J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8

ª 2 0 1 8 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

Risk Stratification in ArrhythmogenicRight Ventricular Cardiomyopathy/Dysplasia Without an ImplantableCardioverter-Defibrillator

Carole Maupain, MD,a,b Nicolas Badenco, MD,a Françoise Pousset, MD,a,b Xavier Waintraub, MD,a

Guillaume Duthoit, MD,a Thomas Chastre, MD,a Caroline Himbert, MD,a Jean-Louis Hébert, MD, PHD,a

Robert Frank, MD,a Françoise Hidden-Lucet, MD,a,b Estelle Gandjbakhch, MD, PHDa,b,c

ABSTRACT

ISS

Fro

Pa

Un

çai

to

All

sti

the

Ma

OBJECTIVES The purpose of this study was to identify clinical factors associated with arrhythmic events and sudden

cardiac death (SCD), and to evaluate the prognostic value of electrophysiological study (EPS) in arrhythmogenic right

ventricular cardiomyopathy/dysplasia (ARVC/D) patients without implantable cardioverter-defibrillators (ICDs).

BACKGROUND ARVC/D is an inherited cardiomyopathy characterized by a risk of SCD. Few studies have evaluated

predictive factors of ventricular arrhythmias (VAs) in patients without ICDs.

METHODS Between 2000 and 2010, all consecutive patients with ARVC/D without ICDs and with EPS at diagnosis were

enrolled. Patients that received an ICD during follow-up were censored at the date of implantation, and in that case, only

VAs that occurred before ICD implantation were analyzed. Risk factors for any VA event were determined by Cox

regression. Patients that only experienced SCD or aborted cardiac arrest (ACA) were reported.

RESULTS A total of 137 consecutive patients (78% male) diagnosed with ARVC/D without ICD were enrolled. 31% had

sustained ventricular tachycardia at diagnosis. After mean follow-up of 42 � 31 months, 19 patients experienced an

episode of sustained VA and 5 patients experienced a SCD/ACA. No event occurred in asymptomatic patients. Left

ventricular ejection fraction #50% (p ¼ 0.024), positive EPS (p ¼ 0.017), and physical activity >6 h/week (p ¼ 0.025)

were independently associated with occurrence of VAs. SCD/ACA exclusively occurred in male probands with definite

diagnosis and syncope.

CONCLUSIONS In this cohort of ARVC/D patients without ICD, left ventricular ejection fraction #50%, positive EPS,

and physical activity >6 h/week were independent predictors of VAs, whereas asymptomatic patients at diagnosis were

at low risk. EPS predicted all VAs but had limited value to predict SCD/ACA. (J Am Coll Cardiol EP 2018;4:757–68)

© 2018 by the American College of Cardiology Foundation.

A rrhythmogenic right ventricular cardiomyop-athy/dysplasia (ARVC/D) is an inheritedcardiomyopathy (1,2) associated with a high

occurrence of right ventricular arrhythmias (VAs)

N 2405-500X/$36.00

m the aAP-HP, Groupe Hospitalier Pitié-Salpêtrière, L’institut de Cardiomé

ris, France; bCentre de Référence des Maladies Cardiaques Héréditaires, P

iv Paris 06, Paris, France. This work was supported by grants from the “

se de Cardiologie” and “Ligue contre la Cardiomyopathie.” The authors ha

the contents of this paper to disclose.

authors attest they are in compliance with human studies committees

tutions and Food and Drug Administration guidelines, including patient co

JACC: Clinical Electrophysiology author instructions page.

nuscript received March 7, 2018; revised manuscript received March 19, 2

especially ventricular tachycardia (VT). MonomorphicVT is present at diagnosis in 37% to 82% (3) of index pa-tients. Sudden cardiac death (SCD) or progressive heartfailure is the main cause of death (4). Although SCD

https://doi.org/10.1016/j.jacep.2018.04.017

tabolisme et Nutrition, Département de Cardiologie,

aris, France; and the cSorbonne Universités, UPMC

Fédération Française de Cardiologie”/“Société Fran-

ve reported that they have no relationships relevant

and animal welfare regulations of the authors’ in-

nsent where appropriate. For more information, visit

018, accepted April 26, 2018.

ABBR EV I A T I ON S

AND ACRONYMS

AAR = antiarrhythmic

ACA = aborted cardiac arrest

ARVC/D = arrhythmogenic

right ventricular

cardiomyopathy/dysplasia

EPS = electrophysiological

study

ICD = implantable

cardioverter-defibrillator

LV = left ventricle/ventricular

LVEF = left ventricular ejection

fraction

PVC = premature ventricular

complex

RV = right ventricle/ventricular

RFAC = right ventricular

fractional area change

SCD = sudden cardiac death

VA = ventricular arrhythmia

VF = ventricular fibrillation

VT = ventricular tachycard

Maupain et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8

Arrhythmia Risk Stratification in ARVC/D J U N E 2 0 1 8 : 7 5 7 – 6 8

758

remains a rare event in ARVC/D (<1%/year[4]), it accounts for 14% to 42% (5) of deathsof patients age <35 years. ARVC/D wasthe predominant cause of cardiomyopathy-related SCD in a recent autopsy series (6).Thus, ARVC/D patients are candidates foractive therapeutic management, includingan implantable cardioverter-defibrillator(ICD), which can lead to long-term complica-tions, such as inappropriate shocks or leadfailures (7).

Although risk factors of ventricular ar-rhythmias are well studied in ARVC/D pa-tients implanted with an ICD (8–11), fewstudies (12) evaluate this issue in patientswithout an ICD. (Online Table 1).

The International Task Force ConsensusStatement recently proposed the electro-physiological study (EPS) as a useful tool forarrhythmia risk stratification of asymptom-atic patients (13), but positive EPS is notconsidered as a risk factor leading to ICDimplantation, and its role is still debated.

We determined risk factors associated with allarrhythmic events (primary endpoint) and SCD/aborted cardiac arrest (ACA) (secondary endpoint)and evaluated the EPS contribution to stratifyingarrhythmogenic risk in the real-life setting in a largeARVC/D population without an ICD.

ia

SEE PAGE 769

METHODS

STUDY DESIGN AND POPULATION. We included allconsecutive ARVC/D patients with definite orborderline diagnosis from January 2000 throughDecember 2010 who underwent EPS at diagnosis andwho did not have an ICD implanted. ARVC/D diag-nosis was prospectively made by multidisciplinaryconsensus experts, and final diagnosis according tothe International Task Force Criteria (14) was retro-spectively assessed. According to our institution’spolicy, no authorization approval from our Institu-tional Committee on Human Research was requiredfor this retrospective study.

DATA COLLECTION. Each patient’s detailed historywas obtained by reviewing medical records, clinicalevaluation, and patient interview at admission:clinical information, drugs used, symptoms (seedefinition in the Online Appendix), 12-lead electro-cardiogram, 24-h Holter monitoring, exercise stresstesting, signal-averaged electrocardiogram, priorcatheter ablation, and family history. Morphologicalabnormalities were assessed through echocardiography,

which was performed by a single experienced oper-ator who specialized in ARVC/D echocardiographyimaging (F.P.). Right ventricular fractional areachange (RFAC) was measured in the apical 4-chamberview, and left ventricular ejection fraction (LVEF) wasassessed by the biapical Simpson disk method ac-cording to the guidelines (15).

ELECTROPHYSIOLOGICAL STUDY. All patients un-derwent EPS with a programmed ventricular stimu-lation at ARVC/D diagnosis after written informedconsent. Under local anesthesia, a standard quad-ripolar diagnostic electrode catheter (2-mm electrode,10-mm interelectrode spacing) was inserted byfemoral venous access. Programmed ventricularstimulation (PVS) was performed at 2 sites (rightventricular [RV] apex and RV outflow tract) at twicepacing threshold and a 2-ms duration. At each site,PVS was first performed without isoproterenol at 600-and 400-ms basal cycle length (8 paced S1 beats) andup to 3 extrastimuli with a 10-ms decrement intervalfrom 350 ms until the ventricular refractory period ora minimum 200-ms coupling interval. If no sustainedVT or ventricular fibrillation (VF) was induced asbaseline, PVS was performed under isoproterenol(1 to 4 mg/min) infusion (target heart rhythm of 120beats/min or 50% increase of basal cardiac fre-quency), and PVS was performed at 2 sites (RV apexand RV outflow tract) at a 400-ms basal cycle length(8 S1 beats) with up to 3 extrastimuli with a 10-msdecrement from 350 ms to the ventricular refractoryperiod or a minimum 200-ms coupling interval. Rapidbursts were not used for induction. EPS was consid-ered positive when sustained VT or VF was induced(see definitions in the Online Appendix). If sustainedVT/VF was induced at baseline, isoproterenol infu-sion was not performed. Antiarrhythmic drugs werecontinued for patients who were taking themroutinely.

THERAPEUTIC MANAGEMENT OF PATIENTS AFTER

ARVC/D DIAGNOSIS. Treatment of patients afterARVC/D diagnosis was standardized according to ourlocal protocol. Beta-blockers were advised for allpatients with definite ARVC/D diagnosis. The addi-tion of class I or III antiarrhythmic (AAR) therapieswere advised in case of evidence of ventricular hy-perexcitability (frequent premature ventricular com-plex [PVC], nonsustained VT, or sustained VT).Detailed medications prescribed before diagnosis andat the end of follow-up or the time of the censoredevent are summarized in the Online Appendix. Weadvised VT ablation for VT recurrence despite AARdrug therapy or positive EP study under treatment.ICD implantation in the follow-up was recommended

FIGURE 1 Flow Diagram of the Full Cohort (Including Excluded and Censored Patients)

ARVC/D diagnosis2000-2010

n=160- No EPS n=10- « Possible » ARVC/D diagnosis n=2

Patients without ICD atdiagnosis included in the

studyn= 137

ICD at diagnosis n=11Causes for ICD Implantation- Well tolerated VT n=3- Aborted SCD n=3- Syncopal VT n=3- Unexplained syncope n=1- Severe biventricular failure n=1

Primary end-point n= 19- Sustained VT n=14- ACA/SCD n=5 (1 ACA and 4 SCD)

ICD during FU (censored) n=9Causes for ICD implantation during FU (see

supplementary table 6)

- ICD therapy for VT>240 CL n=3- ICD therapy for VT<240 CL / VF n=3

VT ablation n=3

excluded

excluded

VT ablation n=25

ICD implantation

n=8

VT ablation n=13

Hearttransplantation

n=2

Deathn= 2

- ICD therapy for VT>240 CL n=2 - ICD therapy for VT<240 CL / VF n=2

Deathn=1

(electrical stormdespite ECMO)

Hearttransplantation

n=1 (still alive)

Deathn=0

VT ablation

n=2

ACA ¼ aborted cardiac arrest; ARVC/D ¼ arrhythmogenic right ventricular cardiomyopathy/dysplasia; CL ¼ cycle length; ECMO ¼ extracor-

poreal membrane oxygenation; EPS ¼ electrophysiological study; FU ¼ follow-up; ICD ¼ implantable cardioverter-defibrillator; SCD ¼ sudden

cardiac death; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8 Maupain et al.J U N E 2 0 1 8 : 7 5 7 – 6 8 Arrhythmia Risk Stratification in ARVC/D

759

for nontolerated VTs, syncope, SCD survivors, leftventricular (LV) dysfunction, or failed catheterablation.

FOLLOW-UP. Follow-up survival data were availablefor all patients and were obtained by hospital chartreview and telephone interviews of the patients, theirrelatives, or treating physicians. The primary com-posite endpoint included syncope, spontaneous sus-tained VT (see definition in the Online Appendix), orSCD/ACA. The secondary endpoint was SCD/ACA. Forpatients with multiple endpoint events, the first wasthe censoring event. If ICD implantation was per-formed during follow-up, patients were censored atthe date of implantation, and in that case, only VAsthat occurred before ICD implantation were recordedas events. If ICD implantation was performed duringfollow-up because of ventricular arrhythmia corre-sponding to a primary or secondary endpoint, pa-tients were considered as meeting the endpoint. Allevents and ICD implantation were adjudicated by 2independent clinicians.

STATISTICAL ANALYSIS. Continuous variables areexpressed as mean � SD and compared across groupsusing t-test when normally distributed or Mann-Whitney U test when non-normally distributed. Cat-egorical variables are reported as n (%) and comparedbetween groups with the chi-square or Fisher exacttest.

RFAC and LVEF threshold values were determinedas follows: the log-rank test of all threshold valuesbetween the 20th and 80th percentiles were calcu-lated, and the one with the lowest p value for theprimary endpoint was retained.

Survival after an arrhythmic event was estimatedwith the Kaplan-Meier method, and cumulative sur-vival rates were compared with the log-rank test.Because no events were observed in asymptomaticpatients, univariate and multivariate Cox analyseswere computed for symptomatic patients to assessrelationships between EPS inducibility, clinical andmorphological variables, and primary endpoint.Proportional-hazards assumptions were confirmed bySchoenfeld’s tests.

TABLE 1 Baseline Clinical Characteristics of the Population at

the Time of ARVC/D Diagnosis (N ¼ 137)

Male 107 (78)

Age, yrs 37 � 13

Proband 113 (82)

Definite diagnosis 105 (77)

Sport >6 h/week 50 (36)

Symptoms 95 (69)

Unexplained syncope 19 (14)

Palpitations 53 (39)

Congestive heart failure 2 (1)

Pre-syncope 21 (15)

Sustained VT at diagnosis 42 (31)

Familial history of SCD 24 (18)

Inverted T waves $V3 32 (23)

Epsilon wave 31 (23)

Late potentials (n ¼ 111) 93 (84)

Nonsustained VT or PVCs >500/24 h 52 (38)

RFAC, %* 46 � 11

RFAC #40% 37 (27)

LVEF, %* 61 � 9

LVEF #50%* 12 (9)

AAR drug therapy† 70 (51)

Beta-blockers 24 (18)

Sotalol 11 (8)

Flecainide only 7 (5)

Beta-blockerþ flecainide 21 (15)

Amiodarone 3 (2)

Positive EPS 34 (25)

With isoproterenol 5 (4)

Without isoproterenol 29 (21)

Values are n (%) or mean � SD. *Assessed by echocardiography. †before diagnosis(details available for 66 patients, online Table 5).

AAR ¼ antiarrhythmia, ARVC/D ¼ arrhythmogenic right ventricular cardiomy-opathy/dysplasia; EPS ¼ electrophysiological study; LVEF ¼ left ventricular ejec-tion fraction; PVC ¼ premature ventricular complex; RFAC ¼ right ventricularfractional area change; SCD ¼ sudden cardiac death; VT ¼ ventricular tachycardia.

TABLE 2 Clinical Parameters Associated With Inducibility

at the EPS

Inducible(n ¼ 34)

Noninducible(n ¼ 103) p Value

Male 31 (91) 76 (74) 0.03

Age, yrs 38 � 15 35 � 13 0.15

Proband status 30 (88) 83 (81) 0.30

Symptoms 31 (91) 64 (62) 0.001

Syncope 5 (15) 15 (15) 0.98

Sustained VT at diagnosis 24 (71) 18 (17) <0.001

Inverted T waves $V3 16 (47) 16 (16) <0.001

Epsilon wave 10 (29) 21 (20) 0.26

Nonsustained SVT or PVCs>500/24 h

8 (24) 44 (43) 0.04

RFAC #40% (TTE) 16 (47) 21 (20) 0.001

LVEF #50% (TTE) 5 (15) 7 (7) 0.14

AAR drug therapy* 21 (62) 49 (48) 0.12

All VAs (primary endpoint) 11 (32) 8 (8) <0.001

SCD/ACA (secondaryendpoint)

1 (3) 4 (4) 0.79

Values are n (%) or mean � SD. *At the time of diagnosis including beta-blockers,class Ic or III.

ACA ¼ aborted cardiac arrest; TTE ¼ transthoracic echocardiography; VA ¼ventricular arrhythmia; other abbreviations as in Table 1.

Maupain et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8

Arrhythmia Risk Stratification in ARVC/D J U N E 2 0 1 8 : 7 5 7 – 6 8

760

A p value <0.05 defined significance. Analysesused STATA/SE version 13.0 (StataCorp, College Sta-tion, Texas).

RESULTS

PATIENT CHARACTERISTICS AT DIAGNOSIS. Among160 consecutive ARVC/D patients, 10 were excludedbecause they did not undergo EPS at diagnosis, 11were excluded because they already had an ICD atdiagnosis, and 2 were excluded because of a possiblediagnosis (Figure 1). The reasons for ICD implantationat presentation are described in Online Table 2.Clinical characteristics of the 137 retained are detailedin Table 1. A total of 78% were men, mean age atdiagnosis was 37 years, 82% were probands, and 77%had a definite and 23% had a borderline ARVC/Ddiagnosis (Online Tables 3 and 4). Among 95 (69%)symptomatic patients, 42 (31%) had a history of

monomorphic VT. All patients had echocardiograms.The RFAC ranged from 21% to 65%, and the LVEFfrom 30% to 77%.

ELECTROPHYSIOLOGICAL STUDY. All 137 patientsunderwent EPS at diagnosis. Sustained VT wasinduced in 31 (23%) patients and VF in 3 (2%). Amongthe 34 patients with positive EPS, VT/VF was inducedunder isoproterenol in 5 (Table 1, Online Figure 1).The characteristics of patients with positive or nega-tive EPS are compared in Table 2. At EPS, 51% ofpatients were taking an AAR drug(s) (including beta-blockers, amiodarone, sotalol, or flecainide þ beta-blockers) because of previous VT/nonsustained VTor frequent PVCs (details in Online Table 5). VT/VFinducibility was not different between patients withor without AAR drug therapy.

PREDICTORS OF SUSTAINED VENTRICULAR

ARRHYTHMIA (PRIMARY ENDPOINT). Details offollow-up of the entire cohort are included in Figure 1.Over a mean follow-up of 42 � 31 months, 19 (14%)patients experienced sustained ventricular arrhyth-mias (primary endpoint) (Figure 2A, Table 3): 14 pa-tients had monomorphic sustained VT, 4 experiencedSCD, and 1 had an ACA. All patients were prescribedAAR drug therapy during follow-up (details in OnlineTable 5). A total of 17 patients (12%) received an ICDduring follow-up, of which 8 had an ICD implantedbecause of occurrence of ventricular arrhythmia cor-responding to the primary endpoint. All reasons forICD implantation during follow-up are reported in

FIGURE 2 Ventricular Arrhythmias and SCD/ACA-Free Survival (Kaplan-Meier Analysis)

Kaplan-Meier Analysis of cumulative survival from all ventricular arrhythmias (primary endpoint) (A) and SCD/ACA (secondary endpoint) (B) in all ARVC/D patients.

Ventricular arrhythmia (VA) was defined as syncope, spontaneous sustained VT, or SCD/ACA. Abbreviations as in Figure 1.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8 Maupain et al.J U N E 2 0 1 8 : 7 5 7 – 6 8 Arrhythmia Risk Stratification in ARVC/D

761

Online Table 6. During follow-up, 25 patients under-went 32 VT ablations (mean range 1.3, range 1 to 3).The indication for VT ablation was spontaneous VT(n ¼ 22), inducible VT despite AAR therapy (n ¼ 6),nonsustained VT/frequent PVCs (n ¼ 3), and undoc-umented (n ¼ 1) (Online Table 7).

None of the asymptomatic patients (n ¼ 42) atdiagnosis experienced any events (Figure 3C). A totalof 35% of the asymptomatic patients had more than500 PVCs/24 h or a nonsustained VT episode at pre-sentation. Among predictors of the primary endpointfor symptomatic patients selected by univariate ana-lyses, multivariate analyses retained LVEF #50%,positive EPS, and physical activity >6 h/week(Figures 3A, 3B, 3D, and 4). Results remained un-changed if patients with borderline diagnosis wereexcluded. History of sustained VT at diagnosis wasnot a predictor of recurrence of VAs in the multivar-iate analysis.

PREDICTORS OF SCD/ACA. During follow-up, 5 (4%)patients experienced SCD/ACA (secondary endpoint)(Figure 2B); their characteristics are detailed in Table 3.The odds for SCD/ACA were difficult to estimatebecause of the low incidence in this sample. All SCD/ACA occurred in male probands with definite diag-nosis and previous syncope, suggesting that thispopulation is at higher risk of SCD. Of the 5 patients, 2had a history of syncopal VT, 2 refused ICD implanta-tion, and 1 had poor compliance with no appropriatefollow-up. Overall, 26% of patients with previoussyncope (n ¼ 5 of 19) experienced SCD/ACA. Syncope

had a 100% sensitivity and an 89% specificity to pre-dict SCD/ACA. LVEF #50% and positive EPS had 60%and 20% sensitivity and 81% and 75% specificity,respectively, for SCD/ACA. Among patients with SCD/ACA, only 20% (n ¼ 1 of 5) had a positive EPS and 80%(n ¼ 4 of 5) trained more than 6 h/week. No patientswith history of monomorphic hemodynamically well-tolerated VT experienced SCD/ACA.

DISCUSSION

ARVC/D is characterized by a broad spectrum ofclinical pictures, ranging from asymptomatic patients(16,17) to recurrent episodes of hemodynamicallyunstable VAs or VF (18). ARVC/D mortality is mainlyattributable to the evolution to end-stage heart fail-ure or SCD. Although factors predictive of VAs havebeen thoroughly studied in patients implanted withan ICD, they have been little studied in patientswithout any ICD (12). In this study, we focused onarrhythmic events and SCD/ACA in this particularpopulation in a real-life setting. Our cohort thusincluded lower-risk patients, which were oftenexcluded from previous studies.

ARVC/D RISK STRATIFICATION

The presence of symptoms is a key information forrisk stratification in ARVC/D. In our cohort, asymp-tomatic patients at diagnosis were at very low risk ofarrhythmic events (no event during follow-up), evenin the presence of other reported risk factors. This

TABLE 3 Characteristics of ARVC/D Patients Who Met the Primary (All Ventricular Arrhythmias) and the Secondary Endpoint (SCD/ACA)

Patient #Event

Number

Age atDiagnosis,

yrs

Age at Primary/SecondaryEndpoint Sex Mutation

DiagnosisScore†

Sport >6 hper Week Symptoms

Documented VentricularArrhythmia at Diagnosis ECG

SA-ECG40 Hz

#16 #1 21 23/— M PKP2 7 No Palpitations Inaugural HD-toleratedLBBB VT with sup axis

TWI V1–2 NA

#18 #2 39 39/— M PKP2 5 Yes Palpitations Exercise-inducedpolymorphic PVCs

TWI V1–2 iRBBB NA

#23 #3 40 43/— M PKP2 8 No Palpitations 1,439 PVCs/24 h TWI V1–2 3 0/3

#31 #4 52 54/54 M no 4 No Syncope duringexercise

PVCs TWI V1–3 iRBBB NA

#41 #5 53 58/— M PKP2 6 No Palpitations Inaugural HD-toleratedVT

TWI V1–2 0/3

#57 #6 17 18/18 M no 4 Yes Syncope duringexercise

LBBB PVCs with inf andsup axis, exerciseinduced RVOT nsVT

RBBBTWI V1–2

3/3

#61 #7 38 39/ M no 3 No Palpitations nsVT iRBBB 1/3

#62 #8 67 69/— M PKP2 9 No Palpitations Inaugural HD-toleratedLBBB VT with sup axis

TWI V1–5 3 1/3

#73 #9 49 51/— M NA 7 No Palpitations Inaugural HD-toleratedLBBB VT, PVCs, nsVT

TWI V1–3 2/3

#79 #10 32 32/— M NA 5 Yes PalpitationsPresyncope,Chest Pain

Inaugural HD-toleratedRVOT VT 250 beats/min

TWI V1–3 0/3

#87 #11 18 20/20 M Double PKP2mutation

8 Yes Syncope,Palpitations

Inaugural exercise-induced HD-nontolerated RVOTVT 244 beats/min

TWI V1–3 1/3

#92 #12 26 28/— M NA 4 Yes Palpitations Inaugural exercise HD-tolerated RVOT VT240 beats/min

TWI V1–2 0/3

#93 #13 30 34/34 M NA 4 Yes Syncope Inaugural HD-nontolerated VT,polymorphic PVCs

TWI V1–6 0/3

#99 #14 45 46/— M no 6 Yes Palpitations Inaugural HD-toleratedVT

TWI V1–6 3 1/3

#108 #15 21 22/— F no 5 No Palpitations Inaugural HD- toleratedVT

TWI V1–4 3 2/3

#118 #16 29 31/— M no 7 Yes Presyncope duringexercise

Polymorphic PVC andRVOT nsVT

TWI V1–4 3 1/3

#120 #17 21 24/— M NA 5 Yes Syncope Inaugural HD-nontolerated VT,nsVT, LBBB with supaxis PVCs>500/24h

TWI V1–5 3 3/3

#126 #18 39 42/42 M NA 4 Yes Syncope LBBB and RBBB PVCs>500/24 h

iLBBB 1/3

#149 #19 52 53/— M no 5 No Presyncope,Palpitations

Inaugural HD-nontolerated LBBBVT with sup axis 200beats/min

Parietal block V1 1/3

Maupain et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8

Arrhythmia Risk Stratification in ARVC/D J U N E 2 0 1 8 : 7 5 7 – 6 8

762

TABLE 3 Continued

EP Study (Treatment)RFAC (TTE)

at Diagnosis (%)LVEF (TTE)

at Diagnosis (%)

VTCABeforeEvent

Arrhythmia DuringFU (Treatment Before)

ICD AfterEvent

VTCAAfter Event Htx

HD-tolerated LBBB VT with sup axisat baseline (none)

32 65 No VT, 200 beats/min, LBBB-superior axis, HD-tolerated,duration<1 h, spontaneously achieved (flecainide200 mg, bisoprolol 10 mg)

Yes Yes No

HD-tolerated LBBB VT at baseline(BB þ flecainide)

50 56 No VT, 200 beats/min, LBBB, HD-tolerated, duration 3–4 h,stopped by overdrive pacing (flecainide 200 mg,bisoprolol 10 mg)

Yes Yes No

HD-tolerated LBBB VT At baseline(BB)

54 65 Yes VT, 150–180 beats/min, RVOT, HD-tolerated, duration4 h, spontaneously achieved (nadolol 160 mg)

No Yes No

Syncopal LBBB VT at baseline (ontreatment)

23 45 Yes ACA on fast VT,* LBBB-superior axis, immediatedefibrillation (flecainide 200 mg þ bisoprolol7.5 mg) ICD implantation has been delayed by thepatient after diagnosis

Yes No No

HD-tolerated LBBB VT withintermediate axis onisoproterenol (sotalol þdisopyramide)

39 66 No VT, 90 beats/min, RBBB, HD-tolerated, spontaneouslyachieved (sotalol 320 mg þ flecainide 200 mg)

No Yes No

Negative (bisoprolol 5 mg þflecainide 200 mg)

37 50 No SCD* — — —

Negative (flecainide þ bisoprolol) 57 68 No VT, HD-tolerated (flecainide þ bisoprolol) No No No

HD-tolerated LBBB VT with sup axison isoproterenol (none)

<35 65 No VT, 140 beats/min, LBBB-sup axis, HD-tolerated,duration 2 days, pharmacologic conversion (none,stopped by patient)

Yes Yes No

HD-tolerated LBBB VT with sup axisat baseline (flecainide 200 mg þbisoprolol 1.25 mg)

34 58 No VT, HD-tolerated (bisoprolol 1.25 mg þ flecainide200 mg)

No Yes No

HD-tolerated RVOT VT at baseline(nadolol 80 mg)

38 60 Yes VT, 160 beats/min, RVOT, HD-tolerated, duration 2 h,DC cardioversion (sotalol 320 mg)

No Yes No

Negative (bisoprolol 10 mg) 40 60 No SCD* (bisoprolol 10 mg) ICD has been refused atdiagnosis by the patient

— — —

Negative (atenolol 50 mg) 64 60 Yes VT, 200 beats/min, Exercise HD-tolerated, duration 50 s(flecainide 250 mg þ bisoprolol 10 mg)

No Yes No

Negative (none) 40 64 No SCD* (sotalol 320 mg, no appropriate follow-up) — — —

HD-tolerated LBBB VT at baseline(flecainide 200 mg þ sotalol320 mg)

<35 58 Yes VT, 160 beats/min, LBBB, HD-tolerated (flecainide250 mg þ sotalol 320 mg)

Yes Yes Yes

Negative (bisoprolol 10 mg) 36 43 Yes VT (flecainide 200 mg þ bisoprolol 7.5 mg) Yes Yes Yes

Negative (bisoprolol 10 mg) 45 60 Yes VT, 120 beats/min, RVOT, HD-tolerated, duration 1 hspontaneously achieved (sotalol 160 mg þ flecainide200 mg)

Yes Yes No

VF at baseline (none) 48 66 Yes VT, 200beats/min, syncopal, DC cardioversion(bisoprolol 10 mg)

Yes Yes No

Negative (none) 47 40 No SCD* (bisoprolol) — — —

HD-tolerated LBBB VT supaxis 200 beats/min atbaseline (none)

29 66 Yes VT, 160 beats/min, RVOT, HD-tolerated,overdrive pacing (flecainide 200 mg þbisoprolol 5 mg)

No (Refused) Yes No

*Ventricular arrhythmia considered as a secondary endpoint. †Diagnosis score was calculated as follows: major criteria ¼ 2 points, minor criteria ¼ 1 point.

BB ¼ beta-blockers; DC ¼ direct-current; EP ¼ electrophysiological; FU ¼ follow-up; HD ¼ hemodynamically; Htx ¼ heart transplantation; ICD ¼ implantable cardioverter-defibrillator; LBBB ¼ left bundlebranch block; NA ¼ data not available; nsVT ¼ nonsustained VT; RBB ¼ right bundle branch block; iRBBB ¼ incomplete right bundle branch block; RVOT ¼ right ventricular outflow tract; S-A ¼signal-averaged; TWI ¼ T-wave inversion; VF ¼ ventricular fibrillation; VTCA ¼ ventricular tachycardia catheter ablation; 3¼ Epsilon wave; other abbreviations as in Tables 1 and 2.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8 Maupain et al.J U N E 2 0 1 8 : 7 5 7 – 6 8 Arrhythmia Risk Stratification in ARVC/D

763

FIGURE 3 Ventricular Arrhythmia-Free Survival According to Risk Factors

Kaplan-Meier analysis of cumulative survival from all VAs (primary endpoint, defined as syncope, spontaneous sustained VT, or SCD/ACA)

according to LVEF (A), EPS results (EPS was considered positive when sustained VT or VF was induced [see definitions in the Online

Appendix]) (B), presence of symptoms (defined as palpitations, syncope, pre-syncope, or congestive heart failure) (C), or physical activity

(D). Asympt ¼ asymptomatic patients; LVEF ¼ left ventricular ejection fraction; Sympt ¼ symptomatic patients; other abbreviations as in

Figures 1 and 2.

Maupain et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8

Arrhythmia Risk Stratification in ARVC/D J U N E 2 0 1 8 : 7 5 7 – 6 8

764

finding may be explained partly by the fact that allasymptomatic patients in our cohort were takingbeta-blockers during follow-up according to our localprotocol and the recent guidelines for ARVC/D man-agement (13). However, there is no randomized trialindicating that beta-blockers are effective in pre-venting arrhythmias and SCD in this population. Ourfindings are also in accordance with Corrado et al. (9),who reported that asymptomatic patients whoreceived an ICD solely because of a family history ofSCD had no appropriate ICD therapy during follow-up. These observations suggest that asymptomaticpatients at diagnosis are at low risk and would notbenefit from preventive ICD, in regard to the risk ofICD-related complications (19).

We found LVEF #50% to be an independent factorfor arrhythmia risk stratification. Impaired LVEF waspreviously identified as a predictor of life-threateningarrhythmias in patients with ICD (10,20,21) (Online

Table 1) and in those without (12). In addition, LVinvolvement was previously reported to be a riskfactor for global cardiac death or need for hearttransplantation, suggesting that this parameter is amajor determinant of ARVC/D mortality (22,23).However, LV involvement and the LVEF thresholdhave never been well defined and were mostly basedon LVEF measured by contrast angiography (13).Therefore, LVEF #50% measured by echocardiogra-phy should be an indication to consider ICDimplantation.

Sustained physical activity (>6 h/week) was asso-ciated with an almost 3-fold increased risk of VAs inmultivariate analysis. The deleterious effect ofcompetitive and sustained physical activity onoccurrence of VAs, which has been reported previ-ously (24,25), could be due to exercise-related me-chanical stress in the RV wall leading to myocytedetachment, cell death, and abnormal healing with

FIGURE 4 Predictors of All Sustained Ventricular Arrhythmias (Primary Endpoint)

*Assessed by echocardiography. †At the time of diagnosis. **Extreme HR values due to the absence or 100% events in presence of this factor.

These values were thus impossible to include in the multivariate analysis. AAR ¼ antiarrhythmia; CI ¼ confidence interval; HR ¼ hazard ratio;

LVEF ¼ left ventricular ejection fraction; NSVT ¼ nonsustained ventricular tacchycardia; PVC ¼ premature ventricular complex; RFAC ¼ right

ventricular fractional area change; SVT ¼ sustained ventricular tacchycardia; other abbreviations as in Figure 1.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8 Maupain et al.J U N E 2 0 1 8 : 7 5 7 – 6 8 Arrhythmia Risk Stratification in ARVC/D

765

fibrofatty replacement of the myocardium (26) exac-erbating ARVC/D phenotype, or to exercise-relatedtriggering of VT/VF. This supports the current AHA/ACC guidelines (27) that recommend restraining ac-tivity to moderate recreational exercise for patientswith ARVC/D diagnosis.

The incidence of lethal arrhythmic events wasrather low in our cohort (3.6% over a mean follow-upof 3.5 years) avoiding multivariate survival analysis.

However, we found that only male probands withprevious syncope and a definite ARVC diagnosis sta-tus experienced SCD/ACA. Syncope had a high 100%sensitivity and 89% specificity to predict SCD/ACA.Several studies have also reported syncope as asso-ciated with adverse events (e.g., VAs or cardiovascu-lar death). It thus appears to be a major risk factor forSCD/ACA (4,9,10,28,29) (Online Table 1). Male sex hasbeen reported earlier to be predictive of any VAs

Maupain et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8

Arrhythmia Risk Stratification in ARVC/D J U N E 2 0 1 8 : 7 5 7 – 6 8

766

(30,31). Bhonsale et al. (32) recently showed that menwere more likely to be symptomatic and have earlierand more severe arrhythmic expression of the dis-ease. Causes of sex-related penetrance and diseaseseverity remain unknown, although different levelsof participation in competitive and intensive sportshave been hypothesized (25,33).

In the present study, no patients with well-tolerated VTs (nonsyncopal) experienced fatalevents. Association of hemodynamically well-tolerated VTs and SCD/ACA is controversial (10,34).Thus, the benefit of ICDs in those patients is uncer-tain, given the risk of ICD-related complications (13).The efficacy of VT catheter ablation needs furtherinvestigation in that setting (13,19).

EPS CONTRIBUTION IN RISK STRATIFICATION. Weobserved that positive EPS reached statistical signif-icance on predicting VAs and therefore could identifysymptomatic patients at higher risk for VAs. How-ever, EPS had a poor 20% sensitivity on predictingSCD/ACA. These findings suggest that EPS can besuitable for identifying a substrate for developing re-entrant monomorphic VTs (35) but is less effective topredict lethal arrhythmic events. Thus, SCD/ACAcould be caused by alternative pathophysiologicalmechanisms, for example, focal VT, or PVC-triggeredVF, hardly predictable by EPS. Moreover, SCD couldbe triggered by an acute event, such as myocarditis,that would probably not be detected by initial EPS.These findings are in accordance with those of Cor-rado et al. (9), where EPS inducibility was not asso-ciated with SCD/ACA in an ARVC/D population withICD in primary prevention. In addition, no data areavailable on the EP study reproducibility at an indi-vidual level in ARVC/D, underlying questions aboutits accuracy.

INFLUENCE OF TREATMENT. One point that couldexplain discrepancies between studies relies on thetherapeutic management of ARVC/D patients. Ac-cording to our local protocol and recent therapeuticguidelines, all patients were on medical therapy(beta-blockers � AAR drugs) during follow-up, whichhave probably influenced the outcome. From 52% (9)to 83% (10) of patients were on medical therapy inother studies. However, Corrado et al. (10) reportedthat most life-saving ICD interventions in high-riskpatients occurred despite concomitant AAR drugs,suggesting that medical treatment has little effect onSCD events. This point could not be assessed in thepresent study, as all patients were treated afterdiagnosis. However, we observed a significant rateof arrhythmic events during follow-up (14% over

3.5 years) despite beta-blockers � AAR therapy, sug-gesting incomplete efficacy of medical therapy onVAs. Another point is the possible effect of VT abla-tion on the outcome, as 18% of patients underwentVT ablation.

STUDY LIMITATIONS. First, although the studycohort was relatively large in the setting of ARVC/D,which is a rare disease, the small number of eventshas limited the statistical power. Thus, largermulticenter registries are needed to devise a SCD riskscore and refine ICD indications for primary pre-vention. Nonetheless, we believe that our resultsindicate important trends of clinical relevance forarrhythmia risk stratification in ARVC/D. Second,because genetic information was lacking for manypatients (especially those diagnosed before 2006),this parameter was not included in the analysis.Third, the echocardiogram parameters were notblindly recorded and were reviewed retrospectively.Finally, we cannot exclude that medical treatment atthe time of EPS and isoproterenol infusion couldhave altered the results of the EP study and haveinfluenced its accuracy to predict the outcome.Although details of AAR therapy were available for97% of patients at diagnosis, the details of AARtherapy during follow-up was available for only 68patients.

CONCLUSIONS

Analysis of the long-term arrhythmic history of alarge cohort of ARVC/D patients without ICD sub-jected to EPS enabled us to identify patient groupswith low- and high-risk profiles. We identified anechocardiographic LVEF threshold of 50%, positiveEPS, and physical activity >6 h/week as predictors ofVAs. Asymptomatic patients remained at very lowrisk independently of other risk factors. EPS providedlow accuracy to predict SCD/ACA. As ARVC/D is aprogressive disease, arrhythmic risk should be regu-larly reassessed during follow-up. Our results couldhelp physicians to choose the optimal therapeuticstrategy and should certainly encourage further in-vestigations to define ICD indications for primaryprevention in ARVD/C.

ACKNOWLEDGMENT The authors thank Mrs. Jacob-son for the critical reading of the manuscript.

ADDRESS FOR CORRESPONDENCE: Dr. EstelleGandjbakhch, Institut de Cardiologie, APHP, HôpitalPitié-Salpêtrière, 45-87 boulevard de l’hôpital, 75013Paris, France. E-mail: estelle.gandjbakhch@aphp.fr.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE ICD

implantation can be proposed for ARVC/D patients to

prevent SCD, exposing them to long-term complications.

The identification of specific risk factors associated with

life-threatening arrhythmic events is highly important for

themanagement of these patients. Patients with high- and

low-risk profiles for ventricular arrhythmia have been

identified in this cohort.

TRANSLATIONAL OUTLOOK An important percent-

age of patients will not experience any lethal ventricular

arrhythmia, when a significant proportion of patients will

experience monomorphic VT that may be accessible to

catheter ablation. This would help physicians to identify

ARVC/D patients that would most benefit from prophy-

lactic ICD. Further investigation is needed to determine

the place for catheter ablation of hemodynamically-

tolerated VT without back-up ICD.

J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8 Maupain et al.J U N E 2 0 1 8 : 7 5 7 – 6 8 Arrhythmia Risk Stratification in ARVC/D

767

RE F E RENCE S

1. Marcus FI, Fontaine GH, Guiraudon G, et al.Right ventricular dysplasia: a report of 24 adultcases. Circulation 1982;65:384–98.

2. Nava A, Bauce B, Basso C, et al. Clinical profileand long-term follow-up of 37 families witharrhythmogenic right ventricular cardiomyopathy.J Am Coll Cardiol 2000;36:2226–33.

3. Cox MGPJ, van der Zwaag PA, van der Werf C,et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome muta-tions in index-patients predict outcome of familyscreening: Dutch arrhythmogenic right ventriculardysplasia/cardiomyopathy genotype-phenotypefollow-up study. Circulation 2011;123:2690–700.

4. Hulot J-S, Jouven X, Empana J-P, Frank R,Fontaine G. Natural history and risk stratificationof arrhythmogenic right ventricular dysplasia/car-diomyopathy. Circulation 2004;110:1879–84.

5. Cho Y, Park T, Yang DH, et al. Arrhythmogenicright ventricular cardiomyopathy and sudden car-diac death in young Koreans. Circ J 2003;67:925–8.

6. Naneix A-L, Périer M-C, Beganton F, Jouven X,Lorin de la Grandmaison G. Sudden adult death: anautopsy series of 534 cases with gender andcontrol comparison. J Forensic Leg Med 2015;32:10–5.

7. Schinkel AFL. Implantable cardioverter de-fibrillators in arrhythmogenic right ventriculardysplasia/cardiomyopathy: patient outcomes,incidence of appropriate and inappropriate in-terventions, and complications. Circ ArrhythmElectrophysiol 2013;6:562–8.

8. Te Riele ASJM, Bhonsale A, James CA, et al.Incremental value of cardiac magnetic resonanceimaging in arrhythmic risk stratification ofarrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal muta-tion carriers. J Am Coll Cardiol 2013;62:1761–9.

9. Corrado D, Calkins H, Link MS, et al. Prophy-lactic implantable defibrillator in patients witharrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation orsustained ventricular tachycardia. Circulation2010;122:1144–52.

10. Corrado D, Leoni L, Link MS, et al. Implantablecardioverter-defibrillator therapy for preventionof sudden death in patients with arrhythmogenicright ventricular cardiomyopathy/dysplasia. Cir-culation 2003;108:3084–91.

11. Bhonsale A, James CA, Tichnell C, et al.Incidence and predictors of implantablecardioverter-defibrillator therapy in patients witharrhythmogenic right ventricular dysplasia/car-diomyopathy undergoing implantablecardioverter-defibrillator implantation for primaryprevention. J Am Coll Cardiol 2011;58:1485–96.

12. Brun F, Groeneweg JA, Gear K, et al. Riskstratification in arrhythmic right ventricular car-diomyopathy without implantable cardioverter-defibrillators. J Am Coll Cardiol EP 2016;2:558–64.

13. Corrado D, Wichter T, Link MS, et al. Treatmentof arrhythmogenic right ventricular cardiomyopa-thy/dysplasia: an International Task Forceconsensus statement. Circulation 2015;132:441–53.

14. Marcus FI, McKenna WJ, Sherrill D, et al.Diagnosis of arrhythmogenic right ventricularcardiomyopathy/dysplasia: proposed modificationof the Task Force Criteria. Eur Heart J 2010;31:806–14.

15. Lang RM, Bierig M, Devereux RB, et al. Rec-ommendations for chamber quantification: areport from the American Society of Echo-cardiography’s Guidelines and Standards Commit-tee and the Chamber Quantification Writing Group,developed in conjunction with the European As-sociation of Echocardiography, a branch of theEuropean Society of Cardiology. J Am Soc Echo-cardiogr 2005;18:1440–63.

16. Li C-H, Lin Y-J, Huang J-L, et al. Long-termfollow-up in patients with arrhythmogenic rightventricular cardiomyopathy. J Cardiovasc Electro-physiol 2012;23:750–6.

17. Corrado D, Basso C, Thiene G. Arrhythmogenicright ventricular cardiomyopathy: an update.Heart 2009;95:766–73.

18. Dalal D, Jain R, Tandri H, et al. Long-term ef-ficacy of catheter ablation of ventricular tachy-cardia in patients with arrhythmogenic right

ventricular dysplasia/cardiomyopathy. J Am CollCardiol 2007;50:432–40.

19. Olde Nordkamp LRA, Postema PG, Knops RE,et al. Implantable cardioverter-defibrillator harmin young patients with inherited arrhythmia syn-dromes: a systematic review and meta-analysis ofinappropriate shocks and complications. HeartRhythm 2016;13:443–54.

20. Pezawas T, Stix G, Kastner J, Schneider B,Wolzt M, Schmidinger H. Ventricular tachycardia inarrhythmogenic right ventricular dysplasia/car-diomyopathy: clinical presentation, risk stratifica-tion and results of long-term follow-up. Int JCardiol 2006;107:360–8.

21. Peters S. Long-term follow-up and riskassessment of arrhythmogenic right ventriculardysplasia/cardiomyopathy: personal experiencefrom different primary and tertiary centres.J Cardiovasc Med (Hagerstown) 2007;8:521–6.

22. Pinamonti B, Dragos AM, Pyxaras SA, et al.Prognostic predictors in arrhythmogenic rightventricular cardiomyopathy: results from a 10-year registry. Eur Heart J 2011;32:1105–13.

23. Lemola K, Brunckhorst C, Helfenstein U,Oechslin E, Jenni R, Duru F. Predictors of adverseoutcome in patients with arrhythmogenic rightventricular dysplasia/cardiomyopathy: long termexperience of a tertiary care centre. Heart 2005;91:1167–72.

24. Ruwald A-C, Marcus F, Estes NAM, et al.Association of competitive and recreational sportparticipation with cardiac events in patients witharrhythmogenic right ventricular cardiomyopa-thy: results from the North American multidis-ciplinary study of arrhythmogenic rightventricular cardiomyopathy. Eur Heart J 2015;36:1735–43.

25. James CA, Bhonsale A, Tichnell C, et al. Exer-cise increases age-related penetrance andarrhythmic risk in arrhythmogenic right ventriculardysplasia/cardiomyopathy-associated desmo-somal mutation carriers. J Am Coll Cardiol 2013;62:1290–7.

26. Benito B, Gay-Jordi G, Serrano-Mollar A, et al.Cardiac arrhythmogenic remodeling in a rat model

Maupain et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 4 , N O . 6 , 2 0 1 8

Arrhythmia Risk Stratification in ARVC/D J U N E 2 0 1 8 : 7 5 7 – 6 8

768

of long-term intensive exercise training. Circula-tion 2011;123:13–22.

27. Maron BJ, Udelson JE, Bonow RO, et al.Eligibility and disqualification recommendationsfor competitive athletes with cardiovascular ab-normalities: task force 3: hypertrophic cardiomy-opathy, arrhythmogenic right ventricularcardiomyopathy and other cardiomyopathies, andmyocarditis: a scientific statement from theAmerican Heart Association and American Collegeof Cardiology. Circulation 2015;132:e273–80.

28. Watkins DA, Hendricks N, Shaboodien G, et al.Clinical features, survival experience, and profile ofplakophylin-2 gene mutations in participants of thearrhythmogenic right ventricular cardiomyopathyregistry of South Africa. Heart Rhythm 2009;6:S10–7.

29. Silvano M, Corrado D, Köbe J, et al. Riskstratification in arrhythmogenic right ventricularcardiomyopathy. Herzschrittmachertherapie Elek-trophysiologie 2013;24:202–8.

30. Roguin A, Bomma CS, Nasir K, et al.Implantable cardioverter-defibrillators in patientswith arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2004;43:1843–52.

31. Protonotarios A, Anastasakis A,Panagiotakos DB, et al. Arrhythmic risk assess-ment in genotyped families with arrhythmogenicright ventricular cardiomyopathy. Europace 2016;18:610–6.

32. Bhonsale A, Groeneweg JA, James CA, et al.Impact of genotype on clinical course in arrhyth-mogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. EurHeart J 2015;36:847–55.

33. Cruz FM, Sanz-Rosa D, Roche-Molina M, et al.Exercise triggers ARVC phenotype in miceexpressing a disease-causing mutated version ofhuman plakophilin-2. J Am Coll Cardiol 2015;65:1438–50.

34. Mazzanti A, Ng K, Faragli A, et al. Arrhyth-mogenic right ventricular cardiomyopathy: clinicalcourse and predictors of arrhythmic risk. J Am CollCardiol 2016;68:2540–50.

35. Piccini JP, Dalal D, Roguin A, et al. Predictorsof appropriate implantable defibrillator thera-pies in patients with arrhythmogenic rightventricular dysplasia. Heart Rhythm 2005;2:1188–94.

KEY WORDS arrhythmogenic rightventricular cardiomyopathy/dysplasia,electrophysiological study, riskstratification, sudden cardiac death,ventricular arrhythmia

APPENDIX For an expanded Methods sectionas well as supplemental tables and figure,please see the online version of this paper.