, changes in HDL particle composition are characterized by an abnormal ratio of cholesteryl ester (CE)-to-TG and by a reduction in HDL phospholipid content. In addition, acute and chronic inflammation induces displacement and/or exchange of the HDL protein content.105 Under these conditions, HDL or apoA-I exhibit a reduced capacity to promote ABCA1-CEC from macrophages.106 Qualitative changes in HDL, such as glycation and/or oxidation modifications (Figure 2), have also been suggested to affect the functional properties of HDL in T1DM.107 In this context, in vitro ABCA1-CEC was impaired 14

Journal Pre-proof in T1DM, probably due to advanced glycation of HDL-associated proteins.108 Functionality of glycated HDL particles was also reduced and in turn affecting selective uptake of hepatic cholesterol via SR-BI.109 This was associated with impaired biliary elimination of cholesterol, which could also contribute to the increased incidence of CVD among subjects with T1DM.109 In a case control study, low ABCA1-CEC was negatively associated with small and positively with large HDL particles as measured by NMR in young subjects with T1DM, suggesting that small size of HDL particles could be used as a surrogate marker for low CEC.110 In another study of young subjects with T1DM, HDL was shown to undergoes an altered protein composition profile compared to healthy controls, suggesting a possible 105

. However, no differences in HDL/ABCA1-CEC

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connection with increased risk for CVD

were detected between the healthy controls and T1DM groups in this study. Insulin treatment of patients with T1DM and autoimmune polyglandular syndrome may improve CV risk, but

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its role on HDL function has not been studied.104 Thus, future studies should examine the specific alterations in the protein composition of HDL that can affect its protective functions,

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such as anti-inflammatory activity or CEC in T1DM.

Inflammatory

rheumatic

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IV. 2 Inflammatory rheumatic diseases diseases

(IRD),

including

RA,

psoriatic

arthritis

and

spondyloarthritis, are associated with an increased risk of atherosclerosis and CV mortality,

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independently of traditional CV risk factors.111 People with psoriatic arthritis have more CV risk factors than people with RA. Of note, CV predictors are different in patients with RA,

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psoriatic arthritis, and psoriasis.100 Thus, effective risk reduction strategies possibly need to be

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disease-specific. Further investigation of biomarkers reflecting alterations of the composition of HDL in IRD could potentially improve CV risk stratification in these patients. IV. 2.1 HDL function in RA RA is the most common IRD and is associated with excess CV morbidity and mortality that cannot be explained by traditional CV risk factors alone.111 In patients with active RA, profound modifications in HDL composition, especially with respect to protein content, have been noted.112 Proteomic analysis of HDL in patients with active RA suggested an altered profile with loss of its anti-inflammatory function, where acute phase proteins, such as SAA and complement factors (B, C3, C9) were identified.113 Importantly, apoB-depleted serum used as a cholesterol acceptor from subjects with RA has a reduced capacity to promote CEC, particularly via ABCA1 and ABCG1.114 Notably, HDL particles derived from RA patients with higher disease activity had a significantly reduced ability to induce HDL/ABCA1-CEC 15

Journal Pre-proof when compared to HDL from patients with very low disease activity as measured using 28 joint count < 2.6.115 It is possible that reduced HDL-CEC might contribute to vessel inflammation and immune reaction in RA patients. However, the exact nature of HDL alterations leading to impairment of ABCA1-CEC and ABCG1-CEC in RA has not yet been elucidated. IV. 2.2 HDL function in relation to CVD in psoriasic arthritis Psoriatic arthritis is a seronegative, chronic and inflammatory arthropathy often associated with psoriasis.116 Emerging comorbidities of psoriasis include CV complications.117 There may be a small yet significantly increased risk of CV events without CV mortality in psoriasis

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arthritis patients.118 A recent study confirmed that the prevalence of CV risk factors and history of CVD is higher in psoriasis arthritis patients than in control groups.119 The psoriasisattributable CV risk remains nonetheless difficult to assess due to confounding factors, and

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thus explains the ongoing controversy of the association between psoriasis and CV mortality/morbidity. In psoriasis patients, the lipid profile is generally characterized by higher

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levels of apoB-containing lipids and normal HDL-C levels.120 Regarding HDL function, decreased ABCA1-CEC has been reported in psoriasis patients compared to patients without

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psoriasis (Table 1).121 HDL particles from patients with psoriasis and from healthy subjects inhibited dihydrorhodamine oxidation to a similar extent, but psoriatic HDL particles were

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comprised of accumulated pro-inflammatory SAA.122 Proteomic analysis indicated that HDL antioxidant activity mediated by paraoxonase 1 (PON1) seems to be conserved in psoriasis

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patients despite a compositional shift towards a pro-inflammatory HDL particle. Because such a shift has been associated with impaired ABCA1-CEC, these findings may provide a link

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between psoriasis and CVD.122 Impaired antioxidant activity of HDL is associated with more severe acute ischemic stroke and might also predict worsened functional outcomes in these patients.123 While further studies are needed to confirm these preliminary findings, the current available data suggest a decrease of HDL-CEC in psoriasis patients. IV. 2.3 HDL function in spondyloarthritis Axial spondyloarthritis (axSpA) is another chronic rheumatic disease, which primarily affects the spine and other joints. AxSpaA involves a number of inflammatory spine conditions, including ankylosing spondylitis (AS), non-radiographic axSpA, and spondyloarthritisassociated with inflammatory bowel diseases.124 Previous studies have confirmed the presence of premature subclinical atherosclerosis in patients with axSpA.125 Furthermore, it has been reported that HDL from patients with axSpA have an impaired endothelial Akt kinase activating response, leading to lower antiatherogenic properties.126 Gkolfinopoulou and 16

Journal Pre-proof colleagues were the first to evaluate ABCA1-CEC and antioxidant signalling capacity of HDL from patients with axSpA.126 They reported that HDL from patients with axSpA have decreased antioxidant capacity and decreased HDL/ABCA1-CEC from macrophages compared to controls (Table 1). The attenuation of some atheroprotective HDL properties may suggest a molecular link between axSpA and CVD. In accordance with the conclusions of a recent review, the role of dyslipidaemia in CVD risk associated with axSpA requires further investigation.127 IV. 3 HDL function in systemic lupus erythematous Consistent with most autoimmune diseases, patients with SLE display an elevated CVD risk,

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independently of traditional CV risk factors.128 The inflammatory disease activity scores of these patients contributes to the development of atherosclerosis.101 Regarding the functionality of HDL particles, one study has investigated ABCA1-CEC and ABCG1-CEC in

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SLE patients.114 This study demonstrated a modification in HDL composition with respect to cholesterol metabolism that was unrelated to disease activity, in addition to a marked

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reduction in ABCG1-CEC and ABCA1-CEC from the serum of SLE patients.114 IV. 4 Autoantibodies against HDL or apoA-I, and HDL function

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Several studies have shown the presence of IgG autoantibodies against HDL particles,129 and their association with CV risk in various autoimmune diseases.130 High levels of

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autoantibodies against apoA-I (anti‐apoA‐I IgG) have been shown to be prevalent in the general population, in patients with acute coronary syndromes,131 in patients suffering from

ur

RA,132 and in renal transplant recipients.133 The presence of anti‐apoA‐I IgG was shown to represent an independent CV risk factor associated with increased risk of all-cause mortality

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and/or incident CV events.134 Furthermore, in vivo studies have indicated that passive immunization of apoE knock-out mice induced atherosclerotic plaque vulnerability, myocardial necrosis and death, supporting a possible causal relationship between anti-apoA-I IgG levels and CVD.135 Interestingly, increased levels of these autoantibodies can be prompted by niacin treatment and are associated with the loss of antioxidant HDL functions.136 The presence of these autoantibodies was investigated by Vuilleumier and colleagues, who highlighted a correlation between plasma apoA-I (r = -0.72, p = 0.013), plasma SAA concentration (r = 0.76, p = 0.0066), and anti-apoA-I IgG titer in SLE patients (Table 1).137 In another study, the presence of anti-HDL and anti-apoA-I IgG autoantibodies in SLE patients has been shown to be associated with reduced PON1 activity in plasma.138 In particular, the levels of anti-apoA-I IgG and anti-HDL IgG were higher in the SLE patients who experienced CVD.130 More recently, Lopez and colleagues confirmed that anti-HDL IgG 17

Journal Pre-proof antibodies were associated with higher risk of CVD (odds ratio: 3.69; p = 0.012), while antiPON1 IgG antibodies were associated with increased carotid intima-media thickness in SLE (β = 0.201, p = 0.008).139 These studies suggest that levels of anti-HDL, anti-apoA-I, and anti-PON1 IgG antibodies could serve as potential early biomarkers of endothelial damage and premature atherosclerosis in SLE. Nevertheless, a recent multicentre study including SLE patients indicated that these autoantibodies were not associated with a history of CV events, despite being strongly associated with disease activity (captured by Safety of Estrogens in Lupus Erythematosus National Assessment).140 Further investigations are

necessary to elucidate the absence of an association between anti‐apoA‐I IgG and CVD in

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SLE patients. Regarding CEC, two recent publications indicated that anti-apoA-I IgG levels were inversely associated with ABCA1-CEC in control and T2DM patients,129 in addition to an inverse macrophage passive diffusion ability in healthy obese individuals.141 In the latter

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study, the phenotypic impact of HDL-functionality of these autoantibodies led to foam cell formation in vitro, which was accompanied by an ABCA1-CEC increase as part of a feedback

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loop.141 Furthermore, the results from this study indicate that in the presence of high antiapoA-I IgG levels, the inverse association between ABCA1-CEC and increased

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atherosclerosis may be reverted. Therefore, a deeper understanding of the mechanisms by

function is required.

na

which anti-apoA-I IgG complex disrupts macrophage cholesterol homeostasis and HDL-CEC

V. Cholesterol efflux capacity: limitations and challenges

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Cholesterol efflux capacity is a key metric of the anti-atherosclerotic functionality of HDL.6 Several methodologies have been proposed to measure cholesterol efflux in vitro and in vivo

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and remain complex and diverse.6 The differences reside not only in the cell types used, but also in the choice of different cholesterol acceptors (apoA-I, isolated HDL particles, apoBdepleted serum or full serum), forms of cholesterol, and cell membrane transporters (ABCA1, ABCG1, SR-BI or passive diffusion), as well as whether or not the cells are artificially stimulated. Assessment of HDL-CEC mediated through the ABCA1 transporter has the potential to improve risk stratification of atherosclerotic CVD.46 Unfortunately, differences between efflux assay protocols increase the difficulty of interpreting and generalizing the results and may underlie some of the discrepancies between studies. These methodological aspects related to cholesterol efflux assays represent the most important limitation in the field and emphasize the need to standardize existing assays.6 With this in mind, extrapolating HDL functionality data derived from pathological mouse and human models has been challenging.142 18

Journal Pre-proof VI. Conclusion HDL acceptor capacity for cholesterol efflux is influenced by various determinants, including but not limited to environmental factors, and the presence of autoimmune diseases. Altogether, it appears that ABCA1-CEC can predict arteriosclerotic CVD and incidence of CV events. The specific association pattern may vary according to pre-existing clinical conditions. The effects of traditional CV risk factors remain controversial, with various studies showing either an impairment or no association with ABCA1-CEC. The impact of smoking, gender, and aging on ABCA1-CEC and ABCG1-CEC is not clear, but there is an indication that the presence of diabetes and autoimmune diseases alter ABCA1-CEC and

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ABCG1-CEC. In MetS or obesity-conditions, the association between ABCA1-CEC and CV risk remains controversial. In CKD, evidence suggests that an association between ABCA1CEC and CV events is blunted. Thus, the presence of inflammatory conditions and altered

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HDL particles impedes the straightforward interpretation of ABCA1-CEC as an independent biomarker of CV risk. All these conditions influence the complex and dynamic composition

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of HDL particles beyond the mass of HDL-C, which in turn positively or negatively affect HDL-mediated CEC. Several other aspects of HDL function should be assessed and

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importantly considering the patients’ baseline clinical characteristics. Given the numerous pleotropic effects of HDL in the CV system, we propose that the assessment of HDL

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functionality should not be limited to ABCA1-CEC alone, but should be considered together with other forms of CEC and other HDL biomarkers such as autoantibodies against HDL

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particle or HDL protein fraction. Further studies are needed to address these knowledge gaps

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and to determine whether, and how CEC could improve current CV-risk stratification tools. Acknowledgments

We greatly acknowledge Dr. Richard James for his advice and support. Financial support The research of MAF is supported by Fondation Prévot, Fondation Schmidheiny and Fondation pour la lutte contre le cancer et investigations médico-biologiques. Dr. Hafiane is supported by a Postdoctoral Fellowship from the Research Institute of the McGill University Health Centre, Montreal, Canada. Dr. Daskalopoulou is supported by a Fonds de recherche du Québec – Santé Senior salary award.

Conflicts of interest

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Journal Pre-proof AH, EF, SSD and MAF have no conflict of interest to declare. NV received restricted

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research grants from Roche.

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Journal Pre-proof Tables Table 1. Cohort studies of HDL functionality Name of disease

Total cohort

Association of HDL function with disease

30 individuals from families with ABCA1 mutations and 110 matched controls 42 442 CAD patients and 351 controls

Inverse correlation thickness 42

43

and

arterial-wall

HDL-CEC was significantly lower in in-patients with CVD compared to controls 44

2924 participant from the Dallas Heart Study 45

ro of

HDL-CEC was associated with a decrease in cardiovascular risk 45 HDL-CEC was found to be an atheroprotective mechanism for 48 CHD but not for stroke

69 IHD and 407 stroke patients 48

ACS was associated with impaired HDL-CEC 35

1150 undergoing angiography and 577 subjects with cardiac risk factors

Paradoxical enhanced cholesterol efflux with increased incident cardiovascular risks 50

with atherogenic during primary

Serum-CEC via SR-BI and ABCG1 was significantly associated with established MetS 75

re

1202 patients dyslipidaemia prevention 75

-p

40 subjects with ACS 35

50

MetS

HDL-CEC

Strong inverse association with both carotid intima-media thickness and the likelihood of angiographic CAD 43

1745 patients with CHD and 1749 control participants 44 ASCVD

between

ABCA1-CEC was enhanced, linked to increased pre-β1-HDL and slightly reduced in LCAT mass 49 HDL-ABCA1-CEC was independently and inversely associated with the presence of ASCVD 78 Significant increase of HDL-ABCA1-CEC from FH patients without CHD to that of their non-FH siblings 80

Diabetes T1D

7 FH patients with no symptoms of CHD, 6 with developed symptomatic CHD. Compared to their non‐FH 80 brothers 7 and 6 respectively 18,000 patients, and 415 patients without AVS 143 293 T1D patients 111 healthy control 106

T2D

44 T2D patients without CVD 84

No correlation between the concentration of small HDL particles (59%) and HDL-CEC 84

93 T2D patients 27

HDL was associated with atherosclerotic burden and cardiovascular outcomes* 27 Loss of vasoprotective properties; Not capable of preventing LDL oxidation 95

Chronic kidney disease

na

ur

AVS

Jo

FH

lP

35 non-treated MetS patients and 15 healthy controls 49 227 patients with heterozygous FH: 76 have ASCVD 78

45 adults, 22 children both with CKD, and 15 adults, 10 children as control 95

No significant difference in measures of efflux capacity or (LCAT) activity with prevalent AVS 143 Abnormal ratio of cholesteryl ester-to-triglyceride; Reduced phospholipid content; Reduced capacity to promote CEC; Impaired anti-inflammatory and anti-oxidant activities* 106.

Less able to accept cholesterol from lipid-loaded macrophages 27 hemodialysis patients before the dialysis session and 19 control subjects 96 Renal transplant recipients ESRD

495 patients, follow-up period of 7 years 91. 1147 patients on hemodialysis (German Diabetes Dialysis Study) 70

31

96

CEC from macrophage foam cells is not associated with CVD; however, it is a strong predictor of graft failure independent of plasma HDL-C 91. No association of efflux capacity was found with cardiac events 70 or cause of mortality .

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Rheumatic diseases

40 patients with RA healthy, and 40 controls 115

Reduced CEC particularly via ABCA1 and ABCG1. Correlated with systemic inflammation and HDL's antioxidant capacity 115.

132 RA patents 144.

Pro inflammatory HDL function 144 114

Psoriasic arthritis Spondylarthritis

ankylosing spondylitis Systemic lupus erythematosus

114

30 RA, 30 healthy controls 122 patients with and 134 patients without psoriasis 122.

CEC is impaired HDL-CEC was decreased ; There was a shift to a proinflammatory condition; HDL psoriatic antioxidant activity was unaltered 122

35 patients with AS and 35 age- and sex-matched controls 126

Decreased HDL antioxidant capacity; Impaired endothelial Akt kinase activating properties; Decreased ability to promote 126 cholesterol efflux 114 Increased cardiovascular risk and with impairment of CEC

30 SLE patients and 30 healthy 114 controls 92 patient and 92 healthy 137

High levels of anti-HDL and anti-ApoA-I antibodies 137

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ASCVD, arteriosclerotic cardiovascular disease; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; AVS, aortic valve stenosis; ACS, acute coronary syndrome; ApoA-I, apolipoprotein A-I; AS, ankylosing spondylitis; CVD, cardiovascular disease; CAD, coronary artery disease; CHD, coronary heart disease; CEC, cholesterol efflux capacity; CKD, Chronic kidney disease; ESRD, end-stage renal disease; FH, familial hypercholesterolemia; HDL-C, highdensity lipoprotein cholesterol; IHD, ischemic heart disease; LDL, low density lipoprotein; LCAT, Lecithin–cholesterol acyltransferase; MetS, metabolic syndrome; RA, rheumatoid arthritis; T1D, type 1 diabetes; T2D, type 2 diabetes. *. HDL function was quantified by HDL-apoA-I exchange (HAE) 27.

Table 2. Pathways characteristics of cholesterol efflux from cells

na

Cholesterol efflux mediated pathways

Unidirectional

Jo

Flux direction

ur

ABCA1

7

ABCG1

Unidirectional

SR-BI 145

Bidirectional

Aqueous diffusion

146

Acceptor

preβ-HDL Lipid-poor apoA-I

HDL2, HDL3

HDL2, HDL3

Characteristic

Rate limiting step of RCT

Participate in RCT

Selective Uptake CE, drive RCT

Bidirectional

146

HDL2, HDL3

Unmediated uptake of FC

ABCA1; ATP-binding cassette transporter A1, ABCG1; ATP-binding cassette transporter G1, HDL; high density lipoprotein, RCT; reverse cholesterol transport, ApoA-I; apolipoprotein A-I, FC; free cholesterol, CE; cholesterol ester, SR-BI; scavenger receptor class B, type I.

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Journal Pre-proof Table 3. Factors that allude to aging and HDL-CEC associations Associated modifications

HDL cholesterol efflux function in elderly patients > 70 years old

HDL fractions

Decreased HDL3 CEC when compared to HDL2

Oxidative stress

Impaired CEC 62

HDL composition

Reduction in HDL membrane fluidity, which is a factor that decreases CEC 58

ABC transporters

Reduced ABCA1/ABCG1 expression in macrophages 58,61

59

Jo

ur

na

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ABCA1; ATP-binding cassette transporter A1, ABCG1; ATP-binding cassette transporter G1, CEC; cholesterol efflux capacity, FC; free cholesterol, HDL; high density lipoprotein.

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Journal Pre-proof Table 4. Mechanisms altering HDL-functionality and consequences in CKD Mechanisms and consequences Reduced ability of the HDL to bind to ABCA1 and impairment of ABCA1-CEC

Ref. 147,148

148

Transformation in noxious particle inducing endothelial dysfunction and inflammation

95

Loss of its ability to prevent LDL oxidation or induce monocyte migration

96

Decreased ability to accept cholesterol from lipid-loaded macrophages

96

More abundant HD2 than HDL3 particles in haemodialysis patients

149

Accumulation of symmetric dimethylarginine (SDMA)

ro of

Disrupted HDL maturation due to decreased LCAT

Loss of apoA-I/apoA-II, decrease in phospholipids and FC and an increase in TG and

150

96

-p

lysophosphatidylcholine content in haemodialysis patients

re

Impaired ability of HDL-ABCA1 and SR-BI to promote CEC

91,96

Jo

ur

na

lP

ABCA1, ATP-binding cassette transporter A1; ApoA-I, apolipoprotein A-I; CEC, cholesterol efflux capacity; FC, free cholesterol; HDL-C, high-density lipoprotein; LCAT, lecithin–cholesterol acyltransferase; LDL, low density lipoprotein; SAA, serum amyloid; SDMA, symmetric dimethylarginine; S1P, sphingosine-1-phosphate; SR-BI, scavenger receptor class B, type I; TG, triglyceride.

34

Journal Pre-proof

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Highlights  Autoimmune/non-autoimmune diseases influence the composition and function of HDL  Inflammation impede the straightforward interpretation of ABCA1-cholesterol efflux  The impact of smoking/gender/aging on ABCA1/ABCG1 efflux role remains inconclusive  Diabetes and autoimmune diseases may alter ABCA1/ABCG1 cholesterol efflux function  ABCA1-cholesterol efflux and CV risk in obesity or MetS remains controversial

35

Figure 1

Figure 2