JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 72, NO.

7, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Clinical Diagnosis, Imaging, and Genetics

of Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia
JACC 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

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 a
specific entity in the 1970s by our group
when several patients with drug-resistant right ven-
tricular (RV) tachycardia had surgery guided by
epicardial mapping. Interventions provided evidence
of their RV origin, with RV dilatation, late potentials,
left-sided extension, and fibrofatty infiltration in RV
biopsy specimens (1). Guy Fontaine coined the term
dysplasia, appropriate for this condition, and pub-
lished the first large series in 1982 with Frank Marcus,
including 22 severe cases with RV arrhythmia, 12 of
which needed surgery (2). All had local or global RV
enlargement and showed electrocardiography (ECG)
abnormalities with T-wave inversions in the RV pre-
cordial leads from V 1 to V4 and late potentials, either
obvious by ECG (called epsilon waves) or signal-
averaged ECG.
ARVC/D has been included in the classification of
the European group for cardiomyopathies since 1994.
The denomination of this cardiomyopathy has been
discussed for years. The “ARVC” and “ARVD”

Listen to this manuscript’s

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aSorbonne Universités, UPMC Univ Paris 06, INSERM 1166, Paris, France; bAPHP, Pitié-Salpêtrière University Hospital,
Institute of Cardiology, Paris, France; cCentre de Référence des Maladies Cardiaques Héréditaires, Paris, France; dInstitute of
Cardiometabolism and Nutrition (ICAN), Paris, France; eAPHP, Pitié-Salpêtrière University Hospital, Department of Cardiovascular
and Thoracic, Imaging and Interventional Radiology, Institute of Cardiology, Paris, France; fSorbonne Universités, UPMC Univ
Paris 06, INSERM 1146, CNRS 7371, Laboratoire d’Imagerie Biomédicale, Paris, France; and gAPHP, Pitié-Salpêtrière University
Hospital, Department of Genetics, Paris, France. The authors have reported that they have no relationships relevant to the
contents of this paper to disclose.

Manuscript received March 13, 2018; revised manuscript received May 24, 2018, accepted May 31, 2018.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2018.05.065

JACC VOL. 72, NO. 7, 2018 Gandjbakhch et al. 785
AUGUST 14, 2018:784–804 Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia

terminology represents 2 different visions of its most often segmental and usually do not ABBREVIATIONS

pathophysiology: degenerative process or develop- involve the interventricular septum. LV his- AND ACRONYMS

ment abnormality. Although the terminology of tological involvement is frequently reported

2D = 2-dimensional
“dysplasia” is probably questionable, this term has in autopsy cases or explanted hearts, even in
3D = 3-dimensional
been used and accepted for 40 years. Several com- the absence of macroscopic LV involvement
4D = 4-dimensional
bined diagnostic criteria (task force criteria [TFC]) (11).
were proposed, classified as major or minor (3), and Various histological forms have been ARVC/D = arrhythmogenic
right ventricular
implemented in 2010 (4) (Table 1) for a better speci- described depending on the predominance of cardiomyopathy/dysplasia
ficity, particularly in family members and young fibrous or adipose tissue. Nevertheless, a
CT = computed tomography
athletes. The diagnosis of ARVC/D is probably the systematic study of myocardial biopsy speci-
DCM = dilated cardiomyopathy
most challenging in the field of inherited cardiomy- mens revealed the absence of specific RV fat
ECG = electrocardiography
opathies because of the absence of specific unique infiltration in contrast to extensive fibrous
LBBB = left bundle branch
diagnostic criteria, its variable expressivity, and its tissue and myocyte loss (12). Fatty infiltration
block
incomplete penetrance in relatives. The main prob- is thus not required as a histological diag-
LGE = late gadolinium
lem is that a definitive pathological diagnosis is only nostic criterion (4). Lymphocytic or histio- enhancement
given by a seldom available histological study ob- cytic inflammatory infiltrates, focal necrosis, LV = left ventricular
tained by biopsy, surgery, or necropsy. Indirect evi- and signs of apoptosis are frequent (13). The
MDCT = multidetector
dence can be obtained by multimodal cardiac imaging association of ARVC/D with clinical and his- computed tomography
studies. ECG data show RV disease, but other RV tological features of myocarditis is thus not MRI = magnetic resonance
cardiomyopathies may alter it in a similar way, such rare, underlying the relation between the 2 imaging

as myocarditis (5), which interacts with ARVC/D (6,7), diseases (7). However, the role of viruses in RBBB = right bundle branch

sarcoidosis (8,9), or the rare Uhl’s disease (Table 2). ARVC/D pathogenesis remains unknown block

The revision of ARVC/D diagnostic criteria in 2010 (14,15). A decrease in desmosomal protein RV = right ventricular

increased the specificity of the diagnosis, but it still staining (e.g., plakoglobin, desmosomal cad- RVOT = right ventricular
outflow tract
lacks sensitivity, especially in the early stages of the herins) has been reported in immunostaining
disease (4,10). In addition, most diagnostic criteria studies, but the reproducibility and the SCD = sudden cardiac death

were assessed relative to healthy controls and
possibly lack specificity for differential diagnosis with
other arrhythmogenic diseases involving the right
ventricle. Genotype/phenotype studies have shown
that ARVC/D, which was initially described as an
isolated or predominant RV disease, exhibits frequent
left ventricular (LV) involvement. This involvement
may be present or predominant at early stages in
some mutation carriers, expanding the clinical spec-
trum of the disease to a larger group of scar-related
cardiomyopathies or arrhythmic cardiomyopathies
according to the suggestion of some authors.
The present review provides an update on the
pathological, clinical, and genetic abnormalities
associated with ARVC/D, focusing on the contribution
of emerging imaging techniques and genetics for
diagnosis.
PATHOLOGY
The main anatomopathological feature of ARVC/D is
the replacement of myocytes by fibrous or fibro-
adipose tissue in the RV free wall. Lesions extend
from the epicardium to the endocardium and
predominantly involve the area between the anterior
part of the pulmonary infundibulum, the apex, and
the infero-posterior wall (the so-called “triangle of
dysplasia”). Myocyte loss and fibrous replacement are
diagnostic accuracy of these techniques in SSFP = steady-state free
precession
routine practice were not assessed (16,17).
TFC = task force criteria
Fibrofatty replacement is not specific to
desmosomal ARVC/D, as a similar pattern was found
in TMEM-43, PLN, and LMNA-related “ARVC/D”
(18–20), as well as arrhythmogenic mitochondrial
cardiomyopathy associated with PPA2 mutations and
arrhythmogenic dilated cardiomyopathy (DCM)
caused by FLNC mutations (21,22).
The diagnostic yield of endomyocardial biopsies is
relatively low and largely depends on the location and
number of targeted sites because of the patchy nature
of fibrous replacement and the subepicardial location
of lesions. Endomyocardial biopsies are generally
noncontributive on the right side of the interventric-
ular septum. Voltage-guided endomyocardial biopsy
probably increases the diagnostic yield, but questions
remain on the safety of performing biopsies on the RV
free wall (12,23). However, voltage-guided biopsies
may 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/D
is initiated in 2 clinical situations. For patients with
ventricular arrhythmia, mainly of RV origin on the
ECG, the diagnosis is approached through RV
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Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia AUGUST 14, 2018:784–804

T A B L E 1 Current 2010 TFC Diagnosis

Major Minor

I. Global or regional dysfunction By 2D echocardiogram: By 2D echocardiogram:

and structural alterations
Regional RV akinesia, dyskinesia, or aneurysm and 1 of the
following (end-diastole):
PLAX RVOT $32 mm (PLAX/BSA $19 mm/m 2 )
PSAX RVOT $36 mm (PSAX/BSA $21 mm/m 2 )
Or RFAC #33%
Regional RV akinesia or dyskinesia, and 1 of the following (end-
diastole):
29 #PLAX RVOT <32 mm (16 #PLAX/BSA <19 mm/m 2)
32 #PSAX RVOT <36 mm (18 #PSAX/BSA <21 mm/m 2 )
Or 33% < RFAC #40%

II. Tissue characterization of wall
III. Repolarization abnormalities
IV. Depolarization/conduction
abnormalities
V. Ventricular Arrhythmias
VI. Family history
By MRI:
Regional RV akinesia or dyskinesia or dyssynchronous RV
contraction and 1 of the following:
RV end-diastolic volume/BSA $110 ml/m 2 (male)
or $100 ml/m 2 (female)
Or RV ejection fraction #40%
By RV angiography:
Regional RV akinesia, dyskinesia, or aneurysm
Residual myocytes <60% by morphometric analysis (or <50% if
estimated), with fibrous replacement of the RV free wall
myocardium in $1 sample, with or without fatty replacement
of tissue on endomyocardial biopsy
Inverted T waves in right precordial leads (V1, V2, and V3) or
beyond in individuals >14 yrs of age (in the absence of
complete RBBB QRS $120 ms)
Epsilon wave in the right precordial leads (V1 to V3)
Nonsustained or sustained VT of LBBB morphology with superior
axis (negative or indeterminate QRS in leads II, III, and aVF
and positive in lead aVL)
ARVC/D confirmed in a first-degree relative who meets
current TFC
ARVC/D confirmed pathologically at autopsy or surgery in a
first-degree relative
Identification of a pathogenic mutation categorized as
associated or probably associated with ARVC/D in the
patient
By MRI:
Regional RV akinesia or dyskinesia or dyssynchronous RV contrac-
tion and 1 of the following (end-diastole):
100 ml/m 2 # RV end-diastolic volume/BSA <110 ml/m 2
(male) or 90 ml/m 2 # RV end-diastolic volume/
BSA <100 ml/m 2 (female)
Or 40% < RV ejection fraction #45%
Residual myocytes 60% to 75% by morphometric analysis (or 50%
to 65% if estimated), with fibrous replacement of the RV free
wall myocardium in $1 sample, with or without fatty
replacement of tissue on endomyocardial biopsy
Inverted T waves in leads V 1 and V 2 in individuals >14 yrs of
age (in the absence of complete RBBB) or in V 4, V 5 , or V 6
Inverted T waves in leads V 1 , V 2 , V 3, and V 4 in individuals
>14 yrs of age in the presence of complete RBBB
Late potentials by SAECG in $1 of 3 parameters in the
absence of a QRS duration $110 ms on the standard ECG
Filtered QRS duration $114 ms
Duration of terminal QRS <40 mV (low-amplitude signal
duration) $38 ms
Root mean square voltage of terminal 40 ms #20 mV
Terminal activation duration of QRS $55 ms measured from
the nadir of the S-wave to the end of the QRS, including R’, in
V 1 , V 2 , or V 3, in the absence of complete RBBB
Nonsustained or sustained RVOT VT of LBBB morphology with
inferior axis (positive QRS in leads II, III, and aVF and negative
in lead aVL) or with unknown axis
>500 ventricular extrasystoles per 24 h (Holter)
History of ARVC/D in a first-degree relative in whom it is not
possible or practical to determine whether the family member
meets current TFC
Premature sudden death (<35 yrs of age) due to suspected
ARVC/D in a first-degree relative
ARVC/D confirmed pathologically or by current TFC in
second-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 magnetic
resonance 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 right
ventricular outflow tract; SAECG ¼ signal-averaged electrocardiography; TFC ¼ task force criteria; VT ¼ ventricular tachycardia.

morphological criteria, irrespective of the ECG data.
For asymptomatic patients, family members of an
overt case, or screening of athletes, an abnormal ECG
orients the focus to the subject’s right ventricle.
ECG has the great advantage of being universal,
easy to perform, and to easily reveal abnormalities in
most patients (24,25). It can be enhanced by opening
the usual 40-Hz low-pass filters, which smooth fast
signals as fragmentations (26) and epsilon waves. It
can be performed from 100 to 250 Hz with some ECG
recorders, as those used for the signal-averaged ECG
recordings (27). Signal interpretation is made easier
by double amplification, 50-mm speed recording
tracings, and bipolar precordial recordings that in-
crease ECG sensitivity (28) (Table 3). All reflect losses
of normal RV myocardium and their consequences,
regardless of the etiology. For example, in a recent
study (9) on 100 consecutive patients referred for
ventricular tachycardia ablation of scar-related RV
cardiomyopathies from 1999 to 2015, a total of 51 had
TFC for ARVC/D, 22 for sarcoidosis, and 27 for a car-
diomyopathy of “unknown source,” which could be
early 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 localization
of the disease, and their incidence varies widely be-
tween series (Table 4). Early-stage ARVC/D exhibits
minor abnormalities, which increase over time in
JACC VOL. 72, NO. 7, 2018 Gandjbakhch et al. 787
AUGUST 14, 2018:784–804 Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia

QRS fragmentation (24). Several recent studies have

T A B L E 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 dysfunction
Ebstein’s anomaly
Left to right shunt: interatrial septal defect, anomalous
pulmonary venous return
Tricuspid regurgitation
Inferior infarct with RV extension
PVC ¼ premature ventricular contraction; other abbreviations as in Table 1.
most patients. Endocardial three-dimensional (3D)
mapping, with map-directed biopsies (30), and
endo-epicardial mapping, combined with magnetic
resonance imaging (MRI) scar data, have shed light on
the electrical features of ARVC/D (31).
ECG-based TFC diagnostic criteria include right
precordial T-wave inversions,
epsilon waves, and increased duration of the ter-
minal QRS from the nadir of the S-wave to the end
of the QRS, when enlarged above 55 ms (32). How-
ever, up to 30% of patients with morphological
criteria for ARVC/D have a so-called ECG-concealed
form 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
proposed more complex proprietary ECG methods
for better predictive values, such as computerized
S-wave surface and bipolar chest leads (35), vec-
torcardiography derivations (36), or body surface
mapping (37). However, surface ECG remains the
only widely available and simple method using a
combination of repolarization and depolarization
data that can be enhanced by the recording modi-
fications suggested earlier.
REPOLARIZATION DATA. T-wave inversions in the
right precordial leads are present in up to 87% of
adult patients with ARVC/D (38), are directly related
to RV dilatation (39), and may extend to the left
precordium with time. They are rare in normal pa-
tients but can be found in very different clinical
contexts, such as in some young athletes (with a
higher incidence in black athletes), in ischemic car-
diomyopathy, or during acute pulmonary embolism.
Right precordial T-wave inversions are also related to
right bundle branch block (RBBB); ARVC/D can be
suspected, however, if they are present in V1, V2, and
the presence of V3 (40,41) and according to the QRS morphology
(discussed later). T-wave depth in V 1 is not included
in the TFC. However, it is an important feature, with a
high negative predictive value. Two studies found
97% specificity for a negative amplitude, one for a
value $2 mm in V1 (42), and the other $3 mm with a
special bipolar chest CF1 lead (35), but with lower
sensitivities of 94% for the former and 24% for the
latter.

T A B L E 3 Current Diagnostic Criteria and Emerging Diagnostic Tools for ARVC/D Diagnosis

ECG Imaging Ventricular Arrhythmia Pathology Genetics

Current Epsilon wave Regional RV wall motion NSVT/VT with LBBB Myocyte loss with ARVC/D or SCD family
International TWI in precordial leads abnormality in combination morphology (superior fibrous replacement history
2010 TFC QRSt $55 ms in V1,V2,V3 with RV dilatation or global and/or inferior axis) of the RV free wall Presence of a pathogenic
Late potentials (SAECG) RV systolic dysfunction PVC> 500/24h myocardium, with mutation
(TTE/MRI/angiography) or without fatty
replacement of
tissue (EMB)
Additional QRS fragmentation Hypertrophic trabecular or Morphology of VAs: QRSd
diagnostic T-wave depth in V1 $2 mm in hyperreflective moderator lead DI>120 ms, QRS
criteria V1, or $3 mm in bipolar band notching, transition $V5
CF1 lead Decreased TAPSE and peak VAs (PVC, NSVT, VT)
Microvoltage systolic RV annular velocity originating from multiple
Inverted T waves in inferior Intramyocardial fat infiltration in RV sites
leads (LV extension) the RV wall VAs triggered by
RBBB with R’/S ratio <1 in V1 LGE of the RV wall catecholaminergic stress
Low peak systolic RV strain Low sub-epicardial voltage
areas in the right ventricle
Emerging Computerized S-wave surface TTE speckle tracking Isoproterenol test Voltage-map High-throughput
diagnostic and CF leads MRI feature tracking RV electroanatomic guided EMB sequencing and large
tools Vectorcardiography MDCT and 4D-cine CT voltage map panels of genes
derivations
Body surface mapping

4D ¼ four-dimensional; CF leads ¼ bipolar chest leads; CT ¼ computed tomography; EMB ¼ endomyocardial biopsy; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; MDCT ¼ multidetector
computed tomography; NSVT ¼ nonsustained ventricular tachycardia; QRSt ¼ terminal activation duration of QRS; SCD ¼ sudden-cardiac death; TAPSE ¼ tricuspid annular plane systolic excursion;
TTE ¼ transthoracic echocardiography; TWI ¼ T-wave inversion; VA ¼ ventricular arrhythmia; other abbreviations as in Tables 1 and 2.
788 Gandjbakhch et al. JACC VOL. 72, NO. 7, 2018

Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia AUGUST 14, 2018:784–804

extent of activation after the end of QRS was minimal,

T A B L E 4 Frequency of Principal ECG Abnormalities Identified in ARVC/D
mostly subepicardial (Figure 2). The epsilon wave
Nasir et al. Cox et al. Steriotis et al. Peters et al. Saguner et al. corresponds to epicardial perivalvular activation. The
(2004) (2008) (2009) (2008) (2014)
(162) (32) (29) (24) (163) wide S-wave is due to delayed activation in both the
n 50 42 205 360 111 perivalvular and the right infundibular endocardium.
V1V2V3 QRS duration 64% 26% 29% 75% NA The incomplete RBBB reflects an increased delay in
$110 ms
the same zone. It confirmed that the RBBB pattern is
V1 þ V2 þ V3/V4 þ V5 þ V6 77% 35% 18% 98% NA
widths $1.2 not due to an alteration of the RBB but to an exit block
V1V2V3 QRS width $25 ms 52% 13% 13% NA 12% of the bundle branch, related to an extended scar
of V6 (parietal block) zone.
S-wave upstroke $55 ms 95% 24% 18% 83% 32%
QRS fragmentation is a non-TFC ECG feature in
Epsilon wave 33% 10% 9% 23% 20%
ARVC/D. It consists of small deflections or notches, at
iRBBB 14% NA 29% NA 3%
RBBB 8% NA 6% NA 12%
the beginning of the QRS, superimposed on the R
QRS fragmentation NA NA NA 85% 38% wave or the nadir of the S-wave in any right pre-
TWI V1V2V3 87% 67% 35% 75% 40% cordial lead, or in >1 of any lead (24,49), particularly
TWI V1V2 76% 76% 7% NA 19% inferior leads. They can be interpreted as the passing
Inferior TWI NA NA NA NA 54% activation front through a scarred zone earlier than
SAECG late potentials 56% NA Mild 44% 77% NA
the late potentials. They are found in up to 85% of
(according to ARVC/D Moderate 58%
extension: mild, Severe 93% ARVC/D cases, including those exhibiting epsilon
moderate, or severe)
waves. However, fragmentations are nonspecific, as

NA ¼ nonavailable; iRBBB ¼ incomplete right bundle branch block; other abbreviations as in Tables 1 and 3.
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 related
families (43,44).
Several nonspecific ST-segment abnormalities can
be found, from flat precordial T waves to Brugada-like
ECGs. J-point elevation >1 mm in at least 2 inferior
and/or lateral leads (45) is a frequent finding in >20%
of ECGs, reflecting late depolarization. Brugada-like
ECGs are difficult to interpret because of the overlap
between 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 Brugada
ECG pattern (47). The clinical implications of these
overlapping phenotypes are currently unknown.
DEPOLARIZATION DATA. Multiple
been described from V 1 to V3, reflecting the wide
range of RV parietal blocs (Table 4, Figure 1). They
consist of QRS notching (24,49), a wider QRS, larger S
waves, epsilon waves, late potentials at signal-
averaged ECG, and incomplete, complete, or atyp-
ical RBBB, combined or alone. A RBBB block
morphology is suggestive of ARVC/D with an R’/S
ratio <1 in V1 (41).
A recent paper (31) excellently illustrated the great
variety of ECG presentations. It comprised 35 cases,
all with negative precordial T waves, epicardial and
endocardial mapping, and MRI imaging. It showed a
relationship between the QRS and disease localiza-
tion and extent. When the QRS appeared normal, the
they can also be recorded in many other scar-related
cardiomyopathies (50), and their definition is not
straightforward because standard ECG filtering may
erase them. QRS amplitude is also not included in the
TFC (29,51). Microvoltage is not specific but observed
in patients with advanced ARVC/D disease with sig-
nificant RV dilatation and better expressed by the
sum of QRS amplitudes (52). It can be more specific
when limited to the right precordium (53) or with the
ratio of the sums of precordial voltage ratios (54) V 1 to
V 3/V1 to V 6 #0.48.
Signal-averaged ECG reveals microvolt-level late
potentials. However, the Simson method, with XYZ
electrodes, does not have the proximity effect of
precordial leads and reflects any late potential origin.
Nevertheless, its 3 components (filtered QRS dura-
tion, low-amplitude signal, and root mean square
amplitude of the last 40 ms) are highly associated
with ARVC/D. They are found in >50% of ARVC/D
features have
cases, and their incidence and duration increase with
time, up to 93% in severe forms (29). Its specificity is
increased when combined with RV enlargement or
low ejection fraction, and it enhances the sensitivity
of borderline surface ECG (55).
VENTRICULAR ARRHYTHMIAS. ARVC/D ventricular
arrhythmias usually have a left bundle branch block
(LBBB) pattern. They are characterized by several
morphologies. A left-axis deviation is suggestive for
ARVC/D (15,18). The main problem is their differen-
tiation from idiopathic arrhythmias when they only
originate from the RV infundibulum, with a
descending vertical axis. The most sensitive param-
eters are a QRS duration in lead I $120 ms, a QRS
JACC VOL. 72, NO. 7, 2018 Gandjbakhch et al. 789
AUGUST 14, 2018:784–804 Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia

transition in V 6 , notching on any complex, and early

F I G U R E 1 The Variety of ARVC/D ECG in Sinus Rhythm Before VT Ablations
QRS onset in V 1 (56). Polymorphic premature ven- (Except #8)
tricular contraction induction with high-dose isopro-
terenol (45 m g/min for 3 min) has been suggested as a
pharmacological diagnostic test for ARVC/D in pa-
tients with premature ventricular contractions, with a
99% negative predictive value but a low 43% positive
predictive value (57) (Table 3).

MULTIMODAL IMAGING

Noninvasive imaging techniques play a pivotal role in

the diagnosis and management of ARVC/D. Imaging
in ARVC/D diagnosis has been essentially based on
visual assessment of RV segmental motion anomalies
and wall thickness, RV ejection fraction or fractional
area, and fibrofatty replacement. The current chal-
lenges for imaging in ARVC/D diagnosis are earlier
detection of the disease, particularly in cases of
focal involvement without RV dilatation/global
dysfunction, and differential diagnosis from other
arrhythmogenic 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 of
certain imaging parameters (e.g., wall motion abnor-
malities), and the lack of imaging biomarkers tested
in multiparametric models assessing diagnosis and
risk.
ECHOCARDIOGRAPHY. Two-dimensional echocardi-
ography is the most widely available imaging V1 to V3 or V1 to V4 are displayed (amplitude: 10 mm ¼ 1 mV). 1) Normal QRS and inverted
method to evaluate patients with known or sus- T waves in V1 to V2. 2) Enlarged S-wave and normal T waves. 3) Prolonged S-wave and

pected ARVC/D. Histological changes
directly identifiable by echocardiography but lead to
macroscopic changes, with regional wall motion
abnormalities associated with RV dilatation and/or
global RV systolic dysfunction. Thus, the presence
are not 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

of segmental wall motion abnormalities, defined as
regional akinesia, dyskinesia, or dyssynchrony,
combined with RV dilatation and/or RV dysfunction,
is required for diagnosis (2010 TFC) (Table 1). The
degree of RV outflow tract (RVOT) dilatation and
the reduction of RV fractional area determine
whether it is a major or minor criterion (4). These
criteria are highly specific but lack sensitivity,
especially in early stages when RV dilatation/
dysfunction may be absent.
Several robust parameters representing RV systolic
function, such as tricuspid annular plane systolic
excursion and peak systolic RV annular velocity, are
generally lower in ARVC/D (tricuspid annular plane
systolic excursion <16 mm and peak systolic RV
annular velocity <10 cm/s) (58) but usually only in
more advanced forms of the disease. Structural
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.
abnormalities of the right ventricle have been noted in
ARVC/D, such as a hypertrophic trabecular or hyper-
reflective moderator band, but these findings lack
specificity, especially in competitive athletes. The
evaluation of the right ventricle by using echocardi-
ography can be challenging because of its retrosternal
position and its complex geometry. In addition, the
assessment of wall motion abnormalities is highly
subjective and requires specific expertise.
Contrast echocardiography can improve the
assessment of RV wall motion in cases of poor
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F I G U R E 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.

image quality (59). New echocardiographic tech-
niques, such as 3D echocardiography and tissue
deformation imaging, may increase the performance
of echocardiography, especially in early stages.
3D echocardiography allows the measurement of RV
volumes and the RV ejection fraction (60), but its
value in advanced ARVC/D with very large right
ventricles must be established. The two-dimensional
(2D)-strain echocardiographic method can measure
myocardial deformation by tracking localized acous-
tic markers frame by frame (speckle tracking)
(Figure 3). Left and right longitudinal strain derived
from speckle tracking could be sensitive tools for
assessing regional and global myocardial function
(61,62). A cutoff value of –18% peak systolic strain was
proposed to differentiate between normal and
abnormal RV segments (58). RV strain may also be
useful for detecting RV subclinical systolic dysfunc-
tion, especially in first-degree relatives of patients
with ARVC/D (63) (Table 3). Moreover, RV mechanical
dispersion (heterogeneous contraction), assessed by
strain, may reflect electrical dispersion and could be a
prognostic marker of arrhythmic events (64). Tissue
deformation imaging is therefore a promising tech-
nique, but image acquisition, reproducibility, and
quality are still limiting factors. Both multiplane and
3D speckle tracking are promising new applications in
RV deformation imaging.
MAGNETIC RESONANCE IMAGING. S t r e n g t h s a n d
W e a k n e s s e s o f M R I f o r A R V C / D D i a g n o s i s . MRI
can assess biventricular morphology, volumes,
thickness, and mass, as well as regional motion and
myocardial fibrous or adipose content, edema, and
flow, 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 T 1 -
weighted spin echo images, which proved to be
inconsistent and poorly reproducible (65). Similarly,
61% of patients were shown to display late gadolin-
ium enhancement (LGE) of the RV wall, a
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F I G U R E 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.

well-established marker of dense replacement
fibrosis in contrast-enhanced MRI (66). Neither of
these parameters was included as diagnostic criteria
in the 2010 TFC, which focused on RV dilatation
and/or global dysfunction associated with severe
regional contraction anomalies, including akinesia,
dyskinesia, and asynchronous contraction (Table 1).
Indeed, the direct visualization of fibrofatty
replacement by MRI as a diagnostic hallmark faces
several problems. First, direct visualization of RV
intramyocardial fibrosis and fat is made technically
difficult by the thin RV wall in terms of the achievable
spatial resolution of MRI, potentially resulting in
misleading partial volume effects. Second, fatty
infiltration of the myocardium has been shown to be
frequent and nonspecific to ARVC/D (67). Third, LGE
is also nonspecific and present in numerous ischemic
or nonischemic diseases potentially involving the
right ventricle, including myocarditis and sarcoidosis.
Differential diagnosis between ARVC/D and myocar-
ditis may be particularly challenging because some
patients with ARVC/D can present with acute or sub-
acute myocarditis (7,68). Moreover, subepicardial
LV LGE can be present in ARVC/D, leading to over-
diagnosis of myocarditis. Furthermore, if fat and
fibrosis have been approached separately, the direct
visualization and quantification of the fibrofatty mix—
the true hallmark of the disease—is still an unresolved
challenge, as these 2 components are not individually
identifiable 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 segmental
combination of myocardial thinning, severe abnormal
motion, and fatty infiltration is in favor of fibrofatty
replacement, whereas the presence of fat in a
segment of normal thickness and contraction is more
likely to be related to nonspecific fatty infiltration
(69). The absence of RV myocardial fat according to an
MRI does not preclude the diagnosis of ARVC/D, as
shown in pediatric patients (70), nor should the
presence of fat be interpreted alone.
MRI is the reference method to assess ventricular
volumes and regional function independently of
geometric assumptions, with high intra-observer and
interobserver reproducibility (71). However, the
diagnosis of RV wall motion abnormalities remains
subjective and dependent on personal expertise, with
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F I G U R E 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.

only low to moderate intra-observer and interob-
server reproducibility (70). This situation highlights
the importance of standardized and regional biven-
tricular analysis of the right ventricle for optimal
diagnostic performance with high spatial and tem-
poral resolution cine steady-state free precession
(SSFP) imaging that covers all RV segments in several
perpendicular orientations (Online
Figure 4). With comprehensive biventricular analysis,
96% of cardiovascular magnetic resonance examina-
tions from 74 mutation-positive ARVC/D patients
revealed an abnormal right ventricle (72). The most
prevalent RV abnormalities were basal inferior wall
dyskinesia (94% of patients) and basal anterior wall
dyskinesia (87% of patients). In the same study, LV
involvement concerned 52% of patients and led to
redefining the initial dysplasia triangle, including the
posterior lateral wall of the left ventricle, along with
the subtricuspid and anterior wall of the right
ventricle. Typical MRI findings corresponding to this
description are illustrated in Figure 5.
MRI has been shown to be particularly useful in
distinguishing ARVC/D from alternate diagnoses (73).
Several limitations of the MRI criteria in the 2010 TFC
have been discussed (65,74). They include basing the
volumetric RV data thresholds on middle-aged and
elderly patients (45 to 85 years of age) from the MESA
(Multi-Ethnic Study of Atherosclerosis) trial,
excluding younger adults, and measurements from
gradient echo cine-MRI, which provides lower values
than currently used cine-SSFP techniques. Never-
theless, a study in a pediatric population showed that
MRI was associated with good sensitivity (70), despite
these potential limits. A normal MRI was found to
Appendix, have an excellent negative predictive value of 99%
for major clinical events in a 4.3-year follow-up of 369
consecutive patients suspected of having ARVC/D,
and abnormal MRI was an independent predictor of
events 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 of
tissue composition according to MRI, there have been
technical advances since the 2010 TFC. New insights
come from large population studies that provide
normative volumetric data from current cine-SSFP
imaging techniques (76,77), but large-scale compari-
son with ARVC/D probands is still necessary to better
define actual threshold values. Longitudinal data on
the phenotypical evolution of the disease are also
highly desirable. The existing 2010 TFC were
designed to be more specific than sensitive, intro-
ducing a bias favoring more advanced forms of the
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F I G U R E 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.

disease. It is likely that the true value of MRI to detect
early disease and provide incremental value to strat-
ify risk is underestimated. Multiparametric models in
large datasets, including modern imaging biomarkers
and genetics, will likely provide decisive insights in
the near future.
Semi-automated myocardial deformation quantifi-
cation may be a promising approach to lower vari-
ability in assessing RV function, particularly feature
tracking, which, contrary to tagging techniques, can
be applied to routine cine-MRI
Reproducibility for RV strain measurement using
feature tracking has recently been shown to be good
(interobserver, intraclass correlation coefficient
>0.86; interstudy, intraclass correlation coefficient
>0.71) (78). Global longitudinal and circumferential
RV strain and strain rates at the base assessed by
using feature-tracking MRI were shown to be signifi-
cantly lower in ARVC/D probands than in healthy
volunteers and family relatives (79,80). Moreover, the
global longitudinal strain rate was found to be lower
(Table 3). in patients with ARVC/D and preserved RV ejection
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Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia AUGUST 14, 2018:784–804

F I G U R E 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.

fraction. Quantitative measures of asynchronous RV
contraction by feature-tracking MRI, as reported by
Prati et al. (80), may be particularly useful, as this
criterion (included in the 2010 TFC) is particularly
prone to subjectivity. Regional feature-tracking strain
analysis could be more sensitive than global param-
eters. Predominant impairment in the subtricuspid
region allowed the discrimination of preclinical
ARVC/D (mutationþ/phenotype–) from healthy con-
trols, consistent with prior knowledge on the regional
expression of ARVC/D (72), whereas global strain was
nondiscriminant (81). The continued
T 1 -weighted spin echo images to visualize fat lacks
diagnostic performance, but new techniques may
help in characterizing fatty content. In particular,
ECG-gated Dixon techniques allow specific imaging
separating the fat from the water component of the
myocardium (82), but they currently remain insuffi-
ciently available and validated in this disease setting.
Conversely, high-resolution 3D LGE,
isotropic spatial resolution (1.4 mm 3) images using
compressed sensing techniques, has been introduced
and initially applied to the left ventricle with prom-
ising results (83). Further improvements in spatial
resolution may allow reliable RV wall characterization
in the near future.
CARDIAC COMPUTED TOMOGRAPHY
Although computed tomography (CT) scanning is not
included in the 2010 TFC (4), it was considered to be
appropriate in this setting according to a contempo-
use of rary expert consensus (84). This modality, with
excellent isotropic spatial resolution of 0.5 mm,
4-dimensional (4D)-cine capability, and recently
achievable lower radiation doses (1 to 2 mSv), may
play a role in distinguishing ARVC/D from other
causes of ventricular arrhythmias such as coronary
heart disease (65) (Table 3). Seminal studies per-
formed with single-slice, non–ECG-gated CT imaging
with high or electron-beam CT imaging in small patient groups
showed the potential to detect RV enlargement and
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AUGUST 14, 2018:784–804
regional motion abnormalities and a scalloped RV
surface, as well as epicardial or intramyocardial fat of
the RV free wall, trabecular enlargement, and adipose
infiltration (85–90). Good correlations were reported
with histology, albeit on very few samples and with
inevitable 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 RV
fatty infiltration, RV free-wall bulging, and RV dila-
tation for a definite ARVC/D diagnosis, according to
the 2010 TFC, with high performance (87% sensi-
tivity, 94% specificity, and 92% accuracy). Regional
wall motion abnormalities assessed by dynamic RV
datasets (available in 21 patients) were consistent
with MRI or 2D-echo data in all cases but were not
included in the proposed score. However, one of the
main limitations in this study was the use of existing
2010 TFC criteria as the “gold standard” instead of
genetics. Remaining knowledge gaps include the
value of regional wall motion abnormalities in CT
imaging, in addition to RV dilatation, bulging, and
fatty infiltration and the position of MDCT in the
diagnostic and prognostic evaluation of patients
suspected of having ARVC/D.
Modern MDCT allows fast acquisition and high
isotropic spatial resolution (0.5 mm), permitting pre-
cise RV and LV volume measurements validated
versus MRI (96). 4D-cine CT imaging may favorably
replace RV angiography due to its advantages, such as
providing full 4D coverage of RV wall dynamics and
potentially 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 of
the 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 native
contrast of adipose tissue, allows precise depiction of
fatty infiltration within the thin RV wall, with or
without contrast injection, as illustrated in Figure 6
(97); good correlations are achieved with epicardial
and endocardial low-voltage areas (98). These
encouraging image integration methods may help in
focusing ablation therapy of culprit lesions and war-
rant further study. MDCT is widely available, fast, and
affordable. Patients for whom MRI is challenging,
such as those with severe arrhythmia, claustrophobia,
and implantable cardioverter-defibrillators, as well as
those with suspicion of focal ARVC/D, may particu-
larly benefit from this technique.
Gandjbakhch et al. 795
Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia
GENETICS OF ARVC/D
The role of genetic testing has dramatically increased
in ARVC/D diagnosis. Major diagnostic criteria for
ARVC/D have included the presence of a pathogenic
mutation since 2010. To date, 16 genes have been
associated with the ARVC/D phenotype, mostly those
encoding desmosomal proteins (so-called desmo-
somal genes) (Table 5, Central Illustration). Candidate
gene or linkage studies have identified other
cardiomyopathy/channelopathy-associated genes in
patients with an ARVC/D phenotype or arrhythmo-
genic biventricular cardiomyopathy, expanding the
genetic 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 by
mutations 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, Central
illustration) (99). Desmosomes are membrane pro-
tein complexes that play an important role in inter-
cellular adhesion and maintenance of the structural
integrity of tissues subjected to mechanical stress,
such as the heart and skin. These mutations usually
have an autosomal dominant mode of inheritance
with incomplete penetrance, leading to an isolated
cardiac phenotype. Various types of mutations
(missense, nonsense, splice-site, frameshift, and
large deletions) have been reported, and most are
private. Desmosomal gene mutations have been
identified 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% of
mutations 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 carrying
mutations fulfill definitive ARVC/D diagnosis, ac-
cording to international 2010 TFC (10,102). Women
carrying desmosomal gene mutations are at lower
risk of expressing the disease than men and are
thus more likely to be healthy mutation carriers
(105,106). The causes of such sex-related penetrance
are not yet fully understood, but higher levels of
participation in competitive and intensive sports by
men (107) or hormonal factors (108) could explain
some differences.
PKP2 mutations are mostly autosomal dominant
and are more likely to lead to isolated RV involve-
ment and a conventional phenotype than other
desmosomal mutations (72). Bao et al. (101) suggested
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T A B L E 5 List of Genes Associated With ARVC/D

Phenotype AR/ Genotype/

Frequency Type of Mode of Phenotype Compound OMIM Phenotype
Gene Protein in ARVC‡ Structure Mutations Inheritance AD Heterozygous Entry Studies Ref. #

PKP2 Plakophilin-2 20%–45% Desmosome Non-missense þþ AD þþþ, ARVC ARVC† ARVC9 Conventional (10,100–
(splice-site, (AR) DCM† ARVC/D 104,114,
nonsense, ins/ phenotype 115,143,
del, large del) 144)
Missense
DSG2 Desmoglein-2 4%–15% Desmosome Non-missense ADþþþ, ARVC ARVC ARVC10 Frequent LV (10,100–
(splice-site, AR BiVCM BiVCM involvement 104,114,
nonsense, ins/ 115,143,
del) 145,146)
Missense
DSP Desmoplakin 1%–13% Desmosome Non-missense ADþþ, AR ARVC; ALVC, DCM Cardio- ARVC8 Frequent LV (10,43,68,
(splice-site, Cardio-cutaneous cutaneous Sd involvement 100,103,
nonsense, ins/ Sd with ARVC/ High risk of VAs 104,111,
del, large del) CCD† BiVCM or and HF 114,115,
Missense DCM Cardio-cutaneous 143,147–
Cutaneous Sd† Sd 150)
DSC2 Desmocollin-2 1%–7% Desmosome Non-missense ADþþ, AR ARVC, BiVCM BiVCM Cardio- ARVC11 Frequent LV (10,100–
(splice-site, cardiomyopathy cutaneous involvement 103,114,
nonsense, ins/ Sd† 115,143,
del) 151–154)
Missense
JUP Plakoglobin 0%–1% Desmosome Non-missense AD, ARþþþ ARVC Cardiocutaneous ARVC12 Cardio-cutaneous (10,100–
(splice-site, Sd with Sd with ARVC 103,114,
nonsense, ins/ ARVC/D (or 115,143,
del) DCM) 155)
Missense Cutaneous Sd
CTNNA3 Alpha- <1% Intercalated Missense AD ARVC _ ARVC13 Low penetrance (117)
T-catenin disk Del
CDH2 N-Cadherin 2%* of patients Intercalated Missense AD ARVC _ _ (120)
with negative disk
genetic
screening
(missense)
TMEM43 LUMA <1% Nuclear Missense AD ARVC _ ARVC5 LV involvement, (18,122,
envelop, Splice-site EDMD high risk of 156,157)
intercalated SCD and HF
disk, Poor R-wave
sarcolemma progression
on ECG
LMNA Lamin A/C 3%–4% Nuclear Missense AD DCM/BiVCM/ARVC _ _ CCD (19,123,
envelop Nonsense with CCD, AF, Frequent LV 124,158)
VAs  muscular involvement
dystrophy High risk of HF
DES Desmin <1% Intermediate Missense AD DCM/BiVCM/ARVC _ ARVC7 Muscular (125,126,
filament with CDD, AF, dystrophy 159)
VAs  muscular CCD
dystrophy Frequent LV
involvement
TTN Titin 18%* of ARVC/D Sarcomere Missense AD ARVC/BiVCM _ _ Frequent CCD (131)
patients with Frequent LV
negative involvement
genetic
screening
(missense)
PLN Phospholamban 0%–12% Calcium Del AD DCM _ _ Micro-voltage (20)
(Netherlands) regulatory BiVCM LV involvement
protein ARVC High risk of HF
HCM and SCD
Continued on the next page

that patients with PKP2 mutations could be at higher biventricular cardiomyopathy, or isolated LV
risk of ventricular arrhythmias during follow-up, but arrhythmogenic cardiomyopathy. Thus, DSP muta-
this theory was not confirmed in a large U.S./Dutch tions are identified in 3% of patients with DCM (109,
registry (105). 110). Phenotype/genotype studies suggest that DSP
Patients with DSP mutations can present with mutations are associated with a severe ARVC/D
variable phenotypes, such as typical ARVC/D, phenotype, with a higher risk of ventricular
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T A B L E 5 Continued

Phenotype AR/ Genotype/

Frequency Type of Mode of Phenotype Compound OMIM Phenotype
Gene Protein in ARVC‡ Structure Mutations Inheritance AD Heterozygous Entry Studies Ref. #

RYR2 Ryanodine- 9%* of ARVC/D Calcium Missense AD CPVT  right _ ARVC2 Exercise-induced (129,130)
receptor patients with regulatory ventricular polymorphic
type 2 negative protein involvement VAs
genetic ARVC
screening
(missense)
SNC5A Nav1.5 0%–2%* Cardiac sodium Non-missense AD Brugada Sd _ _ Prolonged QRS (127,128)
channel (nonsense, Long QT Sd duration
del) AF
Missense CDD
DCM
ARVC
MEPPC
TP63 P63 1 case report Transcription Missense AD Ectodermic _ _ Ectodermal (160)
factor dysplasia þ dysplasia
ARVC†
ADULT Sd
TGFB3 TGF-beta 3 2 families Transforming 30 and 50 UTR AD ARVC _ ARVC1 _ (161)
growth
factor

*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 conduction
disease; 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 in
Tables 1 and 3.

arrhythmias and sudden cardiac death (SCD) and a
high 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. DSP
mutations may be associated with more frequent T-
wave inversion in leads V4 to V 6 and microvoltage
(106).
DSG2 mutations have been associated
frequent biventricular involvement from 20% (105) to
50% (103). In our experience, DSG2 mutation carriers
present a higher risk of developing end-stage heart
failure that could lead to cardiac transplantation or
death than PKP2 mutation carriers (112). However,
this outcome was not found in the U.S./Dutch registry
(105). Similarly, DSC2 mutations can also lead to
biventricular cardiomyopathy, particularly in the
homozygous state (113).
Rarely, homozygous or compound heterozygous
JUP, DSP, or DSC2 mutations and rare cases of het-
erozygous DSP mutations can lead to
cutaneous syndrome diseases associating right or
biventricular arrhythmogenic cardiomyopathy with
cutaneous (palmoplantar keratoderma, alopecia, and
skin fragility), hair (wooly hair), and/or dental ab-
normalities (oligodontia), such as Naxos and Carvajal
syndromes (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 modifier
role of desmosomal missense variants, especially in
PKP2 (106,114). Patients with a complex genetic status
(homozygous, compound heterozygous, or double
heterozygous) present a more severe phenotype, with
higher penetrance (10,115), earlier onset of ventricular
arrhythmias (105,106), higher risk of SCD (103), and
with more frequent LV involvement and risk of heart fail-
ure (103,105,116).
NON-DESMOSOMAL GENES. Other genes have been
associated with the ARVC/D phenotype (Table 5). Two
mutations 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 the
junction protein N-cadherin, were also recently
identified in 2 white South African families (120).
Funder mutations in TMEM43, which encodes a
cardio- nuclear envelop protein (LUMA), have been identified
in the Newfoundland population (p.S358L) and at a
low 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 and
heart failure, especially in men, with poor R-wave
progression 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
798 Gandjbakhch et al. JACC VOL. 72, NO. 7, 2018

Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia AUGUST 14, 2018:784–804

C E NT R AL IL L U STR AT IO N 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).

patients with arrhythmogenic right predominant or
biventricular cardiomyopathy mimicking ARVC/D.
LMNA and DES mutations classically cause DCM with
conduction disease (atrioventricular block or sinus
node dysfunction), frequent ventricular arrhythmias,
and/or muscular dystrophy. Patients with LMNA- or
DES-related “ARVC/D” usually develop severe heart
failure and display conduction disease (atrioventric-
ular block or sinus dysfunction) (19,123–126). Simi-
larly, the p.R14del founder mutation
encoding the calcium regulatory protein phospho-
lamban, can cause arrhythmogenic DCM and biven-
tricular or predominant right cardiomyopathy. PLN
mutations were found in up to 12% of Dutch patients
with 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 sodium
channel Nav1.5, were identified in Chinese and, more
recently, North American patients with ARVC/D
(127,128). The ARVC/D phenotype associated with
SCN5A variants is unremarkable, except for a pro-
longed duration of QRS with no evidence of a Brugada
or long-QT ECG pattern. SCN5A mutation was also
identified in a patient with overlapping phenotype
between Brugada syndrome and ARVC/D (47). Muta-
in PLN, tions in RYR2, which classically cause catecholamin-
ergic polymorphic ventricular tachycardia, have been
identified in patients presenting with exercise-
induced polymorphic ventricular arrhythmias and
RV cardiomyopathy in a borderline phenotype with
catecholaminergic polymorphic ventricular tachy-
cardia (129). Rare RYR2 missense variants have also
been found in patients with a conventional ARVC/D
JACC VOL. 72, NO. 7, 2018
AUGUST 14, 2018:784–804
phenotype. However, the role of RYR2 in ARVC/D
must still be clarified because of the high background
rate of rare missense RYR2 variants (130). Similarly,
rare missense variants in TTN, encoding the sarco-
meric protein titin, have been found in a high
proportion of patients with ARVC/D. Their pathoge-
nicity is difficult to ascertain, however, due to the
high frequency of rare missense TTN variants in the
general population (131).
IMPACT AND CHALLENGES OF GENETIC SCREENING
IN ARVC. During the last 10 years, genetic screening
and phenotype/genotype analyses have expanded the
clinical and genetic spectrum of the disease. There
are clearly large genetic and phenotypic overlaps
between ARVC/D and DCM and, to a lesser extent,
ARVC/D and the channelopathies, raising the larger
concept of “arrhythmogenic cardiomyopathy.” How-
ever, this terminology is probably too broad to sub-
stitute to ARVC/D. Desmosomal mutations are more
frequent in patients who fulfill an ARVC/D diagnosis
according to international TFC, suggesting that the
conventional ARVC/D phenotype is mainly a desmo-
somal disease (132). Severe or biventricular presen-
tation, as well as atypical features (e.g., conduction
disturbances, early atrial arrhythmias, clinical or
subclinical muscular dystrophy, polymorphic ven-
tricular arrhythmias, arrhythmias originating from
the left ventricle), should raise suspicion of muta-
tions in non-desmosomal genes and lead to broader
genetic screening. Conversely, desmosomal gene
mutations, in particular DSP, should be suspected in
arrhythmogenic DCM. Genotype/phenotype studies
have shown that genotype could be useful for prog-
nostic stratification, especially in terms of the risk of
sudden death or heart failure (Table 5).
The clinical diagnosis of relatives is particularly
difficult in ARVC/D because of the low penetrance of
mutations and variable expressivity. Only one third
fulfill definitive TFC diagnosis (10,105). Thus, clinical
screening is usually not sufficiently accurate to
predict their genetic status. Moreover, phenotype and
penetrance in ARVC/D are age dependent, and
phenotypically negative relatives may present with
symptoms and cardiomyopathy years after initial
screening (133). The identification of the disease-
causing mutation in ARVC/D families is therefore
highly important for identifying relatives at risk of
developing or transmitting the disease and facili-
tating genetic counseling. Genetic testing is recom-
mended for relatives when the disease-causing
mutation is known (133–135). However, genetic
screening in probands is negative for 40% to 50% of
patients with ARVC/D. Thus, a negative genetic
Gandjbakhch et al. 799
Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia
screening result for a proband does not exclude
inherited ARVC/D. If the mutation is unknown,
repeated lifelong screening is recommended for first-
degree relatives, as late expression of the disease is
not rare (136). Genetics can also help in borderline
phenotypes 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 exome
sequencing, whole genome sequencing, or targeted
capture sequencing, now allows rapid and low-cost
screening of a large number of genes. Targeted cap-
ture sequencing of all known ARVC/D–associated
genes represents a cost-effective technique for
routine molecular diagnosis. This strategy can also
detect at the same time point or small ins/del muta-
tions, as well as copy number variations, which have
been recently identified in a significant number (6%
to 7%) of ARVC/D patients with initially negative
genetic screening results (137,138). The use of whole
exome sequencing for routine genetic diagnosis can
be limited by technical issues, such as low coverage of
some regions. Whole exome and whole genome
sequencing are, however, powerful research tools. In
the past 2 years, whole exome sequencing led to the
identification of 2 new candidate genes: SCN5A and
CDH2. In addition, rare genetic variants of unknown
significance were identified in other cardiomyopathy/
channelopathy–associated genes (132,138), possibly
expanding the genetic complexity of the disease.
One major issue for broad genetic screening is the
interpretation of rare genetic variants, especially
missense variants or variants in non-desmosomal
genes (138,139). Several PKP2 missense variants that
were initially considered to be disease causing were
subsequently classified as neutral polymorphisms
(140,141). In addition, the number of genetic variants
of unknown significance increases with the number
of genes tested. These variants of unknown signifi-
cance cannot be used for genetic predictive testing in
relatives. The classification of variants is currently
based on bioinformatics prediction software and
mutation scale frequency (usually <0.01%) in popu-
lation genetics databases, such as Genome Aggrega-
tion Database (gnomAD), according to the American
College of Medical Genetics and Genomics guidelines
(142). However, these tools face limitations, in
particular for classification of new missense variants.
Informative segregation studies within families are
critical to assess the pathogenicity of new genetic
variants but are often limited by the small size of the
families and incomplete penetrance of the disease.
800 Gandjbakhch et al.
Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia
The sharing of genetic results in large databases and
the development of new bioinformatics tools will
certainly improve the interpretation
screening results in the future.
CONCLUSIONS
It is important to classify cardiomyopathies on the
basis of the clinical phenotype. ARVC/D diagnosis is
particularly difficult due to the absence of unique
specific diagnosis criteria, the incomplete penetrance,
and the large spectrum of clinical manifestations
from focal RV involvement to biventricular or left
dominant cardiomyopathy. ARVC/D is to be sus-
pected in case of RV ventricular arrhythmia, a family
history of ARVC/D or SCD, or a major TFC according to
systematic ECG. The main problem with ECG and
imaging manifestations is that they reflect only a RV
cardiomyopathy, of which ARVC/D is the most
frequent etiology. The second limitation is the lack of
sensitivity of actual imaging techniques for early
diagnosis in case of focal RV involvement and the lack
of specificity for differential diagnosis with some
other arrhythmogenic diseases involving the right
ventricle. Third, several ECG and imaging criteria are
prone to subjectivity. We therefore recommend
combining 2 different imaging techniques with stan-
dardized protocols to focus on the right ventricle
to improve the accuracy of imaging diagnostics.
Follow-up of relatives who have minor cardiac
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KEY WORDS ARVC, ARVD, diagnosis,
genetics, imaging
A PPE NDI X For an expanded Methods
section, please see the online version of
this paper.