Andersons pediatric cardiology 2277

Brugadasyndrome,catecholaminergicpolymorphicventriculartachycardia
(CPVT),ARVD,HCManddilatedcardiomyopathy(DCM).Forexceptionally
high-riskpatients,primarypreventionimplantablecardioverterdefibrillators
(ICDs)maybeofferedalthoughmostelectrophysiologistsfollowoneormore
ICDsthatwereplacedinanticipationofahigh-riskoutcomebeforesubsequent
researchhelpeddowngradethepatient'sriskinthepatient'sparticulardisease.
Thereforeextensiverisk-benefitconsiderationandpatientcounselingare
requiredtohelpfamiliesunderstandthebalancebetweenthebenefitsofprimary
preventionICDsandthepotentialrisksofICDplacement,includinginfection,
shocks,devicemalfunction,subsequentinterventions,devicefailure,and
psychosocialimplications.
Otherdiagnosesfoundinsurvivingrelativescallfortherapythatdoesnot
directlyimpactacutearrhythmiarisk,butmaydecreaselong-termmorbidityand
mortality.Forexample,earlyandsevereatheroscleroticcoronaryheartdisease
onautopsyshouldtriggerscreeningforfamilialhyperlipidemia.Autopsymay
alsouncoverconditionssuchasundiagnosedCHD,vascularmalformationsthat
mayhaverupturedorotherwisecausedsuddendeath,toxicologyfindings
consistentwithoverdose,ormyocarditis.Whiletherearesuggestionsthatthere
maybeaheritablecomponenttoseveralofthesedisorders,theprimaryworkto
datehasfocusedonchannelopathiesandcardiomyopathies,whichareamenable
togenetictestingformonogeneticautosomaldominantvariants.
Insummary,asuddendeatheventinapreviouslyhealthyyoungpersonisa
dramaticsignalthatfirst-degreerelatives—siblings,parents,andchildren—
requireriskstratification.77–79

PhenotypeScreeningAmongFirst-Degree
Relatives
Severalcardiacsocietieshaveendorsedasystematicapproachtophenotype
screeningamongfirst-degreerelativesofasudden“unexplained”deathvictim.77
Suddenunexplaineddeathoccurswhenautopsyandtoxicologydonotidentifya
causeofdeathandtoxicologydoesnotsuggestatoxicexposure.The

circumstancesofthedeathshouldbeinvestigatedbyinterviewswithrelativesor
incollaborationwiththemedicalexaminerorcoroner'soffice.Anexpertopinion
oncardiachistologycanbeuseful;slidescanbemailedforasecondopinion.
Overinterpretationofcardiomyopathyorinflammatorycausesinunexperienced
handsismorecommonthanunderinterpretation.80Thedangerof


overinterpretationisthatitnarrowsthespectrumoffurtherinvestigationinfirstdegreerelativesandputstheremainderofthefamilyatriskforamissed
diagnosisofapotentiallyheritabledisorder.81
Whilephenotypicevaluationofthedecedentisbeingcompletedbythe
coroner,medicalexaminer,oranyconsultants,anevaluationoffirst-degree
relativesshouldbeginassoonasthefamilyiswilling.Doctorsandfamilieshave
thesamepriorities:first-degreerelativeswithsymptoms,especiallysyncope,
palpitations,orknownarrhythmias,shouldbescreenedasquicklyasfeasible.
Theinitialstepsarenoninvasive,beginningwithhistoryandphysical
examination.TestingshouldincludeanECGinstandard12-leadpositionandan
ECGinamodifiedpositionwithV1andV2inthesecondintercostalspace.This
positionoversamplestherightventricularoutflowtract,whereBrugada
syndromeandARVDhavetheircentralfocusofhistopathology.77
Echocardiographyprovidesinformationonventriculardimensionsandfunction.
Exercisestresselectrocardiographyprovidesinformationonexercise-sensitive
arrhythmia,especiallyCPVT.Myocardiumwithmarginalperfusioncanalsobe
identifiedbyexercisestresstestinginsomecases(e.g.,severepremature
coronaryarterydisease).Aconsensusstatementendorsesthesenoninvasive
studiesinfirst-degreerelativesofayoungsuddendeathvictimasclassI
recommendations.82Moreinvasiveorcomplexdiagnosticstudieshavebeen
usedwithvaryingefficacy.TheyretainclassIIAandIIBrecommendationsin
theconsensusstatementbecausethetestcharacteristicsshowneitherexcellent
specificitynorexcellentsensitivity.Asoneexample,astudyfromtheCardiac
ArrestSurvivorswithPreservedEjectionFraction(CASPER)registryperformed

provocativetestingwithsodiumchannelblockersamongsurvivorsofcardiac
arrestorfirst-degreerelativeswithafamilyhistoryofsuddendeath.82aInthis
slightlyoldercohort(47yearsofage±15years),testingprovokedaBrugada
patterninonly6.9%ofsubjects,lessthanhalfofwhichwereuncoveredin
subjectswithnormalrestingECGsandonlyoneoftheinducedcohorthada
positivegenotype.Inourcenter,wetakeastagedapproachtoscreeningfirstdegreefamilymembers,beginningwithhistoryandphysical,twoECGs,
echocardiography,andexercisestresstesting(classIindications)andonly
movingtomoreadvancedtestingifhistoryandphysicalorinitialtesting
suggeststhatfurtherscreeningisrequired(seeFig.89.1foradiagrammatic
representationofourscreeningprotocol).Althoughtheconsensusstatement
currentlyrecommendsdischargingasymptomatic,fullygrownadultswith
negativeworkups,alowrateofpersistenteventscontinuestooccurindiagnosis-


negativerelativesandourunderstandingofthegeneticetiologiesremains
imperfect.83Thereforeinourcenter,wecontinuetoseephenotype-negative
familiesatlongfollow-upintervalstorevisitclinicaltestingasneededand
reconsiderthestateofgenotypetestinginthefamily.

FIG.89.1 Protocolforscreeningfirst-degreerelativesafterasudden
unexplaineddeath.First-degreerelativesareevaluatedintheclinical
pathway,beginningwithhistoryandphysical(H&P),electrocardiography
(ECG)instandardandmodifiedrightventricularposition,echocardiogram,
andexercisestresstest.Iftheclinicalhistoryissuspiciousforaspecific
etiologyorinitialtestingdemonstratesabnormalities,butdoesnotresultin
afirmdiagnosis,thenadditionalclinicalinvestigationsareperformedinthe
indeterminatepathway.DNAextractedfromthedecedentistestedinthe
geneticspathwayforapanelofgenesassociatedwithchannelopathyand
cardiomyopathyetiologiesassociatedwithsuddendeath(“molecular
autopsy”).Resultsfrommolecularautopsyandresultsfromtheclinical

testingprotocolareusedtogethertodeterminetheoptimalapproachfor
familycascadescreening.cMRI,Cardiacmagneticresonanceimaging;
SAECG,signal-averagedelectrocardiogram.

GenotypeScreeningAmongFirst-Degree
Relatives