scope & nature of young sudden cardiac death ...scope & nature of young sudden cardiac death...
TRANSCRIPT
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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70
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