Review Article Novel Biomarkers of Abdominal Aortic Aneurysm Disease: Identifying Gaps and ...

14 Pages·2015·1.28 MB·English

Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 925840, 13 pages
http://dx.doi.org/10.1155/2014/925840
Review Article
Novel Biomarkers of Abdominal Aortic Aneurysm Disease:
Identifying Gaps and Dispelling Misperceptions
DemetriosMoris,1EleftheriosMantonakis,1EfthymiosAvgerinos,2MarinosMakris,3
ChrisBakoyiannis,1EmmanuelPikoulis,1andSotiriosGeorgopoulos1
1FirstDepartmentofSurgery,VascularUnit,“Laiko”GeneralHospital,NationalandKapodistrianUniversityofAthens,
AgiouThoma17,11527Athens,Greece
2DivisionofVascularSurgery,UniversityofPittsburgh,Pittsburgh,PA15213-2582,USA
3ImperialCollege,LondonSW72AZ,UK
CorrespondenceshouldbeaddressedtoEleftheriosMantonakis;[email protected]
Received6March2014;Revised29April2014;Accepted4May2014;Published20May2014
AcademicEditor:ThomasSchmitz-Rixen
Copyright©2014DemetriosMorisetal. This is an open access article distributed under the Creative Commons Attribution
License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly
cited.
Abdominalaorticaneurysm(AAA)isaprevalentandpotentiallylife-threateningdisease.Earlydetectionbyscreeningprograms
andsubsequentsurveillancehasbeenshowntobeeffectiveatreducingtheriskofmortalityduetoaneurysmrupture.Theaimofthis
reviewistosummarizethedevelopmentsintheliteratureconcerningthelatestbiomarkers(from2008todate)andtheirpotential
screeningandtherapeuticvalues.OursearchincludedhumanstudiesinEnglishandfoundnumerousnovelbiomarkersunder
research,whichwerecategorizedin6groups.Mostofthesestudiesareeitherexperimentalorhamperedbytheirlownumbersof
patients.Weconcludedthatcurrentlynospecificlaboratorymarkersallowscreeingforthediseaseandmonitoringitsprogression
ortheresultsoftreatment.Furtherstudiesandstudiesinlargerpatientgroupsarerequiredinordertovalidatebiomarkersas
cost-effectivetoolsintheAAAdisease.
1.Introduction countries such as UK [5]. Current guidelines recommend
electiverepairforaneurysmsofmorethan5.5cmindiameter,
Abdominal aortic aneurysm (AAA) is a relatively common whileincreasedriskgroups(women,smokers,andvascular
and potentially life-threatening disease, with a prevalence hypertensionandchronicairwaypatients)maybenefitbya
rangingfrom4.1%to11.5%inEuropeanpopulations[1].The lowerthresholdof5cm[6].
mostfearedcomplicationofAAAdiseaseisrupture,which Advances in the endovascular aneurysm repair (EVAR)
often leads to the patient’s death. While small aneurysms technique over the last two decades have led to a major
may rupture too, the risk is greater for bigger aneurysms, paradigmshiftinsurgicalapproachforaorticaneurysms[7,
soearlydiagnosisthroughscreeningandpromptevaluation 8].Byprovidinglowerperioperativemortalityandmorbidity,
of which aneurysms are likely to rupture are key points in endovasculartechniquesareincreasinglybeingpreferredin
the management and research around AAA. No effective the elective setting [8, 9]. However, late complications of
conservativetreatmentexistsand,whendecidedtointervene, EVAR, such as endoleaks, may result in progression of the
surgical correction remains the only effective and “finite” underlyinganeurysm,evendelayedrupture,thusmandating
treatment of AAA, with the optimal timing for surgery alifelongsurveillanceprogram[10].
beingthemaindebatablepoint.Existingevidenceindicates TraditionalAAAscreening,evaluation,andsurveillance
betteroveralloutcomewhenrepairofAAAisperformedon programsemploytheuseofimagingtechniquessuchasCT
electivebasiscomparedtotheemergencyrepair[2–4].Thus angiogram(CTA),ultrasoundsonography(US),ormagnetic
screeningprogramsofAAAhavebeeninitiatedindeveloped resonance imaging (MRI). Despite the proven efficacy of
2 BioMedResearchInternational
these imaging techniques, the cost associated with such 3.1.BiomarkersRelatedtoExtracellularMatrix
programscanincursignificantfinancialburdenstothehealth HomeostasisorProteolysis
caresystems[11–14],soalternativemethodsarecontinuously
being 3.1.1.CystatinCandCathepsin. CystatinCistheendogenous
researched. inhibitor of the elastolytic enzymes cathepsins, which are
Biomarkershaveattractedmuchattentioninthefieldof strongly expressed in the aneurysmatic wall. Cystatin C
aneurysmresearchandaredefinedasmeasurablemolecules expressionisfoundreducedinAAAdisease,leadingtolack
(peptides, proteins, and metabolic products) that express of inhibition of the elastolytic properties of cathepsins. In
a specific biological process in the organism at a given a prospective study [18], a negative correlation of serum
time [15]. In order for a biomarker to be useful, it should cystatinCvalueswithAAAsizeandannualexpansionrate
be able either to detect the disease itself or to express its wasfound,butwithoutmentionablepotentialforpredicting
progression.Soausefulbiomarkershoulddetectthepresence casesrequiringsurgery.
of a subclinical aneurysm or be a measure of its size and In another large study [19], plasma cathepsin S levels
expansionrate,thuspredictingtheriskofrupture.Itisknown correlatedpositivelywithaorticdiametersbutnegativelywith
that this risk increases when the observed expansion rate lowestankle-branchialindex(ABI).PlasmacathepsinSlevels
isgreaterthantheexpected[16].Furthermore,abiomarker showed no correlation with AAA annual expansion rate, a
coulddefinetheoptimalsurveillanceintervalsandpossibly finding mentioned as inexplicable. After logistic regression
identifypathogenicpathwayswhichcouldguidemonitoring analysis, the study also reflected reduced cystatin C in
and treatment [17]. We should not fail to mention that, in humans with AAA lesions, while no association was found
orderforabiomarkertobeemployedinmodernhealthcare between cystatin C and AAA annual growth rate, likely
system,itsuseshouldbecost-effective.Someofthepatients becauseoftherelativelyshortAAAobservationtime.
selected through this process should be pointed towards
more focused screening by specialized imaging techniques.
3.1.2. Circulating Basement-Membrane (BM) Fragments.
Circulatingbiomarkersthuspresentasattractivealternatives
Types IV and XVIII of collagen are components of the
forscreeningandmonitoringpurposesparticularlyinhealth-
basement membrane. Ramazani et al. [20] have recently
care systems which lack the infrastructure to support other
shown that AAA patients had significantly increased levels
primary or secondary screening programs. In this review,
oftypes IV andXVIII collagen comparedwiththecontrols
we aim to provide a summary of the emerging biomarkers (𝑃 = 0.005and𝑃 < 0.001,resp.).Moreover,AAApatients
implicatedinAAApathophysiology.
had significantly increased level of type XVIII collagen
(𝑃 < 0.01) when compared with the peripheral arterial
disease(PAD)group[20].
2.MaterialsandMethods Thisstudywasconductedinasmallnumberofpatients,
indicating that further studies are required to establish the
The MEDLINE/PubMed database was searched for pub-
potentialroleofBMfragmentsasbiomarkersforAAA.
lications with the medical subject heading “biomarkers
in abdominal aortic aneurysms (AAA).” Two independent
3.1.3. Osteoprotegerin (OPG). It has been suggested that
reviewers (D.M. and E.M.) performed the literature search,
serum osteoprotegerin (OPG) levels are associated with
thestudyselection,andthedataextraction.Allthereferences
growth of AAAs while in vitro experiments showed that
fromtheidentifiedarticlesweresearchedforrelevantinfor-
OPGpromotesmatrixmetalloprotease(MMP)releasefrom
mation.ThestartingdatewasJanuary2008,since,previously,
monocytes and vascular smooth muscle cells [21, 22]. In
bibliography was covered by the review of Urbonavicius et
a recent study [23], the concentration of aortic wall OPG
al. [17] and the end date of the review was April 2014. We
was positively associated with established markers of AAA
focused on human studies that reported the presence of
severity(cathepsinsA,B,andSandtheactivityofMMP-2and
aneurysm,size,expansionrates,andriskofruptureandon
MMP-9),whileitappearedtobeassociatedwithlymphocytes
new biomarkers and their potential value relevant to the
andplasmacells.Thesenewerdatainhumansreinforcethe
management of AAA. We excluded articles that were not
olderfindingsofaroleforOPGinAAApathogenesis.
writteninEnglishorarticlesofwhichfull-textsandabstracts
werenotaccessibleorcomprehensive.
3.1.4. Tenascin-C (TN-C). TN-C is a matricellular (extra-
cellular matrix) protein that is synthesized by various cell
3.Results types including vascular smooth muscle cells (VSMC) in
response to inflammatory cytokines and mechanical stress
Numerousstudieswerefoundandcategorizedinthefollow- [24].TN-Cistypicallysynthesizedinpathologicalconditions
ingcategories:biomarkersrelatedtotheextracellularmatrix like wounds, inflammation, and tumorigenesis [25]. No
homeostasis or proteolysis, biomarkers related to cellular biomarkerisavailableforindicatingthepathologicalstatusof
signaling pathways, proteins releases by the intraluminal VSMCandinterstitialcellsandTN-Cmaybeusefulforthis
thrombus,biomarkersrelatedtocirculatingcellsandinflam- purpose, possibly in combination with other inflammatory
mation, metabolomics, and genetic biomarkers. These are markers and ECM degradation products. TN-C has the
describedseparatelyinthefollowingsection. advantage of being deposited locally in the inflammatory
BioMedResearchInternational 3
lesion (AAA) and it is also released in stable forms into correlationamongPRX-1andAAAdiameterandexpansion
circulation[26]. rate were also found. The combination of PRX-1 and AAA
Further studies are required to elucidate the complete sizeseemstobesignificantlypredictiveofAAAgrowth[36],
function of TN-C and to evaluate whether serum levels or establishingPRX-1asapromisingbiomarker.
bioimaging of TN-C is better suited for the assessment of
diseaseactivityinhumanAAA.
3.3.2. Neutrophil Gelatinase-Associated Lipocalin (NGAL).
NGALplasmaconcentrationshavebeenassociatedwithcar-
3.2.BiomarkersRelatedtoCellularSignalingPathways diovascular diseases [37]. Polymorphonuclear cells (PMNs)
isolated from AAA patients secreted significantly greater
3.2.1.C-ReactiveProtein. ItisknownthatC-reactiveprotein amountsofNGALthanPMNsfromcontrolsandcorrelated
(CRP)isanindependentriskfactorforarteriosclerosis. with retrospective AAA growth [38]. The ILT releases large
In a cohort study in men with small AAAs [27], CRP amountsofNGALcomparedtotheabluminalthrombus,the
levelswerefoundhigherinlargerAAAs,butnoassociation aneurysm wall, and the healthy aortic media [38]. Further
wasfoundwiththeaneurysmexpansionrate.Asapossible studies in larger subjects groups are needed to confirm the
explanation,itwassuggestedthatinflammation,asdepicted association between NGAL and AAA presence and growth
bythelevelsofinflammatorymarkers,ismorearesponseto [38].
expansionratherthantheprimarycause. It has been suggested that the ILT ofAAAs predisposes
Inanotherstudy[28],nocorrelationwasfoundbetween for enlargement and rupture. The growth of the AAA is
levels of circulating CRP and other inflammatory markers dependentonproteolyticdegradationofelastin.NGALcan
and the expansion of small-diameter AAAs, indicating no bindtoMMP-9andinhibititsdegradation,therebypreserv-
clinicaluseofthesemarkersinAAAsurveillance. ingenzymaticactivity[39].ComplexesofNGALandactive
A recent cohort study [29] investigated the association MMP-9werepresentinthrombus,theinterfacefluid,andthe
betweenplasmaCRPlevelsandAAAdiameterandassessed aneurysmwall.Still,theimportanceoftheseobservationsis
the relationship between the gradient of CRP levels and unknownandthecontributionofthecomplexNGAL/MMP-
rates of expansion in asymptomatic AAAs. A statistical 9totheAAAgrowthshouldbefurtherevaluated[39].
association was confirmed between the AAA diameter and
highsensitive-CRP(hs-CRP)plasmalevels,showingapos-
3.3.3.Insulin-LikeGrowthFactorsandTheirBindingProteins
siblecausalassociationandsuggestinghs-CRPplasmalevel
(IGFs and IGFBPs). Lindholt et al. [40] have evaluated the
gradient as a marker of disease progression and rate of
potential role of IGF-I and IGF-II as biomarkers in 115
expansion.
patients with AAA, kept under annual surveillance for 10
Sincetheseresultsareconflicting,further,largerstudies
years.SerumIGF-IcorrelatedpositivelywithAAAsizeand
arerequiredtodrawsafeconclusions. growthrate(𝑃 = 0.016and𝑃 = 0.004,resp.),findingsthat
persist after adjustment for potential confounders. Serum
3.2.2. Diminished Soluble Tumor Necrosis Factor-Like Weak IGF-Ilevelpredictedcasesneedinglatersurgery(95%con-
InducerofApoptosis(sTWEAK). sTWEAKisatypeIItrans- fidenceinterval(CI):0.52–0.73)[40].
membrane glycoprotein of the TNF superfamily that circu- IGFBP-1waslocalizedintheluminalpartofAAAthrom-
latesinplasma[30]andisexpressedinSMCsandleukocytes bus and IGFBP-1 levels were increased in AAA thrombus
inarterialwall[31].sTWEAKwasfoundreducedinpatients conditioned media, compared to media layer and healthy
withcoronaryarterydisease[32],carotidatherosclerosis[33], media [41]. It seemed to facilitate the potentiation of ADP-
orPAD[34].Mart´ın-Venturaetal.[35]measuredsTWEAK inducedplateletaggregationtriggeredbyIGF-1,whileitscon-
plasmalevelsinpatientswithAAAandfoundthatsTWEAK centrations were significantly higher in large AAA patients
concentrationsweredecreasedinsmall(≤5cm,𝑃 = 0.03)as compared with control subjects (normal aortic size) (𝑃 <
wellaslargeAAAs(>5cm,𝑃=0.004)comparedwithhealthy 0.01). Moreover, IGFBP-1 levels correlated with AAA size
subjects.Moreover,sTWEAKconcentrationswerenegatively (𝑃 < 0.001), which remained significant after adjusting for
associatedwithAAAsize(𝑃 = 0.008)andAAAexpansion riskfactors[41].
ratewith5yearsoffollow-up(𝑃=0.031)[35].
These results show that sTWEAK is strongly associated
3.4.BiomarkersRelatedtoCirculatingCellsandInflammation
with the presence of an aneurysm but fails to differentiate
amongsmallandlargeaneurysms[35].
3.4.1. Lymphocytes. Increasing evidence shows that the
autoimmuneresponsecontributesimportantlytothepatho-
3.3.ProteinsReleasedbyIntraluminalThrombus(ILT) genesis of AAA. More specifically, CD4(+), CD25(+), and
FOXP3(+) Tregulatorycells(Tregs)werefoundsignificantly
3.3.1. Peroxiredoxin-1 (PRX-1). Martinez-Pinna et al. [36] decreased in AAA patients compared to the control group
analyzed proteins released by intraluminal thrombus (ILT) (𝑃<0.01),indicatingimpairedimmunoregulation[42].
with proteomic approach and found that PRX-1 was more Additionally,thelossoftheinhibitoryreceptorCD31on
released by the luminal layer compared with the abluminal peripheralTlymphocytesisfoundtobeassociatedwiththe
layer of the ILT. Increased PRX-1 serum levels in AAA incidence of atherosclerotic complications such as AAA in
patients compared with healthy subjects and a positive patients [43]. These findings should be further researched
4 BioMedResearchInternational
in order to establish potential biomarkers of the natural macrophages infiltrating in the adventitia. With the intra-
historyofAAA,aswellaspotentialtherapeutictargetsforthe operative use of indocyanine green lymphography, lymph
inhibitionofthecreationandprogressionofaneurysms. stasis was revealed in the intima/medial in AAA patients,
In another study, increased plasma levels of sCD28 and while fluorescence microscopy confirmed the accumula-
sCD86(𝑃 = 0.0001)anddecreasedplasmalevelsofsCTLA- tion of lymph in the intima/media but not in adventitia.
4 (𝑃 = 0.0018) were found in AAA patients compared These results demonstrate that infiltration of macrophages
with normal individuals. These levels were not related to in intima/media is associated with lymphangiogenesis and
the patient’s age or the size of aneurysm, but there was a angiogenesisinAAA,whilethereisevidenceofinadequate
significantinverserelationshipbetweentheconcentrationsof lymph-drainageintheAAAwall.
sCTLA-4andsCD80withmatrixmetalloproteinase-9[44].
3.4.5. Catalase. PMNs play a key role in AAA progression.
Diminishedcatalaseexpressionandactivitywereobservedin
3.4.2. Monocytes. In a more recent study [45], CD16(+)
PMNsfromAAApatientscomparedwithcontrols.Catalase
monocytesubsets were foundincreased in large abdominal
plasma levels were also decreased in large and small AAAs
aorticaneurysmsandweredifferentiallyrelatedtocirculating
whencomparedwithhealthyindividuals.Thisstudywasalso
and cell-associated (CD143) biochemical and inflammatory
conductedinaverysmallnumberofpatients[49].
biomarkers. A clinical implication of this study is that,
by taking common blood measurements (plasma D-dimer,
creatinine, and age to derive eGFR, uric acid, total white 3.4.6.Pathogens. Onestudy[50]showedthatP.gingivalis,a
blood,andneutrophilcounts),onecoulddiscriminateAAA commonpathogeninvolvedinchronicperiodontitis,acceler-
patients with different monocyte-dependent inflammatory atesAAAprogressionviarecruitmentandactivationofneu-
profiles.Thisstudywashamperedbycross-sectionaldesign trophils,leadingtoproductionofNETswhicharedetectable
and the relatively small number of patients, while it was intheplasmaofAAAsubjects.Theseresultswereconfirmed
unable to find a clear relation of the size of AAA and the byanexperimentinrats.Sincerepeatedsubclinicalepisodes
valuesofcirculatingmonocytesubsetsinpatientsatdifferent ofbacteremiaaresystematicallyassociatedwithperiodontal
stagesofexpansionofaorticdamage. diseases, P. gingivalis could be therefore a key factor in
human AAA progression. Still, more epidemiological and
observational studies in humans should be made before
3.4.3.ProgenitorCells. CD34(+)levelsareaknownmarkerof
organizing therapeutic strategies based on the treatment
circulatingprogenitorcells.VanSpyketal.[46]investigated
of periodontal disease to prevent AAA evolution towards
the role and compared the percentage of CD34(+) cells in
rupture.
AAA disease and peripheral vascular disease (PVD). This
smallstudyrevealedalowerpercentageofCD34(+)cellsin
3.5.Metabolomics. Metabolomicsstandsforsensitiveanalyt-
AAA patients, compared to PVD patients, concluding that
icaltechniquessuchasmetabolicfingerprintingwithmulti-
AAAisalessseverevasculardiseasethanPVD.Furtherstudy
variateanalysis.Metabolomicsseemstobeagoodapproach
isneededinordertoestablishCD34(+)cellsasabiomarker
tofindbiomarkersofAAA[51].
forriskstratification.
Guanidinosuccinicacid(GSA),whichismainlyreleased
from the ILT, is highly increased in the plasma of AAA
3.4.4. Lymphangiogenesis. A study by Scott et al. [47] patientswhencomparedtocontrols.GSAbehaves likenitric
attemptedtoresearchtherelationshipbetweeninflammation oxide(NO),duetoitsvasodilatoryactionsanditsabilityto
and neovascularization in AAA tissue. The results showed activatetheNOgeneratingN-methyl-D-aspartate(NMDA)
thattheaneurysmwallcontainedhighlevelsofinflammatory receptor.AfterbeinggeneratedintheILT,GSAissecretedto
infiltrate, while microvascular densities of blood (𝑃 < bloodstream,andtheamountofsecretedGSAisrelatedto
0.001)andlymphatic(𝑃 = 0.003)vesselsweresignificantly thestageofAAA[52].
increased in AAA samples compared with controls. Vascu- Hippuricacidissecretedonlybytheluminalpartofthe
larity as expressed by positive staining for CD31, CD105, ILT and was found significantly decreased in the plasma of
and D2-40 correlated positively with inflammation, while AAApatients.Thisobservationcorrelateswiththehyperex-
increased VEGFR-3 and VEGF-A expression was observed cretionofhippuricacidinatheroscleroticstate[51].
within inflammatory areas of AAAs. These results suggest Long-chainacylcarnitinesweredecreasedintheplasma
lymphaticvesselinvolvementinAAAdisease,associatedwith of AAA patients compared to controls. There was a clear
theextentofinflammation[47]. decreasingtrendwithincreasingsizeofaneurysmwhichmay
In a recent study [48], infiltration of lymphatic ves- indicatealteredfattyacid𝛽-oxidationordeficiencyofcarni-
sel endothelial hyaluronan receptor- (LYVE-) 1, vascu- tine[51].Additionally,asignificantdecreaseinsphingosine-
lar endothelial growth factor- (VEGF-) C, and matrix 1-phosphate (S1P) and sphinganine-1-phosphate in AAA
metalloproteinase- (MMP-) 9-positive macrophages and patients was also found. Both molecules are sphingolipids;
podoplanin and Prox-1-positive microvessels were identi- sphinganine-1-phosphateisaparentofsphingosineandS1P.
fied by immunohistochemistry in the intima/media in the S1P is a lysophospholipid and significant changes in other
AAA wall, where hypoxia-inducible factors- (HIF-) 1𝛼 was lysophospholipidslikeLysoPEsandLysoPCsarereportedin
expressed. VEGF-C and MMP-9 were not expressed in thisinvestigation.Apossibleexplanationfordecreaseinthe
BioMedResearchInternational 5
amount of LysoPCs/PEs in plasma of AAA patients, with a AAA [60]. The serum HDL concentrations were lower in
trendrelatedtothesizeofaneurysm,istheiraccumulation patientswithAAAsandwereindependentlyassociatedwith
intheILT[51]. a reduced risk of having an AAA, in men not receiving
current lipid-modifying therapy (95% CI 0.56–0.93 per
0.4-mM increase) and in the total cohort (95% CI 0.63–
3.5.1. Vitamin D Binding Protein (DBP) and Vitamin D.
0.91 per 0.4-mM increase). The concentrations of LDL
During last decades, there has been a surge of interest in
and triglycerides were not associated with the presence of
vitaminDanditswiderangeofhealthbenefits,partiallydue
AAAs[61].
tothemanyassociationstudieslinkingvitaminDstatuswith
Past studies [62] have revealed decreased low-density
commonhumandiseases.DBPisthemainserumcarrierof
lipoprotein receptor-related protein 5 (LRP5) gene expres-
vitaminDmetabolites,withalbuminactingasanalternative
sion in peripheral blood cells of AAA patients and an
lower affinity binder [53]. Gamberi et al. [54] showed a
association between decreased expression of LRP5 and
negativecorrelationbetweenDBPandthepresenceofAAA.
increased lipoprotein (a) [Lp(a)] levels in AAA patients. In
Evenifitsvalueisnotwellestablishedyet,DBPispivotalfor
a recent study [63], LRP5 gene polymorphisms rs4988300
vascularremodelinganditmayhaveanimportantroleinthe
and rs3781590 were found independent genetic markers
protectionofvascularwalls.
of AAA, even after adjusting for age, sex, dyslipidemia,
In a more recent observational study [55], 4233 older
hypertension, smoking habit, and chronic obstructive pul-
men (70–88 years old) participated in a randomized con-
monarydisease.AAApatientshadsignificantlyhigherLp(a)
trolledtrialofscreeningforAAA.Thestudymeasuredtheir
levels than control subjects (𝑃 < 0.0001). Further study-
infrarenalaorticdiameterbyultrasoundandtheir25(OH)D
ing of the role of these markers in AAA and of LRP5
plasma levels by immunoassay. An inverse relationship
gene in Lp(a) catabolism and AAA pathophysiology is
between vitamin D status and the presence of larger AAA
necessary.
wasfound,alongwithaninversedose-responseassociation
between 25(OH)D concentrations and the size of AAA,
suggestingaroleofvitaminDintheseverityofaneurysmal 3.5.4. Phospholipases. Wallinder et al. [64] showed that
arterial disease. Further research is needed to clarify the patientswithsmallAAAshadincreasedlevelsoftheenzyme
mechanismsunderlyingtheseassociations. glycosylphosphatidylinositol-specificphospholipaseD(GPI-
PLD)comparedwithcontrolswithoutaneurysmbyusinga
3.5.2.Homocysteine. Wongetal.[56]investigatedinacross- proteomic approach, providing some evidence of the value
sectional study the relationship of homocysteine and the of GPI-PLD as a novel potential plasma biomarker for
presence and diameter of AAAs in older men (70–88 years the detection of AAAs [64]. In the same tone, Golledge
old). Plasma total homocysteine (tHcy) was found to be et al. found [65] that serum secretory phospholipase A(2)
associated with the presence of AAA, while there was also (sPLA(2)) activity is elevated in men with small AAAs but
a positive dose-response relationship between tHcy and isnotassociatedwithAAAprogression.
abdominalaorticdiameter.Theinvestigatorsconcludedthat
further, longitudinal studies and clinical trials of lowering
3.5.5. Iron. A recent study by Martinez-Pinna et al. [66]
tHcyarerequiredinordertoassessiftheserelationshipsare
foundincreasedredbloodcell-(RBC-)borneironretention
causal.
andtransferrin,transferrinreceptor,andferritinexpression
in AAAtissue comparedto controls.In contrast,decreased
3.5.3.LipoproteinsandLipoprotein-RelatedReceptors. Results circulatingiron,transferrin,meancorpuscularhaemoglobin
ofameta-analysissuggestthatcirculatinglipoproteinalpha concentration (MCHC), and haemoglobin concentration,
(Lp(a))concentrationsmaybehigherinpatientswithAAA along with circulating RBC count, were observed in AAA
than those in subjects without AAA, thus playing a role in patients compared to controls, whereas hepcidin concen-
thediagnosisofAAA[57].Low-densitylipoproteinreceptor- trations were increased in AAA subjects. Moreover, iron,
relatedprotein1(LRP1)demonstratedsignificantassociation transferrin, and haemoglobin levels were negatively, and
with AAA size (𝑃 = 0.0042) [58]. In a small pilot study in hepcidinpositively,correlatedwithaorticdiameterinAAA
12 patients by Chan et al. [59], lipoprotein receptor-related patients. MCHC negatively correlated with thrombus area
protein1(LRP1)expressionwasfoundsignificantlylowerin in another cohort of AAA patients. Anemia was signifi-
AAApatientsthanincontrols,whilenosignificantcorrela- cantly more prevalent in AAA patients compared to that
tionwasshownbetweenLRP1expressionandthesizeofAAA in patients with atherosclerotic aortoiliac occlusive disease.
(𝑃 > 0.05). These results suggest that a reduction in LRP1 Finally,themortalityriskamongAAApatientswithanemia
expressioncouldbeassociatedwithaneurysmprogression. was increased by almost 30 as compared to AAA subjects
Other metabolites used to discriminate the natural with normal hemoglobin levels. This study showed that
history of patients with large aneurysm, small aneurysm, local iron retention and altered iron recycling associated
and controls are the metabolites of cholesterol. Decreased with high hepcidin and low transferrin systemic concen-
plasmalevelsofthosemetaboliteswereobservedinpatients trationscouldleadtoreducedcirculatinghaemoglobinlev-
with large and small aneurysms in comparison to con- els in AAA patients and that low haemoglobin levels are
trols [51]. Lower serum HDL cholesterol and higher serum independently associated with AAA presence and clinical
LDL cholesterol may be associated with the presence of outcome.
6 BioMedResearchInternational
3.6.GeneticBiomarkers 4.Discussion
3.6.1. Telomere Length. Telomeres are specialized DNA In this review article, we aimed to give a description of
sequences at the ends of linear chromosomes. Telomere the emerging biomarkers that can correlate with biological
attritionisthephenomenonoftelomerelength“shortening” processesassociatedwiththeexistence(presence/diagnosis)
with each successive cell division, eventually leading to and progression (size/risk of rupture) of abdominal aortic
cell senescence and/or apoptosis. These observations can aneurysms(AAAs).Ourmaingoalwastoenrichthecurrent
contribute to the estimation of the cellular biological age knowledgeonbiomarkersinAAAdisease,asitwaspresented
[67]. In humans, reduced telomere length in circulating by Urbonavicius et al. [17] in their review at 2008, and
leucocytes is associated with premature vascular disease, analyze the progress made in this scientific field from 2008
withthetelomere:genomicDNAcontentbeingsignificantly to date. As stated earlier, the clinical value of biomarkers
reducedinwallbiopsiesofAAAcomparedtonormalaortas is based on their properties to satisfy the goals of early
(𝑃 < 0.001) [67]. This decreased telomerase endothelial detection(screening),surveillanceintermsofearlyandlater
expression implies a protective role of telomerase against progression,andmonitoringofthebiologicperformanceof
AAA formation [68]. Lowest telomere restriction fragment anAAAaftersurgicaltreatment.Anidealbiomarkershould
(TRF)lengthvaluesdoubletheriskofhavingAAAcompared be able to be applied in all of the above. Early detection
with a mean TRF length in the highest values (𝑃 = 0.005) andclosesurveillancecangreatlybenefitpatients,sincethey
[69]. are referred for elective repair with a lower risk, compared
with the emergency setting [2–4]. The mortality of elective
3.6.2. AAA1 Locus on Chromosome 19q13. Several single- AAA repair has been 5% or less, but, once rupture occurs,
nucleotidepolymorphisms(SNPs)werenominallyassociated operative mortality is as high as 48% [77]. Studies have
with AAAs (𝑃 < 0.05) [70, 71]. The SNPs with most alsoshownincreasedcostofopenrepairofrupturedAAAs
significant𝑃valueswerepeptidaseD(PEPD)andCD22[71]. (rAAAs) compared to elective open repair; some are even
Immunohistochemical staining for CD22 revealed protein as high as five times more per life saved per year, with the
expressioninlymphocytespresentintheaneurysmalaortic costsfromemergencyrepairofrAAAviaEVARtobeeven
wallonlyandnodetectableexpressionincontrolaortas[71]. higher[78,79].ManydevelopedcountriesliketheUSA,UK,
PEPDproteinwasexpressedinfibroblastsandmyofibroblasts and Sweden have established national screening programs
in the media-adventitia border in both aneurysmal and for AAA based mostly on ultrasonography with important
nonaneurysmaltissuesamples[71]. resultsinthefieldofearlydetectionandfollow-up[11–14,80].
Unfortunately,thisisnotthecaseinothercountries,which
cannot afford such high cost of implementing such a wide
3.6.3.9p21. AAAisamonganumberofvasculardisordersto
screeningprogram[80].Morespecifically,inarecentstudy
berecentlyassociatedwithacommonallelicvariantsituated
[81],itwasshownthattheindividualcostperinvitedsubject
on chromosome 9p21 [72, 73]. A significant association
wasC60(US$83.2)and0.011additionalqualityadjustedlife
betweenrs10757278-GandthepresenceofAAAwasfound
years(QALY)weregainedperpatientinthescreenedcohort,
(𝑃 = 0.03), an effect size completely consistent with that
corresponding to an incremental cost-effectiveness ratio
originally reported [73]. rs10757278 was not significantly
(ICER) of C5673/QALY (US $7870/QALY). These numbers
associated with altered AAA growth rate [73]. In a newer
areunlikelytobefeasibleinaperiodofworldeconomiccrisis.
study[74],single-nucleotidepolymorphismsrs10757278and
Taking into account the relatively high prevalence of the
rs1333049 of chromosome 9p21-3 region were significantly
diseaseandthehighmortalityratesincasesofrupture,along
associatedwithincreasedriskofAAA.Thisstudyrevealedno
withthehighICUandhospitalcosts[82],evenafterEVAR,
associationbetweenpolymorphismsandaorticdiametersin
itseemsimperativetoestablishandstandardizebiomarkers
AAApatients,whileaspecificgenotype(GGofrs10757278)
thatcanbeappliedindailypracticeandbe
was suggested to interact with the homocysteine biological
cost-effective.
pathwaytostimulatethepresenceofAAA.Thisdataempha-
Aspresented,numerousbiomarkers,relatedtotheAAA
sizedtheneedtofurtherstudytheroleofthesebiomarkers.
disease,arecurrentlybeingresearched.Mostofthesestudies
areeitherexperimentalorhamperedbytheirlownumbersof
3.6.4. Chemokine Receptors (CCRs). Chronic inflammation patients.Still,onecansaythatbiomarkersreflectbiological
plays an important role in AAA formation. The chemokine processesassociatedwithadisease,makingthemmoreinter-
receptors CCR2, CCR5, and CXCR3 are associated with estingforpersonalizedmedicineratherthanforastatistical
pathways implicated previously in aneurysm pathogenesis. pointofview.
Chemokinereceptor-2(CCR2)isinvolvedintheregulation sTWEAKisstronglycorrelatedwithaneurysmexistence
oftheinflammatoryresponse[75].CCR2heterozygoteV64I or expansion rate but fails to differentiate small to large
polymorphism and allele frequency were more frequently aneurysms [35]. TN-C contributes in stratifying risk in
observedintheAAAgroup(𝑃 = 0.01,𝑃 = 0.004)[75],but patientswithAAAbeforeinterventionorafterEVAR[2],but
therewasnosignificantdifferencewiththecontrolgroupin further study is required to elucidate the function of TN-C
relationtotheDelta32allelefrequency[76]. andtoevaluatewhetherserumlevelsorbioimagingofTN-
Table1summarizesthepublishedstudiesonbiomarkers C would be suited for the assessment of disease activity in
inAAAandtheirclinicalvalue. humanAAAs.
BioMedResearchInternational 7
d d d
n n n n
Clinicalvalue Aneurysmprogressio neurysmdetectionaprogression Aneurysmdetection Aneurysmsize Aneurysmdetection Aneurysmgenesis Aneurysmdetection Aneurysmgeneris Aneurysmsizeandprogression Aneurysmsizeandthrombusexistence neurysmdetectionaprogression neurysmdetectionaprogression
A A A
rs(2008–2014)inAAAandtheirclinicalvalue. FindingsAstatisticalassociationwasconfirmedbetweentheAAAdiameterandhighsensitive-CRP(hs-CRP)plasmalevels.Otherstudiesshowcontroversialresults[27,28]sTWEAKplasmalevelsinpatientswithAAAcomparedwithhealthysubjects.sTWEAKconcentrationswerenegativelyassociatedwithAAAsizeandAAAexpansionrateCD4(+),CD25(+),andFOXP3(+)TcellsinAAApatientsarefoundsignificantlylowerthanthoseofthecontrolgroup CD16(+)monocytesubsetswerefoundincreasedinlargeabdominalaorticaneurysmsandweredifferentiallyrelatedtocirculatingandcell-associated(CD143)biochemicalandinflammatorybiomarkers AlowerpercentageofCD34(+)cellsinAAApatients,comparedtoPVDpatients,wasfound LymphaticvesselinvolvementinAAAdisease,associatedwiththeextentofinflammation Infiltrationofmacrophagesinintima/mediaisassociatedwithlymphangiogenesisandangiogenesisinAAA,whilethereisevidenceofinadequatelymph-drainageintheAAAwallDiminishedcatalaseexpressionandactivitywereobservedinPMNsfromAAApatientscomparedwithcontrolsP.gingivalisacceleratesAAAprogressionviarecruitmentandactivationofneutrophils,leadingtoproductionofNETs SerumIGF-IcorrelatedpositivelywithAAAsizeandgrowthrate IGFBP-1concentrationsweresignificantlyhigherinlargeAAApatientscomparedwithcontrolsubjects AAApatientssecretedsignificantlygreateramountsofNGALthanPMNsfromcontrolsandcorrelatedwithretrospectiveAAAgrowthIncreasedPRX-1serumlevelsinAAApatientscomparedwithhealthysubjectsandpositivecorrelationamongPRX-1andAAAdiameterandexpansionratewerealsofound
e
nnovelbiomark Studydesign Cohortstudy secontrolstudy ospectivestudy secontrolstudy secontrolstudy secontrolstudy secontrolstudy secontrolstudy Experimentalstudy ospectivestudy secontrolstudy secontrolstudy ospectivestudy
o Ca Pr Ca Ca Ca Ca Ca Pr Ca Ca Pr
s
e
di
u
anst Year 2012 2011 2010 2013 2013 2013 2014 2011 2011 2011 2012 2012 2011
m
u
h
yofthepublished Author DeHaroetal.[29] ´Martın-Venturaetal.[35] Yinetal.[42] Ghigliottietal.[45] VanSpyketal.[46] Scottetal.[47] Sanoetal.[48] Ramos-Mozoetal.[49] Delboscetal.[50] Lindholtetal.[40] Ramos-Mozoetal.[41] Ramos-Mozoetal.[38] Martinez-Pinnaetal.[36]
r
a
m s
r
Table1:Sum Biomarker CRP sTWEAK Lymphocytecorrelatedbiomarke Monocyte-relatedbiomarkers ProgenitorCells Lymphangiogenesis Catalase(PMNs) Pathogens IGFs NGAL Peroxiredoxin-1
s
y
a
w s
dtopath dtond bymbu
Category Biomarkersrelatecellularsignaling Biomarkersrelatecirculatingcellsainflammation Proteinsreleasedintraluminalthro(ILT)
8 BioMedResearchInternational
ClinicalvalueAneurysmsizeandprogressionAneurysmsizeandprogression Aneurysmdetection neurysmgenesisandgrowth neurysmprogressionndtreatmentefficacy Aneurysmdetection Aneurysmdetection Aneurysmdetection Aneurysmgenesis Aneurysmdetection
A Aa
FindingsNegativecorrelationwithaneurysmsizeandexpansion,nopotentialforpredictingsurgeryPositivecorrelationwithaorticdiameters,nocorrelationwithAAAannualexpansionrate AAApatientshadsignificantlyincreasedlevelsoftypesIVandXVIIIcollagencomparedwiththecontrols AorticwallOPGwaspositivelyassociatedwithestablishedmarkersofAAAseverity,whileitappearedtobeassociatedwithlymphocytesandplasmacellsTN-CisusedtostratifyriskinpatientswithAAAbeforeinterventionandalsoafterendovascularrepairTelomere:genomicDNAcontentbeingsignificantlyreducedinwallbiopsiesofAAAcomparedtonormalaortas CD22revealedproteinexpressioninlymphocytespresentintheaneurysmalaorticwallonlyandnotincontrolaorta.PEPDproteinwasexpressedinfibroblastsandmyofibroblastsinthemedia-adventitiaborderinbothaneurysmalandnonaneurysmaltissuesamples Asignificantassociationbetweenrs10757278-Gandthe𝑃=0.030presenceofAAAwasfound().rs10757278wasnotsignificantlyassociatedwithalteredAAAgrowthrate SNPrs10757278andrs1333049ofchromosome9p21-3regionweresignificantlyassociatedwithincreasedriskofAAA.ThisstudyrevealednoassociationbetweenpolymorphismsandaorticdiametersinAAApatientsCCR2heterozygoteV64IpolymorphismandallelefrequencyweremorefrequentlyobservedintheAAAgroup
able1:Continued. Studydesign Prospectivestudy Prospectivestudy Casecontrolstudy Retrospectivestudy Follow-upstudy Casecontrolstudy GWAS Cohortstudy Casecontrolstudy Casecontrolstudy
T
Year 2001 2012 2011 2012 2010 2008 2011 2009 2014 2011
Author Lindholtetal.[18] Lvetal.[19] Ramazanietal.[20] Kooleetal.[23] Greenhalghetal.[2] Wilsonetal.[67] Lillvisetal.[71] Thompsonetal.[73] Weietal.[74] Katranciogluetal.[75]
e
n
a 3
Biomarker CystatinC CathepsinS Circulatingbasement-membrfragments OPG Tenascin-C(TN-C) Telomerelength AAA1locusonchromosome19q1 9p21 CCRs
s
si
y
elatedtomatrixorproteol
Category Biomarkersrextracellularhomeostasis Genomicbiomarkers
BioMedResearchInternational 9
Clinicalvalue Aneurysmdetection Aneurysmdetection Aneurysmdetection Aneurysmdetection Aneurysmdetection Aneurysmdetection Aneurysmsize Aneurysmdetectionandsize Aneurysmsizeanddetection Aneurysmdetectionandprogression nsitive;Se:selenium;Lp(a):
e
s
FindingsLp(a)concentrationsmaybehigherinpatientswithAAAthanthoseinsubjectswithoutAAA LowerserumHDLcholesterolandhigherserumLDLcholesterolmaybeassociatedwithAAApresenceLipoproteinreceptor-relatedprotein1(LRP1)expressionwasfoundsignificantlylowerinAAApatientsthancontrols,whilenosignificantcorrelationwasshownbetweenLRP1expressionandthesizeof𝑃>0.05AAA()AssociationbetweendecreasedexpressionlevelsofLRP5geneinAAApatientsLRP5genepolymorphismsrs4988300andrs3781590werefoundindependentgeneticmarkersofAAA.AAApatientshadsignificantlyhigherLp(a)levelsthan𝑃<0.0001controlsubjects() NegativecorrelationbetweenDBPandAAApresence AninverserelationshipbetweenvitaminDstatusandthepresenceoflargerAAAwasfound,alongwithaninversedose-responseassociationbetween25(OH)DconcentrationsandthesizeofAAA Plasmatotalhomocysteine(tHcy)wasfoundtobeassociatedwiththepresenceofAAA,whiletherewasalsoapositivedose-responserelationshipbetweentHcyandabdominalaorticdiameterSmallAAAhadincreasedlevelsoftheenzymeglycosylphosphatidylinositol-specificphospholipaseD(GPI-PLD)comparedwiththecontrolswithoutaneurysmLocalironretentionandalteredironrecyclingassociatedwithhighhepcidinandlowtransferrinsystemicconcentrationscouldleadtoreducedcirculatinghaemoglobinlevelsinAAApatients.LowhaemoglobinlevelsareindependentlyassociatedwithAAApresenceandclinicaloutcome or-alpha;IL-6:interleukin-6;CRP:Creactiveprotein;hs:highlyors.
Table1:Continued. Studydesign Meta-analysis Meta-analysis Casecontrolstudy Casecontrolstudy Casecontrolstudy Proteomics Randomizedclinicalstudy Cross-sectionalstudy Casecontrolstudy ha:tumornecrosisfactCRs:chemokinerecept
pC
Year 2009 2010 2013 2009 2013 2011 2013 2013 2012 2014 TNF-alocalin;
ator;dlip
Author Takagietal.[57] Takagietal.[60] Chanetal.[59] Giustietal.[62] Galoraetal.[63] ngGamberietal.[54] Wongetal.[55] Wongetal.[56] Wallinderetal.[64] Martinez-Pinnaetal.[66] tissue-likeplasminogenactiveutrophilgelatinase-associate
ndi e es PA:L:n
Biomarker Lps VitaminDbiprotein Homocystein Phospholipas Iron metalloproteinases;ta1antitrypsin;NGA
dingalph
graAT:
Category Metabolomics MMPs:matrix-delipoprotein(a);a1-
10 BioMedResearchInternational
As far as biomarkers related to ILT are concerned, IGF reviewingthepaper.SotiriosGeorgopouloswasresponsible
and PRX-1 seem to be the most promising due to their forthecriticalandthoughtfulreviewandthesupervisionof
statistically established correlation with AAA diameter and thecompositionofthepaper.
growth[36,40].
Genetic factors did not offer statistically significant References
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