Rheumatology 2006 Tincani Iv8 Iv13

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Heart involvement in systemic lupus erythematosus,anti-phospholipid syndrome and neonatal lupus

A. Tincani, C. B. Rebaioli, M. Taglietti and Y. Shoenfeld1

Cardiac involvement is one of the main complications substantially contributing to the morbidity and mortality of patients

suffering from systemic autoimmune diseases. All the anatomical heart structures can be affected, and multiple pathogenic

mechanisms have been reported. Non-organ-specific autoantibodies have been implicated in immune complex formation and

deposition as the initial triggers for inflammatory processes responsible for LibmanSacks verrucous endocarditis, myocarditis

and pericarditis. Anti-phospholipid antibodies have been associated with thrombotic events in coronary arteries, heart valve

involvement and intra-myocardial vasculopathy in the context of primary and secondary anti-phospholipid syndrome.

Antibodies-SSA/Ro and anti-SSB/La antigens play a major pathogenic role in affecting the heart conduction tissue leading

to the electrocardiographic abnormalities of the neonatal lupus syndrome and have been closely associated with endocardial

fibroelastosis.

Introduction

Nowadays, cardiac involvement is one of the major concerns inthe management of patients suffering from systemic autoimmunediseases. Such an involvement has been recognized since thebeginning of 20th century, but in the last decades, newlyrecognized clinical entities have been detailed due to theintroduction of very sensitive, non-invasive or semi-invasivecardiac imaging techniques [1].

Several autoantibodies, such as anti-phospholipid antibodies(aPL), anti-SSA/Ro antibodies and anti-endothelial cells anti-bodies, can mediate cardiac damage.

These autoantibodies can directly affect heart tissue or,alternatively, can trigger mechanisms able to cause heart

damage: for example, aPL can contribute to cardiac damageenhancing atherosclerosis phenomena, causing thrombosis ofcoronary arteries or starting an immune-complexes-mediatedreaction and deposition at the valves level.

Consequence of autoantibodies damage has been reported inseveral heart structures such as valves, myocardium, pericardium,conduction tissue and cardiac arteries in patients suffering fromsystemic lupus erythematosus (SLE), anti-phospholipid syndrome(APS), Sjogren syndrome and other autoimmune rheumaticdiseases (ARD).

Cardiovascular disease has recently been acknowledged as aprimary cause of morbidity and mortality in SLE as well as inAPS, and numerous factors leading to accelerated atherosclerosishave been characterized.

Other cardiac manifestation, such as pericarditis, myocarditis,

endocarditis and conduction disturbances, when present, are oftenmild and, usually, subclinical features are more prevalent thanclinically apparent disease.

Heart involvement in neonatal lupus

Complete heart block (CHB) is the most serious manifestation ofthe neonatal lupus syndrome (NLS), a congenital syndrome inwhich maternal IgG anti-Ro/SS-A autoantibodies cross theplacenta and injure an otherwise normally developing heart [2].

Fetal/neonatal disease is independent of maternal disease: infact, mothers may have SLE, Sjogren syndrome or otherautoimmune symptoms, or may be entirely asymptomatic [3].

CHB generally appears on an intact heart and must bedifferentiated from secondary heart block due to cardiacmalformations, which is not associated with anti-SSA/Ro oranti-SSB/La antibodies.

CHB is often regarded as a model of passively acquiredautoimmunity in which antibodies are necessary but insufficientto cause CHB, and fetal factors are likely contributory [4]some evidence against the role of anti-SSA/Ro andanti-SSB/La antibodies alone in the pathogenesis of CHB arelisted below: (i) CHB is rare in adults with these antibodies;(ii) there is a discordance of CHB in monozygotic twins [5];

and (iii) there are few babies of Ro/La mothers affected byCHB [3].

Detection of CHB in the fetuses most commonly occurs in uterobetween 17 and 24 weeks of gestation [3]. CHB may be associatedwith fetal myocarditis [6] that can lead to fetal hydrops andstillbirth.

The degree of heart block includes all levels from first degree,discovered accidentally with electrocardiogram after the birth or

in utero by a prolonged PR interval detected on echocardiogram,

through third degree (complete) heart block, the most frequentlyrecognized. Complete CHB, once established, is irreversible. It is

clearly documented that incomplete blocks (including thoseimproving in utero with dexamethasone) can progress after birth

despite the clearance of the maternal autoantibodies from

the neonatal circulation [7]. In Buyons registry, among ninechildren with a CHB of first degree, four have shown block

progression after birth and among others, two of four newborns

with CHB of second degree progressed toward a third degree

CHB.Such post-natal progression of CHB has been described in the

past by others and today justifies performing electrocardiogram inall children born to anti-SSA/Ro positive mothers [8].

CHB carries a significant morbidity and mortality (1530%)most often in utero or in the first few months of life: in fact,

Reumatologia e Immunologia Clinica, Ospedale Civile e Universita` di Brescia, Italy and 1Department Medicine B and Center for Autoimmune Diseases,

Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Hashomer, Israel.

Correspondence to: Angela Tincani, MD, Reumatologia e Immunologia Clinica, Ospedale Civile, Piazza Spedali Civili 1, 25125 Brescia, Italy.

E-mail: [email protected]

Rheumatology 2006;45:iv8iv13 doi:10.1093/rheumatology/kel308

iv8 The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]


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67% of all the recognized cases require a pacemaker insertionbefore reaching adulthood [3]. Risk factors for permanentpacing are represented by very slow heart rates and symptomslike poor exercise tolerance, cardiomegaly, long QRS or QTdurations, ectopy, syncope or structural or functional heartdisease [9].

Cardiac damage may extend beyond the conduction system.There is a 10% incidence of late-onset dilated cardiomyopathy

(CM) developing despite the early successful pacemaker implanta-tion for the associated heart block [3, 10]; in these patients,CM led to congestive heart failure and subsequently death orcardiac transplantation in four and eight infants, respectively. Therisk to develop CM for children with CHB was valuated at 511%[10]: for this reason, children with CHB need a close follow-upof electrocardiogram and function of pacemaker, as well asventricular function. Moreover, CM can be seen in the absence ofheart block.

Recently, Nield et al . [11] have reported an endocardialfibroelastosis associated with CHB in 13 children born toanti-SSA/Ro or anti-SSB/La positive mothers. In all 13 cases(six in prenatal, seven in post-natal), a severe ventriculardysfunction was diagnosed: 11 of them died and two receivedcardiac transplantation.

The incidence of CHB in an offspring of a mother with anti-SSA/Ro antibodies is about 2%, while, if the mother already hada first affected child, the risk of CHB in a subsequent pregnancyrises to 18% [3, 12, 13]. Optimally, all pregnant women withanti-SSA/Ro or -SSB/La antibodies should have a serial fetalechocardiography done by an experienced paediatric cardiologistweekly from 16 to 26 weeks, and every other week until about34 weeks to evaluate the fetal heart during the period of presumedvulnerability [14]; the development of a non-invasive Dopplertechnique to measure the mechanical PR interval may, in this way,allow an earlier diagnosis and treatment opportunities [15]. Theearly diagnosis of the CHB and its potential complications(pericardial effusion, myocarditis) usually can avoid the deteriora-tion of the fetal cardiac function. When imaging techniques show

in utero the presence of incomplete CHB, the suggested treatmentof mothers is based on fluorinated steroids (dexametasone orbetametasone). These cross the placenta and are available to thefetus in an active form [16], inhibiting the immune process in thefetal heart. Fluorinated steroids may also improve the survivalof fetuses with a complete CHB, even if there is no evidence ofa durable recovery [17]. According to some authors, betametasoneshould be preferred because of the reported risks associatedwith high dexamethasone doses to the fetal brain [18, 19].We have recently evaluated the neuropsycological developmentin 13 children born with CHB, of which 11 were exposed to highdoses of dexamethasone during fetal life and two were not: evenif some bias due to the small cohort, interestingly, a clinicallyborderline case of learning disabilities was found in a child notexposed to dexamethasone [20].

The prophylactic therapy of the high-risk mother (those withanti-SSA/Ro antibodies and a previous child with CHB) withfluorinated steroids actually is not recommended because of thesuspected neurological toxicity of dexamethasone [18, 19] and thehigh rate of adverse obstetrical events (including spontaneousabortions, stillbirth, severe intrauterine growth restriction andadrenal suppression) in patients treated with steroids to preventCHB [21].

In addition to the classical complete and incomplete CHB,a high frequency of transient fetal first degree CHB has beenrecently reported, that in most of the cases is spontaneouslyreverted before or shortly after birth [22].

Other possible cardiac manifestations, such as sinus bradycar-dia or prolonged QTc interval in otherwise healthy children ofanti-SSA/Ro positive mothers, have not been confirmed and arecurrently a matter of debate [23, 24].

Heart involvment in systemic lupus erythematosus

The heart is frequently involved in SLE: very sensitive methods ofcardiovascular investigation have found the prevalence of cardiacinvolvement to be >50% [25].

In the past, cardiac manifestations were severe, often leading todeath and they were frequently found in post-mortem examina-tions. Nowadays, cardiac manifestations are often mild and

asymptomatic and they can be recognized by echocardiographyand other non-invasive tests [26].

All three layers of the heartpericardium, myocardium andendocardiumcan be involved by lupus; this section will focus onpericarditis and myocarditis because heart valve abnormalities arecommon lesions in either SLE and APS and will be discussed innext section.

Pericarditis

Pericarditis is the most studied cardiovascular manifestation ofSLE, although often not evident clinically, and it is included in theAmerican College of Rheumatology (ACR) classification criteriafor SLE.

The pericardium can be involved by acute and chronicinflammatory changes; granular deposition of immunoglobulinand C3, demonstrated by direct immunofluorescence, support therole of immune complexes in the development of pericarditis.

The reported prevalence of pericardial abnormalities, detectedby echocardiographic studies, ranges from 11 to 54% [27]: thisvariability is partially attributable to the methods used todocument pericardial disease and whether symptomatic orasymptomatic cases are included. Clinical (symptomatic) pericar-ditis is estimated to occur in 25% of SLE patients at some pointin the course of their disease. Asymptomatic pericardial effusion isclearly more common than clinical pericarditis: in fact, 40% ofunselected patients with SLE have pericardial effusion, detectedusing echocardiography. Moreover, a combined autopsy seriesrevealed pericardial involvement in 62% of patients with SLE [28].

Pericardial involvement appears more frequently at SLE onsetor during SLE relapses, although it can occur at any time of thedisease [26]. Pericarditis usually appears as an isolated attack or asrecurrent episodes [29].

Signs and symptoms of acute pericarditis include a typicalprecordial or substernal chest pain, usually positional (aggravatedby lying down), often with a pleuric quality, sometimes withdyspnoea; moreover, patients may have fever, tachycardia anddecreased heart sounds; pericardial rubs can be heard but usuallyare rare, perhaps because they are present often for only a fewhours and are missed. The diagnosis can be confirmed by ECGfindings of elevated ST segments and peaked T waves (althoughslight T-wave changes or transient elevation of ST segments aremost characteristic). Co-existent pleurisy, effusion or both arecommon [30].

Patients with pericardial effusion (as opposed to thickening) aremore likely to have pericardial pain and active lupus elsewhere;when present, pericardial effusion are usually small and do notcause haemodynamic problems [31]. Echocardiography representsthe standard method to investigate pericardial abnormalitiesand is able to demonstrate mild effusion or thickening ofpericardial layers, therefore, should be performed periodically inSLE patients.

Complications of pericarditis, such as cardiac tamponade,constrictive pericarditis and purulent pericarditis are rare,and invasive procedures such as pericardiocentesis or pericardialwindow are rarely needed.

Non-steroidal anti-inflammatory drugs and/or corticosteroidsare the first line of treatment in mild pericarditis. Intravenousbolus of corticosteroid is necessary in more severe cases or iftamponade is present, while in patients with recurring pericarditis,

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chronic suppression with methotrexate, azathioprine or mycophe-nolate mofetil may be effective.

Myocarditis

Myocarditis is the most characteristic feature of myocardialinvolvement in SLE.

The clinical detection of myocarditis ranges from 3 to 15%,

although it appears to be much more common in autopsy studies(mainly done in the 1950s and 60s), suggesting the largelysubclinical nature of lupus-associated myocarditis [26, 30].A more recent post-mortem study, reflecting the era ofcorticosteroids treatment, found much lower frequencies, from0 to 8% [32].

Immunofluorescence studies demonstrate fine granularimmune complexes and complement deposition in the walls andperivascular tissues of myocardial blood vessels, supporting thehypothesis that lupus myocarditis is an immune complex-mediated disease. Some reports demonstrate an associationbetween anti-SSA/Ro antibodies and myocarditis [33].

Signs and symptoms are similar to those of myocarditis due toother causes (dyspnoea, tachycardia, arrhythmias) and they canprogress to ventricular dysfunction, dilated CM and heart failure.

There are no typical findings on ECG, and cardiac enzymes maybe normal.

Echocardiographic studies cannot definitely diagnosemyocarditis, but global hypokinesis, in the absence of otherknown causes, is strongly suggestive. Large echo series have foundfrequencies of global hypokinesis between 5 and 20%. However,also segmental areas of hypokinesis can be indicative of thedisease [34].

Recently, other non-invasive investigations such as magneticresonance, are employed for diagnosing myocardial involvementin SLE: T2 values sensitively indicated myocardial relaxationabnormalities, even at preclinical stage [35].

However, up to now, endomyocardial biopsy remains thetechnique of choice in diagnosing myocarditis even if theprocedure is invasive and subject to sampling error.

Myocarditis, although mild, has to be treated immediatelywith high-dose steroids; in the most severe forms is necessary touse intravenous pulse corticosteroid followed by high oral doses.The addition of immunosuppressant such as azathioprine,cyclophosphamide or intravenous immunoglobulines (IVIG)may be helpful in the treatment of myocarditis [36].

Efficacy of the therapy can be assessed by serial echocardio-graphic studies or right ventricular endomyocardial biopsies.

Recently, an association of SLE and giant cell myocarditis hasbeen reported. Despite clinical similarities, lupus myocarditisand giant cell myocarditis are histologically distinct entities, andthe latter has a much more unfavourable prognosis [37].

Heart involvement in anti-phospholipid syndrome

Valvular disease

Heart valve abnormalities (vegetations and/or thickening) are themost frequent cardiac manifestations of APS. These alterationswere known as LibmanSacks endocarditis, a verrucous endo-carditis of valve leaflets, papillary muscles and the muralendocardium, originally described in SLE patients [38]; laterboth clinical observations and experimental data showed a closelinkage between aPL and cardiac valvulopathy and documentedthe responsibilities of antibodies in the valvulopathy genesis.

Heart valve lesions (vegetation, valve thickening and dysfunc-tion) are frequently reported in patients with APS with andwithout SLE [39] and in those with aPL alone [40]. Accordingto echocardiographic studies, it is not clear if patients with SLEhave valve disease more or less than in patients with primary APS;

in addition, there is a discrepancy in the prevalence of valvulardisease in SLE patients with or without aPL.

Hojnik et al . [40] reviewed echocardiographic studies ofprimary APS patients: the four largest transthoracic echocardiog-raphy (TTE) studies reported 3238% prevalence of valve lesionsthat most frequently involved left-sided valves, mitral morecommonly, followed by aortic (whereas LibmanSacks involvesthe tricuspid valve most often).

Using transosophageal echocardiography (TEE), which is moresensitive for detection of valve lesions, Turiel et al . [41]demonstrated valve abnormalities in 82% of primary APSpatients and mitral valve thickening in 63%, confirming previousdata. This study also suggested that mitral valve thickeningcorrelated with anti-cardiolipin antibodies (aCL) titre and aCLtitre >40 GPL is a risk factor for thromboembolism, occurringin 25% of patients [40].

Recently Erdogan et al. [42] demonstrated cardiac involvementin 84% of primary APS patients and mitral regurgitation in77.4%; interestingly, valve lesions were present in all strokepatients, confirming that the presence of cardiac valves pathologymay be considered a risk factor for epilepsy, stroke and other CNSinvolvements, particularly in patients with primary APS [43].

The difference in the populations examined, the problems

linked with aPL tests performance and the different echocardiog-raphy techniques (TEE vs TTE) can account for the variableprevalence of valve lesions in the studies mentioned above.

Valve abnormalities associated with aPL are similar to thosereported in SLE, varying from minimal thickening and/orvegetations to severe valve distortion and dysfunction.

Valvular disease, for the most part, is mild and asymptomatic;only rarely (46%) do aPL positive patients develop valve diseasesevere enough to require surgical treatment.

There is no direct evidence that treatment with corticosteroidsor cytotoxic therapy can prevent valvular damage; however,the decline in prevalence of LibmanSacks lesions at autopsyfollowing the introduction of corticosteroids supports a possibleindirect beneficial role.

The valvular abnormalities resulting from LibmanSackslesions may predispose patients to bacterial endocarditis,so prophylactic antibiotics should be used for dental or surgicalprocedures with an increased risk of transient bacteraemia.

Atherosclerosis and coronary artery disease

Epidemiological studies showed an increase of cardio andcerebrovascular events in patients suffering from systemic auto-immune diseases, and autoptic investigations pointed out thatan accelerated atherosclerotic process is largely responsiblefor such manifestations [4446]. These observations supporta possible role of autoimmunity in the genesis of atherosclerosisthat may have clinical or subclinical features. The clinical edge ofthis phenomenon is coronary artery diseases (CAD) (myocardialinfarction, angina, sudden death), while early endothelial dysfunc-

tion, abnormalities of circulation or atherosclerotic plaques,detected by different imaging techniques, identify the subclinicalatherosclerosis expression.

Both preclinical (carotid plaque) and clinical (myocardialinfarction) atherosclerotic diseases are more prevalent in SLEpatients than in the general population; clinically, atherothrom-botic events, such as myocardial infarction (MI), have beenrecognized as risk factors for mortality [26, 4751]; there maybe a bimodal distribution of mortality risk factors in lupus:an early peak in mortality is caused by disease activity andseverity itself, as well as infections, while a late peak is related toCAD [52]. In post-mortem studies, significant atherosclerosis wasobserved in >50% of deceased SLE patients regardless of theactual cause of death [53].

CAD is described with a prevalence ranging from 6 to 10%,and, in SLE patients, the risk of developing any CAD is 48 times

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higher than in controls [47, 48, 50, 51]. In young women withSLE, the risk of MI is increased 50-fold [54]. In variouscohort studies, MI was the cause of death in 330% of SLEpatients [55].

In SLE patients, the role of traditional and non-traditional riskfactors for atherosclerosis is still debated. Some studies haveshown that traditional cardiovascular risk factors are alsomore predictive in SLE patients than in age- and sex-matched

healthy subjects [56]; particularly, older age at diagnosis,hypercholesterolaemia and hypertension were the three mostcommon predictors of CAD [57]. Hyperlipidaemia in SLE hastwo major patterns. Patients with active lupus, especiallychildren, have low high-density lipoprotein-C (HDL-C) andelevated very-low-density lipoprotein-C (VLDL-C) and triglycer-ide levels. Moreover, corticosteroids therapy seems to increase theserum concentration of cholesterol, lipoproteins and triglyceride,whereas hydroxychloroquine seems to reduce them in SLEpatients.

Other non-traditional risk factors associated with the auto-immune-inflammatory pathogenesis of the disease or withimmunosuppressive therapy must also be taken into account:among these SLE-related risk factors, besides cumulative dosageand/or length of corticosteroids therapy, disease duration, highscore of activity or damage could contribute to the development ofatherosclerotic plaque [26].

More recently, some novel risk factors for atherosclerosishave been proposed and reviewed [58]; they include inflammatorymarkers (C-reactive protein, fibrinogen, interleukin-6),co-stimulatory molecules (CD40/CD40L), adhesion molecules,aPL including anti-cardiolipin (aCL) and anti-2 glycoprotein I(anti-2GPI); anti-oxidized low-density lipoprotein (anti-oxLDL),anti-oxidized palmitoyl arachidonoyl phosphocholine (anti-oxPAPC) and anti-hsp antibodies, homocysteine, lipoprotein(a)and HDL.

According to different reports, traditional risk factors were notdifferent in APS and in the general population [48, 49]. Therefore,non-traditional risk factors such as antibodies seem to be involved

in APS-associated atherogenesis.In histological studies of human carotid samples, 2GPI wasshown to co-localize with T CD4 lymphocytes in the sub-endothelial region of atherosclerotic plaques, supporting apossible role of antibodies in the disease progression [59]. Onthe other hand, in vitro, aPL accelerate the process of plaquesformation, enhancing the macrophages transformation intofoam cells by oxLDL. In fact, anti-2GPI, reducing paraxonaseactivity, accelerates the formation of oxLDL [60]. In addition,since 2GPI binds oxLDL, in the presence of anti-2GPI, theoxLDL uptake by human macrophages is enhanced becauseit seems to occur through the Fc receptors (FcR) of the complex2GPIanti-2GPI rather than via the usually employed and lessefficient scavenger receptor [61].

Finally, the immunization with human 2GPI, which stimulates

autologus anti-2GPI antibodies formation, can also accelerateearly atherosclerosis appearance in LDL-receptor-deficient miceor in anti lipoprotein E (APO-E) knock-out mice, withoutalteration of the animals lipids profiles [62]. It is relevant thatoral feeding of the animals with human or bovine 2GPI waseffective in reducing atherosclerosis as compared with control fedanimals [63].

In agreement with these findings, APS patients suffer from anincreased rate of cardiovascular accidents: myocardial infarctionappears at same stage of the disease in up to 5.5% and is thepresenting manifestation in 2.8% of APS patients [39]. Veres andothers [64] showed correlation between serum levels of aCL andanti-2GPI antibodies and the incidence and severity of acutecoronary syndrome, MI and stroke. Lupus anticoagulant (LA)and anti-2GPI are the risk factors for myocardial infarction inthe study of SLE patients cohorts [65, 66].

In contrast, the association of aPL and subclinical athero-sclerosis features is still debated since it is supported by someworks [67, 68] and denied by others [69, 70].

Regarding clinical and diagnostic aspects of APS-associatedatherosclerosis, early endothelial dysfunction and increasedcommon carotid intimalmedial thickness (ccIMT) have beenstudied [48]. Solte sz et al. [71] reported abnormal flow-mediatedvasodilatation of the brachial artery and increased ccIMT in

46 patients with primary APS. Others found a correlation betweenaCL IgG antibody levels and ccIMT [46, 47]. Earlier developmentof carotid plaques were reported in SLE-associated APS incomparison with primary APS [46, 72].

Atherosclerosis treatment strategies in SLE and SLE-associatedsecondary APS include an aggressive control of all traditionalrisk factors including hyperlipidaemia, hypertension, smoking,obesity and diabetes mellitus, which should be performed by usingboth drug treatment and changes in lifestyle [73].

Prophylactic therapy include anti-platelet and, in APS cases,anti-coagulant agents, as well as statins, folic acid, B vitaminsand, as described above, possibly hydroxycloroquine (HCQ) thatexerts evident anti-atherogenic properties. Statin therapy signifi-cantly reduces the risk of CAD and also prevents endothelialdysfunction [74].

Aspirin has been used for a long time to prevent CAD in thegeneral population. Daily aspirin reduces the risk of MI andreduces CAD-related mortality; recent studies suggested thatSLE patients might also benefit from aspirin prophylaxis. Again,there is no evidence from clinical trials to support this proposal.In a decision analysis model, aspirin intake in 40-yr-old lupuspatients was estimated to gain 3 months of quality-adjustedsurvival in APA-negative and 11 months in aPL-positiveindividuals [75]. In a cohort study, the use of aspirin resulted ina 70% reduction of cardiovascular mortality in SLE [76].According to recent guidelines, SLE patients with previous historyof MI, angina or stroke; aPL positive subjects; patients withhypertension, hyperlipidaemia or diabetes mellitus, or smokersshould be prescribed aspirin if there are no contraindications [77].

Lupus patients with secondary APS often take anti-coagulants,

such as warfarin. As aspirin treatment has not been shown to addany benefit over warfarin alone, the use of aspirin may not benecessary in warfarin-treated SLE patients [78].

As described above, the role of corticosteroids in lupus-associated atherogenesis is rather controversial, as these agentsmay themselves be directly atherogenic, but they may alsoindirectly prevent premature atherosclerosis by controlling diseaseactivity [48, 49].

The authors have declared no conflicts of interest.

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