clinical diagnosis, imaging, and genetics of arrhythmogenic right … · 2018-07-30 · the present...

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J O U R N A L O F T H E A M 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 V O L . 7 2 , N O . 7 , 2 0 1 8

ª 2 0 1 8 B Y T H E A M 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 U N D A T I O N

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

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Clinical Diagnosis, Imaging, and Geneticsof Arrhythmogenic Right VentricularCardiomyopathy/DysplasiaJACC State-of-the-Art Review

Estelle Gandjbakhch, MD, PHD,a,b,c,d Alban Redheuil, MD, PHD,d,e,f Françoise Pousset, MD,b,c,d

Philippe Charron, MD, PHD,a,b,c,d,g Robert Frank, MDb,c,d

ABSTRACT

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Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy that can lead to

sudden cardiac death and heart failure. Our understanding of its pathophysiology and clinical expressivity is continuously

evolving. The diagnosis of ARVC/D remains particularly challenging due to the absence of specific unique diagnostic

criteria, its variable expressivity, and incomplete penetrance. Advances in genetics have enlarged the clinical spectrum of

the disease, highlighting possible phenotypes that overlap with arrhythmogenic dilated cardiomyopathy and channelo-

pathies. The principal challenges for ARVC/D diagnosis include the following: earlier detection of the disease, particularly

in cases of focal right ventricular involvement; differential diagnosis from other arrhythmogenic diseases affecting the

right ventricle; and the development of new objective electrocardiographic and imaging criteria for diagnosis. This review

provides an update on the diagnosis of ARVC/D, focusing on the contribution of emerging imaging techniques, such as

echocardiogram/magnetic resonance imaging strain measurements or computed tomography scanning, new electrocar-

diographic parameters, and high-throughput sequencing. (J Am Coll Cardiol 2018;72:784–804)

© 2018 by the American College of Cardiology Foundation.

A rrhythmogenic right ventricular cardiomyop-athy/dysplasia (ARVC/D) was recognized as aspecific entity in the 1970s by our group

when several patients with drug-resistant right ven-tricular (RV) tachycardia had surgery guided byepicardial mapping. Interventions provided evidenceof their RV origin, with RV dilatation, late potentials,left-sided extension, and fibrofatty infiltration in RVbiopsy specimens (1). Guy Fontaine coined the termdysplasia, appropriate for this condition, and pub-lished the first large series in 1982 with Frank Marcus,

N 0735-1097/$36.00

m the aSorbonne Universités, UPMC Univ Paris 06, INSERM 1166, Paris,

titute of Cardiology, Paris, France; cCentre de Référence des Maladies C

rdiometabolism and Nutrition (ICAN), Paris, France; eAPHP, Pitié-Salpêtriè

d Thoracic, Imaging and Interventional Radiology, Institute of Cardiolog

ris 06, INSERM 1146, CNRS 7371, Laboratoire d’Imagerie Biomédicale, Pa

spital, Department of Genetics, Paris, France. The authors have report

ntents of this paper to disclose.

nuscript received March 13, 2018; revised manuscript received May 24, 2

including 22 severe cases with RV arrhythmia, 12 ofwhich needed surgery (2). All had local or global RVenlargement and showed electrocardiography (ECG)abnormalities with T-wave inversions in the RV pre-cordial leads from V1 to V4 and late potentials, eitherobvious by ECG (called epsilon waves) or signal-averaged ECG.

ARVC/D has been included in the classification ofthe European group for cardiomyopathies since 1994.The denomination of this cardiomyopathy has beendiscussed for years. The “ARVC” and “ARVD”

https://doi.org/10.1016/j.jacc.2018.05.065

France; bAPHP, Pitié-Salpêtrière University Hospital,

ardiaques Héréditaires, Paris, France; dInstitute of

re University Hospital, Department of Cardiovascular

y, Paris, France; fSorbonne Universités, UPMC Univ

ris, France; and gAPHP, Pitié-Salpêtrière University

ed that they have no relationships relevant to the

018, accepted May 31, 2018.


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AB BR E V I A T I O N S

AND ACRONYM S

2D = 2-dimensional

3D = 3-dimensional

4D = 4-dimensional

ARVC/D = arrhythmogenic

right ventricular

cardiomyopathy/dysplasia

CT = computed tomography

DCM = dilated cardiomyopathy

ECG = electrocardiography

LBBB = left bundle branch

block

LGE = late gadolinium

enhancement

LV = left ventricular

MDCT = multidetector

computed tomography

MRI = magnetic resonance

imaging

RBBB = right bundle branch

block

RV = right ventricular

RVOT = right ventricular

outflow tract

SCD = sudden cardiac death

SSFP = steady-state free

precession

TFC = task force criteria

J A C C V O L . 7 2 , N O . 7 , 2 0 1 8 Gandjbakhch et al.A U G U S T 1 4 , 2 0 1 8 : 7 8 4 – 8 0 4 Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia

785

terminology represents 2 different visions of itspathophysiology: degenerative process or develop-ment abnormality. Although the terminology of“dysplasia” is probably questionable, this term hasbeen used and accepted for 40 years. Several com-bined diagnostic criteria (task force criteria [TFC])were proposed, classified as major or minor (3), andimplemented in 2010 (4) (Table 1) for a better speci-ficity, particularly in family members and youngathletes. The diagnosis of ARVC/D is probably themost challenging in the field of inherited cardiomy-opathies because of the absence of specific uniquediagnostic criteria, its variable expressivity, and itsincomplete penetrance in relatives. The main prob-lem is that a definitive pathological diagnosis is onlygiven by a seldom available histological study ob-tained by biopsy, surgery, or necropsy. Indirect evi-dence can be obtained by multimodal cardiac imagingstudies. ECG data show RV disease, but other RVcardiomyopathies may alter it in a similar way, suchas myocarditis (5), which interacts with ARVC/D (6,7),sarcoidosis (8,9), or the rare Uhl’s disease (Table 2).

The revision of ARVC/D diagnostic criteria in 2010increased the specificity of the diagnosis, but it stilllacks sensitivity, especially in the early stages of thedisease (4,10). In addition, most diagnostic criteriawere assessed relative to healthy controls andpossibly lack specificity for differential diagnosis withother arrhythmogenic diseases involving the rightventricle. Genotype/phenotype studies have shownthat ARVC/D, which was initially described as anisolated or predominant RV disease, exhibits frequentleft ventricular (LV) involvement. This involvementmay be present or predominant at early stages insome mutation carriers, expanding the clinical spec-trum of the disease to a larger group of scar-relatedcardiomyopathies or arrhythmic cardiomyopathiesaccording to the suggestion of some authors.

The present review provides an update on thepathological, clinical, and genetic abnormalitiesassociated with ARVC/D, focusing on the contributionof emerging imaging techniques and genetics fordiagnosis.

PATHOLOGY

The main anatomopathological feature of ARVC/D isthe replacement of myocytes by fibrous or fibro-adipose tissue in the RV free wall. Lesions extendfrom the epicardium to the endocardium andpredominantly involve the area between the anteriorpart of the pulmonary infundibulum, the apex, andthe infero-posterior wall (the so-called “triangle ofdysplasia”). Myocyte loss and fibrous replacement are

most often segmental and usually do notinvolve the interventricular septum. LV his-tological involvement is frequently reportedin autopsy cases or explanted hearts, even inthe absence of macroscopic LV involvement(11).

Various histological forms have beendescribed depending on the predominance offibrous or adipose tissue. Nevertheless, asystematic study of myocardial biopsy speci-mens revealed the absence of specific RV fatinfiltration in contrast to extensive fibroustissue and myocyte loss (12). Fatty infiltrationis thus not required as a histological diag-nostic criterion (4). Lymphocytic or histio-cytic inflammatory infiltrates, focal necrosis,and signs of apoptosis are frequent (13). Theassociation of ARVC/D with clinical and his-tological features of myocarditis is thus notrare, underlying the relation between the 2diseases (7). However, the role of viruses inARVC/D pathogenesis remains unknown(14,15). A decrease in desmosomal proteinstaining (e.g., plakoglobin, desmosomal cad-herins) has been reported in immunostainingstudies, but the reproducibility and thediagnostic accuracy of these techniques inroutine practice were not assessed (16,17).Fibrofatty replacement is not specific to
desmosomal ARVC/D, as a similar pattern was foundin TMEM-43, PLN, and LMNA-related “ARVC/D”
(18–20), as well as arrhythmogenic mitochondrialcardiomyopathy associated with PPA2 mutations andarrhythmogenic dilated cardiomyopathy (DCM)caused by FLNC mutations (21,22).

The diagnostic yield of endomyocardial biopsies isrelatively low and largely depends on the location andnumber of targeted sites because of the patchy natureof fibrous replacement and the subepicardial locationof lesions. Endomyocardial biopsies are generallynoncontributive on the right side of the interventric-ular septum. Voltage-guided endomyocardial biopsyprobably increases the diagnostic yield, but questionsremain on the safety of performing biopsies on the RVfree wall (12,23). However, voltage-guided biopsiesmay be useful in ruling out some differential di-agnoses, such as sarcoidosis or viral myocarditis (5,8).

ELECTROCARDIOGRAM

ECG DIAGNOSTIC CRITERIA. The search for ARVC/Dis initiated in 2 clinical situations. For patients withventricular arrhythmia, mainly of RV origin on theECG, the diagnosis is approached through RV

TABLE 1 Current 2010 TFC Diagnosis

Major Minor

I. Global or regional dysfunctionand structural alterations

By 2D echocardiogram:Regional RV akinesia, dyskinesia, or aneurysm and 1 of thefollowing (end-diastole):

PLAX RVOT $32 mm (PLAX/BSA $19 mm/m2)PSAX RVOT $36 mm (PSAX/BSA $21 mm/m2)Or RFAC #33%

By MRI:Regional RV akinesia or dyskinesia or dyssynchronous RVcontraction and 1 of the following:

RV end-diastolic volume/BSA $110 ml/m2 (male)or $100 ml/m2 (female)Or RV ejection fraction #40%

By RV angiography:Regional RV akinesia, dyskinesia, or aneurysm

By 2D echocardiogram:Regional RV akinesia or dyskinesia, and 1 of the following (end-diastole):

29 #PLAX RVOT <32 mm (16 #PLAX/BSA <19 mm/m2)32 #PSAX RVOT <36 mm (18 #PSAX/BSA <21 mm/m2)Or 33% < RFAC #40%

By MRI:Regional RV akinesia or dyskinesia or dyssynchronous RV contrac-tion and 1 of the following (end-diastole):

100 ml/m2 # RV end-diastolic volume/BSA <110 ml/m2

(male) or 90 ml/m2 # RV end-diastolic volume/BSA <100 ml/m2 (female)Or 40% < RV ejection fraction #45%

II. Tissue characterization of wall Residual myocytes <60% by morphometric analysis (or <50% ifestimated), with fibrous replacement of the RV free wallmyocardium in $1 sample, with or without fatty replacementof tissue on endomyocardial biopsy

Residual myocytes 60% to 75% by morphometric analysis (or 50%to 65% if estimated), with fibrous replacement of the RV freewall myocardium in $1 sample, with or without fattyreplacement of tissue on endomyocardial biopsy

III. Repolarization abnormalities Inverted T waves in right precordial leads (V1, V2, and V3) orbeyond in individuals >14 yrs of age (in the absence ofcomplete RBBB QRS $120 ms)

Inverted T waves in leads V1 and V2 in individuals >14 yrs ofage (in the absence of complete RBBB) or in V4, V5, or V6

Inverted T waves in leads V1, V2, V3, and V4 in individuals>14 yrs of age in the presence of complete RBBB

IV. Depolarization/conductionabnormalities

Epsilon wave in the right precordial leads (V1 to V3) Late potentials by SAECG in $1 of 3 parameters in theabsence of a QRS duration $110 ms on the standard ECG

Filtered QRS duration $114 msDuration of terminal QRS <40 mV (low-amplitude signalduration) $38 msRoot mean square voltage of terminal 40 ms #20 mV

Terminal activation duration of QRS $55 ms measured fromthe nadir of the S-wave to the end of the QRS, including R’, inV1, V2, or V3, in the absence of complete RBBB

V. Ventricular Arrhythmias Nonsustained or sustained VT of LBBB morphology with superioraxis (negative or indeterminate QRS in leads II, III, and aVFand positive in lead aVL)

Nonsustained or sustained RVOT VT of LBBB morphology withinferior axis (positive QRS in leads II, III, and aVF and negativein lead aVL) or with unknown axis>500 ventricular extrasystoles per 24 h (Holter)

VI. Family history ARVC/D confirmed in a first-degree relative who meetscurrent TFCARVC/D confirmed pathologically at autopsy or surgery in afirst-degree relativeIdentification of a pathogenic mutation categorized asassociated or probably associated with ARVC/D in thepatient

History of ARVC/D in a first-degree relative in whom it is notpossible or practical to determine whether the family membermeets current TFCPremature sudden death (<35 yrs of age) due to suspectedARVC/D in a first-degree relativeARVC/D confirmed pathologically or by current TFC insecond-degree relative

Adapted with permission from Marcus et al. (4).

2D ¼ two-dimensional; ARVC/D ¼ arrhythmogenic right-ventricular cardiomyopathy/dysplasia; ECG ¼ electrocardiography; BSA ¼ body surface area; LBBB ¼ left bundle branch block; MRI ¼ magneticresonance imaging; PLAX ¼ parasternal long-axis view; PSAX ¼ parasternal short-axis view; RBBB ¼ right bundle branch block; RFAC ¼ right fractional area change; RV ¼ right ventricular; RVOT ¼ rightventricular outflow tract; SAECG ¼ signal-averaged electrocardiography; TFC ¼ task force criteria; VT ¼ ventricular tachycardia.

Gandjbakhch et al. J A C C V O L . 7 2 , N O . 7 , 2 0 1 8

Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia A U G U S T 1 4 , 2 0 1 8 : 7 8 4 – 8 0 4

786

morphological criteria, irrespective of the ECG data.For asymptomatic patients, family members of anovert case, or screening of athletes, an abnormal ECGorients the focus to the subject’s right ventricle.

ECG has the great advantage of being universal,easy to perform, and to easily reveal abnormalities inmost patients (24,25). It can be enhanced by openingthe usual 40-Hz low-pass filters, which smooth fastsignals as fragmentations (26) and epsilon waves. Itcan be performed from 100 to 250 Hz with some ECGrecorders, as those used for the signal-averaged ECGrecordings (27). Signal interpretation is made easierby double amplification, 50-mm speed recordingtracings, and bipolar precordial recordings that in-crease ECG sensitivity (28) (Table 3). All reflect lossesof normal RV myocardium and their consequences,

regardless of the etiology. For example, in a recentstudy (9) on 100 consecutive patients referred forventricular tachycardia ablation of scar-related RVcardiomyopathies from 1999 to 2015, a total of 51 hadTFC for ARVC/D, 22 for sarcoidosis, and 27 for a car-diomyopathy of “unknown source,” which could beearly forms of ARVC/D.

The great variety of QRS-T patterns in ARVC/D (29)is due to the progressive loss of RV subepicardial fi-bers and conduction defects for those who survive.These reflect the long and narrow activation paths,with altered gap junctions among fibrofatty tissues.ECG alterations depend on the extent and localizationof the disease, and their incidence varies widely be-tween series (Table 4). Early-stage ARVC/D exhibitsminor abnormalities, which increase over time in

TABLE 2 Main Alternative Diagnosis and/or Potential ARVC/D

Mimicking Diseases

Myocarditis

Sarcoidosis

Dilated cardiomyopathy

Athlete’s heart

Idiopathic infundibular PVC/VT

Brugada syndrome

Uhl’s disease

Other causes of RV dilatation and/or dysfunctionEbstein’s anomalyLeft to right shunt: interatrial septal defect, anomalouspulmonary venous returnTricuspid regurgitationInferior infarct with RV extension

PVC ¼ premature ventricular contraction; other abbreviations as in Table 1.


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most patients. Endocardial three-dimensional (3D)mapping, with map-directed biopsies (30), andendo-epicardial mapping, combined with magneticresonance imaging (MRI) scar data, have shed light onthe electrical features of ARVC/D (31).

ECG-based TFC diagnostic criteria include rightprecordial T-wave inversions, the presence ofepsilon waves, and increased duration of the ter-minal QRS from the nadir of the S-wave to the endof the QRS, when enlarged above 55 ms (32). How-ever, up to 30% of patients with morphologicalcriteria for ARVC/D have a so-called ECG-concealedform that does not fulfill the 2010 ECG criteria (33).However, they may have less specific ECG abnor-malities, such as ST-segment modifications (34) or

TABLE 3 Current Diagnostic Criteria and Emerging Diagnostic Tools f

ECG Imaging

CurrentInternational2010 TFC

Epsilon waveTWI in precordial leadsQRSt $55 ms in V1,V2,V3

Late potentials (SAECG)

Regional RV wall motioabnormality in combwith RV dilatation oRV systolic dysfunct(TTE/MRI/angiograp

Additionaldiagnosticcriteria

QRS fragmentationT-wave depth in V1 $2 mm in

V1, or $3 mm in bipolarCF1 lead

MicrovoltageInverted T waves in inferior

leads (LV extension)RBBB with R’/S ratio <1 in V1

Hypertrophic trabecularhyperreflective modband

Decreased TAPSE and psystolic RV annular

Intramyocardial fat infiltthe RV wall

LGE of the RV wallLow peak systolic RV st

Emergingdiagnostictools

Computerized S-wave surfaceand CF leads

Vectorcardiographyderivations

Body surface mapping

TTE speckle trackingMRI feature trackingMDCT and 4D-cine CT

4D ¼ four-dimensional; CF leads ¼ bipolar chest leads; CT ¼ computed tomography; Ecomputed tomography; NSVT ¼ nonsustained ventricular tachycardia; QRSt ¼ terminaTTE ¼ transthoracic echocardiography; TWI ¼ T-wave inversion; VA ¼ ventricular arrhyt

QRS fragmentation (24). Several recent studies haveproposed more complex proprietary ECG methodsfor better predictive values, such as computerizedS-wave surface and bipolar chest leads (35), vec-torcardiography derivations (36), or body surfacemapping (37). However, surface ECG remains theonly widely available and simple method using acombination of repolarization and depolarizationdata that can be enhanced by the recording modi-fications suggested earlier.

REPOLARIZATION DATA. T-wave inversions in theright precordial leads are present in up to 87% ofadult patients with ARVC/D (38), are directly relatedto RV dilatation (39), and may extend to the leftprecordium with time. They are rare in normal pa-tients but can be found in very different clinicalcontexts, such as in some young athletes (with ahigher incidence in black athletes), in ischemic car-diomyopathy, or during acute pulmonary embolism.Right precordial T-wave inversions are also related toright bundle branch block (RBBB); ARVC/D can besuspected, however, if they are present in V1, V2, andV3 (40,41) and according to the QRS morphology(discussed later). T-wave depth in V1 is not includedin the TFC. However, it is an important feature, with ahigh negative predictive value. Two studies found97% specificity for a negative amplitude, one for avalue $2 mm in V1 (42), and the other $3 mm with aspecial bipolar chest CF1 lead (35), but with lowersensitivities of 94% for the former and 24% for thelatter.

or ARVC/D Diagnosis

Ventricular Arrhythmia Pathology Genetics

ninationr globalionhy)

NSVT/VT with LBBBmorphology (superiorand/or inferior axis)

PVC> 500/24h

Myocyte loss withfibrous replacementof the RV free wallmyocardium, withor without fattyreplacement oftissue (EMB)

ARVC/D or SCD familyhistory

Presence of a pathogenicmutation

orerator

eakvelocityration in

rain

Morphology of VAs: QRSdlead DI>120 ms, QRSnotching, transition $V5

VAs (PVC, NSVT, VT)originating from multipleRV sites

VAs triggered bycatecholaminergic stress

Low sub-epicardial voltageareas in the right ventricle

Isoproterenol testRV electroanatomic

voltage map

Voltage-mapguided EMB

High-throughputsequencing and largepanels of genes

MB ¼ endomyocardial biopsy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; MDCT ¼ multidetectorl activation duration of QRS; SCD ¼ sudden-cardiac death; TAPSE ¼ tricuspid annular plane systolic excursion;hmia; other abbreviations as in Tables 1 and 2.

TABLE 4 Frequency of Principal ECG Abnormalities Identified in ARVC/D

Nasir et al.(2004)(162)

Cox et al.(2008)(32)

Steriotis et al.(2009)(29)

Peters et al.(2008)(24)

Saguner et al.(2014)(163)

n 50 42 205 360 111

V1V2V3 QRS duration$110 ms

64% 26% 29% 75% NA

V1 þ V2 þ V3/V4 þ V5 þ V6

widths $1.277% 35% 18% 98% NA

V1V2V3 QRS width $25 msof V6 (parietal block)

52% 13% 13% NA 12%

S-wave upstroke $55 ms 95% 24% 18% 83% 32%

Epsilon wave 33% 10% 9% 23% 20%

iRBBB 14% NA 29% NA 3%

RBBB 8% NA 6% NA 12%

QRS fragmentation NA NA NA 85% 38%

TWI V1V2V3 87% 67% 35% 75% 40%

TWI V1V2 76% 76% 7% NA 19%

Inferior TWI NA NA NA NA 54%

SAECG late potentials(according to ARVC/D

extension: mild,moderate, or severe)

56% NA Mild 44%Moderate 58%Severe 93%

77% NA

NA ¼ nonavailable; iRBBB ¼ incomplete right bundle branch block; other abbreviations as in Tables 1 and 3.



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Inverted T waves in inferior leads are not uncom-mon in ARVC/D and are related to left-sided exten-sion, as shown by MRI imaging in patients or relatedfamilies (43,44).

Several nonspecific ST-segment abnormalities canbe found, from flat precordial T waves to Brugada-likeECGs. J-point elevation >1 mm in at least 2 inferiorand/or lateral leads (45) is a frequent finding in >20%of ECGs, reflecting late depolarization. Brugada-likeECGs are difficult to interpret because of the overlapbetween ARVC/D and Brugada syndrome (46–48). Re-sults of Ajmaline testing may be positive in up to 16%of patients with ARVC/D (48), and RV wall motion ab-normalities present in 16% of patients with BrugadaECG pattern (47). The clinical implications of theseoverlapping phenotypes are currently unknown.DEPOLARIZATION DATA. Multiple features havebeen described from V1 to V3, reflecting the widerange of RV parietal blocs (Table 4, Figure 1). Theyconsist of QRS notching (24,49), a wider QRS, larger Swaves, epsilon waves, late potentials at signal-averaged ECG, and incomplete, complete, or atyp-ical RBBB, combined or alone. A RBBB blockmorphology is suggestive of ARVC/D with an R’/Sratio <1 in V1 (41).

A recent paper (31) excellently illustrated the greatvariety of ECG presentations. It comprised 35 cases,all with negative precordial T waves, epicardial andendocardial mapping, and MRI imaging. It showed arelationship between the QRS and disease localiza-tion and extent. When the QRS appeared normal, the

extent of activation after the end of QRS was minimal,mostly subepicardial (Figure 2). The epsilon wavecorresponds to epicardial perivalvular activation. Thewide S-wave is due to delayed activation in both theperivalvular and the right infundibular endocardium.The incomplete RBBB reflects an increased delay inthe same zone. It confirmed that the RBBB pattern isnot due to an alteration of the RBB but to an exit blockof the bundle branch, related to an extended scarzone.

QRS fragmentation is a non-TFC ECG feature inARVC/D. It consists of small deflections or notches, atthe beginning of the QRS, superimposed on the Rwave or the nadir of the S-wave in any right pre-cordial lead, or in >1 of any lead (24,49), particularlyinferior leads. They can be interpreted as the passingactivation front through a scarred zone earlier thanthe late potentials. They are found in up to 85% ofARVC/D cases, including those exhibiting epsilonwaves. However, fragmentations are nonspecific, asthey can also be recorded in many other scar-relatedcardiomyopathies (50), and their definition is notstraightforward because standard ECG filtering mayerase them. QRS amplitude is also not included in theTFC (29,51). Microvoltage is not specific but observedin patients with advanced ARVC/D disease with sig-nificant RV dilatation and better expressed by thesum of QRS amplitudes (52). It can be more specificwhen limited to the right precordium (53) or with theratio of the sums of precordial voltage ratios (54) V1 toV3/V1 to V6 #0.48.

Signal-averaged ECG reveals microvolt-level latepotentials. However, the Simson method, with XYZelectrodes, does not have the proximity effect ofprecordial leads and reflects any late potential origin.Nevertheless, its 3 components (filtered QRS dura-tion, low-amplitude signal, and root mean squareamplitude of the last 40 ms) are highly associatedwith ARVC/D. They are found in >50% of ARVC/Dcases, and their incidence and duration increase withtime, up to 93% in severe forms (29). Its specificity isincreased when combined with RV enlargement orlow ejection fraction, and it enhances the sensitivityof borderline surface ECG (55).

VENTRICULAR ARRHYTHMIAS. ARVC/D ventriculararrhythmias usually have a left bundle branch block(LBBB) pattern. They are characterized by severalmorphologies. A left-axis deviation is suggestive forARVC/D (15,18). The main problem is their differen-tiation from idiopathic arrhythmias when they onlyoriginate from the RV infundibulum, with adescending vertical axis. The most sensitive param-eters are a QRS duration in lead I $120 ms, a QRS

FIGURE 1 The Variety of ARVC/D ECG in Sinus Rhythm Before VT Ablations

(Except #8)

V1 to V3 or V1 to V4 are displayed (amplitude: 10 mm ¼ 1 mV). 1) Normal QRS and inverted

T waves in V1 to V2. 2) Enlarged S-wave and normal T waves. 3) Prolonged S-wave and

epsilon wave as a low voltage r’-wave. 4) Fractionated V1 and V2 in a huge right

ventricular (RV) dilatation (181 ml/m2) and dyskinesia from the anterior and inferior

walls. 5) Incomplete right bundle branch block (RBBB) and T-wave inversion in V1 to V3.

6) RBBB, microvoltage, and T-wave inversion in V1 to V4. 7) Atypical RBBB,

microvoltage, and T-wave inversion in V1 to V3 with fragmentations. 8) Large biphasic

QRS, microvoltage, and T-wave inversion in V1 to V4 in biventricular ARVC/D and heart

failure, after several ablations, before heart transplantation. 9) Epsilon waves in V1.

10) Twelve-lead electrocardiography (ECG) showing normal QRS, T-wave negative in D3,

and flat in aVF in a patient with ARVC/D without RV dilatation/dysfunction but with 2

dyskinetic areas (RV anterior wall and subtricuspid region). ARVC/D ¼ arrhythmogenic

right-ventricular cardiomyopathy/dysplasia.


789

transition in V6, notching on any complex, and earlyQRS onset in V1 (56). Polymorphic premature ven-tricular contraction induction with high-dose isopro-terenol (45 mg/min for 3 min) has been suggested as apharmacological diagnostic test for ARVC/D in pa-tients with premature ventricular contractions, with a99% negative predictive value but a low 43% positivepredictive value (57) (Table 3).

MULTIMODAL IMAGING

Noninvasive imaging techniques play a pivotal role inthe diagnosis and management of ARVC/D. Imagingin ARVC/D diagnosis has been essentially based onvisual assessment of RV segmental motion anomaliesand wall thickness, RV ejection fraction or fractionalarea, and fibrofatty replacement. The current chal-lenges for imaging in ARVC/D diagnosis are earlierdetection of the disease, particularly in cases offocal involvement without RV dilatation/globaldysfunction, and differential diagnosis from otherarrhythmogenic diseases affecting the right ventricle(Table 2). Major drawbacks concerning ARVC/D im-aging include the absence of a standardized pheno-typing and reporting strategy, the subjectivity ofcertain imaging parameters (e.g., wall motion abnor-malities), and the lack of imaging biomarkers testedin multiparametric models assessing diagnosis andrisk.

ECHOCARDIOGRAPHY. Two-dimensional echocardi-ography is the most widely available imagingmethod to evaluate patients with known or sus-pected ARVC/D. Histological changes are notdirectly identifiable by echocardiography but lead tomacroscopic changes, with regional wall motionabnormalities associated with RV dilatation and/orglobal RV systolic dysfunction. Thus, the presenceof segmental wall motion abnormalities, defined asregional akinesia, dyskinesia, or dyssynchrony,combined with RV dilatation and/or RV dysfunction,is required for diagnosis (2010 TFC) (Table 1). Thedegree of RV outflow tract (RVOT) dilatation andthe reduction of RV fractional area determinewhether it is a major or minor criterion (4). Thesecriteria are highly specific but lack sensitivity,especially in early stages when RV dilatation/dysfunction may be absent.

Several robust parameters representing RV systolicfunction, such as tricuspid annular plane systolicexcursion and peak systolic RV annular velocity, aregenerally lower in ARVC/D (tricuspid annular planesystolic excursion <16 mm and peak systolic RVannular velocity <10 cm/s) (58) but usually only inmore advanced forms of the disease. Structural

abnormalities of the right ventricle have been noted inARVC/D, such as a hypertrophic trabecular or hyper-reflective moderator band, but these findings lackspecificity, especially in competitive athletes. Theevaluation of the right ventricle by using echocardi-ography can be challenging because of its retrosternalposition and its complex geometry. In addition, theassessment of wall motion abnormalities is highlysubjective and requires specific expertise.

Contrast echocardiography can improve theassessment of RV wall motion in cases of poor

FIGURE 2 Example of an ARVC/D Patient Carrying a PKP2 Mutation Presenting With VT From Subepicardial RVOT and Minor ECG Abnormalities

The ECG only displayed increased duration of the terminal QRS from the nadir of the S-wave to the end of the QRS in right precordial leads and T-wave inversion in V1 to

V2 (A and C; minor criteria). The signal-averaged ECG displayed late potentials (not shown). The patient developed ventricular tachycardia (VT) from right ventricular

outflow tract (RVOT) (B). The endocardial bipolar voltage map (D; 0.5 to 1.5 mV) showed normal endocardial voltage except small patchy area within the anterior RVOT

contrasting with the large low-voltage subepicardial areas extending from the anterior RVOT to the RV inferior wall (E: epicardial bipolar voltage map; 0.5 to 1.5 mV).

Abbreviations as in Figure 1.



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image quality (59). New echocardiographic tech-niques, such as 3D echocardiography and tissuedeformation imaging, may increase the performanceof echocardiography, especially in early stages.3D echocardiography allows the measurement of RVvolumes and the RV ejection fraction (60), but itsvalue in advanced ARVC/D with very large rightventricles must be established. The two-dimensional(2D)-strain echocardiographic method can measuremyocardial deformation by tracking localized acous-tic markers frame by frame (speckle tracking)(Figure 3). Left and right longitudinal strain derivedfrom speckle tracking could be sensitive tools forassessing regional and global myocardial function(61,62). A cutoff value of –18% peak systolic strain wasproposed to differentiate between normal andabnormal RV segments (58). RV strain may also beuseful for detecting RV subclinical systolic dysfunc-tion, especially in first-degree relatives of patientswith ARVC/D (63) (Table 3). Moreover, RV mechanicaldispersion (heterogeneous contraction), assessed by

strain, may reflect electrical dispersion and could be aprognostic marker of arrhythmic events (64). Tissuedeformation imaging is therefore a promising tech-nique, but image acquisition, reproducibility, andquality are still limiting factors. Both multiplane and3D speckle tracking are promising new applications inRV deformation imaging.

MAGNETIC RESONANCE IMAGING. Strengths andWeaknesses of MRI for ARVC/D Diagnos i s . MRIcan assess biventricular morphology, volumes,thickness, and mass, as well as regional motion andmyocardial fibrous or adipose content, edema, andflow, with high spatial and temporal resolution,independently of body size or acoustic windows.

Initial studies focused on the identification of ad-ipose infiltration within a thinned RV wall on T1-weighted spin echo images, which proved to beinconsistent and poorly reproducible (65). Similarly,61% of patients were shown to display late gadolin-ium enhancement (LGE) of the RV wall, a

FIGURE 3 Right Longitudinal Strain in a Patient With ARVC/D and PKP2 Mutation

Example of determination of right longitudinal strain in an apical 4-chamber view with color display of peak systolic strain. Global longitudinal

strain (septum þ RV free wall) is low: –12.4%. Note the low peak systolic strain in the 3 segments of the free wall: basal strain, –7%; mid

strain, –14%; and apical strain, –14% (bottom). Abbreviations as in Figure 1.


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well-established marker of dense replacementfibrosis in contrast-enhanced MRI (66). Neither ofthese parameters was included as diagnostic criteriain the 2010 TFC, which focused on RV dilatationand/or global dysfunction associated with severeregional contraction anomalies, including akinesia,dyskinesia, and asynchronous contraction (Table 1).

Indeed, the direct visualization of fibrofattyreplacement by MRI as a diagnostic hallmark facesseveral problems. First, direct visualization of RVintramyocardial fibrosis and fat is made technicallydifficult by the thin RV wall in terms of the achievablespatial resolution of MRI, potentially resulting inmisleading partial volume effects. Second, fattyinfiltration of the myocardium has been shown to befrequent and nonspecific to ARVC/D (67). Third, LGEis also nonspecific and present in numerous ischemicor nonischemic diseases potentially involving theright ventricle, including myocarditis and sarcoidosis.Differential diagnosis between ARVC/D and myocar-ditis may be particularly challenging because somepatients with ARVC/D can present with acute or sub-acute myocarditis (7,68). Moreover, subepicardialLV LGE can be present in ARVC/D, leading to over-diagnosis of myocarditis. Furthermore, if fat and

fibrosis have been approached separately, the directvisualization and quantification of the fibrofatty mix—the true hallmark of the disease—is still an unresolvedchallenge, as these 2 components are not individuallyidentifiable at the macroscopic scale. ARVC/D diag-nosis is therefore based on demonstrating the conse-quence of intramyocardial fibrofatty replacement,namely static morphological abnormalities (sponta-neous aneurysm or bulging) and dynamic morphology(akinesia, dyskinesia, or asynchrony). The segmentalcombination of myocardial thinning, severe abnormalmotion, and fatty infiltration is in favor of fibrofattyreplacement, whereas the presence of fat in asegment of normal thickness and contraction is morelikely to be related to nonspecific fatty infiltration(69). The absence of RV myocardial fat according to anMRI does not preclude the diagnosis of ARVC/D, asshown in pediatric patients (70), nor should thepresence of fat be interpreted alone.

MRI is the reference method to assess ventricularvolumes and regional function independently ofgeometric assumptions, with high intra-observer andinterobserver reproducibility (71). However, thediagnosis of RV wall motion abnormalities remainssubjective and dependent on personal expertise, with

FIGURE 4 MRI Acquisition Protocol and Corresponding RV Segmentation

Steady-state free precession Sequences are used for classical exploration: 2, 3, 4-cavities and small axis (SA) from the base to the apex of the heart (SA basal; SA mid;

and SA apical). However, for comprehensive exploration of the right ventricle, an axial or 4-chamber stack covering the heart is very useful for the diagnosis of ARVC/D

because it allows overall visualization of the contraction of the lateral free wall and the transverse movement of the pulmonary infundibulum. The 2-cavity view

centered on the right ventricle (RV 2-chamber) allows positioning of the view in the axis of the RVOT, which will itself serve to position an infundibular view unrolling

the right cavities. These last 2 views (RVOT1 and RVOT2), specific to RV exploration, are particularly useful for the diagnosis of localized forms that can involve the

infundibulum. The RV 2-chamber view is particularly useful for tricuspid, apical, and infundibular forms. Abbreviations as in Figures 1 and 2.



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only low to moderate intra-observer and interob-server reproducibility (70). This situation highlightsthe importance of standardized and regional biven-tricular analysis of the right ventricle for optimaldiagnostic performance with high spatial and tem-poral resolution cine steady-state free precession(SSFP) imaging that covers all RV segments in severalperpendicular orientations (Online Appendix,Figure 4). With comprehensive biventricular analysis,96% of cardiovascular magnetic resonance examina-tions from 74 mutation-positive ARVC/D patientsrevealed an abnormal right ventricle (72). The mostprevalent RV abnormalities were basal inferior walldyskinesia (94% of patients) and basal anterior walldyskinesia (87% of patients). In the same study, LVinvolvement concerned 52% of patients and led toredefining the initial dysplasia triangle, including theposterior lateral wall of the left ventricle, along withthe subtricuspid and anterior wall of the rightventricle. Typical MRI findings corresponding to thisdescription are illustrated in Figure 5.

MRI has been shown to be particularly useful indistinguishing ARVC/D from alternate diagnoses (73).Several limitations of the MRI criteria in the 2010 TFChave been discussed (65,74). They include basing thevolumetric RV data thresholds on middle-aged andelderly patients (45 to 85 years of age) from the MESA

(Multi-Ethnic Study of Atherosclerosis) trial,excluding younger adults, and measurements fromgradient echo cine-MRI, which provides lower valuesthan currently used cine-SSFP techniques. Never-theless, a study in a pediatric population showed thatMRI was associated with good sensitivity (70), despitethese potential limits. A normal MRI was found tohave an excellent negative predictive value of 99%for major clinical events in a 4.3-year follow-up of 369consecutive patients suspected of having ARVC/D,and abnormal MRI was an independent predictor ofevents with a cumulative effect of several anomalies(including morphology, wall motion abnormalities,and fat/fibrosis) (75).ADVANCES IN MRI. Although the thin RV wall re-mains a technical challenge for direct assessment oftissue composition according to MRI, there have beentechnical advances since the 2010 TFC. New insightscome from large population studies that providenormative volumetric data from current cine-SSFPimaging techniques (76,77), but large-scale compari-son with ARVC/D probands is still necessary to betterdefine actual threshold values. Longitudinal data onthe phenotypical evolution of the disease are alsohighly desirable. The existing 2010 TFC weredesigned to be more specific than sensitive, intro-ducing a bias favoring more advanced forms of the


FIGURE 5 Typical MRI Findings in a Patient With Definitive ARVC/D and a PKP2 Mutation

High-resolution short-axis cine steady-state free precession (SSFP) (A, diastole; B, systole), showing thinning and akinesia of the RV free wall and left ventricular lateral

wall (arrows), bulging of the inferior RV wall (akinetic), and junction with the free wall (stars), as well as enlargement of the RVOT. Two-chamber RV cine SSFP views

(E, diastole; F, systole), showing bulging of the inferior RV wall, which is akinetic (stars) and dyskinetic infundibular aneurysm (arrows). Orthogonal RVOT 1 (C, D) and

RVOT 2 (G, H) views in diastole and systole from high-resolution cine SSFP, showing bulging of the inferior RV wall, which is akinetic (stars) and dyskinetic infundibular

aneurysm (arrows). Inversion recovery sequences in the short-axis (I) and long-axis (J, K) views, showing late gadolinium enhancement corresponding to the

aforementioned areas of morphological or functional anomalies and of the left ventricular lateral wall (intramural) and inferior basal wall (epicardial) in continuity with

the basal sub-tricuspid RV involvement. Heterogeneous fatty infiltration of the RV free wall and inferior wall on a dark-blood proton-density short-axis image (L),

illustrating the difficulty to diagnose fatty infiltration. Abbreviations as in Figures 1, 2, and 4.


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disease. It is likely that the true value of MRI to detectearly disease and provide incremental value to strat-ify risk is underestimated. Multiparametric models inlarge datasets, including modern imaging biomarkersand genetics, will likely provide decisive insights inthe near future.

Semi-automated myocardial deformation quantifi-cation may be a promising approach to lower vari-ability in assessing RV function, particularly featuretracking, which, contrary to tagging techniques, canbe applied to routine cine-MRI (Table 3).

Reproducibility for RV strain measurement usingfeature tracking has recently been shown to be good(interobserver, intraclass correlation coefficient>0.86; interstudy, intraclass correlation coefficient>0.71) (78). Global longitudinal and circumferentialRV strain and strain rates at the base assessed byusing feature-tracking MRI were shown to be signifi-cantly lower in ARVC/D probands than in healthyvolunteers and family relatives (79,80). Moreover, theglobal longitudinal strain rate was found to be lowerin patients with ARVC/D and preserved RV ejection

FIGURE 6 Cardiac MDCT in ARVC/D

Measuring RV and left ventricular (LV) volumes using LV endocardial (red), epicardial (green), and RV endocardial (yellow) contours in

(A) 4-chamber and (B) short-axis views. Color-coded inversed multidetector computed tomography (MDCT) images demonstrating

intramyocardial fatty infiltration (white) of the RV free wall in (C) 4-chamber view and (D) inferior mid-RV wall in short-axis view.

Four-dimensional CT angiography: anterior view illustrating the usefulness of dynamic four-dimensional imaging with (E) only minor

bulging in diastole, leading to (F) dyskinesia in systole of the free wall/inferior wall junction. Other abbreviations as in Figure 1.



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fraction. Quantitative measures of asynchronous RVcontraction by feature-tracking MRI, as reported byPrati et al. (80), may be particularly useful, as thiscriterion (included in the 2010 TFC) is particularlyprone to subjectivity. Regional feature-tracking strainanalysis could be more sensitive than global param-eters. Predominant impairment in the subtricuspidregion allowed the discrimination of preclinicalARVC/D (mutationþ/phenotype–) from healthy con-trols, consistent with prior knowledge on the regionalexpression of ARVC/D (72), whereas global strain wasnondiscriminant (81). The continued use ofT1-weighted spin echo images to visualize fat lacksdiagnostic performance, but new techniques mayhelp in characterizing fatty content. In particular,ECG-gated Dixon techniques allow specific imagingseparating the fat from the water component of themyocardium (82), but they currently remain insuffi-ciently available and validated in this disease setting.Conversely, high-resolution 3D LGE, with highisotropic spatial resolution (1.4mm3) images using

compressed sensing techniques, has been introducedand initially applied to the left ventricle with prom-ising results (83). Further improvements in spatialresolution may allow reliable RV wall characterizationin the near future.

CARDIAC COMPUTED TOMOGRAPHY

Although computed tomography (CT) scanning is notincluded in the 2010 TFC (4), it was considered to beappropriate in this setting according to a contempo-rary expert consensus (84). This modality, withexcellent isotropic spatial resolution of 0.5 mm,4-dimensional (4D)-cine capability, and recentlyachievable lower radiation doses (1 to 2 mSv), mayplay a role in distinguishing ARVC/D from othercauses of ventricular arrhythmias such as coronaryheart disease (65) (Table 3). Seminal studies per-formed with single-slice, non–ECG-gated CT imagingor electron-beam CT imaging in small patient groupsshowed the potential to detect RV enlargement and


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regional motion abnormalities and a scalloped RVsurface, as well as epicardial or intramyocardial fat ofthe RV free wall, trabecular enlargement, and adiposeinfiltration (85–90). Good correlations were reportedwith histology, albeit on very few samples and withinevitable sampling bias (87).

After these initial studies, several case reports re-ported translation to the use of multidetector CT(MDCT) imaging (91–94). Nakajima et al. (95) evalu-ated the diagnostic performance of MDCT in 77 pa-tients and proposed a scoring system based on RVfatty infiltration, RV free-wall bulging, and RV dila-tation for a definite ARVC/D diagnosis, according tothe 2010 TFC, with high performance (87% sensi-tivity, 94% specificity, and 92% accuracy). Regionalwall motion abnormalities assessed by dynamic RVdatasets (available in 21 patients) were consistentwith MRI or 2D-echo data in all cases but were notincluded in the proposed score. However, one of themain limitations in this study was the use of existing2010 TFC criteria as the “gold standard” instead ofgenetics. Remaining knowledge gaps include thevalue of regional wall motion abnormalities in CTimaging, in addition to RV dilatation, bulging, andfatty infiltration and the position of MDCT in thediagnostic and prognostic evaluation of patientssuspected of having ARVC/D.

Modern MDCT allows fast acquisition and highisotropic spatial resolution (0.5 mm), permitting pre-cise RV and LV volume measurements validatedversus MRI (96). 4D-cine CT imaging may favorablyreplace RV angiography due to its advantages, such asproviding full 4D coverage of RV wall dynamics andpotentially increased sensitivity to detect focal pre-sentations of the disease. An advantage of 4D CT im-aging is its ability to reveal the complex anatomy ofthe right ventricle, alleviating the risk of image su-perposition and limited views of standard 2D angi-ography. In addition to these functional parameters,high spatial resolution, combined with the high nativecontrast of adipose tissue, allows precise depiction offatty infiltration within the thin RV wall, with orwithout contrast injection, as illustrated in Figure 6(97); good correlations are achieved with epicardialand endocardial low-voltage areas (98). Theseencouraging image integration methods may help infocusing ablation therapy of culprit lesions and war-rant further study. MDCT is widely available, fast, andaffordable. Patients for whom MRI is challenging,such as those with severe arrhythmia, claustrophobia,and implantable cardioverter-defibrillators, as well asthose with suspicion of focal ARVC/D, may particu-larly benefit from this technique.

GENETICS OF ARVC/D

The role of genetic testing has dramatically increasedin ARVC/D diagnosis. Major diagnostic criteria forARVC/D have included the presence of a pathogenicmutation since 2010. To date, 16 genes have beenassociated with the ARVC/D phenotype, mostly thoseencoding desmosomal proteins (so-called desmo-somal genes) (Table 5, Central Illustration). Candidategene or linkage studies have identified othercardiomyopathy/channelopathy-associated genes inpatients with an ARVC/D phenotype or arrhythmo-genic biventricular cardiomyopathy, expanding thegenetic and phenotypic spectrum of the disease.However, the genetic cause of ARVC/D remains un-known for 40% to 50% of patients.

DESMOSOMAL GENES. ARVC/D is mainly caused bymutations in genes encoding the desmosomal pro-teins plakophilin-2 (PKP2), desmoglein-2 (DSG2),desmoplakin (DSP), and, more rarely, desmocollin-2(DSC2) and plakoglobin (JUP) (Table 5, Centralillustration) (99). Desmosomes are membrane pro-tein complexes that play an important role in inter-cellular adhesion and maintenance of the structuralintegrity of tissues subjected to mechanical stress,such as the heart and skin. These mutations usuallyhave an autosomal dominant mode of inheritancewith incomplete penetrance, leading to an isolatedcardiac phenotype. Various types of mutations(missense, nonsense, splice-site, frameshift, andlarge deletions) have been reported, and most areprivate. Desmosomal gene mutations have beenidentified in 33% to 63% of ARVC/D probands(10,100–104). PKP2 is the major ARVC/D disease-causing gene, accounting for 36% to 92% ofmutations identified in desmosomal genes.

Data from familial studies showed that desmo-somal mutations are associated with low pene-trance, as only one-third of relatives carryingmutations fulfill definitive ARVC/D diagnosis, ac-cording to international 2010 TFC (10,102). Womencarrying desmosomal gene mutations are at lowerrisk of expressing the disease than men and arethus more likely to be healthy mutation carriers(105,106). The causes of such sex-related penetranceare not yet fully understood, but higher levels ofparticipation in competitive and intensive sports bymen (107) or hormonal factors (108) could explainsome differences.

PKP2 mutations are mostly autosomal dominantand are more likely to lead to isolated RV involve-ment and a conventional phenotype than otherdesmosomal mutations (72). Bao et al. (101) suggested

TABLE 5 List of Genes Associated With ARVC/D

Gene ProteinFrequencyin ARVC‡ Structure

Type ofMutations

Mode ofInheritance

PhenotypeAD

Phenotype AR/Compound

HeterozygousOMIMEntry

Genotype/PhenotypeStudies Ref. #

PKP2 Plakophilin-2 20%–45% Desmosome Non-missense þþ(splice-site,nonsense, ins/del, large del)

Missense

AD þþþ,(AR)

ARVC ARVC†DCM†

ARVC9 ConventionalARVC/Dphenotype

(10,100–104,114,115,143,144)

DSG2 Desmoglein-2 4%–15% Desmosome Non-missense(splice-site,nonsense, ins/del)

Missense

ADþþþ,AR

ARVCBiVCM

ARVCBiVCM

ARVC10 Frequent LVinvolvement

(10,100–104,114,115,143,145,146)

DSP Desmoplakin 1%–13% Desmosome Non-missense(splice-site,nonsense, ins/del, large del)

Missense

ADþþ, AR ARVC; ALVC, DCMCardio-cutaneous

SdCCD†

Cardio-cutaneous Sdwith ARVC/BiVCM orDCM

Cutaneous Sd†


High risk of VAsand HF

Cardio-cutaneousSd

(10,43,68,100,103,104,111,114,115,143,147–150)

DSC2 Desmocollin-2 1%–7% Desmosome Non-missense(splice-site,nonsense, ins/del)

Missense

ADþþ, AR ARVC, BiVCMcardiomyopathy

BiVCM Cardio-cutaneousSd†


(10,100–103,114,115,143,151–154)

JUP Plakoglobin 0%–1% Desmosome Non-missense(splice-site,nonsense, ins/del)

Missense

AD,ARþþþ ARVC CardiocutaneousSd withARVC/D (orDCM)

Cutaneous Sd

ARVC12 Cardio-cutaneousSd with ARVC

(10,100–103,114,115,143,155)

CTNNA3 Alpha-T-catenin

<1% Intercalateddisk

MissenseDel

AD ARVC _ ARVC13 Low penetrance (117)

CDH2 N-Cadherin 2%* of patientswith negative

geneticscreening(missense)

Intercalateddisk

Missense AD ARVC _ _ (120)

TMEM43 LUMA <1% Nuclearenvelop,intercalateddisk,sarcolemma

MissenseSplice-site

AD ARVCEDMD

_ ARVC5 LV involvement,high risk ofSCD and HF

Poor R-waveprogressionon ECG

(18,122,156,157)

LMNA Lamin A/C 3%–4% Nuclearenvelop

MissenseNonsense

AD DCM/BiVCM/ARVCwith CCD, AF,VAs � musculardystrophy

_ _ CCDFrequent LV

involvementHigh risk of HF

(19,123,124,158)

DES Desmin <1% Intermediatefilament

Missense AD DCM/BiVCM/ARVCwith CDD, AF,VAs � musculardystrophy

_ ARVC7 Musculardystrophy

CCDFrequent LV

involvement

(125,126,159)

TTN Titin 18%* of ARVC/Dpatients with

negativegeneticscreening(missense)

Sarcomere Missense AD ARVC/BiVCM _ _ Frequent CCDFrequent LV

involvement

(131)

PLN Phospholamban 0%–12%(Netherlands)

Calciumregulatoryprotein

Del AD DCMBiVCMARVCHCM

_ _ Micro-voltageLV involvementHigh risk of HF

and SCD

(20)

Continued on the next page



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that patients with PKP2 mutations could be at higherrisk of ventricular arrhythmias during follow-up, butthis theory was not confirmed in a large U.S./Dutchregistry (105).

Patients with DSP mutations can present withvariable phenotypes, such as typical ARVC/D,

biventricular cardiomyopathy, or isolated LVarrhythmogenic cardiomyopathy. Thus, DSP muta-tions are identified in 3% of patients with DCM (109,110). Phenotype/genotype studies suggest that DSPmutations are associated with a severe ARVC/Dphenotype, with a higher risk of ventricular

TABLE 5 Continued

Gene ProteinFrequencyin ARVC‡ Structure

Type ofMutations

Mode ofInheritance

PhenotypeAD

Phenotype AR/Compound

HeterozygousOMIMEntry

Genotype/PhenotypeStudies Ref. #

RYR2 Ryanodine-receptortype 2

9%* of ARVC/Dpatients with

negativegeneticscreening(missense)

Calciumregulatoryprotein

Missense AD CPVT � rightventricularinvolvement

ARVC

_ ARVC2 Exercise-inducedpolymorphicVAs

(129,130)

SNC5A Nav1.5 0%–2%* Cardiac sodiumchannel

Non-missense(nonsense,del)

Missense

AD Brugada SdLong QT SdAFCDDDCMARVCMEPPC

_ _ Prolonged QRSduration

(127,128)

TP63 P63 1 case report Transcriptionfactor

Missense AD Ectodermicdysplasia þARVC†

ADULT Sd

_ _ Ectodermaldysplasia

(160)

TGFB3 TGF-beta 3 2 families Transforminggrowthfactor

30 and 50UTR AD ARVC _ ARVC1 _ (161)

*Frequency of rare missense variants. †Unique observation in the literature. ‡Patients with ARVC/D phenotype fulfilling task force criteria.

AD ¼ autosomal dominant; AF ¼ atrial fibrillation; ALVC ¼ arrhythmogenic left ventricular cardiomyopathy; AR ¼ autosomal recessive; BiVCM ¼ biventricular cardiomyopathy; CCD ¼ cardiac conductiondisease; CPVT ¼ catecholaminergic polymorphic ventricular tachycardia; DCM ¼ dilated cardiomyopathy; del ¼ deletion; EDMD ¼ Emery-Dreifuss muscular dystrophy; HCM ¼ hypertrophic cardiomyopathy;HF ¼ heart failure; ins ¼ insertion; MEPPC ¼ Multifocal ectopic Purkinje-related premature contractions; SCD ¼ sudden cardiac death; Sd ¼ syndrome; UTR ¼ untranslated region; other abbreviations as inTables 1 and 3.


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arrhythmias and sudden cardiac death (SCD) and ahigh level of LV involvement (105,106,111), particu-larly in patients with truncating DSP mutations (111),leading to a higher risk of end-stage heart failure. DSPmutations may be associated with more frequent T-wave inversion in leads V4 to V6 and microvoltage(106).

DSG2 mutations have been associated withfrequent biventricular involvement from 20% (105) to50% (103). In our experience, DSG2 mutation carrierspresent a higher risk of developing end-stage heartfailure that could lead to cardiac transplantation ordeath than PKP2 mutation carriers (112). However,this outcome was not found in the U.S./Dutch registry(105). Similarly, DSC2 mutations can also lead tobiventricular cardiomyopathy, particularly in thehomozygous state (113).

Rarely, homozygous or compound heterozygousJUP, DSP, or DSC2 mutations and rare cases of het-erozygous DSP mutations can lead to cardio-cutaneous syndrome diseases associating right orbiventricular arrhythmogenic cardiomyopathy withcutaneous (palmoplantar keratoderma, alopecia, andskin fragility), hair (wooly hair), and/or dental ab-normalities (oligodontia), such as Naxos and Carvajalsyndromes (Table 5).

Patients with multiple desmosomal mutations(compound or digenic heterozygosity) are not rare,ranging from 4% to 6% (103,105) to 16% to 20%

(101,106). Several studies have suggested a modifierrole of desmosomal missense variants, especially inPKP2 (106,114). Patients with a complex genetic status(homozygous, compound heterozygous, or doubleheterozygous) present a more severe phenotype, withhigher penetrance (10,115), earlier onset of ventriculararrhythmias (105,106), higher risk of SCD (103), andmore frequent LV involvement and risk of heart fail-ure (103,105,116).NON-DESMOSOMAL GENES. Other genes have beenassociated with the ARVC/D phenotype (Table 5). Twomutations in CTNNA3, which encodes alpha-T-catenin (a component of the cardiac area compo-sita), were identified in the Italian ARVC/D cohort(117) but were absent from other European cohorts(118,119). Missense variants in CDH2, encoding thejunction protein N-cadherin, were also recentlyidentified in 2 white South African families (120).

Funder mutations in TMEM43, which encodes anuclear envelop protein (LUMA), have been identifiedin the Newfoundland population (p.S358L) and at alow frequency in other populations (18,101,105,121).The founder TMEM43 p.S358L mutation was associ-ated with high penetrance and high risk of SCD andheart failure, especially in men, with poor R-waveprogression and frequent LV dilatation (18, 122).

Mutations in LMNA, encoding the Lamin A/C nu-clear envelop protein, and DES, encoding the inter-mediate filament desmin, have been identified in

CENTRAL ILLUSTRATION Schema of Encoded Proteins Associated With ARVC/D Phenotype

Gandjbakhch, E. et al. J Am Coll Cardiol. 2018;72(7):784–804.

Encoded proteins (genes) associated with arrhythmogenic right-ventricular cardiomyopathy/dysplasia (ARVC/D) phenotype are shown in red: plakophilin-2 (PKP2);

desmoglein-2 (DSG2); Desmoplakin (DSP); desmocollin-2 (DSC2); plakoglobin (JUP); alpha-T-catenin (CTNNA3); N-cadherin (CDH2); LUMA (TMEM43); Lamin A/C

(LMNA); desmin (DES); titin (TTN); phospholamban (PLN); ryanodine-receptor type 2 (RYR2); Nav1.5 (SNC5A); P63 (TP63); and TGF-beta 3 (TGFB3).



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patients with arrhythmogenic right predominant orbiventricular cardiomyopathy mimicking ARVC/D.LMNA and DES mutations classically cause DCM withconduction disease (atrioventricular block or sinusnode dysfunction), frequent ventricular arrhythmias,and/or muscular dystrophy. Patients with LMNA- orDES-related “ARVC/D” usually develop severe heartfailure and display conduction disease (atrioventric-ular block or sinus dysfunction) (19,123–126). Simi-larly, the p.R14del founder mutation in PLN,encoding the calcium regulatory protein phospho-lamban, can cause arrhythmogenic DCM and biven-tricular or predominant right cardiomyopathy. PLNmutations were found in up to 12% of Dutch patientswith ARVC/D, but at a lower frequency in other pop-ulations, and are characterized by frequent micro-voltage and a high risk of SCD and heart failure (20).

Missense variants in SCN5A, encoding the sodiumchannel Nav1.5, were identified in Chinese and, morerecently, North American patients with ARVC/D(127,128). The ARVC/D phenotype associated withSCN5A variants is unremarkable, except for a pro-longed duration of QRS with no evidence of a Brugadaor long-QT ECG pattern. SCN5A mutation was alsoidentified in a patient with overlapping phenotypebetween Brugada syndrome and ARVC/D (47). Muta-tions in RYR2, which classically cause catecholamin-ergic polymorphic ventricular tachycardia, have beenidentified in patients presenting with exercise-induced polymorphic ventricular arrhythmias andRV cardiomyopathy in a borderline phenotype withcatecholaminergic polymorphic ventricular tachy-cardia (129). Rare RYR2 missense variants have alsobeen found in patients with a conventional ARVC/D


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phenotype. However, the role of RYR2 in ARVC/Dmust still be clarified because of the high backgroundrate of rare missense RYR2 variants (130). Similarly,rare missense variants in TTN, encoding the sarco-meric protein titin, have been found in a highproportion of patients with ARVC/D. Their pathoge-nicity is difficult to ascertain, however, due to thehigh frequency of rare missense TTN variants in thegeneral population (131).

IMPACT AND CHALLENGES OF GENETIC SCREENING

IN ARVC. During the last 10 years, genetic screeningand phenotype/genotype analyses have expanded theclinical and genetic spectrum of the disease. Thereare clearly large genetic and phenotypic overlapsbetween ARVC/D and DCM and, to a lesser extent,ARVC/D and the channelopathies, raising the largerconcept of “arrhythmogenic cardiomyopathy.” How-ever, this terminology is probably too broad to sub-stitute to ARVC/D. Desmosomal mutations are morefrequent in patients who fulfill an ARVC/D diagnosisaccording to international TFC, suggesting that theconventional ARVC/D phenotype is mainly a desmo-somal disease (132). Severe or biventricular presen-tation, as well as atypical features (e.g., conductiondisturbances, early atrial arrhythmias, clinical orsubclinical muscular dystrophy, polymorphic ven-tricular arrhythmias, arrhythmias originating fromthe left ventricle), should raise suspicion of muta-tions in non-desmosomal genes and lead to broadergenetic screening. Conversely, desmosomal genemutations, in particular DSP, should be suspected inarrhythmogenic DCM. Genotype/phenotype studieshave shown that genotype could be useful for prog-nostic stratification, especially in terms of the risk ofsudden death or heart failure (Table 5).

The clinical diagnosis of relatives is particularlydifficult in ARVC/D because of the low penetrance ofmutations and variable expressivity. Only one thirdfulfill definitive TFC diagnosis (10,105). Thus, clinicalscreening is usually not sufficiently accurate topredict their genetic status. Moreover, phenotype andpenetrance in ARVC/D are age dependent, andphenotypically negative relatives may present withsymptoms and cardiomyopathy years after initialscreening (133). The identification of the disease-causing mutation in ARVC/D families is thereforehighly important for identifying relatives at risk ofdeveloping or transmitting the disease and facili-tating genetic counseling. Genetic testing is recom-mended for relatives when the disease-causingmutation is known (133–135). However, geneticscreening in probands is negative for 40% to 50% ofpatients with ARVC/D. Thus, a negative genetic

screening result for a proband does not excludeinherited ARVC/D. If the mutation is unknown,repeated lifelong screening is recommended for first-degree relatives, as late expression of the disease isnot rare (136). Genetics can also help in borderlinephenotypes when a definite diagnosis is necessary,such as for competitive athletes.

VALUE OF HIGH-THROUGHPUT SEQUENCING FOR

ARVC/D DIAGNOSIS. The development of high-throughput sequencing, such as whole exomesequencing, whole genome sequencing, or targetedcapture sequencing, now allows rapid and low-costscreening of a large number of genes. Targeted cap-ture sequencing of all known ARVC/D–associatedgenes represents a cost-effective technique forroutine molecular diagnosis. This strategy can alsodetect at the same time point or small ins/del muta-tions, as well as copy number variations, which havebeen recently identified in a significant number (6%to 7%) of ARVC/D patients with initially negativegenetic screening results (137,138). The use of wholeexome sequencing for routine genetic diagnosis canbe limited by technical issues, such as low coverage ofsome regions. Whole exome and whole genomesequencing are, however, powerful research tools. Inthe past 2 years, whole exome sequencing led to theidentification of 2 new candidate genes: SCN5A andCDH2. In addition, rare genetic variants of unknownsignificance were identified in other cardiomyopathy/channelopathy–associated genes (132,138), possiblyexpanding the genetic complexity of the disease.

One major issue for broad genetic screening is theinterpretation of rare genetic variants, especiallymissense variants or variants in non-desmosomalgenes (138,139). Several PKP2 missense variants thatwere initially considered to be disease causing weresubsequently classified as neutral polymorphisms(140,141). In addition, the number of genetic variantsof unknown significance increases with the numberof genes tested. These variants of unknown signifi-cance cannot be used for genetic predictive testing inrelatives. The classification of variants is currentlybased on bioinformatics prediction software andmutation scale frequency (usually <0.01%) in popu-lation genetics databases, such as Genome Aggrega-tion Database (gnomAD), according to the AmericanCollege of Medical Genetics and Genomics guidelines(142). However, these tools face limitations, inparticular for classification of new missense variants.Informative segregation studies within families arecritical to assess the pathogenicity of new geneticvariants but are often limited by the small size of thefamilies and incomplete penetrance of the disease.



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The sharing of genetic results in large databases andthe development of new bioinformatics tools willcertainly improve the interpretation of geneticscreening results in the future.

CONCLUSIONS

It is important to classify cardiomyopathies on thebasis of the clinical phenotype. ARVC/D diagnosis isparticularly difficult due to the absence of uniquespecific diagnosis criteria, the incomplete penetrance,and the large spectrum of clinical manifestationsfrom focal RV involvement to biventricular or leftdominant cardiomyopathy. ARVC/D is to be sus-pected in case of RV ventricular arrhythmia, a familyhistory of ARVC/D or SCD, or a major TFC according tosystematic ECG. The main problem with ECG andimaging manifestations is that they reflect only a RVcardiomyopathy, of which ARVC/D is the mostfrequent etiology. The second limitation is the lack ofsensitivity of actual imaging techniques for earlydiagnosis in case of focal RV involvement and the lackof specificity for differential diagnosis with someother arrhythmogenic diseases involving the rightventricle. Third, several ECG and imaging criteria areprone to subjectivity. We therefore recommendcombining 2 different imaging techniques with stan-dardized protocols to focus on the right ventricleto improve the accuracy of imaging diagnostics.Follow-up of relatives who have minor cardiac

abnormalities by using echocardiography and MRIalso seems reasonable to detect progressive disease.

Recent techniques such as semi-automatedmyocardial deformation quantification by echo/MRIor MDCT with 4D CT imaging are promising tools thatneed to be validated in larger cohorts with geneticvalidation and in multiparametric models. Geneticdiagnosis is particularly useful to confirm the clinicaldiagnosis and to screen relatives at risk but also fordifferential diagnosis from other inherited cardio-myopathy/channelopathy involving the rightventricle and prognostic stratification. However,diagnostic genetics also has limitations, as geneticscreening is only contributive in w50% of cases and issometimes difficult to interpret. The identification ofadditional diagnostic criteria, such as biomarkers,and of the remaining genetic causes of the disease isan important area of research that will certainlyimprove diagnosis in the future.

ACKNOWLEDGMENTS In memory of Pr. Guy Fon-taine (1936 to 2018), who first described ARVC/D anddedicated his life to improving the scientific knowl-edge of this disease.

ADDRESS FOR CORRESPONDENCE: Dr. EstelleGandjbakhch, Institut de Cardiologie, APHP, HôpitalPitié-Salpêtrière, 45-87 boulevard de l’hôpital, 75013Paris, France. E-mail: [email protected]: @egandj, @Inserm, @ICAN_Institute.

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KEY WORDS ARVC, ARVD, diagnosis,genetics, imaging

APPENDIX For an expanded Methodssection, please see the online version ofthis paper.












































































































clinical diagnosis, imaging, and genetics of arrhythmogenic right … · 2018-07-30 · the present...

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