Association of ApoE and HDL.C with cardiovascular and cerebrovascular disease: potential benefits of LDL-apheresis therapy

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1 Clinical Lipidology ISSN: (Print) (Online) Journal homepage: Association of ApoE and HDL.C with cardiovascular and cerebrovascular disease: potential benefits of LDL-apheresis therapy Patrick Moriarty To cite this article: Patrick Moriarty (2009) Association of ApoE and HDL.C with cardiovascular and cerebrovascular disease: potential benefits of LDL-apheresis therapy, Clinical Lipidology, 4:3, To link to this article: Copyright 2009 Future Medicine Ltd Published online: 18 Jan Submit your article to this journal Article views: 106 View related articles Full Terms & Conditions of access and use can be found at

2 Review Association of ApoE and HDL C with cardiovascular and cerebrovascular disease: potential benefits of LDL-apheresis therapy ApoE forms a lipid protein complex with HDL-cholesterols (HDL C) and remnant lipoproteins and is an important regulator of cholesterol and lipid clearance, transport and distribution. In the CNS, ApoE is strictly bound to HDL. Unlike ApoE2 or ApoE3, the ApoE4 isoform is associated with both coronary artery disease and Alzheimer s disease. HDL C levels may possess a U-shaped association with vascular diseases and HDL C size might reflect an alteration in function. Inflammation plays a key role in coronary artery disease and Alzheimer s disease. Elevated inflammatory markers such as C-reactive protein and serum amyloid A are associated with both diseases. Serum amyloid A, similar to ApoE, binds to HDL C and may alter the lipoproteins size and function. Familial hypercholesterolemia (FH) is a genetic disorder resulting in elevated plasma levels of LDL-cholesterol (LDL-C), xanthomas and premature coronary artery disease. FH patient s plasma contains decreased levels of HDL C with increased levels of ApoE4 and ApoE-bound HDL. LDL-apheresis therapy lowers LDL C and is designated for FH patients resistant to pharmacotherapy. LDL apheresis also lowers inflammatory HDL-C, ApoE4, and a host of inflammatory markers such as C-reactive protein and serum amyloid A. LDL-apheresis, adjunct to reducing cholesterol, may provide additional benefit to patients with cardiovascular and cerebrovascular diseases. Keywords: Alzheimer s disease ApoE ApoE4 cardiovascular disease cerebral vascular disease familial hypercholesterolemia HDL C inflammation LDL-apheresis serum amyloid A Genetics play an important role in the development of coronary artery disease (CAD). Familial hypercholesterolemia (FH) is one genetic disorder of cholesterol metabolism resulting in elevated plasma levels of LDLcholesterol (LDL-C) and premature CAD. Genetic abnormalities can also affect apolipoprotein isoforms. For example, individuals may be carriers of the ApoE isoform E4 (ApoE4), which has been associated with Alzheimer s d isease (AD) and potentially increased vascular risk. Normally, ApoE is utilized in cholesterol transport, mobilizing and distributing cholesterol from peripheral tissue to the liver. While this process occurs through binding HDLcholesterol (HDL-C), remnant lipoproteins (RLPs) and LDL receptors (LDLr), the specific mechanism for the potential risk of vascular disease by ApoE4 remains unknown. Substantial evidence suggests a cardioprotective role of HDL-C, but epidemiological studies have demonstrated a potential U-shaped association of HDL-C levels and cardiovascular disease. In addition, a lack of agreement exists on the relationship of HDL-C size to the risk of CAD. When ApoE binds to HDL, a large-sized HDL 1 is formed that contains little to no ApoA-I, which is the antiatherogenic particle of HDL. In fact, individuals with genetic diseases such as cholesterol ester transfer protein (CETP) deficiency and FH are found to have elevated levels of HDL 1. In addition, serum amyloid A (SAA), an inflammatory marker identified in patients with CAD and AD, increases the lipoprotein size and alters function when bound to HDL-C. Low-density lipoprotein-apheresis is used for the reduction of LDL-C (>60%) in FH patients who suffer from CAD and hyperlipidemia. The device lowers plasma levels of LDL-C by removing positive-charged ApoB. Despite having a negative charge, HDL-C is reduced by 10 15% following a treatment of apheresis. Other plasma proteins reduced during apheresis include inflammatory markers and ApoE. This article will review the literature concerning ApoE relative to CAD and cerebral vascular disease. It will also examine the connection Patrick M Moriarty Director of The Atherosclerosis & LDL-apheresis Center, Department of Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA Tel.: Fax: pmoriart@kumc.edu /CLP Future Medicine Ltd Clin. Lipidol. (2009) 4(3), ISSN

3 Review Moriarty between LDL-apheresis and these plasma proteins, including the potential benefit the therapy may have for vascular diseases not necessarily associated with FH. Apolipoprotein E ApoE is a 34-kD polymorphic protein whose primary role includes the mobilization and distribution of cholesterol from peripheral tissue to the liver. Other activities performed by ApoE include coagulation, oxidative processes, macrophage function, glial/neuronal cell homeostasis, adrenal function, CNS physiology, inflammation and cell proliferation [1]. In plasma, ApoE is found on RLPs such as chylomicrons, VLDLs, IDLs and HDLs [2]. In normolipidemic patients, more than 60% of total plasma ApoE is bound to HDL C [3 5]. ApoE biological activity is influenced through modification of either its structure or quantity. In humans, the ApoE phenotype is determined by three alleles (e2, e3 and e4), which are derived from a specific gene locus on chromosome 19. These alleles encode three different protein isoforms: ApoE2, ApoE3 and ApoE4, whose population distribution is approximately 15, 60 and 25%, respectively [6,7]. The three isoforms differ from each other by a cysteine arginine replacement at positions 112 and 158: ApoE2 (Cys112, Cys158), ApoE3 (Cys112, Arg 158) and ApoE4 (Arg112, Arg158) [8]. Furthermore, the ApoE alleles are expressed codominantly, thus producing six different phenotypes: E2/E2, E3/E2, E3/E3, E4/E2, E4/E3 and E4/E4 [9]. The isoforms are distinguished from each other by their isoelectric charge, where ApoE4 is the most p ositive and ApoE2 is the most negative (Table 1) [10]. ApoE4 Unlike ApoE2 and ApoE3, ApoE4 binds less with HDL C (35 40%) than with RLP [11]. The decreased binding of ApoE4 with HDL C is thought to be due to its lack of a cysteine residue, which may prevent it from forming a mixed disulfide bond with ApoA-II, an apolipoprotein found on a number of HDL C particles [12]. Carriers of e4 and the ApoE4 isoform have been linked with impairment of cognitive function [13], AD [14], atherosclerosis [15] and CAD [16 18]. Gerdes et al. found that myocardial infarction survivors, who were carriers of ApoE4, had a nearly twofold increased risk of death when compared to other patients [19]. In contrast to ApoE2 and ApoE3, individuals with the ApoE4 isoform have increased level of small, dense LDL C particles, lower levels of HDL C [6] and increased levels of lipoprotein(a) (Lp[a]) [20]. Antioxidant activity is decreased and vitamin K1 levels are increased with ApoE4 [21,22], while insulin and glucose levels are increased in carriers of the e4 allele. [23]. Conversely, ApoE4 carriers have significantly lower high-sensitivity C-reactive protein (CRP) levels than the other isoforms [24]. Polymorphisms of ApoE may also modulate the lipid response to diet, exercise, h ormone-replacement therapy, tamoxifen, p robucol, omega-3-fatty acids [25], statins [26], niacin [27] and fibrates [28]. ApoE levels The ApoE isoforms circulate in different plasma concentrations and the same isoforms differ between individuals [29]. In a 5-year study examining CAD risk, Mooijaart et al. found that elevated plasma levels of ApoE in 546 elderly patients (>85 years old), independent of ApoE phenotype or lipid levels, were strongly associated with cardiovascular mortality [30]. The authors hypothesized that elevated plasma levels of ApoE may be related to a detrimental lipoprotein profile (particle size, ApoE/HDL binding state) and/or a proinflammatory response of ApoE, as previously suggested by van den Elzen and group [31]. Conversely, Reilly and Rader indicated elevated plasma levels of ApoE may merely represent a surrogate marker for atherogenic RLP particles and not an independent risk factor [32]. A more recent study by Van Vliet et al. examined a group of geriatrics (>85 years old) with elevated plasma levels of ApoE, excluding ApoE2-allele carriers, and discovered they had a significantly higher risk of developing ischemic cerebrovascular disease [33]. Multiple studies examining the relationship of plasma and/or CSF levels of ApoE4 with AD have been inconsistent in p redicting risk or severity of the disease [29,34 38]. ApoE-receptor binding The mechanism relating to CAD is not fully appreciated. ApoE participates in the clearance of RLPs by acting as a ligand for ApoE and hepatic LDLr [2]. Due to their size, as many as four ApoEs can bind with a single LDLr and increase their affinity fold [39]. Each ApoE isoform has a different affinity for the LDLr. ApoE2 has the lowest affinity for the LDLr and is slowly cleared from plasma, which results in an upregulation of LDLr proteins and lowering of plasma cholesterol [40 42]. ApoE4, the isoform with the highest binding affinity for the LDLr [41 43], increases its 312 Clin. Lipidol. (2009) 4(3)

4 Association of ApoE & HDL with cardiovascular & cerebrovascular disease Review Table 1. Characteristics of ApoE isoforms. E2 E3 E4 Residue 112 Cysteine Cysteine Arginine Residue 158 Cysteine Arginine Arginine % of total isoforms Particle charge plasma clearance but downregulates the hepatic receptor resulting in an elevation of plasma chol esterol [41,42,44,45]. Chou et al. suggested that ApoE4 has more flexibility in retaining a bond with the LDLr owing to its lack of disulfide bonds [46]. Additionally, ApoE4 is capable of transforming into a folding intermediate (molten globule) structure, which may maintain ApoE4 s stability under various conditions [8]. Heeren et al. found that in human hepatoma cells, the HDLinduced recycling of triglyceride-rich lipoproteins with ApoE3 resulted in cholesterol efflux and formation of ApoE-containing HDL, while ApoE4 accumulated in the cell s endosomal compartments and produced an increase of intracellular cholesterol [47,48]. HDL-C Multiple prospective studies support an inverse correlation between plasma levels of HDL C and CAD [49 54]. The antiatherogenic effects of HDL C include reverse cholesterol transport (RCT) [55], oxidation of phospholipids within LDL C [56], inhibition of inflammatory cytokines by reducing monocyte chemotaxis assay and vascular cell adhesion molecules [57]. Epidemiology studies have revealed a possible U-shaped relationship between HDL C plasma levels and vascular events (CAD and all-cause mortality) (Figure 1) [58]. A post hoc ana lysis of the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) study examined elevated HDL C levels in 8,888 patients using statin therapy and discovered, after adjustment for ApoA-I and ApoB, patients with elevated levels of HDL C (>70 mg/dl) conferred a higher risk of major coronary events (MCE) (Figure 2) [59]. The study also revealed that elevated levels of ApoA-I exhibited no relationship with increased MCE. Cholesterol ester transfer protein Cholesterol ester transfer protein is an enzyme that shuttles cholesterol esters (CEs) from a mature HDL C (a-hdl) to VLDL C in exchange for triglycerides [60]. Inhibition of CETP, either through genetics or pharmacotherapy, will result in a significant increase of plasma HDL C levels and size [61]. Animal and human studies exhibit both anti- and pro-atherogenic activities for CETP [61 64], leading to a debate on the advantage of inhibiting CETP [65,66]. The multi-year study Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) examined the clinical benefits of torcetrapib, an investigational CETP inhibitor that raises HDL C by more than 70%, with atorvastatin versus atorvastatin alone. The study was prematurely discontinued after 1 year due to torcetrapib s unexpected 60% increase of allcause mortality [67]. The rationale for the drugs increased adverse events is not fully understood; however, it is of interest that epidemiologic studies investigating the atherogenicity of HDL C in patients with CETP deficiency have inferred a negative correlation to CAD when total HDL C levels are less than 70 mg/dl and an increased correlation when HDL C levels are greater than 70 mg/dl [61,68]. One possible mechanism for the adverse correlation with CETP inhibition was proposed by Ishigami et al., who examined human HDL C (in vitro) from CETP-deficient patients and found them functionally abnormal in protecting macrophages from accumulating cholesterol [69]. Fewer events More events Adjusted odds ratio USA 14 n = y Norway 15 n = y Finland 16 n = y Russia 17 n = y Q1Q2Q3Q4Q5 S1S2S3S4S5S6 Q1Q2Q3Q4Q5 T1T2T3 PAVA n = y Q1Q2Q3Q4 Figure 1. Risk ratios for death from any cause based on mean HDL C levels. Reproduced with permission from [58]

5 Review Moriarty HDL-C category (mg/dl) > <40 Adjusted for ApoA-I and ApoB Relative risk for MACE in IDEAL Figure 2. Effect of HDL-C on major adverse cardiac events in the IDEAL trial. HDL-C: HDL-cholesterol; IDEAL: Incremental Decrease in End Points through Aggressive Lipid Lowering; MACE: Major adverse cardiac event. Reproduced with permission from [59]. HDL C size The size of most HDL C lipoproteins is usually less than 10 nm and may increase to 30 nm under circumstances such as CETP deficiency [70] and FH [71]. The size of HDL C (HDL 1, HDL 2 and HDL 3 ) generally determines its density, where the larger the size (HDL 1 ) the less dense the particle. Precursors of HDL C (pre-b HDL) and small-sized HDL 3 are lipidpoor ApoA-I-containing HDLs whose functionality includes accepting unesterfied cholesterol and phospholipids from peripheral tissues [72], which is then esterfied by plasma enzyme lecithin:cholesterol acyltransferase (LCAT) generating large spherical-shaped HDL 2 particles [73]. The large HDL 2 can be converted back to HDL 3 through lipolytic enzymes such as hepatic lipase (HL), following the removal of the liver s scavenger receptor type BI (SR BI), or after trans ferring CEs to VLDL C by CETP [74]. HDL 1 is formed during the LCAT-mediated HDL 3 /HDL 2 interconversion and is usually elevated when patients have ApoB- or ApoE-receptor deficiency (Figure 3) [75]. When evaluating antiatherogenic action, HDL 3 exhibits greater i nhibition of adhesion molecules in endothelial cells [76] and antioxidant activity than HDL 2 [77], while HDL 2 particles appear better ligands for the uptake of CE than HDL 3 [78]. Conflicting evidence exists on whether large- or small-sized HDL C enhances protection from CAD [79,80]. In an attempt to better analyze lipoprotein size, a post hoc ana lysis of the prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk case-controlled study of 25,663 patients, measured HDL C particle size by NMR spectroscopy and found an increased risk of CAD in patients with largesized (>9.53 nm) HDL C when compared with small-sized HDL C (Figure 4) [59]. Apolipoproteins Apolipoproteins are proteins that bind to lipoproteins. They serve as enzyme cofactors, receptor ligands and lipid transfer carriers that regulate the metabolism of lipoproteins and their uptake in tissues. Unlike LDL, which has only ApoB, HDL C contains multiple apolipoproteins bound to its membranes surface [81]. ApoA-I, the most common apolipoprotein found on HDL, is considered a major factor in reducing atherosclerosis and CAD by promoting RCT from tissues to the liver [82]. Even when HDL C levels are reduced, delipidated ApoA-I can independently lower the risk of CAD [83]. Eriksson et al. found the infusion of a recombinant human precursor of ApoA-I in FH patients promoted a net cholesterol excretion from the body, suggesting a stimulation of RCT, while increasing serum levels of small pre-b HDL C [84]. Increased levels of pre-b HDL C can also be found in patients with ApoA-I Milano, an apolipoprotein that is believed to increase cholesterol efflux and fecal sterol secretion [85]. By contrast, the CTEP inhibitor torcetrapib increases the size of HDL C, but has no i nfluence on sterol e xcretion [86]. HDL-altering drugs Pharmacotherapies that raise HDL C levels may vary in their effect on HDL C size. Fibrates elevate HDL C by converting large HDL 2 to HDL 3 through the increase of HL activity [87]. Statins [88], CETP inhibition [86], resins [89], omega-3-fatty acids [90] and nicotinic acid (niacin) [91] all form large-sized HDL. As previously mentioned, studies have found contradictory conclusions when examining the influence of HDL C size on CAD events with medications that raise HDL. The Lopid Coronary Angiography Trial (LOCAT) and Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) demonstrated fibrates ability to protect the progression of atherosclerosis in coronary/vein grafts and negatively predict new CAD, respectively, by elevated HDL 3 levels [92,93]. By contrast, Brown et al. demonstrated in the HDL-Atherosclerosis Treatment Study (HATS), which examined 314 Clin. Lipidol. (2009) 4(3)

6 Association of ApoE & HDL with cardiovascular & cerebrovascular disease Review the progression of coronary stenosis following combination lipid-lowering therapy (statins and niacin), that larger sized HDL C was a predictor of decreased coronary s tenosis [94]. HDL 1 HDL 1 is the largest sized HDL C particle (12 30 nm in diameter) when compared with HDL 3 and HDL 2 (7 10 nm) [95]. HDL 1 has an increased amount of CE and ApoE with minimal to no ApoA-1 [96]. HDL 1 is usually found in patients with CETP deficiency, FH or when placed on high-cholesterol diets [97,98]. The HDL 1 of CETP-deficient patients contains more ApoE (82%) than ApoA-1 (18%) [99], and the CETPinhibitor drug torcetrapib at 120 mg twice-daily, raises HDL 1 levels by 91%, ApoA-1 by 27% and ApoE by 66% [100]. Lower species, who lack ApoE isoforms and CETP, convert HDL C into their main plasma cholesterol transporter [101]. These large-sized HDLs, with an increased amount of ApoE, can intensify their binding to the LDLr by 10- to 100-fold [102]. The enhanced size and spherical shape of HDL 1 is considered a result of ApoE s ability to bind additional CE [103]. Discoid forms of HDL C are intermediates between lipid-poor ApoA-I and the more common mature spherical HDL. ApoA-1 on HDL C wraps around the discoidal phospholipid bilayer in a belt-like manner with a limited amount of CE collected in the core of the HDL-C [103,104]. The ApoE- phospholipid particle structure is spherical in shape and is able to fold into a semicircularlike horseshoe form [105]. The altered structure allows ApoE-containing HDL-C to accommodate a much larger amount of CE compared with ApoA-I [63]. Animal studies examining the function of HDL 1 suggest it may not always play a dominant role in RCT [106]. A canine study by Mahley et al. incubated LDL, VLDL, HDL 1 and normal HDL-C with smooth muscle cells (SMC) of cholesterol-fed dogs, and demonstrated that both LDL C and HDL 1 markedly increased the cholesterol c ontent in SMC while normal HDL C had no effect [96,97,102]. The authors suggested HDL 1 actions on SMC could be a ssociated with a ccelerated atherosclerosis. Inflammation & HDL Inflammation results in changes to lipid metabolism for the protection from toxic agents and tissue repair. Acute inflammation decreases HDL C Peripheral cells (macrophage) ABCA1 ApoE FC/PL SR-B1 ABCG1 FC/PL HDL 3 CE HL LCAT HDL 2 CE TG CETP LCAT CE ApoB-containing lipoproteins HDL 1 (HDL-E) CE LCAT SR-B1 LDLr ApoA-I (pre-β HDL) ABCG1 Liver Figure 3. Role of HDL C in the redistribution of lipids from peripheral cells (macrophage). CE: Cholesteryl ester; CETP: Cholesteryl ester transfer protein; FC: Free cholesterol; HL: Hepatic lipase; LCAT: Lecithin-cholesterol acyltransferase; PL: Phospholipid; TG: Triglyceride. Reproduced with permission from [105]

7 Review Moriarty HDL-C particle size category (mm) > <8.60 Adjusted for ApoA-I and ApoB Odds ratio for MACE in EPIC-Norfolk Figure 4. Effect of HDL-C particle size on major adverse cardiac events in the EPIC-Norfolk Trial. EPIC: European Prospective Investigation into Cancer and Nutrition; HDL-C: HDL-cholesterol; MACE: Major adverse cardiac event. Reproduced with permission from [59]. and impairs RCT, which leads to increased cholesterol in cells [107]. Khovidhunkit et al. found induced inflammation in animals lowered LCAT activity, increased ApoE and SAA, and decreased ApoA-I on HDL C [108,109]. SAA is an inflammatory marker produced mainly in the liver and expressed in the vasculature by IL-1, TNF or IL-6, and is increased 1000-fold in response to inflammation, malignancies, trauma and myocardial infarction [110]. Elevated SAA levels during the time of hospitalization for patients with unstable angina predict a poorer outcome [111]. SAA may be superior to CRP as a marker of clinical outcome in patients with the acute coronary syndrome [112]. SAA binds specifically to HDL-C containing ApoA-I or ApoE [113,114]. More than 80% of HDL C binding sites can be occupied by SAA, which results in the displacement of both ApoA-I and ApoE [110]. Clifton et al. demonstrated that, in humans following a myocardial infarction, SAA accounted for 8 87% (median 52%) of the apolipoproteins bound to HDL 3 with a normal density, but a size in the range of HDL 2 [115]. The authors attributed the increased size of HDL to SAA content, because three molecules of SAA are needed to replace one ApoA-I. The increased protein changes the size of the HDL- C, but maintains its density. Miida et al. found that when adding a recombinant SAA to plasma, the pre-b-hdl-c was increased by more than 150% [116]. Preb1-HDL C contains ApoA-I but no ApoA-II and has been found to be elevated in patients with CAD and unstable angina [117,118]. The binding of SAA to HDL C may alter the lipoproteins ability to protect LDL C from oxidation or monocyte chemotaxis and reduce HDL s anti-inflammatory activity [ ]. When SAA constitutes more than 50% of the HDL C protein the lipoprotein develops a higher affinity for macrophages than hepatocytes, resulting in a 30% reduction of cellular cholesterol efflux [122,123]. In addition to SAA, other proinflammatory mediators (ApoJ and ceruloplasma) bind to HDL C during an inflammatory event [121]. Central nervous system HDL C & ApoE The CNS is only 2% of the body, while its cholesterol content is close to 25% [124]. Due to the blood brain barrier (BBB), both ApoB and LDL C are undetected in the cerebral spinal fluid (CSF) [125]. The absence of ApoB leads to HDL C being the predominate lipoprotein [126]. Most HDLs in the CSF contain either ApoE, ApoA-I or a combination of the two [127]. The largest sized CSF lipoprotein (18 22 nm in diameter), considered to be HDL 1, has a density of less than kg/l and is bound to ApoE but not ApoA-I [128]. Yamauchi et al. found CSF ApoE2 and ApoE3 bound to HDL with densities of greater than kg/l and ApoE4 bound to HDL with densities of less than kg/l [129]. Smaller sized HDL-C (13 18 nm) in the CSF normally contain ApoA-I, but not ApoE [130]. The CSF also uses both (ApoE and ApoA-I) for the transport and delivery of cholesterol [127]. Gong et al. found human ApoE isoforms demonstrated unequal responses to cholesterol metabolism, where ApoE3 HDL-C induced a much stronger release of cholesterol from cultered neurons than ApoE4 HDL-C [131]. The authors suggested that ApoE4 has a higher affinity for lipid particles and the increased affinity forms a complex with the lipid particles, which may inhibit the release of cholesterol. Astrocytes and glial cells synthesize ApoE in the CNS [132]. Non-CNS-produced ApoE is unable to pass through the BBB [133,134] while ApoA-I, which is primarily produced in the liver, is capable of passing through the BBB [135]. CSF ApoE acts as a ligand for cell-surface lipoprotein receptors on glia and neurons [136] and participates in lipid transport, neural development and response to injury [137]. ApoE4 is a risk factor for AD, stroke and post-head trauma [138,139]. AD is characterized by deposits of amyloid plaques and neurofibrillary tangles in 316 Clin. Lipidol. (2009) 4(3)

8 Association of ApoE & HDL with cardiovascular & cerebrovascular disease Review the brain [140]. A possible pathological mechanism for AD includes disruption of cholesterol homeostasis and amyloid b (Ab) protein [141]. Koudinov et al., after sequential flotation ultracentrifugation and ana lysis for the presence of Ab protein via immunoblot, found human CSF Ab proteins were bound to large-sized (16.8 ± 3.2 nm) HDL C particles [142]. Ladu et al. discovered that cell cultures of native ApoE3 but not ApoE4 prevents Ab-induced neurotoxicity through a mechanism dependent on ApoE receptors [143]. Animal studies demonstrating potential adverse effects of ApoE4 with AD include inhibition of neurite growth [144], disruption of neuronal outgrowth [145] and increased neurodegeneration [146]. CNS Inflammation Neuroinflammation plays a major role in AD [ ]. Markers of inflammation, such as SAA, CRP and serum amyloid P (SAP), have been isolated from senile plaques in patients with AD [ ]. CSF levels of SAA in AD patients can be ten-times greater than normal [150,153]. SAA and SAP are primarily synthesized from the liver with small amounts produced in the brain [154,155]. Similar to SAA, SAP is bound to HDL, found in atherosclerotic plaques, and may be associated with CAD [156,157]. SAA dissociates both ApoA-I and ApoE from CSF HDL C and may prevent ApoE from binding or clearing Ab from the CSF [158]. CNS ApoA II-bound HDL C has been identified as the apolipoprotein with the highest resistance to SAA-induced disassociation from CSF-HDL C [159]. Innerarity et al. found ApoA-II forms a disulfide bond with ApoE2 and ApoE3 but not ApoE4 [102], which may be due to ApoA-II having a cysteine at residue 6 [160] and, unlike ApoE2 and ApoE3, carriers of ApoE4 lack the hydrophobic amino acid. Miida et al. suggested ApoE4 s inability to form a disulfide-linked dimer with ApoA-II may produce a CSF-HDL C that is more susceptible to SAA-induced dissociation, and this could inhibit the clearance of Ab from the CSF [161]. Familial hypercholesterolemia Familial hypercholesterolemia is an autosomaldominant disorder of cholesterol metabolism with a phenotypic presentation of excessive plasma levels of LDL C and deposition of cholesterol in tendons, skin (xanthomas) and arteries (artheromas), which may result in premature atherosclerosis and CAD. FH is commonly caused by a loss-of-function mutation in the LDLr gene or by a mutation in the gene encoding ApoB [162]. The most common single gene defect occurs with a frequency of one in 500 for heterozygotes (LDL C levels: mg/dl) while the frequency of homozygotes (LDL C levels: >400 mg/dl) is one per 1,000,000 individuals [163]. HDL C & ApoE Lipid abnormalities seen in FH patients are not restricted to LDL C but can include decreased levels of HDL C [164,165], ApoA-I and ApoA-II [166]. The pre-b-migrating fraction of ApoA-I in FH patients is much higher (20 40%) when compared with normolipidemic patients (4%) [167]. Ferrieres et al. revealed low levels of HDL C seen in FH patients can significantly increase the risk of CAD [168]. In contrast to the general population, FH patients have a fiveto ten-fold increase of ApoE-rich HDL 1 and less HDL 2 or HDL 3 [75]. Despite an increase in ApoE-rich HDL 1 the percentage of ApoEbound HDL-C is lower in FH patients (46%) than the general population (60%) [169]. The ApoE4 phenotype encompasses 50% of total ApoE in FH patients compared with 15% in the general population [ ]. FH patients who are positive with the e4 allele, have lower levels of HDL-C and higher levels of LDL-C [ ]. Eto et al. found, in addition to decreased HDL-C and increased LDL-C levels, FH patients with the ApoE isoform have a significantly higher prevalence of ischemic heart disease (73%) than patients without the ApoE4 isoform [176]. LDL-apheresis LDL-apheresis was developed as a treatment for FH patients with hyperlipidemia (LDL C > 200 mg/dl) and CAD who were unresponsive to lipid-lowering medications. The first published apheresis treatment (1967) for an Table 2. Plasma lipoproteins reductions (%)* following a treatment of LDL-apheresis. Lipids Change (%) LDL-C HDL-C 0 30 Triglycerides Lp(a) *High variation of values may result from the difference in treated plasma volumes

9 Review Moriarty Heparin pump Repriming solution Regeneration solution Blood withdrawal Blood pump Plasma pump Regeneration pump Plasma seperator Liposorber columns Blood return Plasma line Waste line Figure 5. Dextran sulfate LDL C absorption. FH patient used simple centrifugation separation (plasma exchange) [177]. Today s apheresis devices selectively remove LDL and, unlike plasma exchange, do so without significant reductions of nonlipid molecules such as albumin, electrolytes or immunoglobins [178]. On average, over 60% of ApoB lipoproteins are immediately reduced following a single procedure (Table 2). The limited population and ethical question of sham therapy has restricted Table 3. Vascular proinflammatory changes (%)* following a treatment of LDL-apheresis. Marker Change (%) MCP-1-15 to -20 MMP-9-20 TIMP -30 ET-1-25 to -75 LBP -27 Lp-PLA 2-22 VCAM-1-10 to -20 ICAM-1-10 E-selectin -6 to -31 Fibrinogen -20 to -65 Oxidized LDL -65 SAA -80 SAP -90 CRP -65 *High variation of values may result from the difference in treated plasma volumes. CRP: C-reactive protein; ET: Endothelin; ICAM: Intercellular cellular adhesion molecule; LBP: Lipopolysaccharide binding protein; Lp-PLA 2: : Lipopolysaccharide phospholipase A 2 ; MCP: Monocyte chemoattractant protein; MMP: Matrix metalloproteinase; SAA: Serum amyloid A; SAP: Serum amyloid P; scd40l: Soluble CD40 ligand; TIMP: Tissue inhibitor of metalloproteinase; VCAM: Vascular cellular adhesion molecule. Reproduced with permission from [184]. an implementation of a randomized, doubleblinded, placebo-controlled trial. To this day, the Hokuriko study is the largest (130 patients) and longest (6 years) nonrandomized trial to demonstrate the clinical benefits of LDLapheresis [179]. FH patients with CAD on lipid-lowering therapy (statin plus probucol and resin or fibrate) and LDL-apheresis were compared to a control group of 87 FH patients with CAD who were receiving only lipid-lowering therapy. After 6 years of treatment, 10% of the LDL-apheresis-treated group had a coronary event (primary end point) compared with 36% in the control group (p = ). The results demonstrated a 72% relative risk reduction with a number needed to treat of four for patients using LDL-apheresis in addition to pharmacotherapy. The mechanisms of LDL-apheresis that specifically removes LDL C includes antibodies to ApoB, ultrafiltration, or an attraction to positive surface membrane-charged particles such as ApoB [180]. The two devices approved in the USA (Liposorber Kaneka [Osaka, Japan] and Secura, B Braun [Melsungen, Germany]) for LDL C removal are based on ApoB charge. Compared with normal ph, ApoB has a positive isoelectric point [181] while HDL C is negatively charged [182,183]. The negatively charged dextran sulfate filter (Liposorber) (Figure 5) or the low ph (5.12) acetate buffer with polyanion heparin (Secura) (Figure 6) form nonsoluble precipitates with the positively charged amino acid domains on ApoB [184]. 318 Clin. Lipidol. (2009) 4(3)

10 Association of ApoE & HDL with cardiovascular & cerebrovascular disease Review Inflammation Multiple studies support the role of inflammation in the development of atherosclerosis and CAD [185]. Levels of CRP, an inflammatory marker found in plasma and atherosclerotic lesions, improves the global classification of CAD risk [186], and reduction of CRP and LDL C by statin therapy, in healthy patients with elevated CRP and normal lipids significantly lowers CAD events [187]. A treatment of LDL-apheresis will acutely reduce plasma inflammatory markers, such as CRP, fibrinogen, monocyte chemo attractant proteins, lipoproteinassociated phospho lipase A 2 (Lp-PLA 2 ), lipopolysaccharide-binding protein, oxidized LDL, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (Table 3) [184]. Chronic LDL-apheresis therapy reduces pretreatment levels of inflammatory markers such as CRP and Lp-PLA 2 by 50 and 25%, respectively [ ]. As with lipid levels, reductions of inflammatory markers may vary depending on the method of LDL-apheresis and the treated volume. Hemorheology Blood viscosity, the frictional force that develops between adjacent layers of blood, is altered by shear forces, hematocrit, red blood cell (RBC) aggregation, RBC deformability and plasma viscosity [193]. Arterial hemodynamic forces, such as shear stress (the tangential force on the endothelial wall) and blood viscosity, play a major role in determining where vascular pathology Table 4. Vascular hemorheology changes (%)* following LDL-apheresis. Markers Change (%) RBC# aggregation -30 to -50 RBC# deformability 30 to 45 Plasma viscosity -10 to -15 Blood viscosity -5 to -15 *High variation of values may result from the difference in treated plasma volumes and fibrinogen reduction. RBC: Red blood cell. originates [194]. LDL C and triglycerides have a positive relationship with blood viscosity [ ], while HDL C [198] and more significantly ApoA-I [199] are negatively associated with blood viscosity. One mechanism by which HDL C lowers blood rheology is to reduce RBC a ggregation by competing with LDL-C binding to the RBC [200,201]. LDL-apheresis reduces blood viscosity (5 15%) by improving RBC deformability, lowering RBC aggregation and decreasing plasma viscosity (Table 4) [202]. HDL Despite LDL-apheresis selectiveness in removing ApoB, a small percentage (10 15%) of HDL C is acutely reduced, while long-term therapy preserves or enhances baseline HDL C levels [203]. The suggested mechanisms for HDL s acute reduction by LDL-apheresis have included filtration, hemodilution, activation of HL or decreased activity of LCAT [204]. It has been Buffer/heparin Blood withdrawal Blood pump Plasma pump Precipitation Filtration Plasma seperator Blood return Dialysis and ultrafiltration LDL-free plasma LDL precipitate Heparin absorption H 2 O Figure 6. Heparin-induced extracorporeal LDL C precipitation. Reproduced with permission from [121]

11 Review Moriarty demonstrated that allowing LDL-apheresis to remove more HDL C than ApoA-I (three to one) [ ] may involve the lipoproteins surface membrane charge. Owing to its net negative charge, heparin can associate with a number of positively charged plasma proteins [208]. Heparin s negative N- and O-sulfo groups, similar to dextran sulfate, participate in an ionic interaction with the positive charges of the amino acids lysine and arginine of ApoB and ApoE [209]. The inflammatory markers SAA and SAP have the capability to bind with heparin or dextran sulfate [210,211] allowing LDLapheresis to reduce plasma levels of SAA and SAP by 80 90%, respectively [ ]. SAP- and SAA bound HDL C may alter the lipoproteins attraction and removal by LDL-apheresis. We previously tested LDL-apheresis s ability to enhance the function of HDL-C. Inflammation induced major changes to the levels and composition of HDL-C. Navab et al. have suggested the proinflammatory/antiinflammatory properties of HDL-C may be indirectly measured through its inability/ability to inhibit LDL-induced monocyte chemotactic activity [215]. We analyzed the pre- and postplasma inflammatory HDL-C levels of 13 FH patients who were receiving chronic biweekly LDL-apheresis therapy and discovered 37% of the total amount of HDL-C reduced (16%) was of the p roinflammatory type [216]. ApoE LDL-apheresis acutely lowers plasma levels of ApoE by 50 75% [217,218]. To evaluate if and how much ApoE is removed following LDL apheresis, Koizumi et al. examined the post LDL-apheresis adsorption columns (Liposorber) on ten (three homozygous and seven heterozygous) FH patients compared to a control group, and identified ApoE-enriched HDL C bound to the column without any detectable levels of ApoA-I or ApoA-II [219]. The author also discovered the serum molar ratio of ApoE and ApoA-1 was significantly decreased (>50%) after LDL-apheresis. Polyanions, such as heparin and dextran sulfate, have a high affinity for HDL 1 [75]. ApoE-bound HDL-C is less negatively charged than ApoA-bound HDL-C [220] and ApoE-bound HDL-C has a higher attraction to heparin [208,221,222]. Since the negativecharged Liposorber and Secura systems remove more HDL-C than ApoA-I, they appear to be more selective in removing ApoE HDL-C such as HDL 1. ApoE4 ApoE4 has a more positive charge than the other isoforms and this may increase the attraction and removal of ApoE4 by LDL-apheresis. To examine this hypothesis, we analyzed plasma levels of ApoE4 (immunoassay) immediately before and after LDL-apheresis in ten heterozygous FH patients (eight Secura, two Liposorber) who had detectable plasma levels of the apolipoprotein (abstract, XV, International Symposium on Atherosclerosis, June 2009). Following one treatment of LDL-apheresis, ApoE4 levels were lowered by 39% and the change to HDL-C levels was significantly associated with the reduction of ApoE4. These results suggest the reduction of ApoE4 by LDL-apheresis is related to the selective reduction of a particular HDL-C bound to ApoE4. LDL-apheresis & cerebral vascular disease One of the earliest clinical manifestations of AD involves reduced cerebral blood flow (CBF) or cerebral hypoperfusion [223]. Sun et al. revealed mild cognitive impaired (MCI) patients, when compared with controls, had a significant decline in mean systolic and diastolic CBF velocity bilaterally for the middle cerebral artery (MCA) and the anterior cerebral artery (vessels that supply areas for cognitive function) [224]. They also found carriers of the ApoE4 allele in the MCI group had significantly lower blood flow in the MCA when compared to the MCI group who were not carriers of ApoE4. Lautenschlager et al. studied 138 adults with subjective memory impairment who had a 6 month program of physical activity and discovered a modest improvement in cognition following an 18 month follow-up period when they were compared with usual care [225]. The authors suspected the improved cognitive function was due to increased vascular perfusion in the brain. Immediate vascular effects following LDL apheresis include enhancement of endothelial function [226], microvascular flow [227], vascular perfusion [228] and reduction of vascular resistance [229]. Pfefferkorn et al., using trans cranial Doppler sonography, examined CO 2 reactivity as a marker of cerebral vasoreactivity in CAD patients with hyperlipidemia after LDL apheresis. The outcome illustrated an increase of CO 2 reactivity from 22 to 36% (p < 0.05) [230]. The authors proposed the fast and drastic removal of oxidized LDL, Lp(a) and fibrinogen resulted in an improvement of c erebrovascular reactivity. 320 Clin. Lipidol. (2009) 4(3)

12 Association of ApoE & HDL with cardiovascular & cerebrovascular disease Review Using Xenon-133 single photon emission computed tomography (XeSPECT) as a measuring tool, Walzl et al. found one treatment of LDLapheresis improved whole-brain perfusion by 14% (p < 0.009) and regional cerebral perfusion by 10 20% (p < 0.05) in 15 patients suffering from cerebral multi-infarct disease when they were compared with a control group [231]. The authors hypothesized improved vascular flow was due to the immediate and statistically significant reduction of all parameters associated with hemorheology. In another study performed by Walzl et al. [232], 48 non-fh patients, 22 with multi-infarct dementia (MID) and 26 with acute embolic stroke, were administered two treatments of LDL-apheresis over an 8-day period. Both treated groups confirmed a significant enhancement of neuropsychological exams, such as the Mathew scale (MS; pre 85.8/post 94.3; p < 0.05), minimental state examination (MMSE) (pre 26.0/post 29.3; p < 0.05) and activities of daily living (ADL) (pre 85.5/post 92.5; p < 0.05) compared to either baseline or the control group. Finally, Walzl et al. studied 44 non-fh patients with MID in which 24 were exposed to a single Secura LDL-apheresis treatment compared with 20 receiving sham therapy. Results demonstrated a significant enhancement of neuropsychological exams such as the MS (pre 89.2/post 94.1; p < 0.01), MMSE (pre 24.7/ post 27.2; p < 0.03) and ADL (pre 90.1/post 96.7; p < 0.05) up to 56 days post-therapy where no changes could be seen in the controls [233]. A more recent pilot trial examining the cognitive and psychological function of seven FH patients with no known cognitive impairment demonstrated, after one treatment, an improvement of verbal learning that was maintained over the next 2 months [234]. Conclusion & future perspective ApoE isoforms perform key roles in lipid transport throughout the body, including the CNS where they are involved in the maintenance and repair of nervous tissue. The three ApoE isoforms found on RLP and HDL C do not execute the same physiological function in that ApoE4, unlike ApoE2 and ApoE3, is associated with AD and CAD. The pathological mechanism of ApoE4 is unclear but may be related to its positive charge, binding to particular lipoproteins, inability to form a complex with ApoA-II, increased affinity for the LDLr, or through another mechanism presently unknown. Small- and large-sized HDL C has been linked with coronary atherosclerosis [235,236]. The antiinflammatory action of HDL 3 observed in normal situations may be lost during proinflammatory/ proatherogenic conditions. El Harchaoui et al. found in a nested case control study group (EPIC) of 822 patients, that the size of HDL-C was smaller in the patients who developed CAD than in the control group [237]. The authors found the relationship between HDL C size and CAD risk was explained by markers associated with the metabolic syndrome, indicating the correlation of HDL C size and CAD risk may be merely a reflection of the metabolic risk. The alteration in HDL C size and function due to the content of apolipoproteins may account for the inconsistencies of correlating HDL C size to CAD risk or benefit. SAA and ApoE4 have the capability of changing the size, function and electrostatic charge of HDL C while displacing ApoA-I and ApoA-II. HDL 1, found in patients with CETP deficiency and FH, contain elevated levels of ApoE with little or no ApoA-I. ApoEbound HDL C accommodates larger portions of CE than ApoA-I and has a higher affinity for the LDLr than LDL. RCT may be impaired when HDL 1 is bound to specific a polipoproteins, such as ApoE4 or SAA. Another physiologic function of HDL C involves rheology, in particular blood viscosity [198]. HDL C reduces blood viscosity by either inhibiting RBC aggregation or increasing RBC deformability [238]. Lowered rheology will improve vascular flow and microvascular perfusion. Large-sized HDL 1 bound to a particular apolipoprotein may modify the rheology c apability of the lipoprotein. The CNS lacks ApoB and is dependent on HDL, ApoA and ApoE for the transport of cholesterol. ApoE4 may inhibit neuron growth and increase neurodegeneration. CNS inflammation has an association with AD and ApoE4. The binding of SAA or ApoE4 might transfer HDL C into a proinflammatory lipoprotein. The altered HDL C may be unable to clear Ab plaques and result in enhanced Ab production [46]. Familial hypercholesterolemia patients have decreased levels of HDL C with less ApoA-I, ApoA-II and increased ApoE-rich HDL 1. The higher content of ApoE4 observed in FH patients is connected with an increased risk of CAD. How much influence the level and composition of HDL-C have with the progression of premature CAD in FH patients is presently unknown, and the question remains whether HDL-C should be treated as aggressively as LDL-C? LDL-apheresis is a proven therapeutic tool for the reduction of plasma lipoproteins and CAD for patients with FH. In addition to removing 321

13 Review Moriarty charged ApoB lipoproteins, plasma proteins such as SAA, CRP and ApoE4 are attracted to the devices negatively charged polyanions. The abstraction of these pathologic plasma proteins, improved hemorheology and vascular function by LDL-apheresis may account for the potential benefit observed in certain vascular diseases not necessarily associated with FH. Trials implementing LDL-apheresis therapy for non-fh patients have demonstrated clinical improvements in idiopathic deafness [ ], peripheral vascular disease (PVD) [ ], nephrotic syndrome [246,247], ocular micro circulatory diseases [ ] and pre-eclampsia [251]. Presently, non-fh related diseases have been approved for the use of LDL-apheresis by the national Health Insurance program of Japan in hyperlipidemia (LDL-C > 140 mg/dl) patients with end-stage PVD and hyperlipidemia (total cholesterol > 250 mg/dl) and patients with the nephrotic syndrome. LDL-apheresis s compilation of contributions to the vascular system may be regarded as a form of vascular stabilization. Treatments to non-fh patients could be implemented prior to an elective vascular surgery procedure, during an acute vascular event, and/or for maintenance therapy of chronic vascular diseases. Utilization of LDLapheresis in these situations may promote a reduction of morbidity and mortality. Outcome trials are sorely needed to expand the potential clinical implementation of LDL-apheresis. Financial & competing interests disclosure Patrick Moriarty receives research funding from B Braun and Kaneka, and is a consultant for B Braun. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials d iscussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Executive summary ApoE ApoE4 is associated with both cardiovascular disease (CVD) and Alzheimer s disease (AD). The pathology of ApoE4 may be related to its positive charge, binding to particular lipoproteins, inability to form a complex with ApoA-II, or higher affinity for the LDL C receptor (LDLr). HDL Elevated levels of HDL C may be a marker for an increased risk of CVD. The size of HDL C is inconsistent as an accurate measurement of an increased or decreased risk of CVD. Large HDL, in particular HDL 1, contain an increased amount of ApoE with little to no ApoA-I. Serum amyloid A (SAA) binds to HDL C and displaces ApoA-I, altering the lipoproteins ability to protect LDL C from oxidation or monocyte chemotaxis and reducing HDL s anti-inflammatory activity. Central nervous system The CNS has no ApoB lipoprotein as a source of cholesterol but instead employs HDL, ApoA-I and ApoE for cholesterol transport. ApoE4-bound HDL C is less efficient in delivering cholesterol to nervous tissue. SAA-bound HDL C may prevent ApoE from binding or clearing amyloid-b from the cerebrospinal fluid. SAA binds more readily to ApoE4-bound HDL. Familial hypercholesterolemia Familial hypercholesterolemia (FH) patients have decreased levels of HDL C and ApoA-I with increased ApoE-rich HDL 1 and ApoE4. LDL-apheresis LDL-apheresis lowers LDL-C by 60% and HDL C by 15%. Therapy is used for FH patients resistant to pharmacotherapy. The mechanism LDL-C removal involves the electrostatic charge of plasma proteins. Reduction of HDL C levels during LDL-apheresis may be related to apolipoproteins, such as ApoE4 and/or SAA, bound to the lipoprotein. LDL-apheresis & cerebral vascular disease One of the earliest clinical manifestations of AD entails reduced cerebral blood flow. LDL-apheresis improves microvascular flow and vascular perfusion in the CNS. Pilot studies have suggested LDLapheresis may provide neuropsychological benefit for patients suffering from multi-infarct dementia. Future perspective The various contributions to the vascular wall and alteration of plasma proteins seen with LDL apheresis therapy may warrant its use in vascular disease not associated with FH. LDL-apheresis might be considered a form of vascular stabilization in patients preparing for elective surgery, with an acute vascular event, or maintenance therapy for patients with chronic vascular diseases. These potential uses and others will require outcome studies examining the vascular benefits of LDL-apheresis. 322 Clin. Lipidol. (2009) 4(3)

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