PREVENTATIVEPATHOLOGY-LEARNINGFROMSUDDENCARDIACDEATH

A P C S C NOV EMB E R 1 0 T H 2 0 1 6 Dr Jodi White

Forensic Pathologist

Outline•  Suddencardiacdeath(SCD)•  Condi2onsassociatedwithSCD•  SuddendeathinyoungadultsinWA•  Gene2csinthemortuary•  Postmortemprocedure•  Caseexample•  Conclusions

PREVENTATIVE PATHOLOGY LEARNING FROM SUDDEN CARDIAC DEATH

SUDDENCARDIACDEATH

SUDDENCARDIACDEATHOVERVIEWDEFINEDAS“thesudden,abruptlossofheartfunc2oninapersonwhomayormaynothavediagnosedheartdisease,wherebythe2meandmodeofdeathareunexpectedandthedeathoccurseitherinstantlyorshortlyaGersymptomsappear”AmericanHeartAssocia2on

SUDDENCARDIACDEATHOVERVIEW

•  Mostcommonintheelderly•  Coronaryarterydisease•  Uncommonintheyoung•  Devasta2ngcomplica2onofanumbercardiovasculards•  Thedeathmaybethefirstandonlymanifesta2onofa

lethalfamilialdisease•  Manycasesremainedunexplained

SUDDENCARDIACDEATHPASTANDCURRENTISSUES

•  Adiagnosisofexclusion(non-cardiacCODexcluded)•  Havebeeninconsistenciesinautopsyprocedure,

classifica2onofCODandreferralprocesses•  Poten2alformissingcases,incorrectCOD,withnoclosure

forfamiliesandnoclinicalfollowup•  DelaysinestablishingCOD•  Costs

SUDDENCARDIACDEATHOVERVIEW

•  2005TRAGADYini2a2ve(Trans-TasmanResponseAGAinstSuddenDeathintheYoung)standardautopsyprac2ces

•  2008RCPAendorsedSCDautopsyguidelines•  2011HeartRhythmsociety•  2011EuropeanHeartRhythmAssocia2on•  Associa2onforEuropeanCardiovascularPathology

CAUSESOFSUDDENCARDIACDEATH

CONDITIONSASSOCIATEDWITHSUDDENCARDIACDEATH

Structuralabnormali2es•  Gene2c-muta2onsingenesencodingdevelopmental

componentsoftheheartandvessels-  Cardiomyopathies–dilated,hypertrophic,ARVD-  Abnormali2esofthecoronaryarteries-  Connec2ve2ssuedisorders–Marfan’s-  Valvularabnormali2es•  Acquired-Coronaryarteryatherosclerosis

CONDITIONSASSOCIATEDWITHSUDDENCARDIACDEATH

Coronaryarteryatherosclerosisandthrombosis

CONDITIONSASSOCIATEDWITHSUDDENCARDIACDEATH

HYPERTROPHICOBSTRUCTIVECARDIOMYOPATHY(HOCM)

CONDITIONSASSOCIATEDWITHSUDDENCARDIACDEATHNonstructural(grosslyandhistologicallynormal)•  InheritedarrhythmogenicdisordersGene2cmuta2onsingenesencodingfunc2onalunitsincardiaccellsleadtoproblemsinthegenera2onandprogressionofthecardiacimpulse.CardiacChannelopathies-LongQTsyndrome,Catecholaminergicpolymorphicventriculartachycardia,Brugadasyndrome

SUDDENDEATHINYOUNGADULTSINWESTERNAUSTRALIA

SUDDENDEATHINYOUNGADULTS2008-2012period•  Av2000autopsies/year•  Youngadults17-35years>1600deaths•  Average>300coronialautopsies/year(15%)•  Males75%ofcases•  Malesover-representedinalltypesofdeath

SUDDENDEATHINYOUNGADULTS17-35YEARSCAUSESOFDEATH•  Trauma30-35%(MVC,falls,industrial)

•  Suicide25-30%

•  Drugrelated15-20%

•  Natural5-10%(diabetes,malignancy,asthma,epilepsy,sepsis,PE)

•  Homicide>5%

•  Drowning2-4%(somepossiblycardiacrelated?)

•  Unascertained3-5%(someexternal,decomposed)

SuddendeathinyoungadultsCardiacrelated5%(80%male)–(somedrugrel)Coronaryatherosclerosis>50%casesCardiomyopathies>10%Cardiacarrhythmia10%Myocardi2s(6cases)Aor2cdissec2on(4cases)Heartfailure(chronicillnessesdiabetes,obesity)MitralvalveprolapseCongenitalheartds,andothers(anomcoronaryarteries)

GENETICSINTHEMORTUARY

ATHLETESANDSUDDENCARDIACDEATH

•  Rareandhighlyvisible,distressingevent

•  Increasedincidencerela2ngtogreaterriskwithstrenuousexercise

•  Knownorquiescentheartdisease

•  Manystudies-haveshownmostoGenstructuralCOD(HOCMandARVD>50%,coronaryatherosclerosisoranomalies,valveabnormali2es,myocardi2s)

•  Structurallynormalheartsin3%

•  Greatestnumbersfootballcodes/basketball

•  Increasedriskforcertainna2onali2es

•  Ledtoprotocols/regula2onsreplayerworkup/review

GENETICSINTHEMORTUARY

Themolecularautopsy

•  Mul2pleusesineverydayclinicalmedicine

•  Emergingroleinthemortuaryduetomolecularadvances

•  Increasingmolecularautopsyseriessuppor2ngitsuse

•  Autopsynega2vesuddenunexplaineddeathinyoungadults30%inmoststudies

•  Establishingdefini2vepathogenicCODinsomecases,confirma2onofothers

GENETICSINTHEMORTUARY

Themolecularautopsy

•  Formspartofacompletemedico-legalexamina2oninselectedcases

•  Suggestedthatgene2cinves2ga2onofrela2vescanrevealaninheritedheartdiseaseinupto30-40%cases

•  Thenewstandardofcare-addressingcommunityexpecta2on

•  Reducetheriskofaddi2onalSCD

•  Generatenewdatathatmayuncovernewmuta2ons

POSTMORTEMPROCEDUREINSUDDENCARDIACDEATH

ThoroughanddetailedexaminaMonfordeterminaMonofaCOD

Closureforthefamily

Provideinforma2onanddirec2onforthespecialistfollow-upandinves2ga2onofthefamily

POSTMORTEMPROCEDUREINSUDDENCARDIACDEATH

Timelyprovisionofcomprehensivedetailedinforma2onincluding:

•  Death–ac2vityat2me,witnessed,unwellpriortofinalevent,druguse,resuscita2onahempts,posi2onwhenfound

•  Backgroundhistory-habitualsport;medical(cardiac,diab,seizures);druguseincludingprescrip2onmeds-LQTSpast‘episodes’,allergies

•  Familyhistory–knowncardiac,unexplaineddeaths

•  Retrievalofanypreviousinves2ga2ons

•  Postmortem–publishedguidelines(RCPAendorsedfromTRAGADYgroup)

•  Postmortemimaging

•  Thoroughexternalexamina2on–general;druguse,s2gmataofchronicdisease(liverdisease,diabetes,sepsis),syndromes(Marfans),medicalinterven2on,seizureac2vity,injury(collapsetype)

•  Internal–detailedgeneralexamina2onfornon-cardiaccauses

•  Detailedcomprehensiveexamina2onofthehearttoiden2fystructuralheartdisease

•  Furtherinves2ga2ons

GuidedFurtherinvesMgaMonsØ  Extensivehistology(asperprotocol)Ø  ReferralifneededØ  BiochemistryØ  Microbiology/virologyØ  Neuropathology-seizures

GuidedFurtherinvesMgaMonsØ Toxicology–illicitdrugs(amphetamines),synthe2cdrugs,anabolicsteroids,alcohol

Ø Appropriatesamplingoffresh2ssueandbloodsamplesforgene2cstudies

Ø DNAextrac2on/storageindefinite/likelycasesØ Storageinothers

Determina2onofCOD-  SCDwithcardiacstructuralabnormality,-  Undetermined-ExclusionofotherCOD-  SCDnostructuralabnormalityorsubtlechanges–probableinheritedchannelopathy/unascertained

No2fica2onofcoronerReferraloffamilytogene2cservice,specialistreview

SomedeterminedcasesmayalsobearconsideraMon•  Drowningdeaths•  Seizurerelateddeaths•  Drugrelateddeaths–?vulnerableheart;newsynthe2cdrugs•  Restraintdeaths•  Ageshouldnotbealimi2ngfactor

Drowningdeaths•  FirstreportofPMmoleculardiagnosisSCD,LQTin1999aGerneardrowning(TesterandAckerman)

•  Othercasereports•  Highindexofsuspicion-samplestorage•  Don’texcludeoncircumstanceorotherposi2veresults

CASESTUDY

CASESTUDY1

32yearoldmale

Treesurgeon,smoker

Onechild7years,motherandfather,sister

Atthecasinowithfriends,drinkingalcohol

Reportedtobewell

Suddenlycollapsedandtriedtostand,collapsingagaintotheground

SJAresuscita2onatter2aryhospital

PMHreportedtohavehadanabnormalECG3yearsprevious

CASESTUDY1

Atpostmortem–-185cm,105kg

-  Enlarged,soGanddilatedheart518g(range241-481g)

-  ThickenedLVwall15-18mm,prominenttrabeculae

-  Markedfahy2ssueinfiltra2onRV

-  Normalcoronaryarteries

-  Evidentresuscita2on

-  Toxicologyalcohol0.199%

Causeofdeath

ARRHYTHMOGENICRIGHTVENTRICULARDYSPLASIA

ARRHYTHMOGENICRIGHTVENTRICULARDYSPLASIA

•  Aninheritedmyocardialdisease,autosomaldominant

•  Variablepenetranceandexpression

•  Associatedwithabnormalheartrhythm(ventriculararrhythmias)

•  Canfirstpresentassuddencardiacdeath

•  Progressivefibro-fahy2ssuereplacementoftheheartmuscle

•  Mostcommoninmales,Mediterraneandescent

•  Diagnosisbycombina2onofspecificclinical,ECGandradiographicalfeatures

•  Canbeprecipitatedbyexerciseandmedica2ons/drugs

•  Treatmentdeterminedbyconsidera2onofrisk

CONDITIONSTHATMAYBEASSOCIATEDWITHSUDDENCARDIACDEATH

Arrhythmogenicrightventriculardysplasia/cardiomyopathy

PATHWAYSTOPREVENTIONCONCLUSIONSAdevasta2ngeventforfamilyandthecommunityUseofstandardisedpmprac2cesEstablishmentofcoronialreferralprocessforfamiliesTargetedgene2csisenablingustoaccuratelydefining

CODandprovideanswersImplementpreventa2vestrategiestosavelives

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www.rcpa.edu,RCPAGuidelines-“Post-morteminsuddenunexpecteddeathintheyoung:GuidelinesonAutopsyPrac2ce”,PreparedbythemembersofTrans-TasmanResponseAGAinstsuddenDeathintheYoung(TRAGADY)