Brugada syndrome: Diagnosis, risk stratification and management

(1)

HAL Id: hal-01832150

https://hal.archives-ouvertes.fr/hal-01832150

Submitted on 12 Jul 2018

HAL is a multi-disciplinary open access

archive for the deposit and dissemination of

sci-entific research documents, whether they are

pub-lished or not. The documents may come from

teaching and research institutions in France or

abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, est

destinée au dépôt et à la diffusion de documents

scientifiques de niveau recherche, publiés ou non,

émanant des établissements d’enseignement et de

recherche français ou étrangers, des laboratoires

publics ou privés.

Brugada syndrome: Diagnosis, risk stratification and

management

Jean-Baptiste Gourraud, Julien Barc, Aurélie Thollet, Hervé Le Marec,

Vincent Probst

To cite this version:

Jean-Baptiste Gourraud, Julien Barc, Aurélie Thollet, Hervé Le Marec, Vincent Probst.

Bru-gada syndrome: Diagnosis, risk stratification and management.

Archives of cardiovascular

dis-eases, Elsevier/French Society of Cardiology, 2017, Equipe I Equipe IIa, 110 (3), pp.188–195.

�10.1016/j.acvd.2016.09.009�. �hal-01832150�

(2)

Availableonlineat

ScienceDirect

www.sciencedirect.com

REVIEW

Brugada

syndrome:

Diagnosis,

risk

stratiﬁcation

and

management

Diagnostic,

stratiﬁcation

du

risque

rythmique

et

prise

en

charge

du

syndrome

de

Brugada

Jean-Baptiste

Gourraud

a,∗

,

Julien

Barc

b

,

Aurélie

Thollet

a

,

Hervé

Le

Marec

a

,

Vincent

Probst

a

a_l’Institut_du_Thorax,_INSERM,_CNRS,_UNIV_Nantes,_CHU_Nantes,_Nantes,_France b_l’Institut_du_Thorax,_INSERM,_CNRS,_UNIV_Nantes,_Nantes,_France

Received25July2016;receivedinrevisedform13September2016;accepted15September 2016

Availableonline27January2017 KEYWORDS Brugadasyndrome; Prognosis; Diagnosis; Suddencardiac death; Riskstratiﬁcation

Summary Brugadasyndromeisarareinheritedarrhythmiasyndromeleadingtoanincreased riskofsuddencardiacdeath,despiteastructurallynormalheart.Diagnosisisbasedonaspecific electrocardiogrampattern,observedeitherspontaneouslyorduringasodiumchannelblocker test.Amongaffectedpatients,riskstratificationremainsachallenge,despiterecentinsights fromlarge populationcohorts. Asimplantable cardiacdefibrillators — the main therapyin Brugadasyndrome—areassociatedwithahighrateofcomplicationsinthispopulation,the mainchallengeisrisk stratificationofpatients withBrugadasyndrome. Asidefromthetwo mainpredictorsofarrhythmia(symptomsandspontaneouselectrocardiogrampattern),many riskfactorshavebeenrecentlysuggestedforstratifyingriskofsuddencardiacdeathinBrugada syndrome.Wehavereviewedthesedataanddiscusscurrentguidelinesinlightofrecentprogress inthiscomplexfield.

MOTSCLÉS Syndromede Brugada;

Résumé LesyndromedeBrugadaestunearythmiecardiaquehéréditairerare,responsable demortsubite.Enl’absencedecardiopathiestructurelle,lediagnosticreposesurl’ECGau repos oulors d’un test de provocation pharmacologique. Comme le seultraitement ayant

Abbreviations: BrS,Brugadasyndrome;ECG,electrocardiogram;EPS,electrophysiologicalstudy;ICD,implantablecardiacdeﬁbrillator;

SCD,suddencardiacdeath;VF,ventricularﬁbrillation.

∗_{Corresponding}_author_at:_CHU_Nantes_HGRL,_Boulevard_J_Monod,₄₄₀₉₃_Nantes,_France.

E-mailaddress:jeanbaptiste.gourraud@chu-nantes.fr(J.-B.Gourraud).

http://dx.doi.org/10.1016/j.acvd.2016.09.009

(3)

Brugadasyndrome:Diagnosis,riskstratiﬁcationandmanagement 189 Pronostic; Diagnostic; Mortsubite; Stratiﬁcationdu risque

démontrésontefficacitéestl’implantationd’undéfibrillateur,maisqu’ils’accompagned’un risqueélevédecomplicationdanscettepopulation,l’évaluationdurisquerythmiqueest essen-tielleàlapriseenchargedecespatients.UnaspectECGspontanédesyndromedeBrugada etla présencede symptômesrestentleséléments lesplusimportantsdansla stratification durisquemaisdenombreuxautresparamètresontétérécemmentproposéspourstratifierle risquedemortsubite.Nousdiscuteronsl’analysedel’ensembledecesdonnéesauregarddes dernièresrecommandationsdepriseencharge.

Background

Brugadasyndrome(BrS)isarareinheritedarrhythmia dis-easepredisposingtoventricularﬁbrillation(VF)andsudden cardiacdeath(SCD),withoutidentiﬁablestructural abnor-malities[1].BrSmainlyaffectsmiddle-agedpatients(aged

45 years at diagnosis), withan eightfold higher diagnosis

prevalence in men,despite an autosomalmode of

inheri-tance[2,3].

Diagnosisisbasedsolelyonaspeciﬁcbutlabilepattern

onanelectrocardiogram(ECG),deﬁnedasa≥0.2mV

coved-type ST-segment elevation in the right precordial leads.

However,theECGcanbesilent,requiringsodiumblockersto

unmaskthepathology.IdentiﬁcationofBrSpatientsis

cru-cialtoavoidsuddencardiacdeath(SCD),whichisoftenthe

ﬁrstsymptom[2].Amongthegeneralpopulation,the

preva-lenceofBrS appearstobeverylow,affecting 5in10,000

people[4],anditsrealimpactonSCDisuncertain. Inthe

absenceofprovenefﬁcientdrugtherapy,implantable

car-diacdeﬁbrillators (ICD)—themain therapyin BrS—have

beensuggestedforprimarypreventioninmanyBrSpatients.

However, the risk of SCD among asymptomatic patients

remainsrelativelylow(0.5—1.5%peryear)andtherateof

ICD-relatedcomplications is high in thisyoung population

[2,5]. Consequently,the main challenge for the physician

is the identiﬁcation ofpatients at risk of arrhythmia who

requirespeciﬁctreatment.

Thisreviewwillfocusonclinicalaspectsofthediagnosis

ofBrS,riskstratiﬁcationandimpactonmanagement.

Clinical

presentation

and

diagnosis

One-thirdofBrSpatientsareidentiﬁedaftersymptoms (syn-cope or aborted SCD), most of which occur at rest with vagal symptoms or during the night [2]. Syncope can be

caused by either non-sustained VFor a vasovagalepisode

withoutarelevantcharacteristictodistinguisharrhythmic

fromnon-arrhythmicaetiology[6].Fever,alcoholintakeand

medicationscanincreasearrhythmiaoccurrence;these

trig-gerscanunmaskaBrSECGpatterninasymptomaticpatients

[7,8].Theincreasedprevalenceof atrialﬁbrillationinBrS

canalsosuggestaneed forBrSscreeningtothephysician,

particularlyforyoungmen[9].

Figure 1. Electrocardiogram (ECG) patterns of Brugada

syn-drome.ModiﬁedfromRef.[27].ECGpatternsarerepresentedfrom

leftto right inright precordialleads.Only a type1 ECGallows

diagnosisofBrugadasyndrome.

Two-thirdsofBrSpatientsareasymptomaticatdiagnosis

[2,10].Ofthese,morethanone-thirdareidentiﬁedduring

familialscreening[2].Sincethe lastguidelineswere

pub-lished,symptomsarenotrequiredfordiagnosisthatisbased

onaspeciﬁcECGpattern[1].ThisECGpattern,previously

knownasatype1ECG,consistsofacovedST-segment

ele-vationinoneright precordialleadof>0.2mV,endingwith

anegativeTwave(Fig.1).OtherECGpatternsarenot

suf-ﬁcientforthediagnosis[11],butcansuggesttheneedfor

asodiumchannelblockertesttothephysician,whichcan

unmaskatype1pattern.Ajmaline(1mg/kgover5—10min),

ﬂecainide(2mg/kg over 10min) andprocainamidecanbe

used[1,12].Therespectivesensitivitiesandspeciﬁcitiesof

thesedrugshavebeenevaluatedwithageneticgold

stan-dard,butremainamatterofdebatebecauseofthegenetic

heterogeneityof thesyndrome[13,14]. Fornow, itseems

thatﬂecainide and procainamide have a lowersensitivity

thanajmaline[11,15].Besides ventricular arrhythmiaand

theappearanceofatype1ECGpattern,thesodium

chan-nel blocker test is usually stopped if the QRS widens to

130% of the baseline. However, some data argue against

thiscriterion,which does notseem tobeassociated with

theoccurrenceofcomplications[16].Evenifinitial

experi-encesreportedarelativelyhighrateofcomplicationsduring

thistest,morerecentexperienceshavedemonstratedthat,

(4)

Table1 VariablesidentiﬁedasbeingassociatedwithsuddencardiacdeathinBrugadasyndrome.

Variables Deﬁnition EffectonSCD Mainpublications

AbortedSCD — Increasedriska _[2,5,10]

Syncope Causebyarrhythmia Increasedriska _[2,5,10]

SpontaneousECGpattern Type1ECG Increasedrisk [2,5,10]

Oldage Aged>60years Decreasedrisk,but

needstobeconﬁrmedb

[37]

Sex Femalesex Decreasesriskb _[32,37]

EPS VFoccurrence Increasedrisk,with

conﬂictingdata,

particularlywiththree

extrastimulib

[2,10,52]

Sinusdysfunction Infemales Increasedrisk,but

[33]

SwaveinD1 Swave>0.1mV

and/or>40ms

Increasedrisk,but

[38]

QRSfragmentation Atleastfourspikesinoneor

atleasteightspikesinallof

theprecordialleads

Increasedrisk,but

[10,40]

Inferiortype1 Type1ECGininferioror

lateralleads

Increasedrisk,but

[47]

Tpeak—Tendinterval MaximumTpeak—Tend

interval>100msinprecordial

lead

Increasedrisk,but

[48]

Earlyrepolarization Jwave>0.1mVintwo

inferolateralleads

Increasedrisk,with

conﬂictingdatab

[39,45]

Post-exerciseST-segmentelevation ≥0.05mVinV1—V3post

exercise

Increasedrisk,but

[56]

Type1ECGburden 24-hHoltermonitoring Increasedrisk,but

[31]

Youngage Aged<18years Conﬂictingdatac _[34,36]

FamilyhistoryofSCD SCDinﬁrst-degreerelatives Conﬂictingdatac _[2,10,39]

Genetic SCN5Amutations Conﬂictingdatac _[2,10,34]

Atrialﬁbrillation — Conﬂictingdatac _[2,9,10,38]

PRduration PR>200ms Conﬂictingdatac _[41,44]

QRSduration QRS>120ms Conﬂictingdatac _[41,44]

Latepotentials Twoofthreepositivecriteria Conﬂictingdatac _[42,44]

aVrsign Rwave≥0.3mVor

R/q≥0.75inaVr

Conﬂictingdatac _[2,10,43]

ECG:electrocardiogram;EPS:electrophysiologicalstudy;SCD:suddencardiacdeath;VF:ventricularﬁbrillation.

a—c_An_indication_of_the_strength_of_data_associating_the_variable_with_SCD_(froma_for_consistent_and_prospective_data_toc_for_conﬂicting

results).

The diagnosis of a type 1 ECG pattern is usually per-formed in V1—V3 leads at baseline or during the sodium channelblocker test. Diagnosis can alsobe performed by elevatingV1—V2leadsinthethirdandthesecondintercostal space,asthisincreasessensitivitywithoutmodifying prog-nosis[18].Basedonasingletertiary-centrestudy,thelatest

consensusreport alsoproposedacceptanceofthe

diagno-sisof BrSeveninpatientswithonlyoneleadshowingthe

typicalaspect[1,19].Manyconditionsanddiseases,

includ-ing myocardial ischaemia, acute pericarditis, pulmonary

embolism,rightventricularcompressionandmetabolic

dis-order(hyper/hypokalaemia, hypercalcaemia), can exhibit

aBrugada-like type 1ECG pattern [1,20].These BrS

phe-nocopiescannot be differentiated from true BrS because

oftheiridenticalECGpatterns,andargueforasystematic

diagnosticapproachtoavoidmisdiagnosis[21].

TruecongenitalBrS has beenshown tofollow an

auto-somal mode of inheritance in families, and mutation

identiﬁcation has been suggested for diagnosis. Over 20

genes have beenassociated withBrS[13], andSCN5A has

themajorityofmutations.However,studieshaveshownthat

somepreviouslyassociatedvariantsareactuallypresentin

thegeneral population,andareprobablynon-causal [22].

Furthermore, except for the SCN5A gene, the other

BrS-associatedgenespresentasmanyrarevariantsincasesas

in controls, suggesting a minorrole for these genes [23].

Interestingly, the concept of a more complexinheritance

hasemergedfromtheobservationofincompletepenetrance

amongmutationcarriers andof phenocopiesamong

fami-lies[3],andhasbeenrecentlyillustratedbythediscovery

of frequent geneticvariants (>10% in the general

(5)

Brugadasyndrome:Diagnosis,riskstratiﬁcationandmanagement 191

[3,13,24,25]. Thus, the indication for SCN5A screening in

clinical diagnosticsmaybe restrictedtotheidentiﬁcation

ofpatientsatriskinafamily[23].

Risk

stratiﬁcation

Once thediagnosis of BrS has been made,the main chal-lengeistostratifytheriskofVF.Numerousvariableshave beensuggested[26,27],butotherthanprevioussymptoms

(syncopeand abortedSCD)and spontaneousECG pattern,

allremainamatterofdebate(Table1).

Main

risk

factors

Symptoms

Patients with a history of SCD have a 10% annual risk of recurrenceduringtheﬁrst4years[2,10].Althoughthis

inci-dence subsequently decreases, it remains signiﬁcant, and

laterecurrencecanbeobserved[5].Thus,ICDimplantation

isindicatedforallcardiacarrestsurvivors[1].

Amongpatientswhoarediagnosedaftersyncope,therisk

of arrhythmia has been consistently considered as

signiﬁ-cant [2,5,6,10].Withabout 1.5%/year withVF,this riskis

fourfoldhigherthaninasymptomaticpatients[2].However,

benignvasovagalsyncopeisalsofrequentlydescribedinBrS

patients[2,6].Althoughproarrhythmiceffectsofvagal

stim-ulationhavebeendescribed,onlysyncopeprobablycaused

bynon-sustained VFhasbeenconsistentlyassociatedwith

SCD,increasingtheriskto5%/year[6,28].Thus,incaseof

syncopeofarrhythmicorigin,thereisnodoubtthatanICD

isneeded.

However,theabilitytodifferentiatearrhythmicsyncope

fromneutrallymediatedsyncoperemainsarealchallenge.

A detailed clinical history, speciﬁc triggers (pain, seeing

blood, micturition) and prodromes (palpitations, nausea,

visualdisturbance)mayhelptodistinguisharrhythmicfrom

non-arrhythmicsyncope.Unfortunately,noneofthese

varia-blesissufﬁcienttoprovideaccurateprognosticinformation

[28].Given therelatively highrate ofcomplications after

ICDimplantation,thelatestguidelineshaverestrictedthis

implantation to‘‘patients with a spontaneoustype IECG

andhistory ofsyncope judged tobe likelycaused’’by VF

[1]. Although association witha spontaneous type 1 ECG

increasesthe risk of SCD, alarge number of patients are

diagnosedafterthesodiumchannelblockertestorwithan

uncertainclinicalhistory,andthusremaininthegreyzone

forICDimplantation[2].

Spontaneous

ECG

pattern

Identiﬁcation of a spontaneouspattern of BrS on an ECG hasbeen consistentlyassociatedwithan increasedriskof SCD [2,10,29], ranging from 0.81%/year in asymptomatic

patientsto2.3%/yearinsymptomaticpatients[2].Although

therisk of appropriateICDtherapy for thosewith

asymp-tomatic BrS patients is low, it is cumulative over time,

reaching12% at10 years[5]. Regardingthe extreme

con-sequenceswithoutICDimplantation,ithasbeensuggested

that a multifactorial approach could help to stratify the

riskofSCD[5,29].However,becauseofthelimitedsizeof

populationandfollow-up,identiﬁcationofpatientswiththe

highestriskremainsachallenge.

Aspontaneoustype1ECGpatternisvariableovertime,

withmarkedday-to-dayvariabilityintheJwaveelevation

[30].Thus,long-termevaluationofthetype1ECGburden

usingHolterrecordingappears tobeanattractive toolto

stratifythe risk of arrhythmia [31]. Unfortunately,so far,

essentiallybecauseof the lack of efﬁcienttools toeasily

assesstheSTsegmentoveralongperiod,thereisnoclear

demonstrationofthevalueofthisvariable.

Clinical

factors

Sex

AstransmissionofBrSisobservedwithanautosomalmode ofinheritance,theprevalenceofBrSisexpectedtobe sim-ilaramongmenandwomen.However,BrSclearlyhasahigh predominanceinmen,andathreefoldincreaseintherisk ofatype1ECGpatternand/orcardiacevent[32,33].

How-ever,malepredominanceisalsoobservedinasymptomatic

patients,whichleads toanon-signiﬁcant association with

SCD[2,32].

AsmostriskfactorsforSCDwereassessedinpopulations

involvingalargepredominanceofmen,theyappeartobe

lessaccuratefor women.Identiﬁcation of conduction

dis-turbanceandsinusdysfunctioninwomencouldbeabetter

markerofriskthanaspontaneoustype1ECGandsymptoms

[32,33].

Age

SCDduetoBrSisrareinchildren.However,theriskcanbe signiﬁcant,particularlyinchildrenwithprevioussymptoms anda spontaneousECG pattern[34]. A drug-induced

pat-ternhasagoodprognosis,butperformingasodiumchannel

blockertestinchildrenisquestionablebecauseoffrequent

complicationsandfalsenegatives[35,36].

Limiteddataareavailableinolderpatients.However,the

riskofarrhythmiaappearstodecreasesigniﬁcantlyafterthe

ageof60years[37].

Family

history

and

genetics

Given the genetic background of BrS, a family history of SCDandSCN5Amutationsweresuggestedtostratifyriskof arrhythmia[34,38,39].However,largemultivariable

analy-sesdidnotconﬁrmthisassociationfurther[2,10].Age,the

numberofSCDsandthedegreeoftherelationshipmay

mod-ifytheeffectoffamilyhistoryonindividualrisk[34,38,39].

Atrial

arrhythmia

AtrialﬁbrillationismorecommoninBrS,andcanbeginearly, evenin childhood [9,34]; it has been suggested, in

case-control studies, to be associated withprognosis, but the

relationship hasnot been demonstrated in a large cohort

[2,9,10,38].

ECG

variables

ManyECGvariableshavebeenassociatedwiththeprognosis ofBrSpatients,butwithconﬂictingreportsorwithout repli-cationinanindependentcohort[26,27](Fig.2,Table1).

(6)

Figure 2. The main electrocardiogram (ECG) variables associated with prognosis in Brugada syndrome. The ECGs (25mm/s with

0.1mV/mm) illustrate:A:anSwaveinD1;B:atype1ECGpatterninD2;C:aVrsign; D:aprolonged Tpeak—Tendinterval inV1—V3

leads;E:earlyrepolarizationinD2andD3;andF:fragmentedQRSinV1—V3leads.

Conduction

disturbance

ThepresenceoffragmentedQRScomplexeshasbeen con-sistentlyassociated witha twofoldtoninefoldincreasein arrhythmiaoccurrence[10,40].Ofnote,criteriadeﬁnition

andECGrecordingﬁltersettingsvariedamongstudies,

limit-ingthescopeofriskstratiﬁcation,andexplainingitsabsence

fromthelatestguidelines.

Conductiondelayhasalsobeenhighlighted,intermsof

QRSduration[41],latepotential[42]andtheaVrsign[43].

However,thesevariableswerenotconﬁrmedinsubsequent

studies[2,10,44].

Caló et al. found that a wide or large S wave in lead

I was a predictor of VF in a multivariable analysis of

asymptomaticpatientswithaspontaneousBrSpattern[38].

Additionally,these authorsprovidedan interesting ﬁnding

regarding pathophysiology, as this S wave wasassociated

with a conduction delay in the right ventricular outﬂow

tract.

Repolarization

variables

InBrS,somestudiesidentiﬁedamoresevereprognosisinthe presenceofanearlyrepolarizationpattern[39,45],whereas

others did not ﬁnd any relationship between early

repo-larizationandtherisk ofarrhythmia [46].The riskofSCD

appearstoincreasewhenearlyrepolarizationislocatedin

aninferiorleadwithahorizontalSTsegment[39].

Atype1ECGpatterninperipheralleadswasadditionally

describedinabout10%ofpatients,andwasassociatedwith

anincreasedriskofSCD[47].

Finally, a Tpeak—Tend interval >200ms, deﬁning high

transmuraldispersionofrepolarization,hasbeenassociated

withincreasedoccurrenceofVF[48];however,thiswasnot

conﬁrmedinadditionalstudies[49].

Electrophysiological

study

From clinical variables, the incremental prognostic value of an electrophysiological study (EPS) is highly controver-sial. Whereas some authors have proposed an association betweeninducedVFandcardiacevents,largeprospective studieshavedemonstratedthatanEPSdoesnotstratifythe riskofarrhythmia[2,10,50,51].The latestguidelineshave

restrictedtheuseofanEPStoaclassIIbforICDimplantation

[1].

Althoughmostcase-controlstudiesidentifyahighevent

rateafterapositive EPS,themainquestion iswhetherto

integratethisexaminationintotheriskstratiﬁcationofBrS.

Sroubek et al. recently reportedin a large meta-analysis

thattheinductionofventriculararrhythmiawasassociated

with a twofold to threefold increased risk of VF (hazard

ratio2.55;P=0.005)[52].However,theincrementalvalue

of an EPS appears to be small in patients with a high or

low risk of arrhythmia, as deﬁned by clinical variables.

Considering intermediate-riskpatients, theadditional risk

ofapositiveEPSdoesnotexceeda1%/yearVFincidence.

Considering the limitations in EPS reproducibility [10],

and the fact that a negative EPS cannot exclude further

(7)

Figure3. Indicationforimplantationofanimplantablecardioverterdeﬁbrillator(ICD),accordingtotheriskofsuddencardiacdeath

(SCD).ModiﬁedfromRefs.[1,2].TheriskofSCDisrepresentedwitharedarrow.TheredboxesrepresentsanindicationforICDimplantation;

thegreenboxrepresentsapatientwhoshouldnotbeimplanted,accordingtothelatestguidelines;theorangeboxesarenotaddressedin

theguidelines.ECG:electrocardiogram.

appearstobe controversial,and itcannot beusedasthe onlyvariabletodeﬁnethemanagementofthepatient.

Management

of

BrS

Eachpatientshouldﬁrstbereferredtoaspecializedcentre forinheritedarrhythmia.InFrance,theCardiogennetwork involvesthreereferencecentresand22competencecentres specializedinthemanagementofinheritedarrhythmia.

Forallpatients,theﬁrststepofmanagementisfocused oncounsellingindailylife:thisincludesavoidingexcessive alcohol intake,treating fever aggressively anddecreasing exerciseactivityprogressively.Alistoftreatmentsthatcan increase the arrhythmia risk is given to the patient (the updated list is available on brugadadrugs.org). A familial screeningshouldalwaysbeperformedtoachieveearly iden-tiﬁcationofaffectedrelativeswhocouldbeatriskofSCD

[1].

Afterthisﬁrststep,whichappliestoallpatients,the

dis-cussionstartsaboutwhichtherapeuticapproachtopropose

(Fig.3).Untilnow,theonlyprovenefﬁcienttherapyisICD

implantation,but other possibilitieswill certainlyemerge

inthe nextfewyears,suchascatheterablation, whichis

restrictedtopatientswithfrequentarrhythmiarecurrences.

Asymptomaticpatientswithadrug-inducedECGpattern

present with a very low risk of arrhythmia that does not

indicateICDimplantation.Bycomparison,thereisnodoubt

abouttheindicationinsymptomaticpatientswitha

sponta-neousECGpattern.

ThemainquestionremainingrelatestoICDimplantation

inpatientswithintermediaterisk.AspontaneousECG

pat-ternin an asymptomaticpatientdeﬁnesacumulativerisk

ofVFreaching12%at10years[5].Thisriskappearshigher

thaninsymptomaticpatients withvasovagalsyncope,and

argues for an early discussion with the patient about an

ICDimplantation[28].Inthesecases,individualassessment

ofassociatedriskfactorsshouldbeperformedtoincrease

stratiﬁcationaccuracy.However,physicianshaveto

recog-nizethat,fornow,evenifwehavearelativelyclearpicture

oftheriskatapopulationlevel,wearestillunableto

prop-erlystratifypatientriskatanindividuallevel.Thus,inour

view,it is essential toprovide the patientwith complete

informationaboutthelimitsofourknowledge.More

impor-tantly, the patient has to be involved with the decision,

asthe therapeutic choice will have a great psychological

impact,regardlessoftheﬁnaldecision.

Observational studies have suggested that quinidine

should have a beneﬁcial effect on arrhythmia; however,

becauseoflimiteddata,itcannotbeencouragedinprimary

prevention[53,54].Highratesofhydroquinidinesideeffects

andlownumbersofarrhythmiceventsmaypreventfurther

evidencebeingobtained,eveninhigh-riskpatients[55].The

useofquinidinemaybediscussedonacase-by-casebasisin

highlyspecializedcentres.

Conclusions

and

perspectives

Oncethe diagnosis ismade, riskstratification, and there-fore management, is often complex in BrS. Although a spontaneousECG patternandsymptomsarethetwomain predictorsofSCD,manyvariableshavebeensuggested,and theserequirefurtherevaluationinlargepopulations. Iden-tificationofintermediate-riskpatientsunderliestheneedto increasetheaccuracyofsuchstratificationandtoimprove therapywhereprevalenceofcomplicationsisastrong lim-itingfactor.Acombination ofriskfactorsin anintegrated clinicaland geneticscorecouldbe thenextsteptowards suchpersonalizedmedicine.

Thedevelopmentofnewdeﬁbrillationtechnology,such as a subcutaneous ICD, could facilitate the decision, by reducingtherateofcomplicationsarisingfromICD implan-tation, and by making it possible to remove the system

(8)

easily in case of complication. Finally, catheter ablation, whichiscurrentlyrestrictedtohighlysymptomaticpatients, should be another means of decreasing the arrhythmic risk. Although promising, this technique still needs long-termstudies beforeindications caninclude asymptomatic patients.

Sources

of

funding

None.

Disclosure

of

interest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

[1]PrioriSG,WildeAA,HorieM,etal.HRS/EHRA/APHRSexpert consensus statement on the diagnosis and management of patientswithinherited primary arrhythmiasyndromes: doc-ument endorsedbyHRS,EHRA,andAPHRS inMay2013and byACCF,AHA,PACES,andAEPCinJune2013.HeartRhythm 2013;10:1932—63.

[2]Probst V, Veltmann C, Eckardt L, et al. Long-term prog-nosis of patientsdiagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry. Circulation 2010;121:635—43.

[3]Probst V,WildeAA, BarcJ,et al.SCN5Amutations andthe roleofgeneticbackgroundinthepathophysiologyofBrugada syndrome.CircCardiovascGenet2009;2:552—7.

[4]GallagherMM,ForleoGB,BehrER,etal.Prevalenceand sig-niﬁcance ofBrugada-type ECGin12,012apparentlyhealthy Europeansubjects.IntJCardiol2008;130:44—8.

[5]SacherF,ProbstV,MauryP,etal.Outcomeafterimplantationof acardioverter-deﬁbrillatorinpatientswithBrugadasyndrome: amulticenterstudy—Part2.Circulation2013;128:1739—47.

[6]SacherF,ArsacF,WiltonSB,etal.SyncopeinBrugada syn-drome patients: prevalence, characteristics, and outcome. HeartRhythm2012;9:1272—9.

[7]Mizusawa Y, Morita H, Adler A, et al. Prognostic signif-icance of fever-induced Brugada syndrome. Heart Rhythm 2016;13:1515—20.

[8]Ohkubo K, Nakai T, Watanabe I. Alcohol-induced ventric-ular ﬁbrillation in a case of Brugada syndrome. Europace 2013;15:1058.

[9]KusanoKF,TaniyamaM,NakamuraK,etal.Atrialﬁbrillationin patientswithBrugadasyndrome relationshipsofgene muta-tion, electrophysiology, andclinicalbackgrounds. JAm Coll Cardiol2008;51:1169—75.

[10]PrioriSG,GaspariniM,NapolitanoC,etal.Riskstratiﬁcationin Brugadasyndrome:resultsofthePRELUDE(PRogrammed ELec-tricalstimUlationpreDictivevaluE)registry.JAmCollCardiol 2012;59:37—45.

[11]WildeAA,AntzelevitchC,BorggrefeM,etal.Proposed diag-nostic criteriafor theBrugadasyndrome: consensusreport. Circulation2002;106:2514—9.

[12]Arnalsteen-DassonvalleE,HermidaJS,KubalaM,etal. Ajma-linechallengefor thediagnosis ofBrugadasyndrome:which protocol?ArchCardiovascDis2010;103:570—8.

[13]GourraudJB,BarcJ,TholletA,etal.TheBrugadaSyndrome: ARareArrhythmiaDisorderwithComplexInheritance. Front CardiovascMed2016;3:9.

[14]Nattel S. Are all sodium channel blockers created equal? Clinical-basic correlationsbased onobservations in Brugada syndrome.HeartRhythm2005;2:261—2.

[15]WolpertC,EchternachC,VeltmannC,etal.Intravenousdrug challengeusingﬂecainideandajmalineinpatientswith Bru-gadasyndrome.HeartRhythm2005;2:254—60.

[16]Batchvarov VN, Govindan M, Camm AJ, Behr ER. Signiﬁ-cance of QRS prolongation during diagnostic ajmaline test inpatientswithsuspectedBrugadasyndrome.HeartRhythm 2009;6:625—31.

[17]VeltmannC,WolpertC,SacherF,etal.Responsetointravenous ajmaline:aretrospectiveanalysisof677ajmalinechallenges. Europace2009;11:1345—52.

[18]MiyamotoK,YokokawaM,TanakaK,etal.Diagnosticand prog-nosticvalueofatype1Brugadaelectrocardiogramathigher (thirdorsecond)V1toV2recordinginmenwithBrugada syn-drome.AmJCardiol2007;99:53—7.

[19]SarkozyA,SorgenteA,BoussyT,etal.Thevalueofafamily his-toryofsuddendeathinpatientswithdiagnostictypeIBrugada ECGpattern.EurHeartJ2011;32:2153—60.

[20]ShimizuW.AcquiredformsoftheBrugadasyndrome.J Elec-trocardiol2005;38:22—5.

[21]Gottschalk BH, Anselm DD, Brugada J, et al. Expert car-diologists cannot distinguish between Brugada phenocopy andBrugadasyndromeelectrocardiogrampatterns.Europace 2016;18:1095—100.

[22]BehrER,Savio-GalimbertiE,BarcJ,etal.Roleofcommonand rarevariantsinSCN10A:resultsfromtheBrugadasyndrome QRSlocusgenediscoverycollaborativestudy.CardiovascRes 2015;106:520—9.

[23]LeScouarnecS,Karakachoff M,Gourraud JB,et al.Testing theburdenofrarevariationinarrhythmia-susceptibilitygenes providesnewinsightsintomoleculardiagnosisforBrugada syn-drome.HumMolGenet2015;24:2757—63.

[24]BezzinaCR, BarcJ, Mizusawa Y,et al. Common variantsat SCN5A-SCN10A and HEY2 are associated with Brugada syn-drome,ararediseasewithhighriskofsuddencardiacdeath. NatGenet2013;45:1044—9.

[25]HermidaJS,Arnalsteen-DassonvalleE,KubalaM,etal.Dual phenotypictransmissioninBrugadasyndrome.ArchCardiovasc Dis2013;106:366—72.

[26]AdlerA,RossoR,ChorinE,HavakukO,AntzelevitchC,Viskin S.RiskstratiﬁcationinBrugadasyndrome:Clinical character-istics,electrocardiographicparameters,andauxiliarytesting. HeartRhythm2016;13:299—310.

[27]ProbstV,ChatelS,GourraudJB,MarecHL.Riskstratiﬁcation andtherapeuticapproachinBrugadasyndrome.Arrhythm Elec-trophysiolRev2012;1:17—21.

[28]OldeNordkampLR,VinkAS,WildeAA,etal.SyncopeinBrugada syndrome: prevalence, clinical signiﬁcance,and clues from history takingto distinguish arrhythmicfrom nonarrhythmic causes.HeartRhythm2015;12:367—75.

[29]Delise P, Allocca G, Marras E, et al. Risk stratiﬁcation in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clini-cal and electrophysiologic approach. Eur Heart J 2011;32: 169—76.

[30]Richter S, Sarkozy A, Veltmann C, et al. Variability of the diagnostic ECG pattern in an ICD patient population withBrugadasyndrome.JCardiovascElectrophysiol2009;20: 69—75.

[31]ExtramianaF,Maison-BlancheP,BadiliniF,MessaliA,DenjoyI, LeenhardtA.Type1electrocardiographicburdenisincreased insymptomaticpatientswithBrugadasyndrome.J Electrocar-diol2010;43:408—14.

[32]BenitoB,SarkozyA,MontL,etal.Genderdifferencesin clin-icalmanifestations ofBrugada syndrome.JAm CollCardiol 2008;52:1567—73.

(9)

[33] SieiraJ,ConteG,CiconteG,etal.Clinicalcharacterisationand long-termprognosisofwomenwithBrugadasyndrome.Heart 2016;102:452—8.

[34] AndorinA, Behr ER,Denjoy I,et al. Impactof clinicaland geneticﬁndingsonthemanagement ofyoung patientswith Brugadasyndrome.HeartRhythm2016;13:1274—82.

[35] Conte G, de Asmundis C,CiconteG, et al. Follow-upfrom childhood to adulthood of individuals with family history ofBrugada syndrome and normal electrocardiograms.JAMA 2014;312:2039—41.

[36] Conte G, Dewals W, Sieira J, et al. Drug-induced Bru-gada syndrome in children: clinical features, device-based management, and long-term follow-up. J Am Coll Cardiol 2014;63:2272—9.

[37] Conte G, DEA C, Sieira J, et al. Clinical characteristics, management,andprognosisofelderlypatientswithBrugada syndrome.JCardiovascElectrophysiol2014;25:514—9.

[38] CaloL, Giustetto C,Martino A, et al. Anew electrocardio-graphic marker of suddendeath in brugada syndrome: the S-waveinleadI.JAmCollCardiol2016;67:1427—40.

[39] KamakuraS,OheT,NakazawaK,etal.Long-termprognosisof probandswithBrugada-patternST-elevationinleadsV1—V3. CircArrhythmElectrophysiol2009;2:495—503.

[40] MoritaH, Kusano KF, Miura D, et al. Fragmented QRS as a markerofconductionabnormalityandapredictorofprognosis ofBrugadasyndrome.Circulation2008;118:1697—704.

[41] TokiokaK, KusanoKF, Morita H, et al. Electrocardiographic parameters and fatal arrhythmic events in patients with Brugadasyndrome:combination ofdepolarizationand repo-larizationabnormalities.JAmCollCardiol2014;63:2131—8.

[42] TakagiA,NakazawaK,SakuraiT,NankeT,MiyakeF. Prolonga-tionofLAS40(durationofthelowamplitudeelectricpotential component(<40microV)oftheterminalportionoftheQRS) inducedbyisoproterenolin11patientswithBrugadasyndrome. CircJ2002;66:1101—4.

[43] BabaiBigiMA,AslaniA,ShahrzadS.aVRsignasariskfactor forlife-threateningarrhythmiceventsinpatientswithBrugada syndrome.HeartRhythm2007;4:1009—12.

[44] MauryP,RollinA, SacherF,et al.Prevalenceandprognostic roleofvariousconductiondisturbancesinpatientswiththe Brugadasyndrome.AmJCardiol2013;112:1384—9.

[45] Sarkozy A, Chierchia GB, Paparella G, et al. Inferior and lateral electrocardiographic repolarization abnormalities in

Brugada syndrome. Circ Arrhythm Electrophysiol 2009;2: 154—61.

[46]LetsasKP,SacherF,ProbstV,etal.Prevalenceofearly repolar-izationpatternininferolateralleadsinpatientswithBrugada syndrome.HeartRhythm2008;5:1685—9.

[47]RollinA,SacherF,GourraudJB,etal.Prevalence, characteris-tics,andprognosisroleoftype1STelevationintheperipheral ECGleadsinpatientswithBrugadasyndrome.HeartRhythm 2013;10:1012—8.

[48]MauryP,SacherF,GourraudJB,etal.IncreasedTpeak-Tend interval is highly and independently related to arrhyth-mic events in Brugada syndrome. Heart Rhythm 2015;12: 2469—76.

[49]JunttilaMJ,BrugadaP,HongK,etal.Differencesin12-lead electrocardiogram between symptomatic and asymptomatic Brugada syndrome patients. J Cardiovasc Electrophysiol 2008;19:380—3.

[50]BrugadaP,BrugadaR,MontL,RiveroM,GeelenP,BrugadaJ. NaturalhistoryofBrugadasyndrome:theprognosticvalueof programmedelectricalstimulationoftheheart.JCardiovasc Electrophysiol2003;14:455—7.

[51]FauchierL,IsorniMA,ClementyN,PierreB,SimeonE,Babuty D. Prognostic value of programmed ventricular stimulation in Brugada syndrome accordingto clinicalpresentation: an updatedmeta-analysisofworldwidepublisheddata.IntJ Car-diol2013;168:3027—9.

[52]SroubekJ,ProbstV,MazzantiA,etal.Programmedventricular stimulationforriskstratiﬁcationintheBrugadasyndrome:a pooledanalysis.Circulation2016;133:622—30.

[53]BouzemanA,TraulleS,MessaliA,etal.Long-termfollow-up of asymptomatic Brugada patients with inducible ventric-ular ﬁbrillation under hydroquinidine. Europace 2014;16: 572—7.

[54]ProbstV,GourraudJB.QuinidineinBrugadasyndrome:stilla longwaytogo.CircArrhythmElectrophysiol2015;8:1309—10.

[55]AndorinA,FouchardS,LeMarecH,etal.QUIDAMStudy: assess-mentofhydroquinidinetherapyinthemanagementofBrugada syndromepatientsathigharrhythmicriskandimplantedwith anICD.ACVDSuppl2016;8:225—6[abstract0332].

[56]Makimoto H, Nakagawa E, Takaki H, et al. Augmented ST-segment elevation during recovery from exercise predicts cardiaceventsinpatientswithBrugadasyndrome.JAmColl Cardiol2010;56:1576—84.