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Spinal cord injury is associated with an increased risk of atrial fibrillation: A population-based cohort study.

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Spinal cordinjuryisassociatedwithanincreasedriskof atrial

fbrillation: Apopulation-basedcohortstudy

Chun-Cheng

Wang,MD,

*†

Chiz-Tzung Chang,MD,PhD,

‡§

Cheng-Li Lin,MSc,

‡║

Bor-Ren

Huang,MD,

Chia-Hung Kao,MD

*#

Introduction

Spinal cordinjury(SCI)isaseveremedicalconditionthat can

causevariousmotor,sensory,andautonomicdysfunc- tions.1 SCI

mayalsocauselong-lastingdysfunctionin several organsystems,leadingtohighmorbidityandan adverse prognosis.2 Cardiovascular diseaseistheleading cause ofdeathinpatientswithSCI.3–5

Vascularthrom- boembolism, acutemyocardialinfarction,posturalhypoten- sion, orthostatichypotension,andcardiacarrhythmiamay have beenreportedtooccurinpatientswithSCI.6–9 Cardiac arrhythmiaisfrequentlyobservedinpatientswith SCI andisgenerallyconsideredtobecausedbyautonomic dysfunction.Becausethespinalsympatheticpathwaysthat controltheheartandmaintainvasculartoneexitatthe frst thoracicvertebratofourththoracicvertebra(Th1-Th4)levels, anunopposedparasympathetictonemaybepresentatthe cervicalorhighthoracic(aboveTh5)levelinpatientswith SCI.Life-threateningbradyarrhythmiaorsinusarrestrequir- ingtheimplantationofapacemakerhasalsobeenreported.8 Atrial fbrillation(AF),themostcommonsustainedcardiac arrhythmiaencounteredinclinical

practicewithaprevalence of 1.0%–2.0%inthegeneralpopulation,canleadtosubstantial morbidity, reducedqualityoflife,andincreasedmortality.10,11 AF isacomplexdiseasecausedbymultipleunderlying

mechanisms,includingautonomicneuraldysregulation. Despite

theclinicalsignifcanceofAF,toourknowledge,no systemicanalysisofalargecohorthasbeenconductedto investigatetheassociationbetweenSCIandtheincidenceof AF.

Therefore,weconductedthisretrospectivecohortstudy, using

anationwidedatabase,toinvestigatethisissue.

Methods

Data source In thisretrospectivecohortstudy,weuseddatafromthe National

HealthInsuranceResearchDatabase(NHIRD)of Taiwan, whichcontainscomprehensiveinformationon clinical visitsandadmissionsforeachinsurant,including demographic data,visitdates, International Classifcationof Disease, NinthRevision,ClinicalModifcation (ICD-9-CM) diagnostic codes,andprescriptionhistories.Thecompre- hensive NationalHealthInsurance(NHI)program12 was

established in1995andprovidescoverageto 499% ofthe population

of23.7millionpeople.TheTaiwanNational Health ResearchInstituteadministerstheNHIRD,and before theelectronic fles arereleased,personalidentifcation

(2)

informationisencryptedtoprotectpatientprivacy.Inthis study,

weusedclaimsdatafromtheLongitudinalHealth Insurance Database2000,asubsetoftheNHIRDthat contains allmedicalclaimsdataonarandomsampleof 1,000,000 benefciaries

oftheNHIprogram.TheLongitu- dinal HealthInsuranceDatabase2000dataonsex,age,and health carecostshavebeenprovedtoberepresentativeofthe all insurants.Thisstudywasapprovedtofulfll thecondition for exemptionbytheInstitutionalReviewBoardofChina Medical University(CMUH-104-REC2-115).Theinstitu- tional reviewboardalsospecifcally waivedtheconsent requirement. Sampled participants Patients 20yearsandolderwhowerenewlyhospitalizedfor SCI (ICD-9-CM codes 806and952)between2000and2011 comprised theSCIcohort.TheSCIdiagnosisdatewas defned astheindexdate.Weclassifed patientswithSCI into 4subgroups:cervicalSCI(ICD-9-CM codes 806.0, 806.1, 952.0,and952.00–952.09); thoracicSCI(ICD-9-CM codes 806.2,806.3,952.1,and952.10– 952.19); lumbar, sacral, andcoccygealSCI(ICD-9-CM codes 806.4,806.5, 806.6,

806.7,806.8,806.9,952.2,952.3,952.4,952.8,and 952.9);

andmultilevelSCI.Weexcludedpatientsdiagnosed with AF(ICD-9-CM codes427.3and427.31);atrial futter (ICD-9-CM code 427.32);supraventriculartachycardia, ventricular

tachycardia,andheartblock(ICD-9-CM codes 426–427.5

and427.81);andpacemakerimplantationbefore the

indexdate.Forthenon-SCIcohort,werandomlyselected controls ataratioof4:1andfrequency-matchedthemto patients withSCIbyage,sex,andindexyear.Thesame exclusion criteriawereappliedtothenon-SCIcohortas applied totheSCIcohort. Outcomes andcomorbidities Each

studyparticipantwasfolloweduntiladiagnosisofAF, death,

losstofollow-up,withdrawalfromtheNHIprogram, or December31,2011,whicheveroccurred frst. We

usedinpatientdiagnosis fles todeterminebaseline comorbidities, includingdiabetes(ICD-9-CM code 250), hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM code

272),chronicobstructivepulmonarydis- ease (COPD)(ICD-9-CM codes 491,492,and496),heart failure (ICD-9-CM code 428),coronaryarterydisease (CAD) (ICD-9-CM codes 410–414), stroke(ICD-9-CM codes 430–438), cancer(ICD-9-CM codes 140–241), hyper- thyroidism (ICD-9-CM code

242),andchemotherapy. Statistical analysis We frst

comparedthedistributionsofsex,age,andbaseline comorbidities betweentheSCIandnon-SCIcohorts.Then, the χ2 test wasusedtoexaminecategoricalvariablesandthe Student t test

wasusedtoexaminecontinuousvariables.The cumulative incidenceofAFintheSCIandnon-SCIcohorts was assessedusingtheKaplan-Meiermethod,anddiffer- ences wereassessedusingalog-ranktest.Theincidence densities, stratifed accordingtosex,age,andcomorbidities, were

estimatedforbothcohorts.Therelativeriskof developing AFinpatientswithSCI,comparedwiththe non-SCI cohort,wasanalyzedusingunivariateandmulti- variate Coxproportionalhazardsregressionmodels.Hazard ratios (HRs)and95%confdence intervals(CIs)were estimated usingtheCoxmodels.ThemultivariateCox models wereadjustedforage,sex,andthecomorbidities of

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heartfailure(CHF),CAD,stroke,andhyperthyroidism. Further

analysiswasperformedtoassesswhetherAFwas associated withthelevelofSCI.A2-tailed P value of o.05 was consideredtobestatisticallysignifcant. Allanalyses were

performedusingSASstatisticalsoftwareversion9.3 for Windows(SASInstitute,Inc.,Cary,NC).

Results

This studyincluded41,691patientswithSCIand166,764 patients withoutSCI(Table 1).

Nostatisticaldifferencewas observed inthedistributionbetweentheSCIandnon-SCI cohorts.

TheSCIcohortwassignifcantly olderthanthenon- SCI cohort(meanage52.0 _ 18.1 yearsvs51.5 _ 18.2 years; P o .001). Overall,patientswerepredominantlymen (63.4%)

andolderthan50years(52.5%).Comparedwiththe non-SCI cohort,theSCIcohorthadsignifcantly higher proportions ofdiabetes,hypertension,hyperlipidemia, COPD,

heartfailure,CAD,stroke,andhyperthyroidism (P o .001 forall). The

meanfollow-upperiodswere5.69and6.17yearsfor the SCIandnon-SCIcohorts,respectively(P o .001). The median durationfromthestudytothe frst occurrenceofAF in

theSCIcohortwas2.66yearsascomparedwith3.51years in thenon-SCIcohort.Themedianend-pointtimeratiowas 0.76. Asshownin Figure 1, theprobabilityofAFwas signifcantly

higherintheSCIcohortthaninthenon-SCI cohort (log-ranktest, P o .001). The

overallincidenceofAFwas1.36-foldhigherinthe SCI cohortthaninthenon-SCIcohort(2.70casesper1000 person-years vs1.99casesper1000person-years),repre- senting anadjustedHRof1.28(95%CI1.17–1.40)

(Table 2). Comparedwiththenon-SCIcohort,theSCI cohort exhibitedsignifcantly

higherrisksofdevelopingAF in bothmaleandfemalesubgroups(adjustedHR1.40;95% CI 1.23–1.58 andadjustedHR1.16;95%CI1.01–1.32). When stratifed byage,theSCIgrouphadsignifcantly higher risksofdevelopingAFinthe50-to65-yearage subgroup (adjustedHR1.41;95%CI1.11–1.78) andinthe 465-year agesubgroup(adjustedHR1.21;95%CI1.09– 1.34) ascomparedwiththenon-SCIgroup.Therewas no signifcant differenceintheriskofAFbetweenSCIand non-SCI groupsinthe r49-year

agesubgroup.Stratifed according tocomorbidities,therelativeriskofAFwas signifcantly

higherintheSCIcohortthaninthenon-SCI cohort forbothpatientswith(crudeHR1.03;95%CI0.92– 1.15 andadjustedHR1.25;95%CI1.11–1.40) andwithout (crude HR0.88;95%CI0.76–1.02 andadjustedHR1.33; 95% CI1.14–1.54) comorbidity. In themultivariateanalysis,theadjustedHRforAFwas 1.12-fold

higherforwomenthanformen(95%CI1.04– 1.21), whichincreasedwithage(every1year)(adjustedHR 1.10; 95%CI1.09–1.10). Inaddition,thecomorbiditiesof diabetes,

hypertension,COPD,heartfailure,andCADwere signifcantly associatedwithincreasedrisksofAF(Table 3). Compared withpatientswithoutSCI,patientswithmulti- level

SCIwere1.83-foldmorelikelytodevelopAF(95%CI 1.45–2.31), followedbypatientswithlumber,sacral,coccy- geal spinalcordinjury(L-S-Co-spinalinjury)(adjustedHR 1.31; 95%CI1.14–1.50) andthoracicspinalinjury(T-spinal injury) (adjustedHR1.31;95%CI1.09–1.57) (Table 4).

Tofurtherinvestigatetheinteractionbetweencancerand

SCIforthedevelopmentofAF,wedividedtheSCIgroupinto

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associatedSCIsubgroupexhibitedasignifcantlyhigherrisk of developingAF(adjustedHR1.29;95%CI1.17– 1.41). Comparisons ofdifferencesinbaselinecharacteristics between

cancer-andnon–cancer-associatedSCIsubgroups are shownin Table 6. Comparedwiththenon–cancer- associated

subgroup,thecancer-associatedSCIsubgroup was signifcantly older,waspredominantlywomen,andhad signifcantly higherproportionsofdiabetes,hypertension, hyperlipidemia,

hyperthyroidism,stroke,CAD,COPD,and CHF. Accordingtothelevelofinjury,thecancer-associated SCI subgrouphadsignifcantly higherproportionsof T-spinal andL-S-Co-spinalinjuriesthandidthenon–cancer-associated SCIsubgroup. Differences inbaselinecharacteristicsbetweendif- ferent

levelsofSCIwerefurthercompared(Table 7). Compared withpatientswithcervicalspinalinjury (C-spinal injury),patientswithT-spinalinjury,L-S-Co- spinal injury,andmultilevelSCIwerefemalepredominant, were older,andhadhigherproportionsofdiabetes,hyper- tension, hyperlipidemia,COPD,heartfailure,CAD,and stroke.

Discussion

Interpretation ofthestudyresult Our

resultsshowedthattheriskofAFafterlong-term follow-up

washigherintheSCIgroupthaninthenon-SCI group, particularlyinpatientswiththeT-spinalinjury,L-S- Co-spinal injury,andmultilevelspinalinjury. Association

betweentheriskofAFandSCI Cardiovascular dysfunctionshavebeenproposedtobethe most commoncausesofdeathinpatientswithchronicSCI. Among

thesedysfunctions,cardiacfailure,ventricular

tachycardia,AF,CAD,andcerebrovasculardiseasearethe most commoncausesofdeath.13,14 However, despitethe clinical

importanceofAFinpatientswithchronicSCI,

epidemiologicalevidencelinkingtheincidenceofAFtoSCI is lacking.Twocasereports15,16 have demonstratedthatAF occurs

duringepisodesofautonomicdysrefexia. Prakash et al17

comparedelectrocardiographic fndings frompatients with chronicSCIwiththosefromable-bodiedcontrolsand found thattheprevalenceofAFwassimilarbetweenthe2 groups. However,inourstudy,theriskofAFwashigherin the

chronicSCIgroup.Thedifferencesbetweenthestudy results maybeduetothedifferentbaselinedemographic characteristics ofthecontrolgroups.Inourstudy,theSCI group hadsignifcantly

higherproportionsofhypertension, CHF, CAD,andCOPDthandidthenon-SCIgroup. However, Prakashetalreportedsignifcantly higherpropor- tions

ofhypertension,CHF,CAD,andCOPDintheirable- bodied controlgroupthanintheSCIgroup.Chronichyper- tension,

CHF,CAD,andCOPDhavebeensuggestedtobe risk factorsforAF.11,18–22 To

clarifywhetherSCIisan independent riskfactorforpredictingtheriskofAFafter controllingforthesepotentialconfoundingfactors,we performed

(5)

additionalsubgroupanalyses.Theresults revealed

thatinthesubgroupwithoutanycomorbidities, patients withSCIstillhadasignifcantly higherriskofAFin the long-termfollow-upperiod. Electrocardiographic

changesinpatientswithSCI Previous studies23–25 have investigatedtheelectrocardio-

graphic changesinpatientswithchronicSCI.Ravensbergen et al23

investigatedtheelectrocardiographicpredictorsfor arrhythmia

inpatientswithSCIandfoundthatP-wave dispersion (PWD)wassignifcantly higherinpatientswith SCI thanintheable-bodiedgroup.Akbaletal24 reported that

PWD wassignifcantly higherinpatientswithSCIfor Z1 year thaninthosewithSCIfor o1 year.Yasaretal25 compared PWDinpatientswithSCIduringthepostinjury period (SCIfor

46 months)andable-bodiedhealthy controls. TheauthorsconcludedthatPWDinpatientswith an injurylevelofTh6orhigherwassignifcantly higherthan in patientswithaninjurylevelofTh7orlower.Inaddition, PWD inbothgroupswashigherthaninthehealthycontrol group, implyingthatautonomicdysfunction(usuallyseenin an injurylevelofTh6orabove)mayinfuence PWD.Higher PWD

hasalsobeenproposedtobeassociatedwithan increased riskofAF.26 Proposed

mechanismsofcardiacarrhythmia in patientswithSCI The

autonomicnervoussystemplaysanimportantrolein cardiovascular control.AfterSCI,disruptionofthecommu- nication

betweenthebrainstemandtheautonomicnervous system canoccur.8,13

Sympatheticpreganglionic fbers exit at

theTh1-Th4leveltoformsynapsesinthethoracicganglia with postganglionic fbers,

whichmayinnervatetheheart and beresponsibleforincreasingheartrateandcardiac output. Parasympathetic fbers exitthecentralnervous system

atthebrainstemlevelthroughthevagalnerveto innervate theheartandantagonizetheeffectofthesym- pathetic nervoussystem.Therefore,patientswithSCIatthe cervical

orhighthoraciclevel(aboveTh6)couldhave impaired sympatheticimpulsesandunopposedparasympa- thetic activity,therebyleadingtoautonomicdysfunction. Previous studies9,27 reported

thatmostcardiacarrhythmias (eg, sinusbradycardiaandsinusarrest)thatoccurinpatients with SCImainlydosobecauseofautonomicdysfunction and

thattheriskisusuallyattenuatedaftertheacutestage.In our study,thecumulativeincidenceofAFseemedto increase steadilywithtime,implyingthatthepathogenesis of

AFinpatientswithSCIcannotsimplybeexplainedby autonomic dysfunction.Inthechronicstage,cardiacdys-rhythmia suchasAFmayoccursecondarytoautonomic dysrefexia, asyndromeofrefex

sympatheticdischargefrom the preganglionicneuronsinthethoracolumbarspinalcord in responsetoviscerosensitivestimulioriginatingbelowthe level

(6)

ofinjuryinpatientswithSCIaboveT6.However,we observed anincreasedriskofAFinpatientswithT-spinal injury, L-S-Co-spinalinjury,andmultilevelSCI,while patients

withC-spinalinjuryshowedonlyanonsignifcant trend towardanincreasedriskofAF.Thereareseveral possible explanationsforthis.First,somepatientswithC- spinal injurymayhavemultilevelinjuryandweretherefore assigned tothemultilevelSCIsubgroup;hence,theassoci- ation

betweenC-spinalinjuryandAFmaybeunderesti- mated inourcohort.Second,comparedwithpatientswithC- spinal injury,patientswithT-spinalinjury,L-S-Cospinal injury, andmultilevelSCIweresignifcantly olderandhad higher proportionsofcancer,hypertension,diabetes,chronic kidney

disease,COPD,hyperthyroidism,heartfailure,CAD, and stroke,allofwhichmaycontributetoanincreasedrisk of AF.WeproposedthatthepathogenesisofAFinpatients with

chronicSCIinvolvesbothautonomicdysfunctionand other coexistingcardiovascularriskfactors.

Association betweenfemalesexandAF Previous

studieshavesuggestedthattheriskofAFishigher in menthaninwomen.17β-Estradiol mayattenuatethe shortening ofatrialrefractorinessthatoccursafterrapidatrial pacing,

therebydecreasingthesusceptibilitytoAF.28 How-ever, inourstudy,womenhadahigherriskofAFthandid

men. Thepossibleexplanationisthatasignifcant numberof patients

inourcohortwereinpostmenopausalperiod.A previousstudy29 suggestedthatthoughAFislessprevalentin

women, theoverallabsolutenumberofAFishigherinwomen. This maybeexplainedbythefactthatpostmenopausalwomen

havehigherrisksofheartfailureandischemicheartdisease, which maycontributetotheincreasedriskofAF.

Association betweencancerandtheriskofAF It

hasbeenreportedthatpatientswithcancerhadan increased riskofAF.Theexplanationsincludedirectcancer invasion, paraneoplasticmanifestations,physicaloremo- tional stress,increasedinfammation,cancer-relatedmeta- bolic orelectrolytedisorders,andcomplicationsinherentto

chemotherapyorsurgicaltreatment.30 In ourstudy,patients with

SCIwithcancerdidnothaveanincreasedriskofAF compared withthenon-SCIcohort.However,ourresultsare limited byarelativelysmallsamplesizeandinadequate statistical

powerforthepatientswithSCIwithcancer.We cannot concludewhetherpatientswithSCIwithcancerhave a higherriskofAFonthebasisofourresults. Study limitations There

areseverallimitationsofthisstudy.First,allthe informationwasobtainedfromamedicalclaimsdatabase and allpatientswereanonymous.Therefore,wecouldnot review medicalchartsorimagingstudiestoverifythe diagnoses.Theaccuracyof ICD-9-CM codes isamajor concern.

However,thediagnosesofmostcovariatesinour study havebeenvalidatedbefore.31 Second, becausesome

AF casesmaybeasymptomatic,thetrueincidenceofAF may

beunderestimated.SomeasymptomaticAFcasesmay not havebeenidentifed inthenon-SCIgroupbecauseofa lack ofphysicianvisits.However,theestimatedincidence rate

(7)

(0.8–28.3 casesper1000person-years).11 Our dataare

comparablewiththosefrompreviousstudies.Third,the NHIRD

doesnotcontaindetailedinformationonother potential confounderssuchassmokinghabits,alcohol consumption,bodymassindex,typesofheartdisease,heart failure

functionalclass,leftventricularejectionfraction, and metabolicorelectrolyteabnormalities,whichmayalso be involvedintheoccurrenceofAF.Fourth,thisisan

observationalstudy;therefore,wecannotmakedirectcon- clusions

aboutcausalrelationships.Finally,weexcluded patients youngerthan20years;therefore,ourconclusion cannot beextrapolatedtotheyoungerpopulation.

Conclusion

The

long-termriskofAFwashigherintheSCIgroupthanin the non-SCIgroup,particularlyinpatientswithT-spinal injury, L-S-Cospinalinjury,andmultilevelspinalinjury.

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