SCOPE&NATUREOFYOUNGSUDDENCARDIACDEATHINNEWFOUNDLAND&LABRADOR

ByGinaHamilton

AthesissubmittedtotheschoolofGraduateStudiesinpartialfulfillmentofthe

requirementsforthedegreeofMasterofScienceinMedicine

ClinicalEpidemiologyUnit

FacultyofMedicine

MemorialUniversityofNewfoundland

May2016

St.John’sNewfoundland

ii

Abstract

Introduction:Suddencardiacdeath(SCD)inyoungpeople(ages2-40)isatragedy

forfamiliesandcommunitiesalike.Ithasmultiplecauses,oneofwhichisan

underlyinggeneticarrhythmogeniccardiomyopathy.AstudyfromOntario(ON)

usinga2008cohortassessedtheincidenceofSCDinpersonsaged2-40yearstobe

2.64/100,000person-years.WehypothesizedthatNewfoundland&Labrador(NL)

mayhaveahigherincidenceofearlySCDinages2-40duetopossibleunderlying

geneticcausesgiventhehistoricalgeneticisolationofthepopulationandthe

foundermutationsalreadyidentified(ex.PKP2,RYR2,TMEM43).

Methods:WeascertainedcasesofsuddendeathfromthecomprehensiveMedical

Examiners’provincialdatabasefortheyears2008and1997;2008asadirect

comparisontoON,and1997asitrepresentedatimewhentheimplantable

cardioverter-defibrillatorwasnotavailableinNL.Eachcaseofsuddendeathwas

individuallyanalyzedtodeterminelikelihoodofSCD.

Results:Therewere119casesin2008and157casesin1997.TheincidenceofSCD

forages2-40in2008was7.32/100,000persons.Thiswassignificantlyhigherthan

theincidenceinOntario.TheincidenceofSCDwasnotsignificantlyhigherin1997

than2008.Coronaryarterydiseasewasamajorcauseofdeathinallcohorts,similar

toOntario(non-significantdifference).

Conclusion:Ingeneral,therewasatrendofmorearrhythmogenicdeathsinthe

youngandmorestructuralcardiacdeathsasageincreased.Thisreflectsthecauseof

SCDintheyoungisoftengeneticinnature,whileolderdeathsareoftendueto

iii

coronaryarterydisease,adiseaseheavilyinfluencedbyenvironment.Toconclude,

SCDinNLoccursatahigherincidencethanON,furtherresearchisneededonthe

topic.

iv

Acknowledgments

Iwouldliketothankmysupervisor,Dr.KathyHodgkinson,forgivingmethe

opportunitytodothisthesisandforherongoingsupportandguidanceforall

aspectsofmyMasters.Iwouldalsoliketothankmysupervisorycommittee,Dr.

SimonAvisandDr.Terry-LynnYoung,whoseguidanceandsupportwascentralto

thecompletionofthisthesis.IwouldalsoliketothankFionaCurtis,forwillingto

assistmewheneverneededandwhoseexpertisewasinvaluable.AdditionallyI

wouldliketothankDr.SeanConnorsandtheentiresuddencardiacdeathresearch

groupforalloftheirassistancethroughoutthesepastfewyears.Furthermore,I

gratefullyacknowledgetheAtlanticCanadaOpportunitiesAgencyandSt.Jude

Medicalforprovidingfundingformyresearch.

v

TableofContents

Abstract

Acknowledgments

ii

iv

TableofContents v

ListofTables vii

ListofFigures viii

ListofAbbreviations ix

Chapter1-Introduction 1

1.1LiteratureSearch 51.2DescribingSuddenCardiacDeath 61.3GeneticEtiology 111.3.1StructuralDiseases 151.3.2ArrhythmogenicDiseases 161.4Non-GeneticEtiology 171.5CharacterizedPopulationsDealingwithYoungSCD 191.6Newfoundland&Labrador(NL):AFounderPopulation 221.7MedicalExaminerProtocolandReports1.8StudyRationaleandHypothesis

2324

1.9StudyObjectives 25

Chapter2-Methods

26

2.1CohortsofInterest 272.2DataCollection 272.3LikelinessofSCD 332.4StatisticalAnalysis 35

Chapter3-Results 37

3.1Incidences 383.2CauseofDeath 433.3Location,ActivityLevel,&Symptoms 46

vi

Chapter4-Discussion 50

4.1Incidence 514.2CausesofDeath 554.3CircumstancesofDeath 57

4.4Limitations 594.5Strengths 614.6FutureResearchandConclusion 62

References

AppendicesAppendixA:Currentknowngenemutationsdiscoveredwitha

potentialforSCDAppendixB:SampleMedicalExaminer’sreportAppendixC:ChartauditformAppendixD:PrimaryDatausedforanalysisAppendixE:Comparisonofincidencesacrosstheliterature

6370

71

79808283

vii

ListofTables

Table1.1: Examplesofageneticbasisforstructuralandarrhythmogenic

cardiacdiseases.

12

Table2.1: LabelingoftheCohorts 28

Table2.2: Mannersofdeathusedbyforensicpathologists. 31

Table2.3: LikelinessofSCDcategories. 34

Table3.1: ComparisonsofincidenceandgenderforNL2008age’s2-40

(A)andON2008age’s2-40.

41

Table3.2: ComparisonsofincidenceandgenderforNL2008age’s2-50

(B)andNL1997age’s2-50(C).

42

viii

ListofFigures

Figure1.1: TheDeterminantsofSCD. 8

Figure1.2: Categoriesofheartdiseaseswheregeneshavebeenfoundtobe

involved,dividedintostructuralandchannelopathies.

14

Figure2.1: Processofcategorizingdeathsandassigningtocategoryof

SCD.

29

Figure3.1: ReviewofallpotentialSCDcasesinNLin2008age’s2-40,in

comparisontoON.

39

Figure3.2: ReviewofallpotentialSCDcasesinNLinage’s2-50cohort,in

comparisontoNL1997age’s2-50cohort.

40

Figure3.3: CausesofSCDbyageinNL2008cohort(B). 44

Figure3.4: CausesofSCDbyageinNL1997cohort(C). 45

Figure3.5: CausesofSCDinthe2008NL2-40cohort(A). 47

Figure3.6: CausesofSCDinthe2008and1997NLcohort(B&C). 48

ix

ListofAbbreviations

ADLs :Activitiesofdailyliving

ARVC/D :Arrhythmogenicrightventricularcardiomyopathy/dysplasia

BrS :Brugadasyndrome

CAD :Coronaryarterydisease

CPVT :Catecholaminergicpolymorphicventriculartachycardia

DCM :Dilatedcardiomyopathy

DNA :Deoxyribonucleicacid

HCM :Hypertrophiccardiomyopathy

ICD :Implantablecardioverter-defibrillator

LQTS :LongQTsyndrome

NL :NewfoundlandandLabrador

OCME :OfficeoftheChiefMedicalExaminer

ON :Ontario

RV :Rightventricle

SADS :Suddenarrhythmicdeathsyndrome

SCD :Suddencardiacdeath

SES :Socioeconomicstatus

SQTS :ShortQTsyndrome

SUD :Suddenunexpecteddeath

TMEM43 :Transmembraneprotein43

1

1.Introduction

2

Suddendeathisadevastatingeventforfamiliesandcommunitiesalike.

Worldwide,theestimatedburdenofsuddencardiacdeath(SCD)is4-5millioncases

peryear(Chughetal.,2008).Suddenunexpecteddeath(SUD)isdefinedasthe

suddendeathofanindividualwhoappearshealthyanddiessuddenlywithinafew

minutestoseveralhoursduetopre-existingdiseaseorfunctionaldisorder.SUDis

furtherdefinedbytheanatomicalcauseofdeathafterinvestigationi.e.whichsystem

isresponsibleforthedeath:isitthecardiovascularsystem,therespiratorysystem,

thecentralnervoussystemetc.Thecardiovascularsystemisimplicatedwhenan

autopsyfindsevidenceofcardiacinjury,thusSUDbecomesSCD.Thecardiovascular

systemisalsoimplicatedwhenabsolutelynoanatomicalcauseisfoundonautopsy,

asthenacardiacarrhythmiawasassumedtohaveoccurred.Inthelatter,diagnosing

SCDismuchmoredifficultasallothercausesofdeathmustbeexcluded–whichis

tosayallmeansofinvestigationmustbeexhaustedOverall,SCDisadifficult

diagnosistomake,asitiseasytomissgiventheremaynotbeanyphysicalfindings

onautopsyofarrhythmias.

SCDistypicallyobservedintheolderpopulation;however,aportionofcasesdo

occurintheyoung,withoutanypriorsymptoms(Kauferstein,Kiehne,Neumann,

Pitschner,&Bratzke,2009).IntheolderpopulationthecauseofSCDisoftenrelated

tocoronaryarterydisease(CAD).CADisheartdiseasecausedbyabuildupofplaque

inthecoronaryarteriesthatmayeventuallyleadtoblockages.Whendealingwith

theyoung,manyotheretiologiesarepresent,includingstructural,metabolic,and

3

geneticmutationsthatincreasearrhythmogenicpredisposition(Noseworthy&

Newton-Cheh,2008).

Newfoundland&Labrador(NL)isafounderpopulation,withahighincidenceof

somegeneticdiseases(Rahmanetal.,2003).Thisistheresultofthefoundereffect:

alossofgeneticvariationthatoccurswhenanewpopulationisestablishedbya

verysmallnumberofindividualsfromalargerpopulation.Ithasbeenestimated

that90%ofthecurrentNLpopulationhasarisenfrom20,000to30,000original

EuropeansettlersofpredominantlyEnglishandIrishdecent(Parfrey,Davidson,&

Green,2002).Matingsegregation,combinedwithlowimmigration,andgeographical

isolationofcommunitiesresultedinthegeneticisolationofthepopulation(Younget

al.,1999).Whenalimitednumberofindividualsbringadiseasemutationintoa

smallpopulation,thepopulationgrowsthroughnaturalexpansionand(inthe

absenceofsignificantin-migration)ahighproportionofpeoplewillcarrythe

chromosomeonwhichadiseasemutationisfound(Rahmanetal.,2003).Opposite

toafounder,orinbred,populationisanoutbredpopulation.Thisinvolvesnormal

geneticvariation,asmatingmoreoftenoccurswiththosewhohavenofamilial

relations.Ontario(ON)isanexampleofthistypeofpopulationasitgeographically

central,non-isolated,withnormalimmigrationrates.

AfoundereffecthasbeenobservedinNLformanygeneticdisordersOnesuch

diseaseisarrhythmogenicrightventricularcardiomyopathy/dysplasia(ARVC/D),a

knowncauseofSCD,resultingfromonegeneticsubtypeofwhichiscausedbya

4

mutationinthetransmembraneprotein43(TMEM43)gene.Thismutation(c.1073

C>T.pS358L),discoveredbyourlaboratory(Merneretal.,2008),changestheamino

acidserinetotheaminoacidleucineatposition358.Thismutationisfully

penetrant;itwillshowclinicalsignsofthediseaseoverthelifespanineveryonewho

carriesthegenemutation.TheexactincidenceofthemutationinNLisunknown,but

likely>1/1000persons(K.Hodgkinson,personalcommunication,September25th,

2014).Wealsoknowthatthereareotherfoundermutations(RYR2(p.R176L)and

PCP2(p.Q378X))causingothertypesofcardiomyopathiesandchannelopathiesthat

areresponsibleforyoungSCDinseverallargecohortsinNL(Hodgkinsonetal.,

2013;Lausonetal.,2014).Giventheknownmutations,wehypothesizethatNLhasa

higherincidenceofearlySCDthanelsewhereinCanada.

Incidenceandprevalencearebothmeasuresoftheextentofdiseaseina

population.Incidenceistherateofnewcasesofthediseaseamongthepopulation.

Prevalenceincludesbothnewcasesandthosewhohavecontractedthediseasein

thepastandarestillsurviving.WithrespecttoSCD,wearemoreinterestedin

measuringtheincidence,asprevalenceisnotapplicablebecauseSCDisnota

curabledisease,noonecansurviveit.

Accurateincidencedatahasnotbeeneasytocollect,asthereisnogeneral

populationSCDgeneticscreeningavailableinNL.Geneticscreeninginvolvestesting

anindividual’sdeoxyribonucleicacid(DNA)formultipleknowngenemutations.In

comparison,clinicalscreeninginvolvesusingdiagnostictests(suchas

5

electrocardiogram,orechocardiogram)tolookforphenotypicchanges.Clinical

screeningisnotveryeffectiveforSCD,aswehavenotfoundanyprecisemarkers

yet.Geneticscreening,however,canbequitehelpfulinpreventingSCDdepending

onthegenemutationwearedealingwith.

Manyethicalissuesarisewhendebatingwhetherthereshouldbegenetic

screeningavailable,forexampleaspartofnewbornscreening.Factorstoconsider

includecostimplicationsforthehealthcaresystem,potentialclinical,financial,and

emotionalconsequenceswithfalse-positivescreeningresultsforthepatients,andas

well,thecurrentlackofevidence-basedguidelinestodealwithmanagementof

asymptomaticpatientswhoscreenpositive(Kaltmanetal.,2011).Assuch,health

careprofessionalsarenotpreparedtofullydealwithgeneralpopulationgenetic

screening.Unfortunately,youngSCDisoneofthosecaseswhereclinicalscreening

comparedtogeneticscreeningisnoteffective,asSCDcanpresentwithnoprior

symptomsactingasawarning.Thismakesitimportanttoidentifywhichindividuals

areatgreatestriskofpreventableearlySCDinordertoofferprophylactic

medicationsordevices,suchastheimplantablecardioverter-defibrillator(ICD)

(Kaufersteinetal.,2009).

1.1LiteratureSearch

Acomprehensiveliteraturesearchofnumerousrelevantmedicaldatabases

(PubmedandmeSH,EMBASE,CINAHL,GoogleScholar,andScopus)wasperformed

tofullyunderstandthescopeofyoungSCD.Thiswasaccomplishedusingvarious

6

combinationsofthekeywords:“suddencardiacdeath”“suddenunexpecteddeath”

“young”,“genetics”,“epidemiology”,“arrhythmogenicrightventricular

cardiomyopathy”,“arrhythmogenic”,“arrhythmia”,”cardiomyopathy”,

“channelopathy”,and“non-genetic”.Referencelistsofrelevantpaperswerealso

surveyedtoidentifyadditionalliteratureontopicsofinterest.

1.2 DescribingSuddenCardiacDeath

OnceSCDisdiagnosed,therearemorequestionstoanswer.SCDisdefinedas

theunexpectednaturaldeathfromacardiaccausewithinashorttimeperiod,

generally≤1hourfromtheonsetofsymptoms,inapersonwithoutanyprior

potentiallyfatalcondition(Zipes&Wellens,1998).Physiologically,SCDoftenoccurs

whenanelectricallystableheartistransformedintoanunstableone,causingafatal

arrhythmia.Theexactcauseofthistransformationisrichlydiverse,asSCDisthe

finalcommonendpointofmultiplediseaseprocesses;itresultsfromacomplex

interplayofstructural,metabolic,andgeneticdeterminants(Noseworthy&Newton-

Cheh,2008).

SCDisaheterogeneouscondition;CADaccountsforabout80%ofSCDs,andthe

remaining20%isattributedtocardiomyopathiesandgeneticdiseases(Chughetal.,

2008).Tocomplicatethematter,othermedicalconditions,suchasdiabetes(Jouven,

2005),aswellasmoredynamicassociations,suchaslowsocioeconomicstatus

(SES),arealsoassociatedwithSCD(Chughetal.,2008)(Figure1.1).Theagerange

forSCDiswideasitoccursinindividualsofallages,fromages2andbeyond.Asage

7

varies,etiologyofthediseasemayvaryaswell;CADismoreprevalentintheolder

population,andgeneticconditionscanexerttheireffectsatanyage–youngandold.

Allinall,itisclearthatoverallincidenceofSCDincreaseswithage(Deo&Albert,

2012).

Withregardtogender,SCDhasamuchhigherincidenceinmenthanwomen

(Deo&Albert,2012;Zipes&Wellens,1998).AnalysisoftheFraminghamHeart

Studycohortshowedthatatage40thelifetimeriskofSCDformenis1in8,while

womenarethreetimeslesslikely(1in24)(Lloyd-Jones,Berry,Ning,Cai,&

Goldberger,2009).WhilethisreflectssexdifferencesintheincidenceofCAD,a

higherincidenceinmenhasbeenobservedinothergeneticcausesofSCDaswell.

AustralianresearchersstudiedSCDinacohortwithagelessthan35yearsandfound

that63%ofsubjectsweremalewhenCADwasexcluded(Doolan,Langlois,&

Semsarian,2004).Inhypertrophiccardiomyopathy(HCM)bothsexesareaffected

bythecondition,thoughitismorelikelytobedetectedearlierinmen(Christiaans

etal.,2011;Jacoby,Depasquale,&McKenna,2013).Inastudythatevaluatedthe

largestpopulationofpatientswithBrugadasyndrome(BrS)thusfar,theyreported

thatmenhada5.5-foldhigherriskofsuddendeaththandidwomen(Brugada,

Brugada,&Brugada,2003).

8

Figure1.1:TheDeterminantsofSCD.

Whilecardiacconditions,environment,andcomorbidities,contributetheirown

influence(redarrows),thesefactorsalsoareaffectedbyoneanother(blue

dashedarrows).AdaptedfromChughetal.,2008.

9

OtherstudiescorroboratethatmenwithBrSpresentwithagreaterriskclinical

profilethanwomenandhaveaworseprognosis(Benitoetal.,2008).InARVC/D,

multiplestudieshaveidentifiedittobeamale-predominantdisease(Coxetal.,

2011;Merneretal.,2008),howevertherearealsoreportsofequalnumbers

betweenthesexes(Dalal,2005).

GiventhewidevarietyofcausesofSCD,thereisnospecificsymptomsetfor

thecondition.Havingsaidthat,symptomsthataretypicalofanyheartdiseasehave

beenassociatedwithSCD,suchassyncope,dyspnea,andheartpalpitations.

Tragically,itisnotunusualfortheveryfirstsymptomofconditionscausingSCDto

bedeathitself.ItisforthisreasonthatSCDtakessuchaheavytollonfamiliesand

communities.

Fortunately,notallindividualsatriskofSCDareasymptomatic.Bytracing

familyhealthhistoryandgenetictestingapreventativetherapycanbeputinplace.

TreatmentsforconditionsthatincreasetheriskofSCDaresimilar.Thetherapeutic

coursewilldependonsymptoms-previouscardiacarrestorarrhythmia.Standard

therapeuticoptionsincludeanti-arrhythmicdrugs,anICD,cardiacpacing,or

catheterablation.Forheartfailure,theICDisprimarystandardofcare(alongwith

anti-heartfailuremedications)whenthepatienthashigh-riskindicators,suchasleft

ventriculardysfunctionorreducedleftventricularejectionfraction,orheartfailure

symptoms(Marine&Russo,2014a,2014b).EvidencehasshownthattheICDisthe

betteroptionfortreatmentofheartfailurewhencomparedwithanti-arrhythmic

10

drugs.Anti-arrhythmicsarenotoftenprescribedontheirown,butmoreoftenas

adjunctivetherapywiththeICD.CatheterablationisalsoanoptionforwhentheICD

isnotindicated.Cardiomyopathies(HCM,ARVC/Danddilatedcardiomyopathy

(DCM))havesimilartreatments,withtheICDbeingthegoldstandardforhigh-risk

patients(Elliott&McKenna,2014;McKenna,2014).Thedifferencehereisthat

prophylactictreatmentcanbestartedinasymptomaticpatientswhenidentifiedas

highriskduetofamilyhistory(McKenna,2014).TheICDefficacywasexaminedin

11familieswiththeTMEM43mutationinNLandthefive-yearmortalityrateafter

ICDinmaleswaszerocomparedwith28%incontrolsubjects(p<

0.009)(Hodgkinsonetal.,2005).Forchannelopathies,BrS,longQTsyndrome

(LQTS)andcatecholaminergicpolymorphicventriculartachycardia(CPVT)),theICD

isthesuperiortreatmentthoughmaynotbethefirstline.Commonly,Beta-blockers

arethemainstayoftherapyunlesstherearefrequentassociatedsymptoms(Buxton,

2014;Wylie&Garlitski,2014;Zimetbaum,Seslar,Berul,&Josephson,2014).

ManyyoungSCD’sstilloccurdespitetheeffectivenessoftheICDanddrug

therapy,asidentifyingcandidatesclinicallyfortherapycanbedifficult.

Furthermore,geneticscreeningprogramsforSCD-causingconditionsarenotyet

effectivelyused(Kaltmanetal.,2011).Researchhasnotbroughtustothelevelof

proficientpreventativemedicinejustyet,andthus,SCDisanunyieldingburden.

11

1.3 GeneticEtiology

WhileCADaccountsforthemajorityofSCDs,therestcanlikelybeattributedto

geneticcauses,whichincludesnonischemicmyopathicprocesses,suchas

cardiomyopathies,andprimarydefectsofcardiacelectrophysiology,suchasLQTS

(Noseworthy&Newton-Cheh,2008).Manyoftheseconditionsshowmendelian

inheritance,alsocalledmonogenic,patterns.Mendelianinheritanceisadescription

ofthewaytraitsarepasseddownfromonegenerationtoanother–andsometimes

skipsgenerations-asaresultofamutationinonesinglegene(Miko,2008).There

aremultiplepossiblepatternsofinheritancethatcanbelocatedonanautosomeor

onasexchromosome,andthediseasephenotypeisdescribedasbeingdominantor

recessive(Chial,2008).Incardiacgenetics,manydiseasesdisplayanautosomal

dominantorautosomalrecessivepattern(Table1.1).Autosomaldominantdiseases

occurinindividualswhohaveasinglemutantcopyofthedisease-associatedgene,

andcanbeinheritedfromanaffectedmotherorfather.Thus,thismutationwillbe

passeddowntoallfuturegenerations.Autosomalrecessivediseasesoccurin

individualswithtwomutantallelesofthedisease-associatedgene.Theseindividuals

mustinheritonemutantallelefromeachoftheirparents.Autosomalrecessive

single-genediseasesoftenshowapatternwhichthedisease‘skips’oneormore

generations(Chial,2008).

ObservationsofSCDincidenceinfamiliesshowaclearroleforgenetics.For

example,inanIsraelicase-controlstudyofSCDpatients,afamilyhistoryofSCDwas

12

CardiacDisease Gene Locus Protein ModeofInheritance

FrequencyinPatients

HypertrophicCardiomyopathy

TNNT2 1q32 cardiactroponinT Autosomaldominant

3-5%

MYBPC3 11p11.2 cardiacmyosin-bindingproteinC

Autosomaldominant

25-25%

MYH7 14q11.2-q12

β-myosinheavychain Autosomaldominant

25-25%

ArrhythmogenicRightVentricularCardiomyopathy/

Dysplasia

TMEM43 3p25 transmembraneprotein43

Autosomaldominant

rare*

DSP 6p24 desmoplakin Autosomaldominant

10-20%

DSG2 18q12.1-q12.2

desmoglein2 ?Autosomaldominant

10-15%

DilatedCardiomyopathy

DMD Xp21.2 dystrophin X-linked ?DES 2q35 desmin Autosomal

dominant?

TNNI1 1q12 cardiactroponinI Autosomaldominant

?

LongQTSyndrome KCNQ1 11p15.5 Kv7.1 Autosomaldominant,orrecessive

30-35%

SCN5A 3p21-p24 NaV1.5 Autosomaldominant

5-10%

ANKB 4q25-q27 ankyrinB Autosomaldominant

rare*

CatecholaminergicPolymorphicVentricularTachycardia

CASQ2 1p13.3 calsequestrin2 Autosomalrecessive

rare*

RYR2 1q42.1-q43

ryanodinereceptor2 Autosomaldominant

50-60%

BrugadaSyndrome SCN5A 3p21-p24 NaV1.5 Autosomaldominant

20-30%

GPD1L 3p22.3 glycerol-3-phosphatedehydrogenase1-like

Autosomaldominant

rare*

CACNA1C 2p13.3 l-typecalciumchannel Autosomaldominant

?

Table1.1:Examplesofageneticbasisforstructuralandarrhythmogeniccardiac

diseases.

AdaptedfromTester&Ackerman(2009)andJeffries&Towbin(2010).

*:Thesefrequenciesmaybeunderestimatingtruenumbers.ThistableofgenemutationscancauseSCD,andtherebyremovesubjectsfromthepatientcount.“Frequencyinpatients”referstoalivepatients,possibleascertainmentbiashere.SeeAppendixAforfulllistofknowncardiacmutations.

13

associatedwitha46%increasedriskofSCDcomparedwithmatchedcontrols

(relativerisk=1.5)(Friedlanderetal.,1998).IntheParisProspectiveStudyI,a

parentalhistoryofSCDincreasedtheriskoffatalarrhythmiaintheoffspringby

80%;insubjectswithbothparentsaffected,riskofindividualswithanestablished

SCDsyndrome,afamilyhistorycanpotentiateriskofSCD.Forexample,inHCM,a

familyhistoryofSCDisassociatedwitha5-foldincreaseforriskofSCD(Elliottetal.,

2000).Thisislikelyduetotheunderlyingpathogenicityofthemutation,each

mutationwithdifferentclinicalpicture-whichcanevenoccurwithmutationsinthe

samegene(allelicheterogeneity)hencetheimportanceofstudiesexamining

mutationvariations.

Thecurrentknowngeneticconditionsarebrokenintotwogroups,structural

andarrhythmogenic.Structuraldiseases,whicharemoreeasilydetectedvia

autopsy,includeHCM,DCM,andARVC/D-although,thesecanpresentearlyinits

coursewithnoobviousstructuralanomalies.Thearrhythmogenicdiseases,often

referredtoaschannelopathies,tendtobemissedatautopsybecausetheycauseno

structuralchangestotheheart.ThiscategoryincludesBrS,CPVT,LQTS,andshort

QTsyndrome(SQTS)(Figure1.2).

14

Figure1.2:Categoriesofheartdiseaseswheregeneshavebeenfoundtobeinvolved,dividedintocardiomyopathies,CAD,andchannelopathies.

*Rare–notdiscussedindissertation

15

1.3.1 StructuralDiseases

Structuralabnormalitiesoftheheartareasignificantresultofgeneticheart

disorders(Ingles&Semsarian,2007).Thestructuralabnormalitiesthatresultare

notidenticalacrossdiseases,buttypicallycompromisethestructureoftherightor

leftventricle,possiblythroughfatdeposition,hypertrophy,ordilatation.These

abnormalitiescangoundetectedthroughoutanindividual’slife,andmayonlybe

diagnosedafterSCDandameticulousautopsy.DefiningtheexactburdenofSCDdue

tothesecardiomyopathiesisachallengingtask.Overall,thecontributiontoSCD

causedbycardiomyopathiesdifferswithdisease;ARVC/Disrankedthehighest,

followedbyHCM,andthenDCM(Sen-Chowdhry&McKenna,2012).

DCMisthemostcommoncardiomyopathyworldwide,characterizedby

dilatationandimpairedcontractionoftheleftorbothventricles(Jefferies&Towbin,

2010).ThenaturalhistoryofDCMisforpatientstopresentwithheartfailureoran

arrhythmia;heartfailureoranarrhythmiceventcanleadtoSCD(Sen-Chowdhry&

McKenna,2012).

HCMisacommonlyinheritedcardiomyopathy,definedbythepresenceofleft

ventricularhypertrophyintheabsenceofabnormalloadingconditions,suchas

hypertension(Jacobyetal.,2013).Themyocardialhypertrophycancausenumerous

outcomesthatmayleadtoSCD,forexample,obstructionoftheleftventricular

outflowtract,atrialfibrillation,andventriculararrhythmias(Elliott&McKenna,

2004).

16

Arrhythmogenicrightventricularcardiomyopathy/dysplasia(ARVC/D)isa

heritablecardiomyopathywherebypatientsdemonstrateafibrofattyreplacementof

themyocardiumoftherightventricle(RV)(Thiene,Nava,Corrado,Rossi,&Pennelli,

1988).Thelossofhealthymyocardiumincreasesriskofarrhythmia,whichmay

causeSCD.Allofthesecardiomyopathiesinvolveageneticcomponent,meaningthey

areoftencausedbyageneticmutation.AsseeninTable1.1(andAppendixA),there

aremultiplegeneticmutationspercondition,allaffectingadifferentproteinthat

altersthefunctionoftheheart.Forexample,ARVCcanbecausedbyamutationin

TMEM43,desmoplakin,desmoglein2etc.,allofwhichhavedifferentfrequenciesin

differentpopulations.

1.3.2ArrhythmogenicDiseases

Arrhythmogenicheartconditionsarenotanatomicallyapparentintheheart,as

theyoperateonanon-structurallevel.Giventhephysicalsubtlenessofthese

conditions,assessingthetrueburdenisquitedifficult.Toillustrate,a2001Italian

studyexaminingyoungSCDvictims(≤35yearsofage)foundthat16subjects(6%)

diedwithanapparentlynormalheart,andthecauseofSCDunexplained(Corrado,

Basso,&Thiene,2001).ItisthesecasesofSUD,orstudiesthatcannotexplainSCD,

thatlikelyetiologymaybeatypeofchannelopathy.

BrSisanarrhythmicsyndromecharacterizedbyincreasedriskforsuddendeath

resultingfromepisodesofpolymorphicventriculartachyarrhythmia’s(Chen&

Priori,2008).CPVTisanotherheritablearrhythmiathattypicallymanifestswith

17

exertionalsyncopeorsuddendeath(Priori,2002).LQTSisatypeofchannelopathy

thatinvolvesdelayedrepolarizationofthemyocardium,resultinginanincreased

riskofanarrhythmiaandthusSCD(D.Tester&Ackerman,2009).SQTS,amore

recentlyrecognizedclinicalsyndrome,istheoppositeofLQTSinthatitinvolvesa

shortQTintervalwhichincreasesriskofSCD(D.Tester&Ackerman,2009).Again,

alloftheseconditionssignificantlyinvolveageneticcomponent(Table1.1&

AppendixA).

1.4 Non-GeneticEtiology

Aspreviouslymentioned,SCDistheresultofacomplexinterplayofmultiple

factors–notallaregenetic.Firstly,therearemedicalconditionsthatcancauseor

contributetoSCD.DiabetesmellitusisasignificantriskfactorforSCD,provenin

multiplestudies,includingtheParisProspectiveStudyI,whichfoundthrough

multivariateanalysisthatdiabetesindependentlyconferredasignificantriskfor

SCD(relativerisk=2.64,95%confidenceinterval=1.26–5.53)(Jouven,Desnos,

Guerot,&Ducimetiere,1999).Othercomorbiditiesincludedintheequationare

smokingandobesity,oftenduetoalackofphysicalactivityand/ordiet.These

environmentalfactorshavealreadybeenproventohaveanegativeimpacton

cardiachealthbyincreasingriskofCAD,andthusSCD.Arecentcase-controlstudy

onfiremen≤45yearsoldfoundthatofthe87SCDvictims,63%wereobeseand

67%hadCAD(Yangetal.,2013).Cardiomegalywasalsofoundin66%ofvictims

andthiswasassociatedwithfive-foldincreasedriskofSCD(Yangetal.,2013).As

18

well,hypertensionwasassociatedwitha12-foldincreasedriskofSCD,andsmoking

andcardiovasculardiseaseshowedtobeindependentriskfactorsforSCD(Yanget

al.,2013).Finally,anotherenvironmentalfactorthattiesallofthistogetherislow

SES.IntheongoingOregonSuddenUnexpectedDeathStudy,a2-yearprospective

evaluationofthepotentialrelationshipbetweenSESandoccurrenceofSCDwas

performed(Reinieretal.,2006).ThisinvestigationincludedallcasesofSCDina

largeurbanandsuburbanUScounty(populationof670,000).IncidenceofSCD

basedonaddressofresidencewas30%to80%higheramongresidentsof

neighborhoodsinthelowestSESquartilecomparedtoneighborhoodsinthehighest

SESquartile.However,thestudydidnotcorrectforanyadditionalpossible

confoundingfactors(suchassmoking,obesity,diabetesetc.),andthereforeitis

difficulttocommentonthevalidityoftheSES-SCDrelationship.Whileitremains

unexploredtothefullestextent,itiscleartherewillalwaysbemultiple

environmentalfactorsatwork.

Thereareothernon-geneticcausesthatcouldactasamoredirecttriggerofSCD,

suchasalcoholconsumption,physicalactivity,oraviralinfection.Alcoholhaslong

beenknowntobetheculpritofcardiacarrhythmiasamongstheavydrinkers,for

examplebycausinganatrialfibrillationtheheartcannotgetoutofonitsown

(Koskinen,Kupari,Leinonen,&Luomanmaki,1987).Therelationshipbetween

alcoholandarrhythmiasiscomplicatedandcontroversial,dependentonmany

factors,suchasgender,age,amountofalcoholconsumed,andwhetherornotan

individualisalcoholdependent(Wannamethee,Shaper,Macfarlane,&Walker,

19

1995).Forcertain,arrhythmiasduetoalcoholdooccur,mostcommonlyviaatrial

fibrillation,butothermechanismsarepossible,suchasventriculartachycardia

(George&Figueredo,2010).Physicalactivityhasbeenundersuspicionbymanyas

atriggerforSCD,asSCDisacommoncauseofdeathinathletes;however,recent

studieshaveshownthatthemajorityofSCDvictimsdiedwhilesedentary(Chughet

al.,2008;Reddyetal.,2009).ThesestudieshavelookedatSCDinthegeneral

population,andhavenotaccountedforwhichvictimswereathletes,thereforethese

datadoesnotspeaktotherelationshipofSCDandathletes,butmoresotothe

averageindividual.Finally,averyseriousandprovencauseofSCDisabacterial

infection,suchasinfectiveendocarditis(Thunyetal.,2013).

AllofthesefactorscouldpossiblycauseSCD,orcouldalsointeractwith

underlyinggeneticmutationstocauseadiseasephenotype.Whilenon-genetic

factors,suchasobesity,smoking,hypertensionetc.,indisputablyplayaroleinSCD,

themajorityofthemwilltakeeffectinanolderagedpopulation,thatistosaythat

foryoungSCDthesefactorshavelessimpact,butasmiddleagenearstheylikely

playabiggerrole.

1.5CharacterizedPopulationsDealingwithYoungSCD

ThereareanumberofstudiesthathaveexaminedthecausesofyoungSCDin

specificpopulations.Currentliteraturesuggeststhereissignificantmortality

associatedwithgeneticcardiacdisorders.Astudycompletedin2004byDoolanet

al.analyzedsuddendeathsinAustraliansubjects(≤35yearsofage)thatoccurred

20

from1994-2002(Doolanetal.,2004).Intotal,therewere193deathsclassifiedas

SCD.ThesedeathswerecausedbyCAD(24%),HCM(15%),congenitalheartdisease

(7%),agroupclassifiedas‘other’whichincludedaorticdissectionandvalvular

heartdisease(11%),andagroupwithnostructuralanomaliesthuspresumed

arrhythmic(31%).Inthisveryyoungcohort,thereislikelyageneticcomponentat

play,asathirdofthedeathshavenostructuralissuesatall.

A2001ItalianstudybyCorrodoetal.examined273subjectswhohadsuffered

SCD(≤35yearsofage)withapparentlynormalhearts(Corradoetal.,2001).The

heartsofthesubjectswereanalyzedusingadetailedprotocolthatincludedboth

histologicalandmacroscopicanalysis.Theyfound72%ofthevictimshadan

underlyingcardiacabnormality,suchasacardiomyopathyorCAD.Theremaining

28%hadamacroscopicallynormalheart;however,uponfurtherhistologic

examination79%ofthesecasesrevealedconcealedpathologicsubstratessuchas

ARVC/Dandfocalmyocarditis.Atotalof16%showedneithermacroscopicnor

histologicabnormalitiesleavingthemechanismofSCDunexplained.Thereisno

mentionofblindinginthisstudyforthepathologists,whichisasignificantpotential

forbias.Therewasacontrol groupof20heartsfromage-andsex-matchedsubjects

whodiedsuddenlyofdrugabuseorextra-cardiaccauses.Noneofthecontrolhearts

exhibitedsignificantcoronary,myocardial,valve,orconductionsystem

abnormalities.Thisparticularstudyagainhighlightsthattherearepossiblygenetic

abnormalitiespresent,orenvironmentalexposuresthathaveleftnotrace.

21

Tragically,therearealwayscaseswherenoevidenceofSCDispresent,asidefrom

thedeath,whichtypicallyleadstoamisdiagnosisofcauseofdeath.

Astudypublishedin2011byEckartetal.reportedontheincidenceandnature

ofsuddendeathinalargebutselectgroupofUnitedStatesmilitaryrecruits(Eckart

etal.,2011).Theyidentified902predominantlymalesubjects(meanage38+/-11

years)forwhomthecauseofdeathwasofpotentialcardiacetiology.Suddendeath

wasattributedtoacardiacconditionin79%andwasunexplainedin21%.From

reviewingtheliteratureitisclearthatthereisacommontrendofhighratesof

youngSCDmortality.

InCanada,onlytwostudieshavebeencompletedlookingatSCDincidenceinthe

young.OnestudybyLimetal.(2010)inBritishColumbiafoundanincidenceofSUD,

inages0-35,of3.07per100,000peryear,and1.75per100,000peryearofSCD,

demonstratingthereisindeedalargeburdenassociatedwithyoungsuddendeath.

Morerecently,Pilmeretal.(2013)completedastudyfortheyear2008inON,

examiningthescopeandnatureofSCDinages2-40.Theyfoundthatincidenceof

SCDincreasedwithage,andthosebelowage30aremorelikelytosufferfroma

primaryarrhythmiasyndrome(oddsratio=2.97,p<.001).TheseCanadianstudies

showthatyoungSCDisarelevantissuehere,thoughmoreresearchisneededto

fullycharacterizetheissue,asCanadaisageneticallydiversepopulation.

22

1.6 NewfoundlandandLabrador(NL):AFounderPopulation

In2008,Merneretal.identifiedageneticmutationinpatientsandextended

relativesfrom15unrelatedfamilieswithNewfoundlandancestry-inTMEM43gene

thatcausesautosomaldominantARVC/D.Thismutation(p.S358L)changesthe

aminoacidserinetotheaminoacidleucineatposition358.Ourteamshowedthat

theclinicalconsequenceofharboringtheTMEM43mutationisearlySCD(50%of

untreatedmalesdeceasedby40years,80%by50years)(Merneretal.,2008).

TreatmentforARVC/DusingtheICDisaveryeffectivetreatmentmethodifthe

mutationorheartconditionisknown(Hodgkinsonetal.,2005).

AlthoughitiscurrentlyknownthatthismutationispresentintheNL

population,thedeterminationofitsphysicaleffectcomesfromtheascertainmentof

familiesmanifestingearlySCD.Wedonotcurrentlyknowtheexactincidenceofthe

p.S358Lmutationinthepopulation,andongoingstudiesaimtodeterminethe

answer.Wedoknow,however,thatamultitudeofgeneticmutationsarecausing

cardiacproblemsintheNLpopulationsascurrentlytheCardiacGeneticsClinic

underEasternHealthinSt.John’s,NLhasbeenreferred649familieswithvarious

cardiacconditions.Thecondition/reasonforreferralwiththehighestnumberof

familiesisSCD(K.Hodgkinson,personalcommunication,September25th,2014).

Fromanenvironmentalriskfactorpointofview,NLisonthehighendofthe

spectrumwhenitcomestoriskofheartdisease(Asgharietal.,2015;Filate,

Johansen,Kennedy,&Tu,2003).Whenitcomestoobesity,arecentstudyshowed

23

NLtobethe‘heaviest’provinceinCanada,andprojectedthistobethetrendforthe

future(Twells,Gregory,Reddigan,&Midodzi,2014).Whileobesityitselfisnotlife

threatening,thesequelaeitcancausearehighlyrelatedtoheartdisease–

hypertension,diabetestypeII,CAD,andstroke(Luoetal.,2007).NLisalsointhe

toprangefortheprovincesinhighestpercentageofsmokers,hypertension,lackof

physicalactivity,anddiabetes(StatisticsCanada,2014a).Allofthesefactors

contributetothemultifactorialetiologyofheartconditions.Onafinalnote,while

environmentundoubtedlyplaysaroleforthesehealthfactors,thereislikelya

geneticcomponentinvolvedintheseconditionsaswell.Environmentisnotsolelyto

blameassomefactors,suchashypertensionandobesity,haveageneticcomponent

aswell(Bell,Walley,&Froguel,2005).

1.7 MedicalExaminerProtocolandReports

Thedutiesofmedicalexaminersarerelevanttothisprojectasthedatais

collectedfromamedicalexaminer’sdatabase.InCanada,medicalexaminersare

mandatedtoinvestigatealldeathsthataresudden,unexpected,orfromnon-natural

causes.Theseinvestigations,completedregion-by-region,answerthefollowing5

questions:whowasdeceased;how,whenandwherethedeathoccurred;andby

whatmeansthedeathoccurred.Aftercompletionoftheinvestigation,alldeathsare

centralizedtotheOfficeofChiefMedicalExaminer(OCME)fortheprovince.

Themedicalexaminer’sreportincludespersonalinformationandresultsfrom

themedicalinvestigation–dateofdeath,mannerofdeath,reportedcauseofdeath,

24

environmentofdeath,aswellasanarrativesectionthatincludesotherrelevant

informationsuchasmedicalhistory,andinterviewsfromfriends,family,or

eyewitnesses.Onoccasion,whencircumstancesrequireit,policereportsor

insurancecompanyreportsarealsointhereport.SeeAppendixBforasample

MedicalExaminer’sreport.

1.8StudyRationaleandHypothesis

ThescopeandnatureofSCDinNLpopulationisunknown.OnestudyfromON

usinga2008cohortassessedtheincidenceofSCDinpersonsaged2-40yearsoldto

be2.64per100,000(Pilmeretal.,2013).Wehavechosenthisstudyforcomparison

becauseweareabletoreplicatetheirrigorousmethodologyfortheexactsameyear

(2008).Aswell,ON,incontrasttothefounderpopulationinNL,isalargeCanadian

outbredpopulation,thuswewillbeabletodirectlycomparetheincidenceofyoung

SCDofafounderpopulation(NL)toanoutbredpopulation(ON).

WehypothesizethatNLmayhaveahigherincidenceofearlySCDinthisage

categoryduetotheknownmutationscausingheartdiseasesandunknown

underlyinggeneticcauses,giventhehistoricalgeneticisolationofthepopulation.

WehopetobetterunderstandthescopeandnatureofSCDinNLtohelpinform

healthpolicy,therapy,andprevention.

25

1.9 StudyObjectives

Theobjectivesofthisstudyareto:

1. AscertainthenumberofSCDsinyoungpersons(ages2-40)fromaprovincial

registryofmedicalexaminer-referredsuddendeathsin2008.

2. MakeadirectcomparisonwithON,acomparablymoreoutbredpopulation.

Theinitialanalysiswillfocusonages2-40thenwewilladdages41-50tothe

cohort,asweknowthatmanydeathsduetoTMEM43occurinthatdecade,as

wellasduetoCAD.

3. Gatherdataforages2-50fromtheyear1997–ayearbeforetheICDwasan

availabletreatmentinNL–toobserveanySCDratedifferenceswith2008(a

yearwheretreatmentwasreadilyavailableinNL).

26

2.Methods

27

2.1CohortsofInterest

Icollectedqualitativedataontheyears2008and1997.Theyear2008is

significantbecausewecancompareourdatatoanONstudythatcollecteddata

fromtheyear2008(Pilmeretal.,2013).Forcomparisonwithour2008data,we

collectedqualitativedatafrom1997becauseitisayearwhentheICD,an

effectiveheartdiseasetreatment,wasnotavailableforinsertioninNL.Thisisin

comparisonto2008,whentheICDwasreadilyavailableinNL.

Theagegroupswewereinterestedinare2-40and2-50years.The2-40

agegroupistherangetheONstudyused,thereforewewantedtohaveanexact

comparisongroup.Wealsodecidedtocollectfromages41-50becauseweknow

thatmanySCDsoccurinthisagerange,andwewanttocapturethefullspectrum

ofyoungSCD.

Forsimplificationpurposes,IwillrefertotheNL2008ages2-40as

cohortA,NL2008ages2-50ascohortB,andNL1997ages2-50ascohortC

(Table2.1).

2.2DataCollection

Thisepidemiologicstudyincorporatedaretrospectivecohortdesign,withan

emphasisonreplicatingtheONstudy’smethodsascloselyaspossibletoallowusto

directlycomparewiththeirresults.Qualitativedatawascollectedon276cases.

CasesofpotentialrelevancewereidentifiedfromthedatabaseoftheOCMEofNL

(Figure2.1).Allfilescontainedamedicalexaminer’sreport,andanautopsy

28

Table2.1:Labelingofthecohorts

Cohortgroup LabeledCohort

NL2008,age2-40 A

NL2008,age2-50 B

NL1997,age2-50 C

29

Figure:2.1:ProcessofcategorizingdeathsandassigningtocategoryofSCD.

SeeTables2.1&2fordefinitionsofmannersofdeathandcategoriesoflikelinessof

SCD,respectively.RedboxesindicatethecasesweassignedasSCDandthus

analyzed.

30

reportifconducted.Additionalinformation,suchaspolicereportsorreportsfor

insurancecompanieswereavailabledependingonthecircumstancesofthedeath.

SeeAppendicesBandCforasampleMedicalexaminer’sreportandthefullchart

auditform.

SUDwasdefinedasaneventresultingindeathorterminallifesupportwithin

1hourofcollapse,oranunwitnessed,butunexpecteddeathintheabsenceofa

knownorsuspectedconditionthatmaypredisposetoterminalillness(Eckartetal.,

2011).Deathswerefurtherdefinedascardiacinoriginiftherewasautopsy-

confirmedheartdiseasewithcircumstancesconsistentwithapotentialcardiac

causeofdeath.SCDwasalsodeclaredwhentheautopsyshowednoidentifiable

causeofdeath,anditwasthereforepresumedacardiacarrhythmiatookplace.SUD

belowtheageof2yearswasconsideredaseparateentityandwasnotincluded.A

portionofcasesdidnothaveanautopsycompleted,andSUDwasthenclassifiedat

thediscretionoftheChiefMedicalExaminer.

Casesofpotentialrelevancewerereviewedbymyselfaftersatisfying3

inclusioncriteria:(1)dateofdeathin2008(sameyearasON)or1997,(2)ageat

deathbetween2-40or41-50,and(3)mannerofdeath(auniversalpathologist

classificationmethod)listedas“natural-cardiac”,“natural-other”,“accidental”or

“undetermined”(Table2.2).Thisyielded70casesfor2008ages2-40and49cases

for2008ages41-50toreview.For1997,thisyielded90casesages2-40and67

casesages41-50toreview.Consideringthesmallyieldofnumberofsubjects,every

casewasreviewedindetail.Casesthatwerenotsudden,notunexpected,ornotof

31

Table2.2:Mannersofdeathusedbyforensicpathologists.

Manner Definition

Natural-Cardiac Deathduetonaturaldiseaseprocessesin

cardiacnature

Natural-Other Deathduetonaturaldiseaseprocessesof

unknownsystem

Accidental Deathduetoinjurywherethereisno

evidenceofintenttoharm

Undetermined Inadequateinformationregarding

circumstancesofdeathtodetermine

manner

32

possiblecardiacetiologywereexcludedafterreview.Forexample,caseswere

excludedwhencauseofdeathwasclearlynon-cardiac,suchassepsisorpneumonia,

andaswellcasesinvolvingpassengersandpedestriansofmotorvehicleaccidents,

andhousefires.

Datawascollectedonall276cases,whichwereconsideredpossibleSCDs.

Thesedataincludeddemographicinformation,suchasdateofbirth,sex,anddeath

informationincludingdate,location,cause,andmannerofdeath.Autopsyfindings,

especiallyrelatedtocardiacconditions,werenoted,aswasanyknownhistoryof

cardiacorotherdisease.Cardiacpathologydiscoveredonautopsywaslisted

separatelyfromanyknownpreexistingcardiacconditions.Sincethefilesdidnot

containcopiesoftheindividual’smedicalcharts,previousmedicalconditionswere

notedatthediscretionoftheinvestigatingmedicalexaminerandabstractedbya

singleinvestigator.

Additionaldatacollectedincludedpremonitorysymptoms,natureofphysical

activityandintensityatthetimeofdeath,medicationorsubstanceuse,cardiacrisk

factors,andnarrativedetailsaboutthecircumstancesofdeathfromtheavailable

evidence.Premonitorysymptoms,symptomswithin24hourspriortodeathand

alsopriortothe24hours,includedpotentialcardiacsymptoms,suchaschestpain,

shortnessofbreath,andsyncope.Physicalactivitylevelatthetimeofdeathwas

determinedfromthemedicalexaminer’snarrativeandwasclassifiedasduring

sleep,atrest,duringlighttomoderateactivitiesofdailyliving(ADLs),during

moderatetovigorousexerciseorunknown.Subjectswereclassifiedasdyingatrest

33

iftheeventwasdescribedassuchbyaneyewitnessorifthedecedentwasfoundina

positionsuggestingrest.LighttomoderateADLsincludedactivitiessuchas

houseworkandothernonphysicallystrenuousactivitiessuchasdriving.Moderate

tovigorousexerciseincludedanysportingorfitnessactivitiessuchasswimming

andrunning,aswellasanystrenuousphysicalworkorchoressuchasshoveling

snow.Furtherinvestigationssuchasrequestsforadditionalmedicalrecordsor

personalinterviewswerenotobtainedbecauseoftheretrospectivenatureofthe

study.

2.3LikelinessofSCD

AfterIcollectedalldata,eachcasewasreviewedbymyselfandanexpert

panel:anexperiencedexpertingeneticcardiacarrhythmias(K.H.),anexperienced

cardiacgeneticcounselor(F.C.),andanexperiencedexpertincardiacpathologyand

theprovincialdeathinvestigationsystem(S.A.,ChiefMedicalExaminer,Provinceof

NL).TheexpertpanelandI,usingthesamesystemasON,categorizedeachsubject

intolikelinessofSCD.All276subjectswereassignedtoacategoryoflikelihoodof

SCDbyreviewingalldatacollected,incorporatinginformationfromacrossthefile,

includingmedicalcauseofdeath,underlyingpathology,descriptionofthe

environmentandcircumstances,andcontributingfactorsandcomorbidities(Table

2.3).Thefirstcategory,‘suddendeath’,comprisedthosewhodiedofsuddendeath

withnoadditionalfactorscontributingtodeath(ex.alcohol,toxicology,hazardous

conditions)(labeled‘definite’-Table2.3).Thisgroupalsoincludedthosewhohad

onlyonecontributingfactor,otherthancardiacdisease

34

Table2.3:LikelinessofSCDcategories.

Categories Criteria

SuddenDeath

Definite SCDwithnoadditionalfactors

Probable SCDwith1potentialcontributingfactor

Examples:24yearoldmalediedduringnapafterexercising,28

yearoldmalefoundinbedwithhighalcohollevel(notfatallevel)

Possible Accidentswith1contributingfactor

Example:27yearoldmalediedinmotorvehicleaccidentinicy

weather

Unlikely Greaterthan1contributingfactor

Example:49yearoldmale,canoeoverturned,nolifejacket,

alcoholinvolved

35

orprimaryarrhythmiathatwasnotofsufficientgravitytohavecauseddeath

(labeled‘probable’-Table2.3).Forexample,anindividualwithpositivetoxicology

(non-lethal)withnootheranatomicalcauseotherthanapossiblyenlargedheart

wasapresumedarrhythmia.Thenextcategory,‘possiblesuddendeath’,wasfor

‘accidental’caseswherebytherewasonlyonecontributingfactor,asidefromthe

accident.Inessence,thiscategoryhopedtocaptureaccidentsthatmayhavebeen

causedbyanarrhythmia.Tonote,accidentswithzerocontributingfactorswere

placedinthe‘probable’group.Anexampleofthiswouldbeacaraccidentwithno

logicalcontributingfactors(highspeed,badweather,alcohol,etc.).

Finally,thelastcategorywas‘unlikely’,whichcomprisedanydeathsthathadmore

thanonecontributingfactor.Atthispoint,wemovedaportionofthe‘unlikely’sto

anexclusiongroupiftheywerenotsudden,notunexpected,ornotofpossible

cardiacetiology.ThiswasinanefforttokeepmethodologysimilartotheONstudy.

The‘suddendeath’categorywasfurtherbrokendownintowhethertheSCD

wascausedduetoanunderlyingstructuralheartissueornoanatomicalcause.The

structuralcaseswerefurthercategorizedintoischemicandnon-ischemic.Also

notedwaswhetherthestructuralcaseswererecognizedorunrecognizedbythe

subjectpriortodeath(Figure2.1).

2.4StatisticalAnalysis

IperformedallstatisticalanalysisusingSPSSversion20.Descriptive

statisticswerecompleted,andtheChi-squaretestwasusedwiththeadditionof

36

Fisher’sexacttestifthesamplesizewassmall.Ap-valueof<.05wasconsidered

significant.

37

3.Results

38

3.1Incidences

Inthe20082-40cohort(A),17deathswereadjudicatedasSCDfroman

estimatedpopulationof232,210people(StatisticsCanada,2014b).Thenumberof

casesincomparisonwiththeONcohortisn=17forNLvs.n=174forON,shownin

Figure3.1(Pilmeretal.,2013).Basedontheestimatedpopulation,theincidencein

NLofcohortAis7.32/100,000persons.Whenthecohortwasexpandedin2008to

thoseaged50yearsold(B),44deathsoutofapopulationof316,244wereadjudged

tobeSCD(Figure3.2),givinganincidenceof13.9/100,000persons.In1997,66

deathsoutofapopulationof406,173inage’s2-50cohort(C)werefoundtobeSCD

(Figure3.2),givinganincidenceof16.23/100,000persons.Theincidencesforeach

cohort,andtheONcohort,basedonageandthegenderbreakdownisshownin

Table3.1and3.2.SeeAppendixDforprimarydata.

ComparingtheNLcohortAtotheONdata,NLhasasignificantlyhigher

incidenceofSCDthanON(p<.0001)(Table3.1).Whencomparingagegroups

betweenthecohorts,NLbecomessignificantlyhigherforagegroups19-29and30-

40(p=.028&p=.008,respectively)(Table3.1).Thereisalsoacleartrendherethat

SCDincreaseswithage.ThereisagenderdifferenceintheNLdata,asthecohortis

65%male.Whilethismaypresentsomeissuesforthestudy,ONhasthesame

genderbiasandthechi-squarecomparingNLtoONgivesanon-significant

difference(Table3.1).Comparingthe2008NL(B)datato1997NL(C),thereisa

generaltrendofmoreSCDsin1997butitisanon-significantdifference(Table3.2).

39

NL2008Age2-40(A)

Figure3.1:ReviewofallpotentialSCDcasesinNLin2008age’s2-40(A)in

comparisontoON(2008,age’s2-40)(Pilmeretal.,2013).

*:Caseswithnoautopsycouldnotbesegregatedanyfurther(n=1)

40

NL2008and1997Age2-50(B&C)

Figure3.2:ReviewofallpotentialSCDcasesinNL2008inages2-50cohort(B),in

comparisontoNL1997age’s2-50cohort(C).

*:Caseswithnoautopsycouldnotbesegregatedanyfurther(n=10for2008,n=14

for1997)

41

Table3.1:ComparisonsofincidenceandgenderforNL2008age’s2-40(A)andON

2008ages2-40(Pilmeretal.,2013).

*=Significantdifference,p<.05

†=Fishersexacttestused,expectedcellcount<5

SeeAppendixDforprimarydata

NL20082-40(A) ON20082-40 Chi-squarevalue,significance(p-value)

IncidencesOverall 7.32/100,000 2.64/100,000 Χ2=17.625,

p<.0001*Ages2-18 2.15/100,000 0.7/100,000 Χ2=2.418,p=.158†Ages19-29 7.52/100,000 2.4/100,000 Χ2=6.488p=.028*†Ages30-40 13.74/100,000 5.3/100,000 Χ2=8.929p=.008*†GenderMale(%) 65% 76% Χ2=1.024,p=.379†

42

Table3.2:ComparisonsofincidenceandgenderforNL2008age’s2-50(B)andNL

1997age’s2-50(C).

†=Fishersexacttestused,expectedcellcount<5

SeeAppendixDforprimarydata

NL20082-50(B) NL19972-50(C) Chi-squarevalue,significance(p-value)

IncidencesOverall 13.9/100,000 16.23/100,000 Χ2=.626,p=.429Ages2-18 2.15/100,000 2.32/100,000 Χ2=.007,p=1.00†Ages19-29 7.52/100,000 7.70/100,000 Χ2=.002,p=.969Ages30-40 13.74/100,000 18.1/100,000 Χ2=.486,p=.486

Ages41-50 32.1/100,000 43.7/100,000 Χ2=1.496,p=.221GenderMale(%) 80% 76% Χ2=.216,p=.642

43

Gender-wise,weseethesametrendhere,amale-biaspresent,butagainthereisa

non-significantdifferencebetweenthetwocohorts(Table3.2).

3.2CauseofDeath

Afterexcludingthecaseswithoutautopsyforanalysis,incohortAthereare9

caseswithstructuralheartproblems,and7withoutanyidentifiablecause.Inthe

olderagecohorts,BandC,therearemore‘structural’deathsthan‘noanatomical

cause’deaths(B=23‘structural’,11‘noanatomicalcause’,C=43‘structural’,9‘no

anatomicalcause’(Figures3.3&3.4).Thissharpincreasein‘structural’deathsis

likelyobservedduetotheaddedagegroup(41-50’s),asbothcohortspossesslarge

structuralnumbersinthesegroups(2008=14,1997=24).Whencomparingthe

ratioof‘structural’to‘noanatomicalcause’betweencohortAandON,thereisanon-

significantdifference(p=.172).Aswell,comparingcohortBwithcohortCgivesa

non-significantresult(p=.106).Overall,itiscleartherearemorestructuralheart

issuesintheolderpopulation,andmoreunexplainabledeathsappeartobein

youngerage.

Uponfurtherinvestigationofthesubjectswithstructuralcardiacissues,

therewereasmallnumberofsubjectsthatrecognizedaheartissuebeforedeath.In

cohortA11.1%hadarecognizedissue.IncohortB,4.3%hadarecognizedissue.In

cohortC,30.2%hadarecognizedissue.

44

Figure3.3:CausesofSCDbyageinNL2008cohort(B).

45

Figure3.4:CausesofSCDbyageinNL1997cohort(C).

46

CADwasamajorcauseofdeathinall3cohorts.Insubjectsinthe‘structural’

diseasecategory,incohortA,4/9(44%)subjectshadCAD.IncohortB,16/23

subjects(70%)hadCAD,andincohortC,34/43(79%)subjectshadCAD.Lookingat

theentirecohort,causeofdeathaside:cohortAhad6/16(38%)subjectswith

evidenceofCAD,cohortBhad19/34(56%)ofsubjectswithevidenceofCAD,and

cohortChad36/52(69%)ofsubjectswithevidenceofCAD.TheONcohortfor2008

2-40’shad49%(comparison:p=.782)ofthosewithstructuralheartdiseasewith

CAD,and36%ofallSCDs(comparison:p=.918)withCAD.Theredoesnotappearto

beanydifferencebetweenNLandONwithrespecttoCAD.

WhileCADplayedabigroleinallthreecohorts,thesecondmostcommon

causeofdeathwas‘noanatomicalcause’.The3rdmostcommoncategorywas

labeled‘other’,whichisamiscellaneouscategory(Figures3.5&3.6).

3.3Location,ActivityLevel,&Symptoms

IncohortA,65%ofsubjectsdiedintheirhome.ForcohortB,59%diedin

theirhomes,andforcohortC56%diedathome.Thesmallnumberofcasesineach

cohortthatdidnotdieathomesuccumbedatwork,school,orpublicplaces.TheON

cohortfoundthat72%oftheirsubjectsdiedathome(Pilmeretal.,2013).

Examiningactivitylevelattimeofdeathshowsthatthevastmajorityofcases

in2008diedwhileatrestorinsleep(cohortA=71%,cohortB=75%).CohortChad

only36%ofsubjectsdiewhileatrestorsleep,however,therewere

47

Figure3.5:CausesofSCDinthe2008NL2-40cohort(A).

‘Other’categoryincludesvalvulardisease,structuralanomaly,myocarditis,

suspiciouscaraccident,andadrugoverdose.

48

Figure3.6:CausesofSCDinthe2008and1997NL2-50cohort(B&C).

‘Other’categoryincludesvalvulardisease,structuralanomalies,myocarditis,

suspiciousaccidents,adrugoverdose,ageneticcondition,anAVnodetumor,anda

mitralvalveprolapse.

49

16caseswith‘unknown’locationsofdeathinthiscohortduetolackofautopsy

reportdetail.Thesecondlargestcategoryforactivitylevelwaslight-moderate

activity.IncohortA,24%diedduringlight-moderateexercise.IncohortB,14%of

subjectsdiedduringlight-moderateexercise,andincohortC,30%ofsubjectsdied

duringlight-moderateexercise.Thelastcategoryremaining,andalsothesmallest

category,ismoderate-vigorousactivity.CohortA,B,andCallhadsmallnumbers

(5%,11%,and9%,respectively).TheONcohortfoundasimilartrend:11%oftheir

casesdiedduringmoderate-vigorousactivity(Pilmeretal.,2013).Aswell,ONfound

that33%oftheir2-18agegroupdiedduringmoderate-vigorousactivity;however,

inourcohortsallmoderate-vigorousdeathswereabovetheageof30.Some

examplesofmoderate-vigorousactivitiesintheNLcohortsare:playingracquetball,

manuallabor,swimming,andmilitiatrainingexercise.

Ingeneral,therewereveryfewcasesinallcohortsthatexperienced

symptomsbeforedeath.IncohortA,3of17subjectshadchestpains.Twoofthese3

subjectswenttoaphysicianforinvestigation,howeverbothweredismissed

(strainedmuscleinchestandbronchopneumonia).IncohortB,8outof44hadchest

pain,whileoneotherpersonhadshortnessofbreathandoneotherhadpresyncope.

Threeofthe8individualssoughtmedicalattention,butallweredismissed.Incohort

C,7hadchestpains,2hadshortnessofbreath,and8had‘other’symptoms(ex.

stomachsick,dizzy,heartburn).Nineofthese17subjectssoughtinvestigation,and6

weredismissed.Threewereawaitingfurthercardiacinvestigation.

50

4.Discussion

51

ThequestionthiscurrentstudyposesiswhetherthescopeandnatureofSCDin

NLisofsignificance,andwhetheritisagreaterhealthissueinNLthanON.We

hypothesizedthatNLmayhaveahigherincidenceofearlySCDinthisagecategory

duetotheknownmutationscausingheartdiseasesandunknownunderlyinggenetic

causes,giventhehistoricalgeneticisolationofthepopulation.Weascertainedcases

ofsuddendeath(SD)fortheyear2008and1997(priortotheavailabilityofICDsin

NL)andeachcasewasanalyzedtodeterminelikelihoodofSCD.The2008cohort(A)

wascomparedtoasimilarONcohort.Wefoundthatthereisastatistically

significantincreasedincidenceofSCDinages2-40incomparisonwithONin2008.

WealsofoundthattheincidenceofSCDincreaseswithage,andmalesaremore

oftenthevictimswhencomparedtotheoppositegender.Withregardstocauseof

death,youngerindividualsoftenshownoanatomicalcauseonautopsyandolder

individualstendtoshowmorestructuralcardiacissues.Anystructuralconditions

presentweremostoftenpreviouslyundiagnosed.Themajorityofdeathstookplace

whileatrestathome,andsymptomsleadinguptodeathwereuncommon.

4.1Incidence

InallcohortswefoundahighincidenceofSCD.Similarnumbersarenoted

between2008and1997,forallagegroups.Thestudywascreatedwithsimilar

methodologytoPilmeretal.(2013)formakingdirectcomparisonswithanother

Canadianprovince.Theyfoundthatforages2-40intheyear2008theincidencewas

2.64per100,000persons.Asalreadynoted,ourincidencesurpassesthisbyalmost

3times.

52

Findingothercomparablestudiesisadifficulttaskasmethodologyvaries

greatlythroughouttheliterature.Thisvariationofteninvolvesthenatureofthe

study(retrospectiveorprospective),differentagegroups,criteriaforinclusionor

exclusionoftheSDgroup,andinclusionorexclusionofnon-autopsiedcases.There

isoneothersignificantstudyinCanada(BritishColumbia)thatassessedincidence

ofSCDinthoseaged0-35from2005-2007(Limetal.,2010).Limetal.(2010)

examinedalldeathsthatwereplacedinthe‘natural’and‘undetermined’categories,

and‘accidental’deathswerenotincluded.Usingsimilarinclusionandexclusion

criteriatoours,theyfoundtheincidenceofSCDwas1.75per100,000personsper

year(AppendixE).NLtrulyhasahigherincidence.

Otherstudieswithfairlycomparablemethodologywerecompletedin

Ireland,England,andDenmark(SeecomparisontableinAppendixE).InIreland,a

groupofresearcherslookedatSCDinages15-35from2005-2007(Margeyetal.,

2011).ThesamedefinitionofsuddendeathwasusedasourNLstudy.Unlikethe

currentstudy,allcaseswithanypresenceofdrugsthatareknowntocauseSCD(ex.

cocaine,highalcohol)wereexcluded.Theincidencefoundwas2.85/100,000

personsperyear.InEnglandandWales,researchersexamineddeathsfromages1-

34throughyears2002-2005(Papadakisetal.,2009).Theirclassificationsystemdid

includesome‘accidental’deaths,suchasdrowningincidents,astheyrecognized

thesemightrepresentmisclassifiedcardiacdeaths.Overall,theyfoundanincidence

of1.8/100,000personsperyear.

53

ThereweretwostudiescompletedinDenmarkspanningnineyears(2000-

2009)thatusedthesamemethodology(Risgaard,Winkel,Jabbari,Behr,etal.,2014;

Winkeletal.,2011).Thesemethodscloselyresembleours,andtheiragegroup

reachedage49whichwecancomparetowithourage2-50cohort.Another

similarityisthattheyincludednon-autopsiedcases.Wedodifferintheuseofextra

informationoutsidetheautopsyfile:thesestudiesusedtheDanishNationalPatient

Registryforsupplementaryhealthinformationonpatients.Fortheagegroup1-35,

the2011and2014studiesfoundsimilarresults:2.8per100,000personyearsand

2.3per100,000persons,respectively.Interestingly,NLdiffersintheolderage

groups:Risgaardetal.(2014)foundthatforages1-49theincidencewas8.6per

100,000personsandforages36-49theincidencewas21.7/100,000.NLhasan

overallhigherincidenceinour2-50agegroups,however,8.6/100,000isthenext

highestvaluefoundintheliterature.Theincidenceforages36-49ismuchhigher

thanourcomparablevalues(13.7/100,000and18.1/100,000for2008and1997,

cohortsB&C,respectively).Apossibleexplanationforthishikeinincidencemight

beduetotheirgreaterpercentageofnon-autopsiedcases(51%)comparedtoour

23%(2008)and21%(1997)ofnon-autopsiedcases.Aswell,itwasalreadynoted

thesestudieshadaccesstoamuchgreateramountofhealthdataonthesubjects.

Aconsistenttrend,shownineveryoneofthesestudiesreviewed,isSCD

increasesinnumberswithincreasingage,andthatitiscertainlymorecommonin

males(Limetal.,2010;Margeyetal.,2011;Papadakisetal.,2009;Pilmeretal.,

2013;Risgaard,Winkel,Jabbari,Behr,etal.,2014).TheactualincidencesofSCDare

54

notsuchaconsistenttrend;wehaveahigherspectrumofnumbers.Themostlikely

explanationforthespikeinnumbersisthatNLisafounderpopulation.Wedirectly

comparedwithacomparablymoreoutbredpopulation(ON)andfoundNLtohavea

significantlyhigherSCDincidence.IthasbeenestablishedthattherearelethalSCD

genespresentinNL(Merneretal.,2008),andthismayaccountforthehigher

incidence.CertainlyweknowthatTMEM43playsaroleinSCDinNL;however,we

alsoknowthattherearemultiplemutationspresentinNLasourclinichas649

familiesreferredtotal,andthecategory/conditionwiththelargestnumberof

familiesisSCD(K.Hodgkinson,personalcommunication,September25th,2014).

ToconfirmoursuspicionsofgeneticetiologyofyoungSCDinNLwehopeto

performDNAtestingofthevictimsinourpresentcohortwithapanelofgenetic

mutations,TMEM43included.Whengenetictestingiscompletedattimeofautopsy,

itisreferredtoasamolecularautopsy.Itisacrucialstepforidentifyingcauseof

youngSCD,especiallywhentherearenostructuralfindingsonautopsy.Thishas

beendonebeforeinvariousstudiesandhasshowndiagnosticyieldofthemolecular

autopsytobeupto35%(D.J.Tester&Ackerman,2007;D.J.Tester,Spoon,Valdivia,

Makielski,&Ackerman,2004).Otherstudiesreportdifferentnumbers(Deanetal.,

2015;D.J.Tester,Medeiros-Domingo,Will,Haglund,&Ackerman,2012),withina0-

35%range,thatmaybeareflectionofavarietyofclinicalandmethodologicalissues

relatingtoselectionbiasofpopulationstudied,geneticmutationsincludedonthe

paneletc.(Semsarian,Ingles,&Wilde,2015).

55

Thepertinentquestionis:whatelsecouldcausethisincrease?Lifestyle

factorscometomind,andmorespecificallyobesity.ObesityislinkedwithSCD

(Tavoraetal.,2012),andNLisoneofthe‘heaviest’provincesinCanada(Canada,

2011;Twellsetal.,2014).Thecomorbiditiesassociatedwithobesityareprovenrisk

factorsforheartdisease(Luoetal.,2007;VanGaal,Mertens,&DeBlock,2006;

Zalesin,Franklin,Miller,Peterson,&McCullough,2011).Conversely,itispossiblefor

obesepersonstobelivingwithoutanycomorbidityatall,whichbegsthequestion:is

obesityaloneacausativefactorforSCD?Tofurtherunderstandhowobesityis

contributingtoSCD,weneedtoseethehealthrecordsoftheSCDsubjects.Insaying

so,lifestylefactorswillbelookedatmorein-depthinupcomingstudies.

4.2CausesofDeath

Fromautopsyreview,informationoncauseofdeathcanbededucted.We

foundincohortAthat9/16(56%)hadstructuralabnormalitiesnotedonautopsy,

while44%couldnotbegivenacauseofdeath,asnoanatomicabnormalitieswere

present.Thisratiobetween‘structural’and‘noanatomicalcause’wassimilarto

whatPilmeretal.(2013)found(non-significantdifference).Aspreviously

discussed,wehavefoundthatNLhasahigherincidenceofSCDthanON.Theresults

showthatNLhasproportionallymoredeathsinarrhythmicdeathsandstructural

deaths;neithercategoryaloneaccountsforthedifferencebetweenNLandON.With

thenotionthatarrhythmiasareoftenduetoageneticcauseandthatthemajorityof

structuraldeathscomefromCAD,thiscouldpossiblymeanthatNLhasmoregenetic

relatedcardiacdeaths.

56

Similarproportionsofnumberscanbenotedinotherstudiesaswell.Ina

comparableretrospectivestudyinAustralia,autopsieswerereviewedbetween

1994-2002inthoseaged35andless(Doolanetal.,2004).Thisreviewshowedthat

31%ofSCDshadnoestablishedcauseofdeath.IntheIrishreviewconductedby

Margeyetal.(2011)on14-35yearolds,theyfoundthat26.7%ofSCDvictimshad

SADS(suddenarrhythmicdeathsyndrome)–asynonymfornoanatomicalcause

foundonautopsy.Inbothofthesestudies,thecategoryof‘noanatomicalcause’was

consideredthehighestintheircohorts.

Contrarytothis,theEnglishstudyonthoseages1-34yearsfoundischemic

heartdiseasetobethehighestcategory(33.5%)withSADSinthirdat14%

(Papadakisetal.,2009).IntheVenetoregionofItalyastudywascompleted

wherebytheyanalyzed273SCDsinthetimeframeof1979-1998(Corradoetal.,

2001).Thecaseswereanalyzedinasimilarmanneraspreviouslymentioned

studies,howevertherewasfurthermicroscopicandhistologicanalysisthanin

comparablestudies.Theyinitiallyfoundthat28%oftheircasesappearedtohaveno

anatomicalcauseofdeath-anumbersimilartootherreports.However,withfurther

analysis,79%ofthosecaseswerefoundtohaveactualphysiologicalissues

discoveredwithamorethoroughautopsy,leavingonly6%ofthe273victimsto

havediedwithnoanatomicalcauseofdeath.Thisisaninterestingandunique

finding,andspeakstotheideathatwemayneedmorerigorousandthorough

autopsiesonpossibleSCDs.

57

CADwaswidespreadinourstudy,beingthetopcauseofdeathinthe2008

and1997age’s2-50cohorts(B&C),and3rdin20082-40cohort(A).ONshoweda

similaramountofCADintheircohort(non-significantdifference).IntheDanish

studybyRisgaardetal.,they,similartous,examinedanoldercohort,1-49yearsold

(2014).TheirmostcommoncauseofdeathwasCAD(158/439;36%).Another

studywithanolderagesamplewascompletedintheUnitedStatesbyEckartetal.

(2011).Theyfoundthatforsubjects≥35yearstheleadingcauseofdeathwasCAD,

withanincidenceof13.69per100,000person-yearsforthose≥35years.Bothof

thesestudiesreportthesametrendthatourstudyalsocorroborates:inthose≤35

yearsold,SUDissignificantlymorecommonthanCAD(p<.001),andinthose≥35

yearsold,CADissignificantlymorecommonthanSUD(p<.001)(Eckartetal.,2011;

Risgaard,Winkel,Jabbari,Behr,etal.,2014).

Itisclearfromourstudyandpreviousliteraturethatthereisaportionof

deathsthatappeartobeduetoanarrhythmia,asnocauseofdeathisfoundon

autopsy.Thesedeathstendedtooccurintheyoungerages.Genetictestingattimeof

autopsywouldhelpclarifythecauseofthesedeathsbypossiblydiagnosinga

channelopathy.Asforstructuraldiseases,CADisthemostprevalentandmost

commonlyreportedintheliterature,andtendstoeffecttheolderpopulations.

4.3CircumstancesofDeath

ThecurrentstudyshowsthatthemajorityofvictimsofSCDdiedduringrest

orduringsleep,withthesmallestproportiondyingduringmoderatetovigorous

58

activity.IntheSCDfieldofresearch,athleticactivityhaslongbeenundersuspicion

forcausingSCD(Maron,Roberts,McAllister,Rosing,&Epstein,1980).Thereisan

abundanceofevidencetosupportthistheory(Harmon,Drezner,Wilson,&Sharma,

2014);however,itappearsthatSCDismoreprevalentinthegeneralpopulation,and

hereathleticactivityisnotthecausativeagent(Risgaard,Winkel,Jabbari,Glinge,et

al.,2014).TheONstudyfoundasimilarresult,with11%ofSCDsoccurringduring

moderate-vigorousactivity(Pilmeretal.,2013).Thisisfurthercorroboratedbythe

Irishgroupthatfound7.7%(9/116)ofsubjects.SCDsoccurredduringathletic

activitywhilethemajoritydiedduringrestorsleep(Margeyetal.,2011).Finally,the

sameresultwasseeninDenmarkwhereonly11%(43/409)ofsubjectsdiedduring

vigorousactivitywhile84%(347/409)ofsubjectsdiedduringrestorsleep(Winkel

etal.,2010).

Ascertainingwhetherthevictimwassymptomaticornotbeforedeathcanbe

achallengingtask,asitisnotalwaysproperlydocumentedandwedidnothave

accesstomedicalrecords.Wefoundthatonlyasmallpercentageofvictimsinall

cohortsdisplayedanypremonitorysymptoms.Theliteraturetendstoagreewith

thisfinding.Eckartetal.(2011)documentedsymptomsin278(53%)ofthosewho

died,suchaschestpain,dyspnea,andsyncope.Whilethisisindeedahighernumber

thanwefound,theyagreedthatitisdifficulttoobtainanyprodromeasitmostoften

occursimmediatelyantecedenttodeath.Contrarytothesefindings,arecentstudy

examinedCADvictims(age1-35years)bycomparingtheirsymptomswithsexand

agematchedcontrolsthatdiedinaccidents(Jabbarietal.,2013).Theyfoundthat

59

62%ofyoungpersonswithSCDexperiencedanginabeforedeath.Thereisawide

spectrumofcausativediseasesandsyndromesthatcauseSCD,thereforeitislogical

thattheremaybeawidespectrumofsymptomsaswell.

4.4Limitations

Notably,afewlimitationsarepresentregardingdiscrepanciesbetweenour

studyandtheONstudy.Mostimportantly,weendeavoredtodesignourstudybased

directlyontheONpublishedmanuscript(Pilmeretal.,2013),whichwaslackingin

explicitmethodologyinsomeareas.Forexample,themannerinwhichtheymade

exclusionswasunclear,andledtoususingaslightlydifferentprocess.Thatbeing

said,thedatausedforprimaryanalysis(the‘suddendeath’group)wascollected

exactlyasONindicated,thereforeoverallthisisaminorlimitation.It’salso

challengingtodirectlycompareourselvestoONwhenwehaveknowinglyuseda

completelydifferentpanelofindividualstoassessthelikelinessofSCD.However,for

NLtoreachanon-significantdifferencecomparedtoON,wewouldhavehadto

incorrectlyassess6deaths,asnon-significance(p>.05)isreachedat11sudden

deaths(wehad17).Proportionally,thisisalargenumbertohaveerredandisthus

unlikely.

Morelimitationsstemfromtheretrospectivenatureofthisstudy.Data

collectionwaslimitedtowhatwasinthefiles–whichattimeswasmissing

information-astheprimarypurposeofthesefilesistosatisfypathology

requirements,notSCDrequirements.TostaytruetothedesignandtheONstudy,

wedidnotattempttolookforadditionalinformationelsewhere.Forexample,not

60

everyfileincludedtoxicologyinfo,whichmaycontributetoSCD.However,thevast

majorityhadtoxicologyinthefilewhenthecircumstancesofdeathsuggestedit.

Anotherimportantlimitationthatbecameapparentwithfilereviewwasthe

differentstandardofautopsyreportingbetweenpathologists.WhiletheChief

MedicalExaminerreviewsallautopsies,therearecertainlydifferencesbetweenfiles

dependingonthepathologistwhoperformedtheautopsy.Firstly,notallsubjects

hadautopsies,whichistypicallyatthediscretionofthepathologist,andsometimes

thefamilies.Thisoftenoccurredinmotorvehicleaccidents,wherecauseofdeath

waspresumedtobetheaccident.Inouranalysis,however,themain‘suddendeath’

group(2-40)hadonly1subjectwithoutautopsy,thusitlikelydidnotimpactour

finalresult.Alsodependentonthepathologististhelistofmajorfindingsforan

autopsy,notedonthefirstpage.WefoundthatsomelistswouldbemissingaSCD

majorfinding,offorexampleanenlargedheart,whileothersmighthaveincludedit-

itwasnotconsistent.Thiscouldeasilyinfluenceareaderofanautopsytomissthe

findingofanenlargedheart,asthe‘majorfindings’aresummarizedonthefirst

page.Anexampleofthiswasacaseofa27yearoldmaleinvolvedinaskidoo

accident,withcauseofdeathpresumedasphyxia/drowning,andincidentallyhada

650gheartandfatintherightventricle.Thecardiomegalyherewasnotresearched

anyfurtherandwaslistedwithnofurtherinvestigations.Forourstudy,wepaid

attentiontotheentiretyoftheautopsyandthistypeofincidentalfindingwasnot

likelytobehavebeenmissed.

61

Finally,somethingthatismissingfrommostautopsiesisthemolecular

pathology.Thiswouldindicatewhetherthesubjecthadanysignificantgenetic

mutationsthatcouldhavecausedtheirdeath.Veryfewofthereviewedfiles

includedthis,asitisnotyetpartofthestandardautopsy.Wearehopingtoreview

DNAfromfixedblocksinafuturestudy.

Onafinalnote,thesamplesizeinthisstudyissmall,however,itisaslargeas

itcanbegivenourpopulationnumbers.Withthis,itispossiblewearemissing

somesignificantrelationshipsinthedatabecauseournumbersaretoosmallto

showsignificance.Wearecurrentlyworkingtocollectmoredatafromdifferent

yearstohopefullybetterthisissue.

4.5Strengths

Asignificantstrengthofthisstudyisthatweareessentiallyasingle-center

studythatcapturesallcasesinNL.Wedoindeedhaveacentralizeddatabase,but

morethanthatisthatallcasesinNLaresentdirectlytotheChiefMedicalExaminer

(S.A.)tobereviewed,whichlimitsanybiasinascertainmentbecauseweuseda

singleassessor.Additionally,itincreasesthelikelihoodthatwecapturedallSCD

casesinNLin2008and1997.Anotherimportantadvantageofthestudyisthatit

wasdesignedascloselyaspossibletoreplicateanon-founderpopulation(ON)

study,allowingustomakeadirectcomparisonbetweenfounderandnon-founder

populations.

62

4.6FutureResearchandConclusion

Thisstudyistheveryfirstpieceofthepuzzle;itprovidesthebasic

informationweneedtostartunderstandingtheburdenSCDcausesinNL.Weknow

alreadytherearegeneticmutationsintheNLpopulation,andnowwehavea

potentialmeasureofthiseffect.Toconfirmthatthedeathswemeasuredarean

outcomeofgenetics,anextstepwouldbetoinvestigatemolecularstudies;allSCD

subjectsin2008havefixedtissueblocks,wewillbetestingtheseformutations.It

wouldalsobeimportanttoexaminelifestyleandenvironmentalfactorsinfuture

studiesthatmightberesponsiblefortheeffectwehaveseen.Finally,wewillassess

moreyearstoconfirmthenumberswehavedescribed,tomakesuretheincidence

ratesareconsistentovertime.Itisreassuring,however,thatwefoundaverysimilar

incidencefortheyear1997,whichwouldindicatethenumbersfrom2008arenot

outliers.

Toconclude,NLhasasignificantlyhigherincidenceofSCDinthe20082-40

yearoldcohortthanthecomparableONcohort.Thesedeathscompriseboth

structuralandarrhythmogenicdiseases,withthetrendofmorearrhythmogenic

issuesintheyoungandmorestructuraldiseasewithage.TheincidenceofSCD

increaseswithage,andismoreprevalentinmales.TheburdenthattheNL

populationenduresisstillnotfullyunderstood,however,thisstudyhasbroughtto

lightthatSCDisasignificantsourceofyoungdeathintheprovince,andwillinform

healthpolicyinawaythatwillhopefullyworktopreventmanyfuturesudden

deaths.

63

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Appendices

AppendixA–CurrentKnownGeneMutationsDiscoveredwithaPotentialforSCD

("ClinVar,"2014;"Gene,"2014;"MalaCardsHumanDiseaseDatabase,"2014)

71

CardiacDisease Gene Locus OfficialfullnameHypertrophic

CardiomyopathyACTC1 15q14

actin,alpha,cardiacmuscle1

CALR3 19p13.11

calreticulin3

CAV3 3p25 caveolin3 CMH21 7p12.1-q21

cardiomyopathy,familial

hypertrophic,21

COA5 2q11.1 cytochromecoxidaseassemblyfactor4

CSRP3 11p15.1

cysteineandglycine-richprotein3

JPH2 20q13.12

junctophilin2

MT-ATP6 -- mitochondriallyencodedATPsynthase6

MT-TG -- mitochondriallyencoded

tRNAglycine

MT-TH -- mitochondriallyencodedtRNAhistidine

MT-TI -- mitochondriallyencodedtRNAisoleucine

MYBPC2 19q13.33

myosinbindingproteinC

MYBPC3 11p11.2 cardiacmyosin-bindingproteinC,fasttype

MYH6 14q12

myosin,heavychain6,cardiacmuscle,alpha

MYH7 14q11.2-q12

β-myosinheavychain

MYL2 12q24.11 myosin,lightchain2,regulatory,cardiac,slow

MYLK2 20q13.31

myosinlightchainkinase2

HypertrophicCardiomyopathy

Cont’d

MYL3 p21.3-p21.2

myosinlightchain3,alkali;ventricular,skeletal,slow

MYO6 6q13 myosinVI MYOZ2 4q26-q27

myozenin2

72

NDUFV2 18p11.22 NADHdehydrogenaseflavoprotein2,24kDa

NEXN 1p21.1 nexilin(Factinbindingprotein)

PLN 6q22.1 phospholamban PRKAG2 7q36.1 proteinkinase,AMP-

activated,gamma2non-catalyticsubunit

SLC25A4 4q35 solutecarrierfamily25

(mitochondrialcarrier;adeninenucleotide

translocator),member4

TCAP 17q12

titin-cap

TNNC1 3p21.1 troponinCtype1(slow) TNNI3 19q13.4 troponinItype3(cardiac) TNNT2 1q32 cardiactroponinTtype2 TPM1 15q22.1

tropomyosin1(alpha)

TTN 2q31 titin VCL 10q22.2

vinculin

ArrhythmogenicRightVentricularCardiomyopathy/

Dysplasia

CTNNA3 10q22.2 catenin(cadherin-associatedprotein),alpha3

DSC2 18q12.1

desmocollin2

DSG2 18q12.1-q12.2

desmoglein2

DSP 6p24 desmoplakin JUP 17q21 junctionplakoglobin PKP2 12p11 plakophilin2 RYR2 1q43 ryanodinereceptor2

(cardiac)ArrhythmogenicRightVentricularCardiomyopathy/DysplasiaCont’d

TGFB3 14q24 transforminggrowthfactor,beta3

TMEM43 3p25.1 transmembraneprotein43

73

DilatedCardiomyopathy

ABCC9 12p12.1 ATP-bindingcassette,sub-familyC(CFTR/MRP

,member9 ACTC1 15q14

actin,alpha,cardiacmuscle1

ACTN2 1q42-q43 actinin,alpha2 BAG3 10q25.2-

q26.2BCL2-associatedathanogene

3 CMD1B 9q13-q22 cardiomyopathy,dilated1B

(autosomaldominant)

CMD1H 2q14-q22 cardiomyopathy,dilated1H(autosomaldominant)

CMD1K 6q12-q16

cardiomyopathy,dilated1K(autosomaldominant)

CMD1Q 7q22.3-q31.1

cardiomyopathy,dilated1Q(autosomaldominant)

CRYAB 11q22.3-q23.1

crystallin,alphaB

CSRP3 11p15.1

cysteineandglycine-richprotein3

DES 2q35 desmin DMD Xp21.2 dystrophin DNAJC19 3q26.33 DnaJ(Hsp40)homolog,

subfamilyC,member19 DOLK 9q34.11

dolicholkinase

DSG2 18q12.1-q12.2

desmoglein2

DSP 6p24 desmoplakin EYA4 6q23 EYAtranscriptional

coactivatorandphosphatase4

FHL2 2q12.2 fourandahalfLIMdomains2

FKTN 9q31-q33 fukutinDilated

CardiomyopathyCont’d

FOXD4 9p24.3 forkheadboxD4

GATAD1 7q21-q22

GATAzincfingerdomaincontaining1

74

GJA5 1q21.1 gapjunctionprotein,alpha5,40kDa

KCNH2 7q36.1 potassiumvoltage-gatedchannel,subfamilyH(eag-

related),member2

LAMA3 18q11.2

laminin,alpha3

LAMA4 6q21 laminin,alpha4 LDB3 10q22.3-

q23.2LIMdomainbinding3

LMNA 1q22 laminA/C MT-TH -- mitochondriallyencoded

tRNAhistidine MT-TY -- mitochondriallyencoded

tRNAtyrosine

MURC 9q31.1 muscle-relatedcoiled-coilprotein

MYBPC3 11p11.2 myosinbindingproteinC,cardiac

MYH6 14q12

myosin,heavychain6,cardiacmuscle,alpha

MYH7 14q12 myosinheavychain7,cardiacmuscle,beta

MYPN 10q21.3 myopalladin NEXN 1p21.1 nexilin(Factinbinding

protein) PDCD1 2q37.3 programmedcelldeath1 PLN 6q22.1 phospholamban PRDM16 1p36.23-

p33PRdomaincontaining16

PSEN1 14q24.3 presenilin1 PSEN2 1q42.13 presenilin2 RAF1 3p25 Raf-1proto-oncogene,

serine/threoninekinase

DilatedCardiomyopathy

Cont’d

RBM20 10q25.2 RNAbindingmotifprotein20

RYR2 1q43 ryanodinereceptor2(cardiac)

75

SCN5A 3p21 sodiumchannel,voltage-gated,typeV,alphasubunit

SDHA 5p15 succinatedehydrogenase

complex,subunitA,flavoprotein

SGCD 5q33-q34 sarcoglycan,delta(35kDadystrophin-associated

glycoprotein)

TAZ Xq28 tafazzin TCAP 17q12

titin-cap

TMPO 12q22 thymopoietin TNNC1 3p21.1 troponinCtype1(slow) TNNI1 1q12 troponinItype1(skeletal,

slow)

TNNI3 19q13.4 troponinItype3(cardiac) TNNT2 troponinTtype2(cardiac) TPM1 15q22.1 tropomyosin1(alpha) TTN 2q31 titin TXNRD2 22q11.21 thioredoxinreductase2 VCL 10q22.2 vinculin ZASP 7 ZO-2associatedspeckle

proteinLongQTSyndrome

AKAP9 7q21-q22 Akinase(PRKA)anchorprotein9

ALG10 12p11.1 ALG10,alpha-1,2-glucosyltransferase

ANK2 4q25-q27 ankyrin2,neuronal ANKB 4q25-q27 ankyrinB CACNA1C 2p13.3 l-typecalciumchannel CALM2 2p21 calmodulin2(phosphorylase

kinase,delta)

CAV3 3p25 caveolin3 KCNE1 21q22.12

potassiumvoltage-gatedchannel,Isk-relatedfamily,

member1

LongQTSyndromeCont’d

KCNE2 21q22.12

potassiumvoltage-gatedchannel,Isk-relatedfamily,

76

member2 KCNH2 7q36.1 potassiumvoltage-gated

channel,subfamilyH(eag-related),member2

KCNJ2 17q24.3 Kinwardly-rectifying

channel,subfamilyJ,member2

KCNJ5 11q24 potassiuminwardly-rectifyingchannel,subfamily

J,member5

KCNQ1 11p15.5 potassiumvoltage-gatedchannel,KQT-likesubfamily,member1

NOS1AP 1q23.3 nitricoxidesynthase1(neuronal)adaptorprotein

SCN4B 11q23.3 sodiumchannel,voltage-gated,typeIV,betasubuni

SCN5A 3p21-p24 sodiumchannel,voltage-

gated,typeV,alphasubunit

SNTA1 20q11.2 syntrophin,alpha1Catecholaminergic

PolymorphicVentricularTachycardia

ANK2 4q25-q27 ankyrin2,neuronal

ASPH 8q12.1 aspartatebeta-hydroxylase CALM1 14q32.11 calmodulin1(phosphorylase

kinase,delta)

CALR 19p13.3-p13.2

calreticulin

CAMP 3p21.3 cathelicidinantimicrobialpeptide

CatecholaminergicPolymorphicVentricularTachycardia

Cont’d

CASQ2 1p13.3 calsequestrin2

77

FKBP1B 2p23.3 FK506bindingprotein1B,12.6kDa

KCNJ2 17q24.3 Kinwardly-rectifyingchannel,subfamilyJ,member2

RYR1 19q13.1 ryanodinereceptor1(skeletal)

RYR2 1q43 ryanodinereceptor2(cardiac)

TRDN 6q22.21 triadinBrugadasyndrome

CACNA1C 2p13.3 calciumchannel,voltage-dependent,Ltype,alpha1C

subunit

CACNB2 10p12 calciumchannel,voltage-dependent,beta2subunit

GPD1L 3p22.3 glycerol-3-phosphate

dehydrogenase1-like HCN4 15q24.1 hyperpolarizationactivated

cyclicnucleotide-gatedpotassiumchannel4

KCNE3 11q13.4 potassiumvoltage-gated

channel,Isk-relatedfamily,member3

SCN1B 19q13.1 sodiumchannel,voltage-

gated,typeI,betasubunit

SCN3B 11q23.3 sodiumchannel,voltage-gated,typeIII,betasubunit

SCN5A 3p21-p24 sodiumchannel,voltage-

gated,typeV,alphasubunitShortQTSyndrome

CACNA2D1 7q21-q22 calciumchannel,voltage-dependent,alpha2/delta

subunit1

ShortQTSyndromeCont’d

KCNH2 7q36.1 potassiumvoltage-gatedchannel,subfamilyH(eag-related),member2

KCNJ2 17q24.3 Kinwardly-rectifying

78

channel,subfamilyJ,member2

KCNQ1 11p15.5 potassiumvoltage-gatedchannel,KQT-likesubfamily,

member1

79

AppendixB–SampleMedicalExaminer’sreport

80

AppendixC-ChartAuditForm

DataCollection

Autopsy#

StudyNumber

PostalCodeYearofBirth

Dateofdeath

Sex

Height(cm)

Weight(kg)

BMI

MannerofDeath

MedicalCauseofDeath

Underlyingpathology(pick1ormore)

Previouslyknowncardiacdisease

Ifyes,indicateunderlyingpathology(pick1ormore)

Ifyes,indicateadditionalinformationofinterest(testingperformed,previoushealthrecords)

Cardiacriskfactors

Otherpotentiallycontributorymedicalconditions

Medicationsbeforedeath

Non-prescriptionorrecreationaldrugs(notincludingvitamins)

81

Circumstances/locationofdeath

Activitylevelatonsetoffatalevent

Specifyifknown

Symptomsinpreceding24hours

Ifsymptoms,circumstances(samedefinitionsasabove)

Symptomspriortopreceding24hours

Ifsymptoms,circumstances(samedefinitionsasabove)

Weresymptomsprecedingdeathinvestigated?

List/summarizemedicalinvestigations/testresults:

Reportedfamilyhistoryofsuddendeathorarrhythmia

Ifyes,circumstancesofdeath

Ifpositivefamilyhistoryofsuddendeath,closestaffectedindividual

GeneticTesting?

Additionalcommentsfromthenarrative

82

AppendixD-Primarydatausedforanalysis.

NLandONpopulationdata:StatsCanada(StatisticsCanada,2014b)andPilmerel,

2013,respectively.

NL20082-40(A)&2-50(B)

NL19972-50(C) Ontario20082-40

Deaths(n=)

Populationsize

Deaths(n=)

Populationsize

Deaths(n=)

Populationsize

Overall 17(A)44(B)

232,210(A)316,244(B)

66 406,713 174 6,602,680

Ages2-18 2 92,982 3 129,125 19 2,652,751Ages19-29 5 66,452 7 90,909 47 1,945,419Ages30-40 10 72,776 18 99,593 105 1,980,743Ages41-50 27 84,034 38 87,043 Male(n/totaldeaths)

11/17(A)35/44(B)

50/66 132/174

83

AppendixE–Comparisonofincidencesacrosstheliterature

Author Population Year AgeGroup

Incidence(person-years)

KeyDifferences

Currentstudy

NL,Canada 2008 2-40years

7.32/100,000 N/A

Currentstudy

NL,Canada 2008 2-50years

13.9/100,000 N/A

Currentstudy

NL,Canada 1997 2-50years

16.23/100,000 N/A

Pilmeretal.,2013

ON,Canada 2008 2-40years

2.64/100,000 None

Limetal.,2010

BritishColumbia,Canada

2005-2007

0-35years

1.75/100,000 Noaccidentalsincluded

Margeyetal.,2011

Ireland 2005-2007

15-35years

2.85/100,000 Caseswithdruginvolvementexcluded

Papadakisetal.,2009

EnglandandWales

2002-2005

1-34years

1.8/100,000 Noaccesstoautopsyfiles,onlyusedofficeofnationalstatisticsdatabase

Winkeletal.,2011

Denmark 2000-2006

1-35years

2.8/100,000 Usedinfooutsideofautopsyfile

Risgaardetal.,2014

Denmark 2007-2009

1-49years

8.6/100,000 Usedinfooutsideofautopsyfileandusedhighnumberofnon-autopsycases

36-49years

21.7/100,000