HypertensiveRetinopathy

HypertensiveRetinopathyandRiskofStroke
YiTingOng,TienY.Wong,RonaldKlein,BarbaraE.K.Klein,PaulMitchell,
A.RicheySharrett,DavidJ.Couper,M.KamranIkram

SeeEditorialCommentary,pp678679

AbstractAlthoughassessmentofhypertensiveretinopathysignshasbeenrecommendedfordeterminingendorgan
damageandstratifyingvascularriskinpersonswithhypertension,itsvalueremainsunclear.Inthisstudy,weexamine
whetherhypertensiveretinopathypredictsthelongtermriskofstrokeinthosewithhypertension.Atotalof2907
participantswithhypertensionaged50to73yearsatthe1993to1995examination,whohadgradableretinalphotographs,
nohistoryofdiabetesmellitus,stroke,andcoronaryheartdiseaseatbaselineanddataonincidentstroke,wereincluded
fromtheAtherosclerosisRiskinCommunities(ARIC)Study.Retinalphotographswereassessedforhypertensive
retinopathysignsandclassifiedasnone,mild,andmoderate/severe.Incidenteventsofanystroke,cerebralinfarction,and
hemorrhagicstrokewereidentifiedandvalidated.Afterameanfollowupperiodof13.0years,165personsdeveloped
incidentstroke(146cerebralinfarctionsand15hemorrhagicstrokes).Afteradjustingforage,sex,bloodpressure,and
otherriskfactors,personswithmoderatehypertensiveretinopathyweremorelikelytohavestroke(moderateversusno
retinopathy:multivariablehazardratios,2.37[95%confidenceinterval,1.394.02]).Inparticipantswithhypertensionon
medicationwithgoodcontrolofbloodpressure,hypertensiveretinopathywasrelatedtoanincreasedriskofcerebral
infarction(mildretinopathy:hazardratio,1.96[95%confidenceinterval,1.093.55];andmoderateretinopathy:hazard
ratio,2.98[95%confidenceinterval,1.018.83]).Hypertensiveretinopathypredictsthelongtermriskofstroke,
independentofbloodpressure,evenintreatedpatientswithhypertensionwithgoodhypertensioncontrol.Retinal
photographicassessmentofhypertensiveretinopathysignsmaybeusefulforassessmentofstrokerisk. (Hypertension.

2013;62:706711.) OnlineDataSupplement

KeyWords:cerebralinfarctionhypertensionhypertensiveretinopathystroke
riskfactorsorsignsthatmayprovideadditionalinformation.

espitetheoverwhelmingevidencethathypertensionrepresents

thefirstriskfactorforstrokeandthatpreventionofstrokebenefits
themostfrombloodpressurelowering, 13itstillremainsdifficultto
predictamongthosewithhypertensionwhowilldevelopastroke.
Therefore,itisstillpertinenttounravelother

Afundus(retinal)examinationtodeterminethepresenceand
severityofretinopathysignshasbeenrecommendedasameansto
determinethepresenceofendorgandamageinpersonswith
hypertensionandtostratifyrisk.46However,thevalueofaretinal
examinationremainsunclearbecausedifferentclassificationsof
hypertensiveretinopathy(eg,KeithWagnerBarkerclassification)
aredifficulttouseinclinicalpractice, 7andaclinical

ophthalmoscopicexaminationhaslowreliabilityandrepro
ducibility.8Althoughamoresimplifiedhypertensiveretinopathy

Furthermore,ithasbeensuggestedthatretinalphotography,
widelyavailableinprimaryclinics,hospitals,andeveninthe
community(eg,opticalshops),maybeamoreprecisemeans
todocumentretinopathysigns.9Recentstudieshaveshown

system(mild,moderate,andsevere)hasbeenproposed,6its
useinpredictingendorgandamagehasnotbeenvalidated.

thatretinopathysignsarerelatedtotheriskofstroke,1016
includingMRIdefinedcerebralinfarcts,incidentclinical
stroke,ischemicstrokes,andsymptomaticandsubclinical
silentlacunarinfarctsinhealthypopulations,12,1416and
subsequentvasculareventsinpersonswhohaveanacute
stroke.17However,amajorgapintheliteratureiswhether
thesimplifiedhypertensiveretinopathyclassificationis
predictiveofstrokeamongsubjectswithhypertension.

ReceivedMarch18,2013;firstdecisionMarch30,2013;revisionacceptedJuly9,2013.

FromtheNUSGraduateSchoolforIntegrativeSciencesandEngineering(Y.T.O),andMemory,Aging,&CognitionCentre(M.K.I.),NationalUniversityof
Singapore,Singapore;DepartmentofOphthalmology(Y.T.O.,T.Y.W.,M.K.I.),andSingaporeEyeResearchInstitute(T.Y.W.,M.K.I.),YongLooLinSchoolof
Medicine,NationalUniversityofSingapore,Singapore;CentreforEyeResearchAustralia,UniversityofMelbourne,Melbourne,Australia(T.Y.W.);Department
ofOpthalmologyandVisualSciences,UniversityofWisconsinSchoolofMedicineandPublicHealth,Madison,WI(R.K.,B.E.K.K.);Departmentof
OpthalmologyandWestmeadMillenniumInstitute,CentreforVisionResearch,UniversityofSydney,Sydney,Australia(P.M.);DepartmentofEpidemiology,
JohnsHopkinsBloombergSchoolofPublicHealth,Baltimore,MD(A.R.S.);DepartmentofBiostatistics,UniversityofNorthCarolina,ChapelHill,NC(D.J.C.);
andDepartmentofOphthalmology,ErasmusMedicalCenter,Rotterdam,TheNetherlands(M.K.I.).

TheonlineonlyDataSupplementisavailablewiththisarticleat
http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.113.01414//DC1.

CorrespondencetoM.KamranIkram,NationalUniversityHealthSystem,1EKentRidgeRd,NUHSTowerBlock,Level7,Departmentof
Ophthalmology,Singapore119228.Emailkamran_ikram@nuhs.edu.sg
2013AmericanHeartAssociation,Inc.

Hypertensionisavailableathttp://hyper.ahajournals.org

DOI:10.1161/HYPERTENSIONAHA.113.01414

Downloadedfromhttp://hyper.ahajournals706.org/byguestonJune13,2016

OngetalHypertensiveRetinopathyandStroke 707

Assessmentof
Hypertensive
Retinopathy

Inthisarticle,weexaminedin
acohortofpersonswith
hypertension(without
diabetesmellitus)the
relationshipbetween
hypertensiveretinopathy
signsandlongtermriskof
stroke,itsmajorsubtype
cerebralinfarction,and
whetherthisrelationshipis
independentofhypertensive
medicationuseandblood
pressurecontrol.

Methods

StudyPopulation

TheAtherosclerosisRiskin
Communities(ARIC)Studyisa
populationbasedstudythat
included15792participantsaged
44to66yearsfrom1986to
1990.18Ourstudycohortconsists
ofindividualswhoparticipatedat
thethirdexamination(1993
1996),aged49to73years,when
retinalphotographywas
performed.Responseratesof
participantsfromthefirsttothird
examinationhavebeen
previouslyreported.19Ofthe12
887individualswhoparticipated
atthethirdexamination,atotalof
2907participantswithprevalent
hypertension,withnoprevalent
strokeorcoronaryheartdisease,
withoutdiabetesmellitusatthe
timeofretinalphotography,and
hadgradableretinalphotographs
wereincludedinthisstudy
(Figure).Approvalwasgivenby
InstitutionalReviewBoardsat
eachstudysite,andinformed
consentwasobtainedfromall
participants.

Retinalphotographyandthe
gradingprocedurehavebeendocu
mentedelsewhere.19Briefly,a45
nonmydriaticretinalphotograph
centeredontheregionoftheoptic
disc,andmaculawastakenfrom1
randomlyselectedeyeafter5
minutesofdarkadaption.Trained
gradersmaskedtoparticipant
characteristicsandclinicalstatus
evaluatedphotographsforthe
presenceofretinopathysigns.
Retinopathysignswereevaluated
withoutassumptionofcause,noting
thefollowingfindings:retinal
hemorrhages(blotandflame
shaped),microaneurysms,soft
exudates,hardexudates,macular
edema,intraretinalmicrovascular
abnormalities,venousbeading,new
vesselsatthediscorelsewhere,
vitreoushemorrhage,discswelling,
andlaserphotocoagulationscars.14
Generalizedarteriolarnarrowing
wasdeterminedasthosewitha
centralretinalarteriolarequivalent
inthelowestquintileoftheentire
cohort(centralretinalarteriolar
equivalent<148.7micrometers).
Thereliabilitycoefficient(for
retinalarteriolar

thepreviousyear,andby
reviewinglocalhospital
dischargelistsanddeath
certificationfromstatestatistics
offices.20Ahospitalizationwas
consideredeligibleforpossible
validationasastrokeifit
containedadischargediagnosis
codeofcerebrovasculardisease
(InternationalClassificationof
Diseases,NinthRevision,
ClinicalModificationcodes430
438).Outofhospitaldeaths
codedasfatalstrokesinthedeath
certificatewerealsoidentified,
butnotvalidatedandtherefore
excluded.

Figure. Participant flow chart

showing inclusion and exclusion
criteria for this study. CHD
indicates coronary heart
disease.

andvenularcaliber)and
statistics(forretinallesions)
withinandbetweengraders
rangedbetween0.61and1.00.19
Severityofhypertensive
retinopathywasdefinedasnone,
mild,moderate,andsevere,as
describedpreviously(Table1;
FigureS1intheonlineonlyData
Supplementforexamples).

AssessmentofIncident
StrokeandSubtypes

Ascertainmentandclassification
ofstrokeinARIChasbeenprevi
ouslydescribed.20Information
aboutstrokeeventswasobtained
throughannualfollowup
telephoneinterviews,identifying
hospitalizationsanddeathsin

Whenapotentialstrokewas
identified,atrainednursewas
senttoabstracthospitalrecords.
Eacheligiblecasewasclassified
byacomputeralgorithmand
independentlyclassifiedbyan
expertphysicianreviewer.
Disagreementsbetweenthe2
wereadjudicatedbyasecond
physicianreviewer.Detailson
qualityassurancearepresented
elsewhere.20

Forthisanalysis,incidentstroke
isdefinedtoincludeonlystrokes
thatoccurredbetweenthetimeof
retinalphotographyin1993to
1995andDecember31,2008.
Thesearecategorizedascerebral
infarctions(thromboticor
embolicbraininfarction)or
hemorrhagicstrokes(sub
arachnoidorintracerebral
hemorrhage).14

Definitionof
HypertensionandBlood
Pressure

Historyofhypertensionanduse
ofantihypertensivemedication
wereascertainedfromexaminer
ascertainedquestionnairesatthe
thirdexamination(19931996).
Bloodpressuresweretakenwith
arandomzero

sphygmomanometer,andthe
meanofthelast2of3
measurementsateachvisitwas
usedforanalyses.Hypertension
wasdefinedassystolicblood
pressure140mmHg,diastolic
bloodpressure90mmHgatthe
thirdexamination,ortheuseof
antihypertensivemedication
duringtheprevious2weeksfrom
thethirdexamination.Subjects
onmedicationwhohadsystolic
anddiastolicbloodpressures
<140and90mmHg,
respectively,atthethird
examinationwereconsideredto
havegoodcontroloftheir
hypertension,whereasthosewith
systolicordiastolicblood
pressures>140and90mmHg,
respectively,wereconsideredto
havepoorcontrolof
hypertension.Meanarterialblood
pressurewascomputedas2/3of
thediastolicbloodpressureplus
1/3ofthesystolicbloodpressure.

Definitionof
CardiovascularRisk
Factors

None
No detectable signs

Mild
Presence of generalized arteriolar
narrowing (first quintile of

CRAE), focal arteriolar narrowing,

arteriovenous nicking, or a

combination

Moderate

Participantsunderwent
standardizedevaluationsof
cardiovascularriskfactorsateach
examination.Thefollowing
variablesincludedinthisstudy
wereassessedduringthethird
examination.Historyofdiabetes
mellitus,cigarettesmoking,alcohol
consumption,anduseof
antidiabeticmedicationwere
ascertainedfromexaminer
administered

Presence of blot, or flame-shaped

hemorrhage, microaneurysm,

soft exudates, or a combination of

these signs
Severe
Presence of moderate hypertensive
retinopathy signs; and optic

Table 1. Classification of
Hypertensive Retinopathy
disc swelling

Grades
Retinal Signs

CRAE indicates central retinal

arteriolar equivalent.

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708HypertensionOctober2013

questionnaires.
Diabetesmellitus
wasdefinedas
fastingbloodglu
cose126mg/dLor
aselfreported
historyoftreatment
fordiabetesmellitus,
anddiabetic
participantswere
excludedfromour
analysis.Fasting
bloodsampleswere
collectedand
processedfortotal
cholesterol,HDL
cholesterol,
triglycerides,and
glucose.21Height
andweightwere
measuredfor
calculationofbody
massindex.

Statistical
Analysis

Coxproportional
hazardmodelswere
usedtocalculate
hazardratio(HR)
and95%confidence
intervals(CI)for
strokebyseverityof
hypertensive
retinopathy.
Participantswere
followedupfrom
thetimeofretinal
photographytothe
strokeevent,death,
lastcontact,or
December31,2008,
whichevercame
first.KaplanMeier
failurecurveswere
constructedfor
incidentstrokeby
hypertensive
retinopathy
classification.We
initiallyadjustedfor

age,sex,andrace
centercategories,
andadditionallyfor
meanarterialblood
pressure(mmHg)at
thirdexamination
(formingthe
baselineforthe
presentstudy),fast
ingglucose,total
cholesteroland
triglyceridelevels
(mg/dL),bodymass
index(kg/m2),
cigarettesmoking,
andalcohol
consumption.
Analyseswere
repeated,stratifying
foruseof
hypertensionlower
ingmedications.
Proportionalhazard
assumptionswere
testedusingKaplan
Meierandpredicted
survivalplots,and
Schoenfeld
residuals.All
analyseswere
performedusing
SPSSversion17.0
andSTATA/SE
11.2.

Results

Amongthe2907
subjects,themost
commonsignof
hypertensive
retinopathy
(excluding
generalized
arteriolarnar
rowing)wasfocal
arteriolar
narrowing(22.3%
[95%CI,20.8%
23.8%]),
arteriovenous
nicking(17.5%
[95%CI,16.1%
18.9%]),andother

retinopathysigns
(5.1%[95%CI,
4.3%5.9%]),
whichincluded
microaneurysms,
softexudates,
blothemorrhages,
andflamed
shaped
hemorrhages.A
totalof1406
subjects(48.4%
[95%CI,46.5%
50.2%])hadnone,
1354(46.6%
[95%CI,44.8%
48.4%])hadmild,
146(5.0%)had
moderate,and1
subjecthadsevere
hypertensive
retinopathy.
Becauseonly1
participanthad
severe
hypertensive
retinopathy,the
participantwas
includedinto

themoderate
hypertensive
retinopathygroup
(5.1%[95%CI,
4.3%5.9%]).
Table2presents
baseline
characteristicsof
thesubjects
accordingto
severityof
hypertensive
retinopathy.

Afteramean
followupperiodof
13.0years,there
were165incident
strokes,ofwhich
146werecerebral
infarctionsand15
werehemorrhagic

strokes.The
incidenceofstroke
eventsforthe
wholepopulation
was0.436(95%CI,
0.420.45)per100
personyears,0.322
(95%CI,0.305
0.339)per100per
sonyearsforthe
groupwithno
retinopathy,and
0.493(95%CI,
0.4660.519)per
100personyears
and1.073(95%CI,
0.8991.246)per
100personyears
forthegroupwith
mildandmoderate
hypertensive
retinopathy,
respectively.

KaplanMeier
failurecurves
constructedfor
incidentstrokeby
hypertensive
retinopathy
classification
(FigureS2)sug
gestedthatthere
wasasignificant
differenceinriskof
strokeinthe3
groupsbecause
pairwiseMantel
CoxLogRank
comparisonswere
allsignificant
(P<0.05).Table3
showsthatin
personswith
hypertension,
increasingseverity
ofhypertensive
retinopathywas
associatedwithan
increasedriskof
incidentstroke,
includingcerebral
infarction.Adjusted
Coxregression
modelspassedtests
forproportional
hazard
assumptions.

Furthermore,
goodnessoffit
whenevaluated
usingCoxSnell
residuals
demonstrated
reasonablefitwith
thedata.

Toassesswhether
hypertensive
retinopathywas
similarlyassociated
withincidentstroke
duringlonger
periodsoftime,we
censoredpersons
whohadstrokes
within5yearsafter
retinal
photographyand
foundthatHRs

estimatedfromthe
multivariatemodel
remainedrelatively
unchangedforboth
incidentstrokeand
cerebralinfarction
(mildhypertensive
retinopathy:HR,
1.39[95%CI,
0.912.11]for
strokeandHR,
1.68[95%,CI,
1.062.64]for
cerebralinfarction;
moderate
hypertensive
retinopathy:HR,
2.20[95%CI,
1.114.37]for
strokeandHR,
2.46[95%CI,
1.185.10]for
cerebralinfarction).

Table 2. Hypertensive Participant

Characteristics According to Retinopathy
Grade

Retinopathy Status

Characteristics
None (n=1406, 48.4%)
Mild (n=1354, 46.6%)

Moderate/Severe (n=147, 5.1%)

P Value*

Age, y (SD)
59.9
(5.6)
61.0
(5.7)
60.2
(6.1)
0.559
Men, n (%)
525
(37.3)
582
(43.0)
67
(45.6)
0.004
Blacks, n (%)
475
(33.8)
320
(23.6)
76
(51.7)
<0.001
Systolic blood pressure, mmHg (SD)

133.6
(18.5)
140.4
(18.4)
142.5
(24.5)
<0.001
Diastolic blood pressure, mmHg (SD)
75.9
(10.5)
78.9
(10.7)
79.9
(13.1)
<0.001
Blood glucose, mg/dL (SD)
100.3
(10.4)
100.2
(10.6)
99.8
(9.7)
0.564
Body mass index, kg/m2 (SD)
29.5
(5.6)
29.6
(5.8)
29.1
(5.9)
0.435
Total cholesterol, mg/dL(SD)
209.8
(36.2)
207.3
(37.1)

208.0
(38.1)
0.557
HDL-cholesterol, mg/dL (SD)
52.8
(17.7)
52.7
(18.3)
54.5
(19.0)
0.596
Total triglyceride, mg/dL (SD)
145.0
(84.4)
143.5
(83.1)
133.5
(73.1)
0.111
Cigarette smoking, ever, n (%)
774
(55.0)
760
(56.1)
77
(52.4)
0.639
Alcohol use, ever, n (%)
1011
(71.9)
1012
(74.7)
102
(69.4)
0.142
Incident stroke, n (%)

60
(4.3)
86
(6.4)
19
(12.9)
<0.001
Incident cerebral infarction, n (%)
51
(3.6)
81
(6.0)
14
(9.5)
<0.001

For continuous variables, P values were evaluated

from linear regression models by assuming
retinopathy status as a 3-level numeric variable for
unweighted means, whereas for categorical
variables, values quoted are from a 2 test of
trend. HDL indicates high-density lipoprotein.

*P value for trend.

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OngetalHypertensiveRetinopathyandStroke 709

Finally,weexaminedthe
associationbetweenhyperten
siveretinopathyandstrokein
personsusing
antihypertensivemedications
(TableS1).Wefoundthat
despitehavinggoodcontrol
ofhypertensionasdefinedby
bloodpressurelevelsatthe
timeoftheretinal
examination,thosewithmild
(HR,1.96[95%CI,1.09
3.55])andmoderate
hypertensiveretinopathy(HR,
2.98[95%CI,1.018.83])
wereatanincreasedriskof
cerebralinfarction.
Additionally,interaction
termstestingforinteraction
betweenhypertensive
retinopathygradeanduseof
hypertensivemedication,or
goodcontrolofhypertension
werenotsignificant.

Discussion

Inthispopulationbased
study,wefoundthatin
personswithhypertensionbut
withoutdiabetesmellitus,
hypertensiveretinopathywas
associatedwithstrokerisk,
suggestingthatthepresence
oftheseretinalmicrovascular
changesisindicativeof
additionalvascularrisk
beyondthatconferredby
traditionalcardiovascularrisk
factors.

Histopathologyof
VascularLesionsin
RetinaandBrain

Histopathologicstudies
suggestthatthese
hypertensiveretinopathy
lesionsresultfromsmall
vesselarteriolosclerosis,22and
continuedelevatedblood
pressureresultsinretinal
ischemiaandbreakdownof
thebloodretinabarrier.23
Theyparallelhypertensive
microvascularchanges
describedinthebrain,suchas
concentricthickeningofthe
arterialwall,intimal
thickening,medial
hyperplasia,andincreased
vesselpermeability
attributabletobloodbrain
barrierbreakdown,2426sug
gestingthatretinal
photographyisapotential
clinicaltooltoindirectly
assesspotentialmicrovascular
damageinthecerebral
vasculature.

Hypertensive
Retinopathy
Classifications

Severalattemptshavebeen
madetodeviseaclassification
systemforretinopathysigns,
andstudieshaverelatedthese
signstocardiovasculardiseases
andmortality.However,they
arelimitedforseveralreasons.
First,becausetheyinvolved
patientswhohaduncontrolled
oruntreatedhypertension,
generalizationtocontemporary
populationsofpatientswith
lowerbloodpressurelevels
maybeproblematic.Second,in
studiesperformeduptothe
20thcentury,retinopathywas
definedusingonlydirect
ophthalmoscopicexamina
tion.2729Thistechniqueis

subjecttohighinterobserver
7

variability. Third,although
manyearlierstudiescite
increased

mortalityamongpersonswith
hypertensiveretinopathy,few
havedemonstrated
associationsbetween
hypertensiveretinopathyand
specificcardiovascular
outcomes,suchasincident
stroke,orhaveadequately
controlledforrelevant
confoundingfactors.More
recentpopulationbased
studieshaveadoptedretinal
photographyandstandardized
protocolsfortheassessment
ofretinopathysigns.Using
theseprocedures,several
studieshaveshownthat
retinalmicrovascular
changes,including
retinopathysigns,arerelated
tosubclinicalandclinical
cerebrovascularpathology.10
13,15,30,31

However,these
studieshavemainlyexamined
generalelderly
populations.30,31

PossibleClinical
Implications

Inthepresentstudy,we
focusedonsubjectswith
hypertensionandfoundwithin
thisgroupthatthosewithmild
andmoderatehypertensive
retinopathywereatan
additionalincreasedriskof
developingastroke.Our
currentdatasuggestthatwithin
thosewhohavehypertension,
fundusexaminationmaypoten
tiallyprovideadditional
informationonlongterm
strokeriskstratification.The

simplified3grade
classificationweusediseasily
implementableinbothclinical
andresearchsettingswith
accesstofundusexamination
procedures.

Furthermore,clinicalguidelines
stronglyrecommendthat
loweringbloodpressurecan
leadtosignificantreductionof
strokerisk1,2;however,our
findingssuggestthatdespite
havinggoodcontrolofblood
pressure,patientswith
hypertensiveretinopathyareat
anincreasedriskofstroke.This
suggeststhatclosely
monitoringbloodpressuresand
medicationcompliancemay
notbesufficientforstroke
preventioninpatientswith
hypertension.Retinal
assessmentmaybeusefulespe
ciallyinthosewithgood
controlofhypertension.

Methodological
Considerations

Becausehypertensive
retinopathyisdifficultto
distinguishfromdiabetic
retinopathyinpatientswith
bothcomorbidities,withthe
actualcauseofpresent
retinopathysignsunde
terminable,weexcluded
participantswithhypertension
whohaddiabetesmellitusin
ouranalyses.Becausepersons
withaprevioushistoryof
coronaryheartdiseasemay
alreadybeatanincreasedrisk
ofstroke,includingthese
subjectsmayconfoundthe
associationbetween
hypertensiveretinopathyand
incidentstroke.Therefore,
participantswithcoronaryheart
diseaseatbaselinewere
excluded,whichresultedina
smallersamplesizeandwider

CIsinthecurrentstudy.
Becausewedidnothave

detailedinformationonother
cardiovascular

Table 3. Hazard Ratios (95% Confidence Intervals) for Stroke

and Cerebral Infarction by Severity of Hypertensive Retinopathy
Grades

Unadjusted

Model 1*

Model 2

Hypertensive

Cerebral Infarction

Cerebral Infarction

Cerebral

Retinopathy Grades
Stroke (n=165)
(n=146)

Stroke (n=165)
(n=146)

Stroke (n=165)
Infarction (n=146)

None (1406)
1.00 (ref)
1.00 (ref)

1.00 (ref)
1.00 (ref)
1.00 (ref)
1.00 (ref)

Mild (1354)
1.53 (1.102.13)
1.70 (1.202.41)

1.50 (1.072.09)
1.67 (1.172.38)
1.35 (0.961.89)
1.52 (1.062.19)

Moderate/severe (147)
3.36 (2.005.63)

2.86 (1.595.17)

2.71 (1.614.56)
2.29 (1.264.15)
2.37 (1.394.02)
2.01 (1.103.70)

*Adjusted for age, sex, and race-center.

Adjusted for age, sex, race-center, mean arterial blood pressure,

fasting blood glucose, high-density lipoprotein cholesterol, triglyceride
levels (mg/dL), body mass index (kg/m2), cigarette smoking, and
alcohol consumption.

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710Hypertension
October2013

diseasesubtypes,wewere
unabletofullyaccountfortheir
confoundingeffectonthe
associationbetween
hypertensiveretinopathyand
theriskofstroke.Weuseda
45nonstereoscopicfundus
photographtakenthroughthe
nondilatedpupilof1eye,
makingretinopathygrading
morevariable.Unilateral
retinopathywouldbemissedif
themoreinvolvedeyewasnot
examined.However,this
misclassificationofret
inopathyislikelytobe
independentofaperson
developingastrokeand,thus,
wouldresultinbiastowardthe
null,suggestingthatthetrue
associationmaybestronger.
Becauseofthesmallnumberof
hemorrhagicstrokes,wecould
notexaminetheassociation
withthissubtype.Furthermore,

becausebloodpressure
measurementswerenot
obtainedfromparticipants
aftertheexaminationvisitin
whichretinalphotographywas
performed,wecouldnotadjust
forbloodpressureduringthe
followupperiod.Several
strengthsofthecurrentstudy
includealargesampleof
subjectswithhypertension,
longfollowupforperiodof
stroke,andstandardized
proceduresfortheassessment
ofretinopathy.

Perspectives

Amongpersonswith
hypertensionwithoutdiabetes
mellitus,hypertensive
retinopathyisassociatedtoan
increasedlongtermriskof
stroke,independentofother
vascularriskfactors.
Furthermore,amongthosewho
haveseeminglygoodcontrolof
hypertension,personswith
hypertensiveretinopathyarenev

erthelessatanincreasedriskof
developingcerebralinfarction.
Thesefindingssuggestthata
retinalexaminationmaybe
valuablefortheassessmentof
strokeriskinpatientswith
hypertension.

Acknowledgments

Wethankthestaffand
participantsoftheARICstudy
fortheirimportantcontributions.

SourcesofFunding

TheAtherosclerosisRiskin
CommunitiesStudyisperformedasa
collaborativestudysupportedby
NationalHeart,Lung,andBlood
Institutecontracts
(HHSN268201100005C,HHSN26820
1100006C,HHSN268201100007C,
HHSN268201100008C,
HHSN268201100009C,
HHSN268201100010C,
HHSN268201100011C,and
HHSN268201100012C).DrIkram
receivedadditionalfundingfromthe
SingaporeMinistryofEducation
AcademicResearchFund(Tier1
WBSR191000014112)andthe
SingaporeMinistryofHealths
NationalMedicalResearchCouncil
(NMRC/CSA/038/2013).The
fundingsourceshadnoroleinthis
study.

Disclosures

Primarypreventionofischemic
stroke:aguidelinefromtheAmerican
HeartAssociation/AmericanStroke
AssociationStrokeCouncil.Stroke.
2006;37:15831633.

ZhangH,ThijsL,StaessenJA.Blood
pressureloweringforprimaryand
secondarypreventionofstroke.
Hypertension.2006;48:187195.

RavenniR,JabreJF,CasigliaE,
MazzaA.Primarystrokeprevention
andhypertensiontreatment:whichis
thefirstlinestrategy?NeurolInt.
2011;3:e12.

ChobanianAV,BakrisGL,BlackHR,
CushmanWC,GreenLA,IzzoJLJr,
JonesDW,MatersonBJ,OparilS,
WrightJTJr,RoccellaEJ;National
Heart,Lung,andBloodInstituteJoint
NationalCommitteeonPrevention,
Detection,Evaluation,andTreatmentof
HighBloodPressure;NationalHigh
BloodPressureEducationProgram
CoordinatingCommittee.The

SeventhReportoftheJointNational
CommitteeonPrevention,Detection,
Evaluation,andTreatmentofHigh
BloodPressure:theJNC7report.
JAMA.2003;289:25602572.

WilliamsB,PoulterNR,BrownMJ,
DavisM,McInnesGT,PotterJF,Sever
PS,ThomSM;BHSguidelinesworking
party,fortheBritishHypertension
Society.BritishHypertensionSociety
guidelinesforhypertension
management2004(BHSIV):summary.
BMJ.2004;328:634640.

None.

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Novelty and Significance

What Is New?

Retinal fundus photography may be a valuable tool for the assessment of

Hypertensive retinopathy is associated with an increased long-term risk

long-term stroke risk in patients with hypertension.

of stroke and cerebral infarction, independent of vascular risk factors in

Summary

persons with hypertension.

Hypertensive retinopathy predicts long-term risk of stroke and

What Is Relevant?

cerebral infarction in hypertensives, independent of traditional risk

Hypertensive retinopathy in persons on medication with seemingly good

factors.

control of blood pressure was nevertheless at an increased risk of devel-

oping cerebral infarction.

Downloadedfromhttp://hyper.ahajournals.org/byguestonJune13,
2016

HypertensiveRetinopathyandRiskofStroke
YiTingOng,TienY.Wong,RonaldKlein,BarbaraE.K.Klein,PaulMitchell,A.Richey
Sharrett,DavidJ.CouperandM.KamranIkram

Hypertension.2013;62:706711;originallypublishedonlineAugust12,2013;doi:
10.1161/HYPERTENSIONAHA.113.01414

HypertensionispublishedbytheAmericanHeartAssociation,7272GreenvilleAvenue,Dallas,TX75231
Copyright2013AmericanHeartAssociation,Inc.Allrightsreserved.
PrintISSN:0194911X.OnlineISSN:15244563

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theWorldWideWebat:

http://hyper.ahajournals.org/content/62/4/706

DataSupplement(unedited)at:
http://hyper.ahajournals.org/content/suppl/2013/08/12/HYPERTENSIONAHA.113.01414.DC1.html

Permissions:Requestsforpermissionstoreproducefigures,tables,orportionsofarticlesoriginallypublishedin
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ONLINE SUPPLEMENT

Hypertensive Retinopathy and Risk of Stroke

1,2

Yi-Ting Ong , Tien Y. Wong

7

2,3,4

, Ronald Klein , Barbara E.K. Klein , Paul Mitchell , A.

8

Richey Sharrett , David J. Couper , M. Kamran Ikram

2,3,9

NUS Graduate School for Integrative Sciences and Engineering, National University of
Singapore, Singapore
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore
Singapore Eye Research Institute, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore
Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia
Department of Opthalmology and Visual Sciences, University of Wisconsin School of Medicine
and Public Health, Madison, WI, USA
Department of Opthalmology and Westmead Millennium Institute, Centre for Vision Research,
University of Sydney, Sydney, Australia
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore,
MD USA
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands

Corresponding Author:

M. Kamran Ikram, MD PhD

National University Health System, 1E Kent Ridge Road, NUHS Tower Block, Level 7,
Department of Ophthalmology, Singapore 119228; E-mail: kamran_ikram@nuhs.edu.sg; Phone:
+65 8126 1594; Fax: +65 6323 1903

Table S1: Hazard ratios (95% confidence intervals) for stroke and cerebral infarction by severity of hypertensive retinop participants on hypertensionlowering medication.

Use of Anti-hypertensive medication

On medication and good control*
On medication and always good

Hypertensive

control

Retinopathy

Stroke
Cerebral

Stroke
Cerebral

Stroke
Cerebral

Grade
N

infarction
N

infarction
N

infarction

(n=116)

(n=58)

(n=44)

(n = 101)

(n=51)

(n=38)

None
1084
1.00 (ref)
1.00 (ref)
826
1.00 (ref)
1.00 (ref)
585
1.00 (ref)
1.00 (ref)

Mild
917

1.25
1.55
579
1.62
1.96
379
1.88
2.29

(0.83-1.87)
(1.00-2.39)

(0.94-2.80)
(1.09-3.55)

(1.00-3.53)
(1.15-4.54)

Moderate/Severe
102
2.94
2.67
58
2.25
2.98
42
2.30

3.09

(1.61-5.38)
(1.33-5.35)

(0.77-6.55)
(1.01-8.83)

(0.67-7.88)
(0.89-10.8)

All models are adjusted for age, sex, race-center, mean arterial blood pressure, fasting blood glucose, HDL- cholesterol, triglyceride levels (mg/d cigarette smoking and alcohol consumption.
*

On medication and good control defined as hypertensive participants on medication with systolic and diastolic blood pressures below 140mmH retinal examination.

On medication and always good control defined as hypertensive participants on medication with systolic and diastolic blood pressures below 1 respectively at all 3 visits over 6 years.

On medication and poor control defined as hypertensive participants on medication with systolic or diastolic blood pressures above 140mmHg retinal examination.

Figure S1:

Examples of (A) no hypertensive retinopathy; (B) mild hypertensive retinopathy showing focal
arteriolar narrowing (black arrow); (C) moderate hypertensive retinopathy showing arteriovenous nicking (black arrow), blot hemorrhages and microaneurysms; (D) moderate
hypertensive retinopathy showing soft exudates and arterio-venous nicking (black arrow).

Figure S2:

Kaplan-Meier failure curve of cumulative hazards of stroke by severity of hypertensive

retinopathy against follow-up time (years) in participants with hypertension but without diabetes.