High-density Lipoprotein and Inflammation and Its Significance to Atherosclerosis

REVIEW ARTICLE

High-density Lipoprotein and Inflammation and Its Significance to Atherosclerosis Jing Hu, PhD, Dan Xi, PhD, Jinzhen Zhao, MMed, Tiantian Luo, MMed, Jichen Liu, MMed, Hao Lu, MD, Menghao Li, MD, Haowei Xiong, MD and Zhigang Guo, PhD, MD ABSTRACT Great advances are being made in the understanding of the structural and functional diversity of high-density lipoprotein at the mechanistic level. High-density lipoprotein possesses numerous physiological activities, the most studied of which is the ability to promote excess cholesterol efflux from peripheral tissues to the liver for excretion via a mechanism believed to confer protection against atherosclerosis. Accumulating evidence has demonstrated that atherosclerosis is a chronic inflammatory response. Recent studies have suggested that high-density lipoprotein possesses anti-inflammatory properties and regulates both innate and adaptive immune responses. However, further complicating this very complex system is the finding that inflammation, via alteration of the proteomic and lipidomic composition of high-density lipoprotein species, can modulate at least some of their functional activities. Modified high-density lipoprotein exhibits a reduced ability to mediate cholesterol efflux from peripheral tissues and to inhibit cytokine-induced adhesion molecule expression and even promotes the occurrence of inflammation. This review focuses on the underlying mechanism of the interaction between high-density lipoprotein and inflammation to clarify the pathologic process of atherosclerosis. Key Indexing Terms: Atherosclerosis; High-density lipoprotein; Inflammation; Immunity. [Am J Med Sci 2016;](]):]]]–]]].]

INTRODUCTION ince the seminal publication by Miller and Miller,1 high-density lipoprotein (HDL) has been associated with the risk of cardiovascular disease (CVD). Therefore, much work has focused on understanding the metabolism and function of HDL. In 2003, ETC-216 (rapoA-IMilano, a synthetic variant of HDL) was tested in a small proof-of-concept clinical trial in which sequential intravascular ultrasound examinations were performed before and after 5 weekly infusions of ETC216 or placebo. That study showed rapid coronary plaque regression following administration of apoAIMilano.2 CER-001, an engineered pre-β HDL mimic, consists of recombinant human apolipoprotein A-I (apoA-I) and 2 different phospholipid carriers. In a preclinical study, CER-001-enhanced reverse lipid transport reduced vascular inflammation and promoted regression of atherosclerosis in hypercholesterolemic low-density lipoprotein (LDL) receptor– deficient mice.3 Furthermore, CER-001 stimulated cholesterol mobilization and reduced arterial wall thickness and inflammation in patients with the orphan disease familial hypoalphalipoproteinemia.4 These findings support for the concept that HDL plays an important role in reducing atherosclerosis and inflammation. Therefore, HDL has become one of the most commonly measured biomarkers of atherosclerosis and has been regarded as a major therapeutic target in the setting of CVD.

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Nowadays, atherosclerosis is seen as an inflammatory disease characterized by inflammatory and immune responses that contribute to disease initiation and progression and to plaque destabilization. Recent results have suggested that HDL may play additional roles in the regulation of inflammation, including the inhibition of monocyte activation and the modulation of the immune system. However, chronic inflammation induces significant changes to HDL, resulting in the reduction of the plasma HDL levels, HDL-mediated reverse cholesterol transport (RCT) and the inhibition of enzymes. These enzymes consist of lecithin cholesterol acyltransferase (LCAT), cholesterol ester transfer protein (CETP), phospholipid transfer protein, hepatic lipase, apoA-I and paraoxonase-1 (PON-1).5 HDL activity related to inflammation is also affected, as demonstrated by increased serum amyloid A (SAA) content in patients with atherosclerosis. Furthermore, HDL is depleted in cholesterol esters but is enriched in free cholesterol, triglycerides and free fatty acids.6 These alterations to HDL structure and function result in the conversion of HDL to a proinflammatory molecule. Several large randomized controlled trials in which plasma HDL-C levels were elevated failed to identify benefits with respect to CVD events or the progression of atherosclerosis.7,8 This unexpected finding raises the question of whether HDL is an innocent bystander or acts as a mediator of atherogenesis and CVD. This review summarizes the cross talk between HDL and inflammation in the setting of atherosclerosis.

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HDL STRUCTURE AND BIOLOGY HDL, the smallest and densest of the plasma lipoproteins, has a density ranging from 1.063-1.21 g/mL. HDL exists as various subclasses of particles in plasma, differing in shape, size and protein and lipid composition. HDL is a macromolecular complex of proteins and lipids, including apoA-I, apoA-II, apoCs, apoE, apo-D, apoJ and enzymes such as LCAT, PON-1 and plateletactivating factor acetylhydrolase.9 The primary apolipoproteins in HDL are apoA-I and apo-AII, which represent up to 70% and 20% of the total HDL protein, respectively. Furthermore, based on 2-dimensional gel electrophoresis results, HDL particles can be subdivided into large cholesterol-rich spherical HDL particles, intermediate spherical HDL particles and small discoidal HDL particles.10 The atheroprotective role of HDL in the cardiovascular system has been attributed to its pleiotropic effects, including anti-inflammatory,11 antithrombotic,12 antioxidative,13 antiapoptotic14 and vasodilatory effects. Among many components included in HDL, apoA-I possesses many HDL effects ranging from scavenging of RCT, LPS and LTA to inhibition of different proinflammatory, pro-oxidant and prothrombotic pathways. HDL and apoA-I appear to defend against many biological and chemical hazards.

THE ANTI-INFLAMMATORY MECHANISMS OF HDL Inhibition of the Transendothelial Migration of Immunocompetent Cells and T Cell Contact– Mediated Monocyte Activation ApoA-I inhibits the cytokine-induced expression of cell adhesion molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and Eselectin, which are key mediators in the diapedesis of immunocompetent cells from the circulation to the arterial wall.15 This physiological effect of apoA-I demonstrates that it could regulate the transendothelial activity of immunocompetent cells. Additionally, apoA1 could inhibit both shear stress and phorbol-12 myristate 13-acetate (PMA) induced monocytic expression of CD11b, which is involved in the early stages of transendothelial migration. Research on this topic showed that inhibition of CD11b expression was accompanied by decreased transendothelial migration of monocytes toward chemotactic agents such as monocyte chemoattractant protein-1 (MCP-1). Furthermore, inhibition of CD11b expression in monocytes is increased with asymmetry and hydrophobicity but decreased with increasing numbers of positively charged residues, emphasizing the importance of the conformation of apoA-1 to its anti-inflammatory properties.15,16 Upon the transendothelial migration of inflammatory cells, interactions between macrophages and T cells represent another important step in the modulation of

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the chronic inflammatory response. Direct contact between activated T cells and monocytes or macrophages drives the production of several inflammatory cytokines such as IL-1β, IL-6, IL-8, MCP-1 and TNF-α, which are involved in atherogenesis and tissue destruction. However, apoA-1 inhibits contact-mediated monocyte stimulation and the subsequent production of IL-1β and TNF-α. A previous study determined that apoA-1 blocks T cell-monocyte interactions at the T cell level.17 Additional studies using cell-cell interaction models demonstrated that HDL or apoA-1 inhibits T cell contact–activated expression of specific proinflammatory genes in monocytes.18 These studies support the concept that apoA-I could inhibit inflammation by regulating the transendothelial migration of immunocompetent cells and T cell contact–mediated monocyte activation. Inhibition of Lipid Oxidation It is known that HDL can inhibit LDL oxidation. Several HDL-associated proteins, including PON-1 and -3, apoA-I, LCAT and CETP, are associated with this inhibitory effect. Among these proteins, PON-1 alone appears to be responsible for the attenuation of oxidative damage to macrophages,19 stimulation of cholesterol efflux from macrophages20 and attenuation of oxidative stress in atherosclerotic lesions.21 Furthermore, PON-1 is believed to contribute to the antiinflammatory activity of HDL by destroying biologically active lipids within mildly oxidized LDL particles,22 which result in decreased inflammation within the arterial wall. Several studies have found that PON-1 decreases monocyte chemotaxis and adhesion to endothelial cells,23 inhibiting monocyte-to-macrophage differentiation.24 PON-1 significantly inhibited both the production and the secretion of the proinflammatory cytokines TNFα and IL-6 in LPS-stimulated macrophages. The absence of PON-1 was associated with the overexpression of adhesion molecules.25 These observations are suggestive of an anti-inflammatory role for PON-1. Modulation of Inflammation by Activating Transcription Factor 3 (ATF3) Most functions of HDL have been established. However, a new pathway of HDL activity that regulates inflammation has recently been reported. De Nardo et al26 described a novel and cholesterol transport– independent mechanism by which HDL exerts its antiinflammatory effects. HDL could stimulate ATF3, an ancient transcriptional modulator that provides negative feedback to toll-like receptor (TLR)–mediated innate immune signaling. ATF3 is a key transcriptional regulator of innate immune response genes that are induced by TLR and other innate immune ligands and inhibits TLR signaling by inactivating target genes via reduced histone acetylation. HDL increased ATF3 mRNA and protein expression in bone marrow–derived macrophages (BMDMs), and this effect was potentiated upon THE AMERICAN JOURNAL

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stimulation with TLR ligands. HDL significantly reduced the CpG-induced production of IL-6 and IL-12p40 in wild-type BMDMs but not Atf3-deficient BMDMs. HDLmediated protection against carotid artery injury and TLR ligand–induced inflammation was lost in ATF3deficient mice. Additionally, apoE/ mice deficient in ATF3 experienced accelerated atherosclerosis.27 These researches provide new perspective regarding the regulation of inflammation by HDL. Modulation of the Immune System HDL and the Complement System Elevated serum HDL cholesterol concentrations exert protective effects against liposomes and poloxamer-mediated complement activation.28,29 A proteomic analysis of the composition of HDL identified HDL particles enriched in complement pathway and complement regulatory proteins such as C3, C4a, C4b, C9, clusterin and vitronectin. Those results supported the findings of previous studies suggesting that HDL may regulate complement activation.30,31 Several recent studies have provided new insight into the mechanism by which HDL exerts atheroprotective effects via the modulation of the complement system. Long pentraxin 3 (PTX3) modulates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DCs.32,33 The results of several studies have demonstrated the cardioprotective functions of PTX3. Norata et al34 demonstrated that HDL induced the expression of PTX3 both in vitro and in vivo, primarily via PI3K/Akt activation. S1P, a lysosphingolipid carried by HDL, is responsible for HDL-mediated NO-dependent vasorelaxation, antiapoptotic activities and TGF-β induction, and S1P activity has been linked to PTX3 induction. These findings suggest that the complement system is involved in the regulation of inflammation by HDL. HDL and the Innate Immune Response HDL sequesters LPS, preventing the initiation of proinflammatory cascades via TLR4/CD14 complex interaction and blocking upstream TLR4 activation by impeding its interactions with apoA-1 and hindering its transport into lipid rafts.35 These processes may be mediated by the promotion of cholesterol efflux by the ABCA1/G1 pathway.36 Functional lipid rafts, the integrity of which is crucial to appropriate proinflammatory TLR signaling,37 facilitate interactions with other coreceptors associated with the activation of specific signaling pathways. ApoA-I induces cholesterol depletion from lipid rafts, thereby decreasing TLR4 functionality and inhibiting LPS-induced inflammation.38 SR-BI is an important effector of the various anti-inflammatory functions of HDL. Song et al39 noted that the anti-inflammatory effects of HDL are primarily mediated by SR-BI in macrophages. SR-BI knockdown may abolish the ability of recombinant HDL to inhibit

the expression of cytokines, and the mechanism underlying this process involves the anti-inflammatory effects of HDL via the inhibition of NF-kB, as reported by van der Vorst et al.40 Furthermore, the interactions of apoA-I with SR-BI are crucial for cholesterol efflux (Figures 1-3). HDL and the Adaptive Immune Response Lipid rafts compartmentalize key signaling molecules during various stages of B cell activation. The responses of T cell to an antigen are orchestrated by several molecules that cluster within lipid rafts. All of these observations suggest that lipid rafts play an important role in regulating inflammation. Major histocompatibility (MHC) class II molecules are widely known as antigenpresenting and signal-transducing molecules. The absolute density of MHC class II molecules on the surface of antigen-presenting cells (APCs) is a crucial parameter related to the MHC-restricted activation of T cells. Lipid rafts may effectively concentrate MHC class II peptide complexes on the surfaces of APCs and decrease the amount of antigen required for T cell activation. Therefore, disrupting lipid rafts on the surface of peptide-loaded APCs inhibits the MHC class II-mediated presentation of low concentrations of antigen. HDL stimulates cholesterol efflux from cells, resulting in cholesterol depletion and the disruption of lipid rafts, and this event induces profound functional changes38 to macrophages and BCR signaling, TCR signaling and antigen presentation.18 The activation of S1P receptors ultimately facilitates the egress of T cells from lymphoid organs41 and plays a role in the lineage determination of peripheral T cells.42 S1P inhibits the differentiation of forkhead box P3 (FoxP3)þ regulatory T cells (Tregs) and promotes the development of T helper type 1 cells. S1P receptor activity antagonizes transforming growth factor beta (TGF-β) receptor function via the inhibition of small mother against decapentaplegic-3 activity to control the balance between the 2 T cell lineages.42 In animal models, apoA-I reduces inflammation in LDL receptor/ and apoAI/ mice by augmenting the effectiveness of lymph nodal Treg responses that are characterized by an increase in the abundance of Tregs and a decrease in the percentage of effector or effector memory T cells.43 Significant changes in Treg abundance or function have been associated with atheroprotective activities in animal models.44,45 The composition of HDL could inhibit inflammation via interactions with T and B cells.

THE EFFECTS OF INFLAMMATION ON HDL HDL Remodeling in the Setting of Inflammation In the setting of inflammation, HDL undergoes significant changes to both composition and structure. The reduction in the HDL apoA-I levels under inflammatory conditions is related to both decreased hepatic

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FIGURE 1. Potential anti-inflammation mechanisms of HDL in the development of atherosclerotic lesions. Activating or promoting HDL activities are shown in green, and inhibitory activities of HDL are shown in red. HDL has the ability to inhibit monocyte adhesion by inhibiting VCAM-1, ICAM-1 and E-selectin expression and suppresses monocyte chemotaxis by inhibiting chemokine secretion such as MCP-1. HDL promotes cholesterol efflux from macrophage foam cells thereby preventing the secretion of proinflammatory cytokines from lipid-laden macrophages. HDL blocks interactions between the macrophages and T cells. HDL, high-density lipoprotein; ICAM-1, intercellular adhesion molecule-1; MCP1, monocyte chemoattractant protein-1; VCAM-1, vascular cell adhesion molecule-1.

apoA-I synthesis and the replacement of apoA-I with SAA in HDL particles.46 Van Lenten et al47 reported that the acute-phase response (APR) resulted in displacement of

FIGURE 2. HDL functional differences. HDL prevents inflammation in the absence of systemic inflammation or an acute-phase response. However, with the onset of systemic inflammation, HDL becomes proinflammatory and enhances the inflammatory response. HDL, high-density lipoprotein.

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apoA-I from HDL via SAA in rabbits, which was associated with decreased PON activity and the conversion of HDL to a proinflammatory particle. HDL in patients with end-stage renal disease displays a lower antiinflammatory capacity to inhibit monocyte chemotactic activity in cultured human aortic ECs than HDL from control subjects.48 During APR, proinflammatory cytokines increase SAA expression via NF-κB transactivation, simultaneously decreasing both apoA-I and PON-1 expression by inhibiting the activation of PPAR-α. SAAenriched HDL exhibits a reduced capacity to inhibit the oxidation of LDL and to bind biglycan, thereby reducing the atheroprotective effects of HDL.49 Recent studies have demonstrated that SAA itself may act as a proinflammatory and atherogenic mediator. SAA performs various biological functions in the vascular system, including the regulation of immune cell migration and the stimulation of inflammatory factor production. Lee et al50 demonstrated that SAA induced the production of the chemokine MCP-1 in human monocytes. THE AMERICAN JOURNAL

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FIGURE 3. Protein component changes. During inflammation, liver produces acute-phase proteins including SAA and sPLA2. These acutephase proteins displace apoA-I and enzymes from HDL, thus generating SAA- and sPLA 2-enriched HDL, known as acute-phase HDL, which lack most of the anti-inflammation functions. apoA-I, apolipoprotein A-I; HDL, high-density lipoprotein; SAA, serum amyloid A.

Additionally, a study noted that SAA stimulates monocytes and macrophages, resulting in vascular inflammation via the enhancement of foam cell formation by upregulating lectin-like oxidized LDL receptor 1 expression.51 Another explanation for the observation of decreased HDL levels during inflammation may be remodeling by acute-phase group II phospholipases, particularly sPLA2-IIA.52,53 Overexpression of this enzyme in mice results in decreased HDL levels and enhanced HDL catabolism.54 The combined remodeling actions of sPLA2-IIA and CETP during the APR may also result in increased HDL catabolism. The incorporation of SAA and sPLA2-IIA into acute-phase HDL particles results in the loss of PON activity. Acute-phase HDL is also enriched in triglycerides,55 and this enrichment might lead to impaired HDL stability and enhanced apoA-I catabolism. These structural and related functional alterations in HDL may at least partially explain the elevated risk of cardiovascular events in patients with systemic inflammatory diseases. Translational and Posttranslational apoA-I Modifications ApoA-1 Modifications Driven by Myeloperoxidase The posttranslational modifications of apoA-1 include the chlorination, nitration, carbamylation and oxidation of tyrosine residues, and these reactions are catalyzed by myeloperoxidase (MPO). Physiologically relevant concentrations of MPO generate dysfunctional HDL particles characterized by reduced cholesterol efflux capacities.56 Protein carbamylation is mediated by cyanate, which is produced by either MPO or urea decomposition. Previous studies have demonstrated that the in vitro carbamylation of apoA-I inhibits SR-B1 but not ABCA1-mediated cholesterol efflux, thus

resulting in significant cholesterol accumulation in THP-1 macrophages.57 These findings are indicative of a causal link between specific apoA-I modifications that induce HDL dysfunction and proinflammatory states via a specific MPO-driven pathway. ApoA-1 Modifications Driven by Reactive Carbonyls Reactive carbonyls are generated by either carbohydrate oxidation, which gives rise to proinflammatory advanced glycation end products, or lipid peroxidation, which produces advanced lipoxidation end products.58 Nobecourt and colleagues demonstrated that apoA-I lost its capacity to activate LCAT following its glycation and incorporation into reconstituted discoidal HDL particles. This loss of activity was associated with modifications to its arginine, lysine and tryptophan residues.59 The same group recently demonstrated that apoA-I glycation induced by methylglyoxal, both in vitro and in vivo, resulted in the inability of apoA-I to inhibit either the infiltration of neutrophils into the intima of rabbit carotid arteries or the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in endothelial cells. When exposed to methylglyoxal, recombinant HDL particles exhibited the same loss anti-inflammatory activities as lipid-free apoA-I. This finding suggests that the apoA-I modifications driven by carbonyl-reactive species generate forms of HDL with dysfunctional cholesterol efflux and anti-inflammatory and antioxidant properties. Effects of Inflammatory Proteins on HDL Considerable evidence indicates that heat-shock protein 65 (HSP65) contributes to both the initiation and the development of autoimmunity and atherosclerosis. Guo et al60 reported that HSP65 promoted atherosclerosis via the impairment of HDL. HDL from mice

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injected with HSP65 exhibited reduced RCT and antiinflammatory and antioxidative capacities. The HDL inflammatory index values of HSP65-treated mice were significantly higher than those of either untreated or PBS-treated mice. Additionally, they observed that mice treated with HSP65 exhibited decreased PON-1 activity and increased MPO activity. MPO/PON-1 ratio has been suggested as a novel biomarker for CAD.61 HSP65 downregulated the expression of ABCA1, ABCG1 and SR-BI in both macrophages and the liver. This downregulation decreased the removal and transfer of free cholesterol and cholesterol esters from macrophages to lipid-poor acceptors such as apoA-I and HDL. Further results indicated that HSP65 significantly suppressed the expression of PPAR-γ and LXR-α. These findings confirm that the regulation of ABCA1-mediated cholesterol efflux and intracellular cholesterol processing by HSP65 may occur via the PPAR-γ pathway. Effects of Cholesterol Overload on HDL HDL in its large, cholesterol-enriched form may exert proinflammatory effects.62 Qi et al63 suggested that cholesterol-overloaded HDL particles were associated with enhanced progression of carotid atherosclerosis. These findings are in accordance with previous data demonstrating that low levels of the small, denser HDL subfraction carried higher risk than the large, less-dense HDL subfraction with respect to primary prevention64 and secondary prevention65 because individuals harboring less-denser HDL would be in a more cholesterolloaded state and would exhibit a reduced capacity for cholesterol efflux.66 The enrichment of HDL particles results in impaired HDL-mediated RCT.67 Moreover, this enrichment reduces the selective uptake of cholesterol by the liver, a process mediated by SR-BI.68 Therefore, the status of cholesterol-overload of HDL would affect the physiological function of HDL. Humoral Autoimmune Responses to apoA-1/HDL A low HDL-C level is associated with an increased risk of not only CVD but also autoimmune disease. Hypercholesterolemic mice lacking plasma apoA-I exhibit increased susceptibility to autoimmune disease, as characterized by enlarged lymph nodes, cellular activation and cellular proliferation and lipid accumulation.69 The levels of autoantibodies specific for apoA-1 are increased in autoimmune conditions associated with increased cardiovascular risk. From a pathophysiological perspective, these autoantibodies exert proinflammatory effects via TLR2/CD14 complex signaling70 and neutrophil chemotaxis in vitro, as well as via the promotion of atherogenesis and atherosclerotic plaque vulnerability in vivo.71 The results of both clinical and animal studies indicate that these autoantibodies impede HDL-related antiatherogenic activities, resulting in HDL dysfunction. Among patients with SLE and primary antiphospholipid syndrome, as well as in lupus-prone mice, the presence

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of these autoantibodies has been associated with decreased antioxidant capacity of HDL because of decreased PON-1 activity72-74 and with increased proinflammatory reactive oxygen species (ROS) levels.75 Therefore, these antibodies may act as oxidative proteins, generating a pro-oxidant microenvironment by generating reactive oxygen species via water oxidation.76 If antibody-related oxidative activities induce oxidative modifications to their targets, autoantibodies against apoA-I/HDL may cause the formation of proinflammatory apoA-I/HDL species. Therefore, the microenvironment of autoimmune diseases could change the function of HDL.

CONCLUSIONS Several studies have shown that it is not the amount of HDL but rather the quality of HDL that is important. A high level of HDL does not necessarily decrease the risk of cardiovascular events. The importance of HDL functionality to cardiovascular events has now been confirmed in the EPIC-Norfolk study.77 However, in the setting of inflammation, the function and composition of HDL are altered. These alterations are intimately associated with impaired biological activities of HDL, and these impairments have been associated with decreased PON-1 activity and the conversion of HDL to a proinflammatory factor. Animal models and in vitro studies could help us understand the mechanisms underlying HDL dysfunction. HDL functionality itself might represent a new target for approaches to treat atherosclerosis. Continuous improvement in our understanding of the detailed mechanisms underlying the cross talk between HDL and inflammation would lead to the development of novel therapeutics for atherosclerosis and other inflammatory diseases.

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From the Division of Cardiology (JH, DX, JZ, TL, JL, HL, ML, HX), Nanfang Hospital, Southern Medical University, Guangzhou Guangdong, PR China. Submitted August 27, 2015; accepted June 24, 2016. This work was supported by the National Natural Science Foundation of China [81370380]; the Natural Science Foundation of Guangdong Province of China [S2013010014739]; the Science and Technology Foundation of Guangdong Province of China [2012B091100155]; the Innovative Foundation of Guangdong Province of China [2014KZDXM020]; and the Science and Technology Foundation of Guangzhou City of China [201510010090]. The sponsors had no role in the study design, data collection and analysis, our decision to publish, or the preparation of the manuscript. The authors have no conflicts of interest to disclose. Correspondence: Zhigang Guo, MD, PhD, Division of Cardiology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, Guangdong, PR China (E-mail: guozhigang126@ 126.com).

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