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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-
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-
tricular (RV) tachycardia had surgery guided by cordial leads from V 1 to V4 and late potentials, either
epicardial mapping. Interventions provided evidence obvious by ECG (called epsilon waves) or signal-
of their RV origin, with RV dilatation, late potentials, averaged ECG.
left-sided extension, and fibrofatty infiltration in RV ARVC/D has been included in the classification of
biopsy specimens (1). Guy Fontaine coined the term the European group for cardiomyopathies since 1994.
dysplasia, appropriate for this condition, and pub- The denomination of this cardiomyopathy has been
lished the first large series in 1982 with Frank Marcus, discussed for years. The “ARVC” and “ARVD”

Listen to this manuscript’s


audio summary by From the aSorbonne Universités, UPMC Univ Paris 06, INSERM 1166, Paris, France; bAPHP, Pitié-Salpêtrière University Hospital,
JACC Editor-in-Chief Institute of Cardiology, Paris, France; cCentre de Référence des Maladies Cardiaques Héréditaires, Paris, France; dInstitute of
Dr. Valentin Fuster. 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 diagnostic accuracy of these techniques in SSFP = steady-state free
precession
possibly lack specificity for differential diagnosis with routine practice were not assessed (16,17).
TFC = task force criteria
other arrhythmogenic diseases involving the right Fibrofatty replacement is not specific to
ventricle. Genotype/phenotype studies have shown desmosomal ARVC/D, as a similar pattern was found
that ARVC/D, which was initially described as an in TMEM-43, PLN, and LMNA-related “ARVC/D”
isolated or predominant RV disease, exhibits frequent (18–20), as well as arrhythmogenic mitochondrial
left ventricular (LV) involvement. This involvement cardiomyopathy associated with PPA2 mutations and
may be present or predominant at early stages in arrhythmogenic dilated cardiomyopathy (DCM)
some mutation carriers, expanding the clinical spec- caused by FLNC mutations (21,22).
trum of the disease to a larger group of scar-related The diagnostic yield of endomyocardial biopsies is
cardiomyopathies or arrhythmic cardiomyopathies relatively low and largely depends on the location and
according to the suggestion of some authors. number of targeted sites because of the patchy nature
The present review provides an update on the of fibrous replacement and the subepicardial location
pathological, clinical, and genetic abnormalities of lesions. Endomyocardial biopsies are generally
associated with ARVC/D, focusing on the contribution noncontributive on the right side of the interventric-
of emerging imaging techniques and genetics for ular septum. Voltage-guided endomyocardial biopsy
diagnosis. probably increases the diagnostic yield, but questions
remain on the safety of performing biopsies on the RV
PATHOLOGY
free wall (12,23). However, voltage-guided biopsies
may be useful in ruling out some differential di-
The main anatomopathological feature of ARVC/D is
agnoses, such as sarcoidosis or viral myocarditis (5,8).
the replacement of myocytes by fibrous or fibro-
adipose tissue in the RV free wall. Lesions extend ELECTROCARDIOGRAM
from the epicardium to the endocardium and
predominantly involve the area between the anterior ECG DIAGNOSTIC CRITERIA. The search for ARVC/D
part of the pulmonary infundibulum, the apex, and is initiated in 2 clinical situations. For patients with
the infero-posterior wall (the so-called “triangle of ventricular arrhythmia, mainly of RV origin on the
dysplasia”). Myocyte loss and fibrous replacement are ECG, the diagnosis is approached through RV
786 Gandjbakhch et al. JACC VOL. 72, NO. 7, 2018

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

By MRI: By MRI:
Regional RV akinesia or dyskinesia or dyssynchronous RV Regional RV akinesia or dyskinesia or dyssynchronous RV contrac-
contraction and 1 of the following: tion and 1 of the following (end-diastole):
RV end-diastolic volume/BSA $110 ml/m 2 (male) 100 ml/m 2 # RV end-diastolic volume/BSA <110 ml/m 2
or $100 ml/m 2 (female) (male) or 90 ml/m 2 # RV end-diastolic volume/
Or RV ejection fraction #40% BSA <100 ml/m 2 (female)
Or 40% < RV ejection fraction #45%
By RV angiography:
Regional RV akinesia, dyskinesia, or aneurysm
II. Tissue characterization of wall Residual myocytes <60% by morphometric analysis (or <50% if Residual myocytes 60% to 75% by morphometric analysis (or 50%
estimated), with fibrous replacement of the RV free wall to 65% if estimated), with fibrous replacement of the RV free
myocardium in $1 sample, with or without fatty replacement wall myocardium in $1 sample, with or without fatty
of tissue on endomyocardial biopsy replacement of tissue on endomyocardial biopsy
III. Repolarization abnormalities Inverted T waves in right precordial leads (V1, V2, and V3) or Inverted T waves in leads V 1 and V 2 in individuals >14 yrs of
beyond in individuals >14 yrs of age (in the absence of age (in the absence of complete RBBB) or in V 4, V 5 , or V 6
complete RBBB QRS $120 ms) 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
IV. Depolarization/conduction Epsilon wave in the right precordial leads (V1 to V3) Late potentials by SAECG in $1 of 3 parameters in the
abnormalities 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
V. Ventricular Arrhythmias Nonsustained or sustained VT of LBBB morphology with superior Nonsustained or sustained RVOT VT of LBBB morphology with
axis (negative or indeterminate QRS in leads II, III, and aVF inferior axis (positive QRS in leads II, III, and aVF and negative
and positive in lead aVL) in 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 meets History of ARVC/D in a first-degree relative in whom it is not
current TFC possible or practical to determine whether the family member
ARVC/D confirmed pathologically at autopsy or surgery in a meets current TFC
first-degree relative Premature sudden death (<35 yrs of age) due to suspected
Identification of a pathogenic mutation categorized as ARVC/D in a first-degree relative
associated or probably associated with ARVC/D in the ARVC/D confirmed pathologically or by current TFC in
patient 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. regardless of the etiology. For example, in a recent
For asymptomatic patients, family members of an study (9) on 100 consecutive patients referred for
overt case, or screening of athletes, an abnormal ECG ventricular tachycardia ablation of scar-related RV
orients the focus to the subject’s right ventricle. cardiomyopathies from 1999 to 2015, a total of 51 had
ECG has the great advantage of being universal, TFC for ARVC/D, 22 for sarcoidosis, and 27 for a car-
easy to perform, and to easily reveal abnormalities in diomyopathy of “unknown source,” which could be
most patients (24,25). It can be enhanced by opening early forms of ARVC/D.
the usual 40-Hz low-pass filters, which smooth fast The great variety of QRS-T patterns in ARVC/D (29)
signals as fragmentations (26) and epsilon waves. It is due to the progressive loss of RV subepicardial fi-
can be performed from 100 to 250 Hz with some ECG bers and conduction defects for those who survive.
recorders, as those used for the signal-averaged ECG These reflect the long and narrow activation paths,
recordings (27). Signal interpretation is made easier with altered gap junctions among fibrofatty tissues.
by double amplification, 50-mm speed recording ECG alterations depend on the extent and localization
tracings, and bipolar precordial recordings that in- of the disease, and their incidence varies widely be-
crease ECG sensitivity (28) (Table 3). All reflect losses tween series (Table 4). Early-stage ARVC/D exhibits
of normal RV myocardium and their consequences, 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
proposed more complex proprietary ECG methods
for better predictive values, such as computerized
Myocarditis
Sarcoidosis
S-wave surface and bipolar chest leads (35), vec-
Dilated cardiomyopathy torcardiography derivations (36), or body surface
Athlete’s heart mapping (37). However, surface ECG remains the
Idiopathic infundibular PVC/VT only widely available and simple method using a
Brugada syndrome combination of repolarization and depolarization
Uhl’s disease
data that can be enhanced by the recording modi-
Other causes of RV dilatation and/or dysfunction
Ebstein’s anomaly
fications suggested earlier.
Left to right shunt: interatrial septal defect, anomalous
REPOLARIZATION DATA. T-wave inversions in the
pulmonary venous return
Tricuspid regurgitation right precordial leads are present in up to 87% of
Inferior infarct with RV extension
adult patients with ARVC/D (38), are directly related
PVC ¼ premature ventricular contraction; other abbreviations as in Table 1.
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
most patients. Endocardial three-dimensional (3D) contexts, such as in some young athletes (with a
mapping, with map-directed biopsies (30), and higher incidence in black athletes), in ischemic car-
endo-epicardial mapping, combined with magnetic diomyopathy, or during acute pulmonary embolism.
resonance imaging (MRI) scar data, have shed light on Right precordial T-wave inversions are also related to
the electrical features of ARVC/D (31). right bundle branch block (RBBB); ARVC/D can be
ECG-based TFC diagnostic criteria include right suspected, however, if they are present in V1, V2, and
precordial T-wave inversions, the presence of V3 (40,41) and according to the QRS morphology
epsilon waves, and increased duration of the ter- (discussed later). T-wave depth in V 1 is not included
minal QRS from the nadir of the S-wave to the end in the TFC. However, it is an important feature, with a
of the QRS, when enlarged above 55 ms (32). How- high negative predictive value. Two studies found
ever, up to 30% of patients with morphological 97% specificity for a negative amplitude, one for a
criteria for ARVC/D have a so-called ECG-concealed value $2 mm in V1 (42), and the other $3 mm with a
form that does not fulfill the 2010 ECG criteria (33). special bipolar chest CF1 lead (35), but with lower
However, they may have less specific ECG abnor- sensitivities of 94% for the former and 24% for the
malities, such as ST-segment modifications (34) or 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.
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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.
they can also be recorded in many other scar-related
cardiomyopathies (50), and their definition is not
straightforward because standard ECG filtering may
Inverted T waves in inferior leads are not uncom-
erase them. QRS amplitude is also not included in the
mon in ARVC/D and are related to left-sided exten-
TFC (29,51). Microvoltage is not specific but observed
sion, as shown by MRI imaging in patients or related
in patients with advanced ARVC/D disease with sig-
families (43,44).
nificant RV dilatation and better expressed by the
Several nonspecific ST-segment abnormalities can
sum of QRS amplitudes (52). It can be more specific
be found, from flat precordial T waves to Brugada-like
when limited to the right precordium (53) or with the
ECGs. J-point elevation >1 mm in at least 2 inferior
ratio of the sums of precordial voltage ratios (54) V 1 to
and/or lateral leads (45) is a frequent finding in >20%
V 3/V1 to V 6 #0.48.
of ECGs, reflecting late depolarization. Brugada-like
Signal-averaged ECG reveals microvolt-level late
ECGs are difficult to interpret because of the overlap
potentials. However, the Simson method, with XYZ
between ARVC/D and Brugada syndrome (46–48). Re-
electrodes, does not have the proximity effect of
sults of Ajmaline testing may be positive in up to 16%
precordial leads and reflects any late potential origin.
of patients with ARVC/D (48), and RV wall motion ab-
Nevertheless, its 3 components (filtered QRS dura-
normalities present in 16% of patients with Brugada
tion, low-amplitude signal, and root mean square
ECG pattern (47). The clinical implications of these
amplitude of the last 40 ms) are highly associated
overlapping phenotypes are currently unknown.
with ARVC/D. They are found in >50% of ARVC/D
DEPOLARIZATION DATA. Multiple features have
cases, and their incidence and duration increase with
been described from V 1 to V3, reflecting the wide
time, up to 93% in severe forms (29). Its specificity is
range of RV parietal blocs (Table 4, Figure 1). They
increased when combined with RV enlargement or
consist of QRS notching (24,49), a wider QRS, larger S
low ejection fraction, and it enhances the sensitivity
waves, epsilon waves, late potentials at signal-
of borderline surface ECG (55).
averaged ECG, and incomplete, complete, or atyp-
ical RBBB, combined or alone. A RBBB block VENTRICULAR ARRHYTHMIAS. ARVC/D ventricular
morphology is suggestive of ARVC/D with an R’/S arrhythmias usually have a left bundle branch block
ratio <1 in V1 (41). (LBBB) pattern. They are characterized by several
A recent paper (31) excellently illustrated the great morphologies. A left-axis deviation is suggestive for
variety of ECG presentations. It comprised 35 cases, ARVC/D (15,18). The main problem is their differen-
all with negative precordial T waves, epicardial and tiation from idiopathic arrhythmias when they only
endocardial mapping, and MRI imaging. It showed a originate from the RV infundibulum, with a
relationship between the QRS and disease localiza- descending vertical axis. The most sensitive param-
tion and extent. When the QRS appeared normal, the 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 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
directly identifiable by echocardiography but lead to
walls. 5) Incomplete right bundle branch block (RBBB) and T-wave inversion in V1 to V3.
macroscopic changes, with regional wall motion 6) RBBB, microvoltage, and T-wave inversion in V1 to V4. 7) Atypical RBBB,
abnormalities associated with RV dilatation and/or microvoltage, and T-wave inversion in V1 to V3 with fragmentations. 8) Large biphasic
global RV systolic dysfunction. Thus, the presence QRS, microvoltage, and T-wave inversion in V1 to V4 in biventricular ARVC/D and heart

of segmental wall motion abnormalities, defined as 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,
regional akinesia, dyskinesia, or dyssynchrony,
and flat in aVF in a patient with ARVC/D without RV dilatation/dysfunction but with 2
combined with RV dilatation and/or RV dysfunction, dyskinetic areas (RV anterior wall and subtricuspid region). ARVC/D ¼ arrhythmogenic
is required for diagnosis (2010 TFC) (Table 1). The right-ventricular cardiomyopathy/dysplasia.
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 abnormalities of the right ventricle have been noted in
criteria are highly specific but lack sensitivity, ARVC/D, such as a hypertrophic trabecular or hyper-
especially in early stages when RV dilatation/ reflective moderator band, but these findings lack
dysfunction may be absent. specificity, especially in competitive athletes. The
Several robust parameters representing RV systolic evaluation of the right ventricle by using echocardi-
function, such as tricuspid annular plane systolic ography can be challenging because of its retrosternal
excursion and peak systolic RV annular velocity, are position and its complex geometry. In addition, the
generally lower in ARVC/D (tricuspid annular plane assessment of wall motion abnormalities is highly
systolic excursion <16 mm and peak systolic RV subjective and requires specific expertise.
annular velocity <10 cm/s) (58) but usually only in Contrast echocardiography can improve the
more advanced forms of the disease. Structural 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- strain, may reflect electrical dispersion and could be a
niques, such as 3D echocardiography and tissue prognostic marker of arrhythmic events (64). Tissue
deformation imaging, may increase the performance deformation imaging is therefore a promising tech-
of echocardiography, especially in early stages. nique, but image acquisition, reproducibility, and
3D echocardiography allows the measurement of RV quality are still limiting factors. Both multiplane and
volumes and the RV ejection fraction (60), but its 3D speckle tracking are promising new applications in
value in advanced ARVC/D with very large right RV deformation imaging.
ventricles must be established. The two-dimensional
(2D)-strain echocardiographic method can measure MAGNETIC RESONANCE IMAGING. S t r e n g t h s a n d
myocardial deformation by tracking localized acous- 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
tic markers frame by frame (speckle tracking) can assess biventricular morphology, volumes,
(Figure 3). Left and right longitudinal strain derived thickness, and mass, as well as regional motion and
from speckle tracking could be sensitive tools for myocardial fibrous or adipose content, edema, and
assessing regional and global myocardial function flow, with high spatial and temporal resolution,
(61,62). A cutoff value of –18% peak systolic strain was independently of body size or acoustic windows.
proposed to differentiate between normal and Initial studies focused on the identification of ad-
abnormal RV segments (58). RV strain may also be ipose infiltration within a thinned RV wall on T 1 -
useful for detecting RV subclinical systolic dysfunc- weighted spin echo images, which proved to be
tion, especially in first-degree relatives of patients inconsistent and poorly reproducible (65). Similarly,
with ARVC/D (63) (Table 3). Moreover, RV mechanical 61% of patients were shown to display late gadolin-
dispersion (heterogeneous contraction), assessed by 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 have been approached separately, the direct
fibrosis in contrast-enhanced MRI (66). Neither of visualization and quantification of the fibrofatty mix—
these parameters was included as diagnostic criteria the true hallmark of the disease—is still an unresolved
in the 2010 TFC, which focused on RV dilatation challenge, as these 2 components are not individually
and/or global dysfunction associated with severe identifiable at the macroscopic scale. ARVC/D diag-
regional contraction anomalies, including akinesia, nosis is therefore based on demonstrating the conse-
dyskinesia, and asynchronous contraction (Table 1). quence of intramyocardial fibrofatty replacement,
Indeed, the direct visualization of fibrofatty namely static morphological abnormalities (sponta-
replacement by MRI as a diagnostic hallmark faces neous aneurysm or bulging) and dynamic morphology
several problems. First, direct visualization of RV (akinesia, dyskinesia, or asynchrony). The segmental
intramyocardial fibrosis and fat is made technically combination of myocardial thinning, severe abnormal
difficult by the thin RV wall in terms of the achievable motion, and fatty infiltration is in favor of fibrofatty
spatial resolution of MRI, potentially resulting in replacement, whereas the presence of fat in a
misleading partial volume effects. Second, fatty segment of normal thickness and contraction is more
infiltration of the myocardium has been shown to be likely to be related to nonspecific fatty infiltration
frequent and nonspecific to ARVC/D (67). Third, LGE (69). The absence of RV myocardial fat according to an
is also nonspecific and present in numerous ischemic MRI does not preclude the diagnosis of ARVC/D, as
or nonischemic diseases potentially involving the shown in pediatric patients (70), nor should the
right ventricle, including myocarditis and sarcoidosis. presence of fat be interpreted alone.
Differential diagnosis between ARVC/D and myocar- MRI is the reference method to assess ventricular
ditis may be particularly challenging because some volumes and regional function independently of
patients with ARVC/D can present with acute or sub- geometric assumptions, with high intra-observer and
acute myocarditis (7,68). Moreover, subepicardial interobserver reproducibility (71). However, the
LV LGE can be present in ARVC/D, leading to over- diagnosis of RV wall motion abnormalities remains
diagnosis of myocarditis. Furthermore, if fat and 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- (Multi-Ethnic Study of Atherosclerosis) trial,
server reproducibility (70). This situation highlights excluding younger adults, and measurements from
the importance of standardized and regional biven- gradient echo cine-MRI, which provides lower values
tricular analysis of the right ventricle for optimal than currently used cine-SSFP techniques. Never-
diagnostic performance with high spatial and tem- theless, a study in a pediatric population showed that
poral resolution cine steady-state free precession MRI was associated with good sensitivity (70), despite
(SSFP) imaging that covers all RV segments in several these potential limits. A normal MRI was found to
perpendicular orientations (Online Appendix, have an excellent negative predictive value of 99%
Figure 4). With comprehensive biventricular analysis, for major clinical events in a 4.3-year follow-up of 369
96% of cardiovascular magnetic resonance examina- consecutive patients suspected of having ARVC/D,
tions from 74 mutation-positive ARVC/D patients and abnormal MRI was an independent predictor of
revealed an abnormal right ventricle (72). The most events with a cumulative effect of several anomalies
prevalent RV abnormalities were basal inferior wall (including morphology, wall motion abnormalities,
dyskinesia (94% of patients) and basal anterior wall and fat/fibrosis) (75).
dyskinesia (87% of patients). In the same study, LV ADVANCES IN MRI. Although the thin RV wall re-
involvement concerned 52% of patients and led to mains a technical challenge for direct assessment of
redefining the initial dysplasia triangle, including the tissue composition according to MRI, there have been
posterior lateral wall of the left ventricle, along with technical advances since the 2010 TFC. New insights
the subtricuspid and anterior wall of the right come from large population studies that provide
ventricle. Typical MRI findings corresponding to this normative volumetric data from current cine-SSFP
description are illustrated in Figure 5. imaging techniques (76,77), but large-scale compari-
MRI has been shown to be particularly useful in son with ARVC/D probands is still necessary to better
distinguishing ARVC/D from alternate diagnoses (73). define actual threshold values. Longitudinal data on
Several limitations of the MRI criteria in the 2010 TFC the phenotypical evolution of the disease are also
have been discussed (65,74). They include basing the highly desirable. The existing 2010 TFC were
volumetric RV data thresholds on middle-aged and designed to be more specific than sensitive, intro-
elderly patients (45 to 85 years of age) from the MESA 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 Reproducibility for RV strain measurement using
early disease and provide incremental value to strat- feature tracking has recently been shown to be good
ify risk is underestimated. Multiparametric models in (interobserver, intraclass correlation coefficient
large datasets, including modern imaging biomarkers >0.86; interstudy, intraclass correlation coefficient
and genetics, will likely provide decisive insights in >0.71) (78). Global longitudinal and circumferential
the near future. RV strain and strain rates at the base assessed by
Semi-automated myocardial deformation quantifi- using feature-tracking MRI were shown to be signifi-
cation may be a promising approach to lower vari- cantly lower in ARVC/D probands than in healthy
ability in assessing RV function, particularly feature volunteers and family relatives (79,80). Moreover, the
tracking, which, contrary to tagging techniques, can global longitudinal strain rate was found to be lower
be applied to routine cine-MRI (Table 3). in patients with ARVC/D and preserved RV ejection
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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 compressed sensing techniques, has been introduced
contraction by feature-tracking MRI, as reported by and initially applied to the left ventricle with prom-
Prati et al. (80), may be particularly useful, as this ising results (83). Further improvements in spatial
criterion (included in the 2010 TFC) is particularly resolution may allow reliable RV wall characterization
prone to subjectivity. Regional feature-tracking strain in the near future.
analysis could be more sensitive than global param-
eters. Predominant impairment in the subtricuspid CARDIAC COMPUTED TOMOGRAPHY
region allowed the discrimination of preclinical
ARVC/D (mutationþ/phenotype–) from healthy con- Although computed tomography (CT) scanning is not
trols, consistent with prior knowledge on the regional included in the 2010 TFC (4), it was considered to be
expression of ARVC/D (72), whereas global strain was appropriate in this setting according to a contempo-
nondiscriminant (81). The continued use of rary expert consensus (84). This modality, with
T 1 -weighted spin echo images to visualize fat lacks excellent isotropic spatial resolution of 0.5 mm,
diagnostic performance, but new techniques may 4-dimensional (4D)-cine capability, and recently
help in characterizing fatty content. In particular, achievable lower radiation doses (1 to 2 mSv), may
ECG-gated Dixon techniques allow specific imaging play a role in distinguishing ARVC/D from other
separating the fat from the water component of the causes of ventricular arrhythmias such as coronary
myocardium (82), but they currently remain insuffi- heart disease (65) (Table 3). Seminal studies per-
ciently available and validated in this disease setting. formed with single-slice, non–ECG-gated CT imaging
Conversely, high-resolution 3D LGE, with high or electron-beam CT imaging in small patient groups
isotropic spatial resolution (1.4 mm 3) images using showed the potential to detect RV enlargement and
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regional motion abnormalities and a scalloped RV GENETICS OF ARVC/D


surface, as well as epicardial or intramyocardial fat of
the RV free wall, trabecular enlargement, and adipose The role of genetic testing has dramatically increased
infiltration (85–90). Good correlations were reported in ARVC/D diagnosis. Major diagnostic criteria for
with histology, albeit on very few samples and with ARVC/D have included the presence of a pathogenic
inevitable sampling bias (87). mutation since 2010. To date, 16 genes have been
After these initial studies, several case reports re- associated with the ARVC/D phenotype, mostly those
ported translation to the use of multidetector CT encoding desmosomal proteins (so-called desmo-
(MDCT) imaging (91–94). Nakajima et al. (95) evalu- somal genes) (Table 5, Central Illustration). Candidate
ated the diagnostic performance of MDCT in 77 pa- gene or linkage studies have identified other
tients and proposed a scoring system based on RV cardiomyopathy/channelopathy-associated genes in
fatty infiltration, RV free-wall bulging, and RV dila- patients with an ARVC/D phenotype or arrhythmo-
tation for a definite ARVC/D diagnosis, according to genic biventricular cardiomyopathy, expanding the
the 2010 TFC, with high performance (87% sensi- genetic and phenotypic spectrum of the disease.
tivity, 94% specificity, and 92% accuracy). Regional However, the genetic cause of ARVC/D remains un-
wall motion abnormalities assessed by dynamic RV known for 40% to 50% of patients.
datasets (available in 21 patients) were consistent DESMOSOMAL GENES. ARVC/D is mainly caused by
with MRI or 2D-echo data in all cases but were not mutations in genes encoding the desmosomal pro-
included in the proposed score. However, one of the teins plakophilin-2 (PKP2), desmoglein-2 (DSG2),
main limitations in this study was the use of existing desmoplakin (DSP), and, more rarely, desmocollin-2
2010 TFC criteria as the “gold standard” instead of (DSC2) and plakoglobin (JUP) (Table 5, Central
genetics. Remaining knowledge gaps include the illustration) (99). Desmosomes are membrane pro-
value of regional wall motion abnormalities in CT tein complexes that play an important role in inter-
imaging, in addition to RV dilatation, bulging, and cellular adhesion and maintenance of the structural
fatty infiltration and the position of MDCT in the integrity of tissues subjected to mechanical stress,
diagnostic and prognostic evaluation of patients such as the heart and skin. These mutations usually
suspected of having ARVC/D. have an autosomal dominant mode of inheritance
Modern MDCT allows fast acquisition and high with incomplete penetrance, leading to an isolated
isotropic spatial resolution (0.5 mm), permitting pre- cardiac phenotype. Various types of mutations
cise RV and LV volume measurements validated (missense, nonsense, splice-site, frameshift, and
versus MRI (96). 4D-cine CT imaging may favorably large deletions) have been reported, and most are
replace RV angiography due to its advantages, such as private. Desmosomal gene mutations have been
providing full 4D coverage of RV wall dynamics and identified in 33% to 63% of ARVC/D probands
potentially increased sensitivity to detect focal pre- (10,100–104). PKP2 is the major ARVC/D disease-
sentations of the disease. An advantage of 4D CT im- causing gene, accounting for 36% to 92% of
aging is its ability to reveal the complex anatomy of mutations identified in desmosomal genes.
the right ventricle, alleviating the risk of image su- Data from familial studies showed that desmo-
perposition and limited views of standard 2D angi- somal mutations are associated with low pene-
ography. In addition to these functional parameters, trance, as only one-third of relatives carrying
high spatial resolution, combined with the high native mutations fulfill definitive ARVC/D diagnosis, ac-
contrast of adipose tissue, allows precise depiction of cording to international 2010 TFC (10,102). Women
fatty infiltration within the thin RV wall, with or carrying desmosomal gene mutations are at lower
without contrast injection, as illustrated in Figure 6 risk of expressing the disease than men and are
(97); good correlations are achieved with epicardial thus more likely to be healthy mutation carriers
and endocardial low-voltage areas (98). These (105,106). The causes of such sex-related penetrance
encouraging image integration methods may help in are not yet fully understood, but higher levels of
focusing ablation therapy of culprit lesions and war- participation in competitive and intensive sports by
rant further study. MDCT is widely available, fast, and men (107) or hormonal factors (108) could explain
affordable. Patients for whom MRI is challenging, some differences.
such as those with severe arrhythmia, claustrophobia, PKP2 mutations are mostly autosomal dominant
and implantable cardioverter-defibrillators, as well as and are more likely to lead to isolated RV involve-
those with suspicion of focal ARVC/D, may particu- ment and a conventional phenotype than other
larly benefit from this technique. 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 (101,106). Several studies have suggested a modifier
high level of LV involvement (105,106,111), particu- role of desmosomal missense variants, especially in
larly in patients with truncating DSP mutations (111), PKP2 (106,114). Patients with a complex genetic status
leading to a higher risk of end-stage heart failure. DSP (homozygous, compound heterozygous, or double
mutations may be associated with more frequent T- heterozygous) present a more severe phenotype, with
wave inversion in leads V4 to V 6 and microvoltage higher penetrance (10,115), earlier onset of ventricular
(106). arrhythmias (105,106), higher risk of SCD (103), and
DSG2 mutations have been associated with more frequent LV involvement and risk of heart fail-
frequent biventricular involvement from 20% (105) to ure (103,105,116).
50% (103). In our experience, DSG2 mutation carriers NON-DESMOSOMAL GENES. Other genes have been
present a higher risk of developing end-stage heart associated with the ARVC/D phenotype (Table 5). Two
failure that could lead to cardiac transplantation or mutations in CTNNA3, which encodes alpha-T-
death than PKP2 mutation carriers (112). However, catenin (a component of the cardiac area compo-
this outcome was not found in the U.S./Dutch registry sita), were identified in the Italian ARVC/D cohort
(105). Similarly, DSC2 mutations can also lead to (117) but were absent from other European cohorts
biventricular cardiomyopathy, particularly in the (118,119). Missense variants in CDH2, encoding the
homozygous state (113). junction protein N-cadherin, were also recently
Rarely, homozygous or compound heterozygous identified in 2 white South African families (120).
JUP, DSP, or DSC2 mutations and rare cases of het- Funder mutations in TMEM43, which encodes a
erozygous DSP mutations can lead to cardio- nuclear envelop protein (LUMA), have been identified
cutaneous syndrome diseases associating right or in the Newfoundland population (p.S358L) and at a
biventricular arrhythmogenic cardiomyopathy with low frequency in other populations (18,101,105,121).
cutaneous (palmoplantar keratoderma, alopecia, and The founder TMEM43 p.S358L mutation was associ-
skin fragility), hair (wooly hair), and/or dental ab- ated with high penetrance and high risk of SCD and
normalities (oligodontia), such as Naxos and Carvajal heart failure, especially in men, with poor R-wave
syndromes (Table 5). progression and frequent LV dilatation (18, 122).
Patients with multiple desmosomal mutations Mutations in LMNA, encoding the Lamin A/C nu-
(compound or digenic heterozygosity) are not rare, clear envelop protein, and DES, encoding the inter-
ranging from 4% to 6% (103,105) to 16% to 20% mediate filament desmin, have been identified in
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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 Missense variants in SCN5A, encoding the sodium
biventricular cardiomyopathy mimicking ARVC/D. channel Nav1.5, were identified in Chinese and, more
LMNA and DES mutations classically cause DCM with recently, North American patients with ARVC/D
conduction disease (atrioventricular block or sinus (127,128). The ARVC/D phenotype associated with
node dysfunction), frequent ventricular arrhythmias, SCN5A variants is unremarkable, except for a pro-
and/or muscular dystrophy. Patients with LMNA- or longed duration of QRS with no evidence of a Brugada
DES-related “ARVC/D” usually develop severe heart or long-QT ECG pattern. SCN5A mutation was also
failure and display conduction disease (atrioventric- identified in a patient with overlapping phenotype
ular block or sinus dysfunction) (19,123–126). Simi- between Brugada syndrome and ARVC/D (47). Muta-
larly, the p.R14del founder mutation in PLN, tions in RYR2, which classically cause catecholamin-
encoding the calcium regulatory protein phospho- ergic polymorphic ventricular tachycardia, have been
lamban, can cause arrhythmogenic DCM and biven- identified in patients presenting with exercise-
tricular or predominant right cardiomyopathy. PLN induced polymorphic ventricular arrhythmias and
mutations were found in up to 12% of Dutch patients RV cardiomyopathy in a borderline phenotype with
with ARVC/D, but at a lower frequency in other pop- catecholaminergic polymorphic ventricular tachy-
ulations, and are characterized by frequent micro- cardia (129). Rare RYR2 missense variants have also
voltage and a high risk of SCD and heart failure (20). been found in patients with a conventional ARVC/D
JACC VOL. 72, NO. 7, 2018 Gandjbakhch et al. 799
AUGUST 14, 2018:784–804 Diagnosis, Imaging, and Genetics of Arrhythmogenic RV Cardiomyopathy/Dysplasia

phenotype. However, the role of RYR2 in ARVC/D screening result for a proband does not exclude
must still be clarified because of the high background inherited ARVC/D. If the mutation is unknown,
rate of rare missense RYR2 variants (130). Similarly, repeated lifelong screening is recommended for first-
rare missense variants in TTN, encoding the sarco- degree relatives, as late expression of the disease is
meric protein titin, have been found in a high not rare (136). Genetics can also help in borderline
proportion of patients with ARVC/D. Their pathoge- phenotypes when a definite diagnosis is necessary,
nicity is difficult to ascertain, however, due to the such as for competitive athletes.
high frequency of rare missense TTN variants in the VALUE OF HIGH-THROUGHPUT SEQUENCING FOR
general population (131). ARVC/D DIAGNOSIS. The development of high-
IMPACT AND CHALLENGES OF GENETIC SCREENING throughput sequencing, such as whole exome
IN ARVC. During the last 10 years, genetic screening sequencing, whole genome sequencing, or targeted
and phenotype/genotype analyses have expanded the capture sequencing, now allows rapid and low-cost
clinical and genetic spectrum of the disease. There screening of a large number of genes. Targeted cap-
are clearly large genetic and phenotypic overlaps ture sequencing of all known ARVC/D–associated
between ARVC/D and DCM and, to a lesser extent, genes represents a cost-effective technique for
ARVC/D and the channelopathies, raising the larger routine molecular diagnosis. This strategy can also
concept of “arrhythmogenic cardiomyopathy.” How- detect at the same time point or small ins/del muta-
ever, this terminology is probably too broad to sub- tions, as well as copy number variations, which have
stitute to ARVC/D. Desmosomal mutations are more been recently identified in a significant number (6%
frequent in patients who fulfill an ARVC/D diagnosis to 7%) of ARVC/D patients with initially negative
according to international TFC, suggesting that the genetic screening results (137,138). The use of whole
conventional ARVC/D phenotype is mainly a desmo- exome sequencing for routine genetic diagnosis can
somal disease (132). Severe or biventricular presen- be limited by technical issues, such as low coverage of
tation, as well as atypical features (e.g., conduction some regions. Whole exome and whole genome
disturbances, early atrial arrhythmias, clinical or sequencing are, however, powerful research tools. In
subclinical muscular dystrophy, polymorphic ven- the past 2 years, whole exome sequencing led to the
tricular arrhythmias, arrhythmias originating from identification of 2 new candidate genes: SCN5A and
the left ventricle), should raise suspicion of muta- CDH2. In addition, rare genetic variants of unknown
tions in non-desmosomal genes and lead to broader significance were identified in other cardiomyopathy/
genetic screening. Conversely, desmosomal gene channelopathy–associated genes (132,138), possibly
mutations, in particular DSP, should be suspected in expanding the genetic complexity of the disease.
arrhythmogenic DCM. Genotype/phenotype studies One major issue for broad genetic screening is the
have shown that genotype could be useful for prog- interpretation of rare genetic variants, especially
nostic stratification, especially in terms of the risk of missense variants or variants in non-desmosomal
sudden death or heart failure (Table 5). genes (138,139). Several PKP2 missense variants that
The clinical diagnosis of relatives is particularly were initially considered to be disease causing were
difficult in ARVC/D because of the low penetrance of subsequently classified as neutral polymorphisms
mutations and variable expressivity. Only one third (140,141). In addition, the number of genetic variants
fulfill definitive TFC diagnosis (10,105). Thus, clinical of unknown significance increases with the number
screening is usually not sufficiently accurate to of genes tested. These variants of unknown signifi-
predict their genetic status. Moreover, phenotype and cance cannot be used for genetic predictive testing in
penetrance in ARVC/D are age dependent, and relatives. The classification of variants is currently
phenotypically negative relatives may present with based on bioinformatics prediction software and
symptoms and cardiomyopathy years after initial mutation scale frequency (usually <0.01%) in popu-
screening (133). The identification of the disease- lation genetics databases, such as Genome Aggrega-
causing mutation in ARVC/D families is therefore tion Database (gnomAD), according to the American
highly important for identifying relatives at risk of College of Medical Genetics and Genomics guidelines
developing or transmitting the disease and facili- (142). However, these tools face limitations, in
tating genetic counseling. Genetic testing is recom- particular for classification of new missense variants.
mended for relatives when the disease-causing Informative segregation studies within families are
mutation is known (133–135). However, genetic critical to assess the pathogenicity of new genetic
screening in probands is negative for 40% to 50% of variants but are often limited by the small size of the
patients with ARVC/D. Thus, a negative genetic families and incomplete penetrance of the disease.
800 Gandjbakhch et al. JACC VOL. 72, NO. 7, 2018

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

The sharing of genetic results in large databases and abnormalities by using echocardiography and MRI
the development of new bioinformatics tools will also seems reasonable to detect progressive disease.
certainly improve the interpretation of genetic Recent techniques such as semi-automated
screening results in the future. myocardial deformation quantification by echo/MRI
or MDCT with 4D CT imaging are promising tools that
CONCLUSIONS
need to be validated in larger cohorts with genetic
validation and in multiparametric models. Genetic
It is important to classify cardiomyopathies on the
diagnosis is particularly useful to confirm the clinical
basis of the clinical phenotype. ARVC/D diagnosis is
diagnosis and to screen relatives at risk but also for
particularly difficult due to the absence of unique
differential diagnosis from other inherited cardio-
specific diagnosis criteria, the incomplete penetrance,
myopathy/channelopathy involving the right
and the large spectrum of clinical manifestations
ventricle and prognostic stratification. However,
from focal RV involvement to biventricular or left
diagnostic genetics also has limitations, as genetic
dominant cardiomyopathy. ARVC/D is to be sus-
screening is only contributive in w50% of cases and is
pected in case of RV ventricular arrhythmia, a family
sometimes difficult to interpret. The identification of
history of ARVC/D or SCD, or a major TFC according to
additional diagnostic criteria, such as biomarkers,
systematic ECG. The main problem with ECG and
and of the remaining genetic causes of the disease is
imaging manifestations is that they reflect only a RV
an important area of research that will certainly
cardiomyopathy, of which ARVC/D is the most
improve diagnosis in the future.
frequent etiology. The second limitation is the lack of
sensitivity of actual imaging techniques for early ACKNOWLEDGMENTS In memory of Pr. Guy Fon-

diagnosis in case of focal RV involvement and the lack taine (1936 to 2018), who first described ARVC/D and
of specificity for differential diagnosis with some dedicated his life to improving the scientific knowl-
other arrhythmogenic diseases involving the right edge of this disease.
ventricle. Third, several ECG and imaging criteria are
prone to subjectivity. We therefore recommend ADDRESS FOR CORRESPONDENCE: Dr. Estelle
combining 2 different imaging techniques with stan- Gandjbakhch, Institut de Cardiologie, APHP, Hôpital
dardized protocols to focus on the right ventricle Pitié-Salpêtrière, 45-87 boulevard de l’hôpital, 75013
to improve the accuracy of imaging diagnostics. Paris, France. E-mail: estelle.gandjbakhch@aphp.fr.
Follow-up of relatives who have minor cardiac Twitter: @egandj, @Inserm, @ICAN_Institute.

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