Circulation Journal

Official Journal of the Japanese Circulation Society

FOCUS REVIEWS ON ARRHYTHMIA
http://www. j-circ.or.jp

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

– Three Decades of Progress –
Hugh Calkins, MD

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare, inherited cardiomyopathy character-

ized by ventricular arrhythmias, sudden cardiac death, and right ventricular dysfunction. Since the first major descrip-
tion of this disease, much has been learned about ARVD/C. One of the main breakthroughs was the discovery that
mutations in desmosomal proteins are the most frequent genetic basis of ARVD/C. Today, genetic testing plays an
important role in both the diagnosis of ARVD/C and cascade family screening. Much has also been learned concern-
ing the optimal approaches to diagnosis. The 2010 Task Force Diagnostic criteria for ARVD/C represent the standard
for diagnosis today. We have also learned much about the importance of proband status and the 24-h PVC count
to assess sudden death risk, and the importance of exercise both in the development of ARVD/C in susceptible
individuals and in defining the course of the disease. From a treatment perspective, placement of ICDs in specific
subsets of patients with ARVD/C who are at increased risk of sudden death is important. The techniques of VT abla-
tion have also evolved over time and are valuable components of our management strategies for the ARVD/C patient
today. This review will provide an update on ARVD/C, with specific attention to some of the contributions to this field
reported by the Johns Hopkins ARVD/C Program.   (Circ J 2015; 79: 901 – 913)

Key Words: Ablation; Cardiomyopathy; Exercise; Ventricular arrhythmia; Ventricular fibrillation

T
he Johns Hopkins ARVD/C Program was founded in
1999, following the tragic death of a 32-year-old
patient with arrhythmogenic right ventricular dyspla-
sia/cardiomyopathy (ARVD/C). The 12-lead ECG of this patient
is shown in Figure 1, demonstrating the typical ARVD/C
findings including an epsilon wave. She presented with syn-
cope, an electrophysiologic study (EPS) revealed inducible
ventricular tachycardia (VT), ARVD/C was diagnosed, and an
implantable cardioverter defibrillator (ICD) was recommended.
However, the patient died suddenly. Of particular note is that
her father died suddenly playing squash at the age of 32 years.
Subsequent family screening revealed that the patient’s younger
brother also had mild evidence of ARVD/C with an ECG
revealing T wave inversion (TWI) in the right precordial
leads. An MRI revealed mild evidence of ARVD/C, a Holter
recording revealed less than 100 premature ventricular con-
tractions (PVCs), and no VT was inducible at EPS. A decision
was made to place an ICD in this patient and he was advised
to avoid exercise. He has done well since then with no ICD
therapies, and no evidence of progression of his ARVD/C.
Genetic testing has revealed that he harbors a mutation in PKP2.
In response to this tragic case, and the very limited under-
standing of ARVD/C in 1999, the ARVD/C program at Johns
Hopkins was founded. The goals of this program were three-
fold. First, it sought to further the scientific understanding of
ARVD/C, a second goal was to help educate the medical and
patient communities about ARVD/C, and a final goal was to
serve as a referral center for ARVD/C patients. Since the ini-
tiation of the program much has been learned about ARVD/C.
ARVD/C is an inherited cardiomyopathy that is character-
ized by ventricular arrhythmias (VAs), an increased risk of
sudden cardiac death (SCD), and abnormalities of right (and
less commonly left) ventricular structure and function. Struc-
tural involvement of the right ventricle (RV) predominates
and a left-dominant form is rarely seen. In most patients in the
United States, structural abnormalities of the RV predominate.
The pathologic hallmark of ARVD is myocyte loss with fibro-
fatty replacement (Figure 2). Since the first detailed clinical
description of the disorder in 1982,1 significant advances have
been made in our understanding of all aspects of this disease.
Over the past decade, mutations predominantly in desmo-
somal proteins have been determined to be the genetic basis
of ARVD/C. Today, a pathogenic mutation can be identified
in more than 60% of affected individuals.2,3 Consistent with
this, genetic testing has emerged as an important diagnostic
tool and plays a critical role in cascade family screening. The
purpose of this review is to summarize the current state of
knowledge regarding the natural history, clinical presentation,
diagnosis, and treatment of patients with ARVD/C.

Received March 16, 2015; accepted March 17, 2015; released online April 15, 2015
The Johns Hopkins Hospital, Baltimore, MD, USA
Mailing address:  Hugh Calkins, MD, The Johns Hopkins Hospital, Sheikh Zayed Tower – Room 7125R, 1800 Orleans Street, Baltimore,
MD 21287, USA.   E-mail: hcalkins@jhmi.edu   URL: http://www.arvd.com/
ISSN-1346-9843  doi: 10.1253/circj.CJ-15-0288
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.79, May 2015

902
Clinical Presentation and Natural
History of ARVD/C
ARVD/C is an inherited condition with an estimated preva-
lence of 1 per 5,000. Patients usually present during the sec-
ond to fifth decade of life with palpitations, lightheadedness,
syncope, or sudden death.3,4 It is exceedingly rare to manifest
clinical signs or symptoms of ARVD/C prior to 12 years of
age. It is also uncommon to develop clinical signs or symp-
Circulation Journal  Vol.79, May 2015
CALKINS H
Figure 1.   Twelve-lead ECG from a patient
with advanced ARVDCC. T wave inver-
sion is present in leads V1 through V5.
Also present in this ECG is an epsilon
wave clearly visible in lead V1.
Figure 2.  (A) Gross specimen of an
explanted heart showing a massive right
ventricle (RV) with extensive fat that has
replaced the entire RV epicardium leav-
ing a thin rim of fibrotic endocardium.
Also note the relative sparing of the left
ventricle and the interventricular septum.
(B) Near total fatty replacement of the RV
wall with loss of myocytes renders the RV
translucent. (C) Transmural low-resolu-
tion histopathologic image shows the fat
replacement extending from epicardium
to the endocardium. (D) Trichrome stain-
ing reveals fibrous tissue interspersed
with fat tissue characteristic of this dis-
ease. (Reproduced with permission from
Tandri H, et al.35)
toms of ARVD/C after the age of 60 years. Symptoms corre-
late with the presence of VA. Heart failure (HF) is an uncommon
and late manifestation of the disease. Figure 3 summarizes the
major presenting clinical features, clinical course, and arrhyth-
mia and survival outcomes of 439 index patients (mean age at
presentation 36±14 years).4 Of them, 419 (95%) presented
with symptoms and the remaining 20 (5%) were asymptom-
atic but came to medical attention because of abnormal tests
in diverse settings. A total of 48 index patients (11%) presented
Arrhythmogenic RV Dysplasia 903

Index patients
n=439

416 23

Alive w/o sust Alive with sust Resuscitated SCD

VA, n=171 VA, n=220 SCD, n=25 n=23

No ICD ICD
n=65 n=351

31 81
34 270

No recurrent Recurrent
sust VA, n=115 sust VA, n=301

FU w/o ICD Transplant FU with ICD

n=63 n=18 n=335
14 4 325 10
11

52 Alive Dead 23
n=391 n=48

Figure 3.   Schematic representation of the presentation, clinical course and outcome in arrhythmogenic right ventricular dysplasia/
cardiomyopathy (ARVD/C) index patients. The majority present with sustained ventricular arrhythmias (VA) and receive an implant-
able cardioverter defibrillator (ICD) during follow-up (FU). (Reprinted with permission from Groeneweg J, et al. 3)

with a cardiac arrest, among whom 25 were resuscitated and
23 died with the diagnosis established at autopsy (median age
at cardiac arrest, 25 years, interquartile range 21, range
13–70). An additional 220 index patients (50%) presented
with a sustained VA. During the clinical disease course, an
ICD was implanted in 212 (87%) of the 245 index patients
with a sustained VA or resuscitated SCD and in 139 (81%) of
the 171 index patients presenting without sustained VA; 65
index patients did not have an ICD implanted during follow-
up (33 with and 32 without sustained VA at presentation).
Sustained VA during follow-up was seen in more than two-
thirds of index patients (301, 72%). Of the 65 index patients
without an ICD, 31 (48%) experienced a sustained VA during
follow-up.
Among the index patients with an ICD, 10 died (3%; median
follow-up 7 years): 2 of SCD, 3 of HF, 2 of a combination of
HF and arrhythmias, and 3 of non-cardiac causes. Among the
index patients without an ICD, 11 died (17%; median follow-
up 5 years): 10 of these 11 patients died of SCD and 1 of HF.
The SCD incidence was higher in index patients without an
ICD than in those with an ICD (16% vs. 0.6%, P<0.001). Dur-
ing long-term follow-up, 54 index patients (13%) developed
symptomatic HF and 18 (4%) had a cardiac transplantation; 4
patients who underwent transplantation died during follow-up.
Overall, 391 of the 416 index patients (94%) who presented
alive were alive at last follow-up.
Figure 4 shows the results of Kaplan-Meier survival analy-
sis by age for these 416 index patients for the following out-
comes: (1) any ARVD/C-related symptoms, (2) sustained VA,
(3) cardiac mortality, and (4) cardiac transplantation. Of par-
ticular note is that all patients presented in their teenage years
or later (range 10–78 years). The development of symptoms
correlated closely with the development of a sustained VA,
with cardiac mortality and the need for cardiac transplantation
being low.
Although ARVD/C is predominantly a disease of the RV,5–8

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904 CALKINS H

Figure 4.   Survival free from any arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-related symptoms, sus-
tained ventricular arrhythmias (VA), cardiac death and cardiac transplantation in ARVD/C index patients with (A) pathogenic
mutations and (B) without identified mutations. Symptoms (P=0.005) and sustained VA (P=0.020) occurred more often at younger
age in index patients with mutations. Survival free from cardiac death (P=0.644) and transplantation (P=0.704) was similar in both
groups. (Reprinted with permission from Groeneweg J, et al.3)

it is now well established that involvement of the left ventricle
(LV) may occur, particularly when MRI is used to detect
subtle abnormalities in LV function and also in patients with
advanced disease. Left-dominant arrhythmogenic cardiomy-
opathy also is defined by early disease of the LV, often affect-
ing the posterolateral LV wall, in the absence of significant
RV systolic dysfunction. Left-dominant disease is more com-
monly seen in patients with desmoplakin mutations.8
Genetic Basis of ARVD/C
In most cases, ARVD/C is inherited in an autosomal-dominant
pattern with significantly variable penetrance and expressivity.
Among probands diagnosed with this disease, screening of

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Arrhythmogenic RV Dysplasia 905

first-degree relatives identifies other affected individuals in
approximately 50% of cases. In a minority of cases, ARVD/C
is inherited in an autosomal recessive pattern as part of a car-
diocutaneous syndrome such as Naxos disease or Carvajal
syndrome, which is characterized by woolly hair and palmo-
plantar keratodermia.
Linkage mapping and candidate gene evaluation studies
performed in patients with the autosomal-dominant form of
ARVD/C initially was not productive because of the signifi-
cant variability in penetrance and expressivity of the disease.
It was the evaluation of patients with Naxos syndrome, a dis-
ease with 100% penetrance by adolescence, that identified a
disease-causing mutation: a homozygous deletion of 2 base
pairs found in the plakoglobin gene located in the 17q21
locus.9 The gene encodes a key component of desmosomes,
which are complex intercellular adhesion structures found in
stratified epithelial cells of the skin as well as in myocytes.
Desmosomes are composed of 3 major groups of proteins:
Cadherins are transmembrane proteins that provide the actual
mechanical coupling between individual cells and include
desmoglein and desmocollin. Desmoplakin is a plakin-family
protein that serves to anchor the desmosomal structure to the
intermediate filaments of the cell. Lastly, Armadillo proteins,
including plakoglobin and plakophilin, link desmoplakin and
the cadherin tails.
The identification of defective desmosomal proteins in
Naxos syndrome led to studies investigating their role in other
arrhythmogenic cardiomyopathies. The Carvajal syndrome,
another cardiocutaneous syndrome that has left-dominant
arrhythmogenic cardiomyopathy, was shown to be associated
with a recessive mutation in desmoplakin.10 Other genetic
mutations were subsequently identified in the autosomal-dom-
inant form of ARVC/D and include the desmoplakin (DSP),
desmoglein (DSG)-2, desmocollin (DSC)-2 and plakophillin
(PLN)-2 genes.2,8 Mutations in several extra-desmosomal genes,
such as those encoding transforming growth factor β3, cardiac
ryanodine receptor, Titin, and transmembrane protein 43
(TMEM43), have been also implicated in specific types of
atypical forms of ARVC/D. In the United States, a desmo-
somal protein mutation can be identified in approximately 60%
of ARVD/C patients.3,8
The genetic findings of a large transatlantic cohort of
patients with ARVD/C, selected according to the presence of
an ARVD/C-related mutation, were recently reported.8 The
study population consisted of 577 patients from 241 unrelated
families and was derived from the Johns Hopkins ARVD/C
registry (259 patients: 102 probands, 157 family members)
and the Dutch ARVD/C cohort (318 patients: 128 probands,
190 family members). The registries were statistically similar
in terms of sex, race and proband/family member ratios. Men

Table.  2010 Task Force Criteria for ARVD/C*

1  Global or regional dysfunction and structural alterations
  Major
    2nd echo criteria
       Regional RV akinesia, dyskinesia, or aneurysm AND 1 of the following measured at end diastole
        PLAX RVOT ≥32 mm or
        PSAX RVOT ≥36,
        Fractional area change ≤33%
    MRI criteria
       Regional RV akinesia or dyskinesia or dyssynchronous RV contraction AND 1 of the following
         Ratio of RV end-diastolic volume to BSA ≥100, 110 ml/m2 (male) or ≥100 ml/m2
        RV ejection fraction >40% ≤45%
    RV angiography criteria
        Regional RV akinesia, dyskinesia, or aneurysm
  Minor
    2nd echo criteria
       Regional RV akinesia or dyskinesia or dyssynchronous RV contraction AND 1 of the following measured at end diastole
        PLAX RVOT ≥29 <32 mm or
        PSAX RVOT ≥32 <36
        Fractional area change >33% ≤40%
    MRI criteria
       Regional RV akinesia or dyskinesia or dyssynchronous RV contraction AND 1 of the following
        Ratio of RV end-diastolic volume to BSA ≥110 ml/m2 (male) or ≥100 ml/m2
        RV ejection fraction ≤40%
2  Tissue characterization of wall
  Major
    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
  Minor
    Residual myocytes 60–75% by morphometric analysis (or 50–65% if estimated), with fibrous replacement of the RV free wall myocardium
in ≥1 sample
       with or without fatty replacement of tissue on endomyocardial biopsy

(Table continued the next page.)

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906 CALKINS H

3  Repolarization abnormalities
  Major
    Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 years of age (in the absence of complete RBBB
QRS ≥120 ms)
  Minor
    Inverted T waves in V1 and V2 in individuals >14 years of age (in the absence of complete RBBB) or in V4, V5, and V6
    Inverted T waves in leads V1, V2, V3, and V4 in individuals >14 years of age in the presence of a complete RBBB
4  Depolarization/conduction abnormalities
  Major
    Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of T wave) in the right precordial leads (V1–3)
  Minor
    Late potentials by SAECG in ≥1 of 3 parameters in the absence of a QRSd ≥110 ms on standard ECG
    Filtered QRS duration (fQRS) ≥114 ms
    Duration of terminal QRS <40 microV ≥38 ms
    Root-mean-square voltage of terminal 40 ms ≤ micro V
    Terminal activation duration ≥55 ms measured from the nadir of the end of the QRS, including R’, in V1, V2, or V3 in absence of complete
RBBB
5 Arrhythmias
  Major
    Nonsustained or sustained VT of LBBB morphology with superior axis
  Minor
    Nonsustained or sustained VT of RVOT configuration, LBBB morphology with inferior axis or of unknown axis
    >500 PVCs per 24 h (Holter)
6  Family history
  Major
    ARVD/C in first-degree relative who meets Task Force Criteria
    ARVD/C confirmed pathologically at autopsy or surgery in first-degree relative
    Identification of pathogenic mutation categorized as associated or probably associated with ARVD/C in the patient under evaluation
  Minor
    History of ARVD/C in first-degree relative in whom it is not possible to determine whether the family member meets Task Force Criteria
    Premature sudden death (<35 years of age) due to suspected ARVD/C in a first-degree relative
    ARVD/C confirmed pathologically or by current Task Force Criteria in second-degree relative
*Adapted from Marcus FI, et al.11 ARVD/C, Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy; BSA, body surface area; LBBB, left
bundle branch block; PVC, premature ventricular contraction; RBBB, right bundle branch block; RVOT, right ventricular outflow tract; SAECG,
signal-averaged ECG; VT, ventricular tachycardia.

constituted 55% of the overall population, with the average
age at presentation being 35±17 years. The majority of par-
ticipants (463, 80%) carried a single copy of a PKP2 mutation
(164 probands, 299 family members), with significantly fewer
heterozygous carriers of mutations in other ARVD/C-associated
genes (31 DSG2, 31 PLN, 19 DSP, 8 DSC2, 2 JUP, and 1
TMEM43). A total of 22 individuals (4%) carried 2 or more
pathogenic mutations (compound heterozygote, homozygote,
or digenic mutation carriers). Among carriers of single muta-
tions, premature truncating, splice site, and missense muta-
tions were identified in 342 (60%), 130 (23%), and 83 (14%)
patients, respectively. Patients with SCD/ventricular fibrilla-
tion (VF) at presentation (n=36) were younger (median 23 vs.
36 years; P<0.001) than those presenting with sustained
monomorphic VT. Among 541 subjects presenting alive, over
a mean follow-up of 6±7 years, 12 (2%) died, 162 (30%) had
sustained VT/VF, 78 (14%) manifested LV dysfunction (ejec-
tion fraction <55%), 28 (5%) experienced HF and 10 (2%)
required cardiac transplantation. Patients (n=22; 4%) with >1
mutation had significantly earlier occurrence of sustained VT/
VF (mean age 28±12 years), lower VT/VF-free survival
(P=0.037), more frequent LV dysfunction (29%), HF (19%)
and cardiac transplantation (9%) as compared with those with
only 1 mutation. DSP mutation carriers experienced >4-fold
occurrence of LV dysfunction (40%) and HF (13%) than
PKP2 carriers. Missense mutation carriers had similar death/
transplant-free survival and VT/VF penetrance (P=0.137) as
compared with those with truncating or splice site mutations.
Men are more likely to be probands (P<0.001), symptomatic
(P<0.001) and have earlier and more severe arrhythmic
expression.
Pathophysiologic Basis of ARVD/C
The genetics of ARVD/C has provided support for the hypoth-
esis that ARVD/C is a disease of desmosomal dysfunction.
The pathogenic mechanisms are not fully clear, but several
theories have been advanced. Defective desmosomal proteins
may lead to impaired mechanical coupling between individual
cells, leading to myocyte uncoupling especially under condi-
tions that increase myocardial strain. The resulting inflamma-
tion, fibrosis and adipocytosis may be a nonspecific response
to injury similar to that seen in other forms of myocardial
damage. This pathogenic model can explain the observation
that prolonged strenuous exertion, which increases myocardial
strain, significantly increases the risk of an earlier clinical
onset of the disease and augments the risk of SCD. It also
explains why the RV, which is more distensible than the LV

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Arrhythmogenic RV Dysplasia
because of its thinner wall and asymmetric shape, is more
often involved in ARVC, especially in the early stages. Fur-
thermore, defects in mechanical coupling of myocytes may
also lead to impairment in electrical coupling. Other hypoth-
eses concerning the mechanisms of ARVD/C involve complex
intracellular signaling pathways, which is an active area of
investigation.
Diagnostic Criteria and Diagnostic Approach
Diagnosis of ARVD/C relies on a scoring system with major
and minor criteria based on the demonstration of a combina-
tion of defects in RV morphology and function, characteristic
depolarization/repolarization ECG abnormalities, characteris-
tic tissue pathology, VAs, family history, and the results of
genetic testing. The original 1994 Task Force Criteria (TFC)
were recently revised to improve upon the subjectivity of
some of the original criteria and to increase sensitivity by
integrating new knowledge and technology (Table).11 These
criteria should now be relied on to make a diagnosis of
ARVD/C. Patients are diagnosed as having ARVD/C if they
have “4 points” with a major criteria equal to 2 points and a
minor criteria equal to 1 point. Patients whose score totals “3
points” are classified as having probable ARVD/C, whereas
those with “1 or 2 points” are classified as not meeting the
criteria for ARVD/C.
When considering these guideline recommendations it is
important to note that there is no single gold-standard diagnos-
tic test. The initial evaluation of all patients should include a
physical examination and clinical history including family
history of arrhythmias or sudden death, ECG, signal-averaged
Circulation Journal  Vol.79, May 2015
907
Figure 5.  Cardiac MRI of a patient with
ARVC. Bright blood images in the right ven-
tricular outflow tract (RVOT) plane obtained
in end diastole (A) and end systole (B)
show microaneurysms (arrows) in the RV
free wall with persistent bulge in both
phases. Short-axis bright blood images
obtained in end diastole (C) and end sys-
tole (D) demonstrate dyskinesis (bulge in
systole, arrows) at the acute angle of the
RV and hypokinesis in the inferior wall
(arrowheads).
ECG (SAECG) 24-h Holter monitoring, and comprehensive
noninvasive imaging of both ventricles. MRI can be of great
value but is also a common cause of misdiagnosis.12 If this
noninvasive workup is suggestive but not diagnostic of
ARVD/C, further testing should be considered to establish the
diagnosis, including EPS. Although endomyocardial biopsy
was used in the past, it is rarely done today, which reflects
current, extensive experience with MRI. Similarly, right ven-
triculography is rarely needed because of the availability of
high-quality echocardiography and MRI.
The standard 12-lead ECG is abnormal in the majority of
patients with ARVD (Figure 1).13–15 Because of this observa-
tion, the finding of a normal ECG in a patient with ARVD/C
renders the diagnosis of ARVD/C extremely unlikely.14 TWI
in the right precordial leads (V1–3) is the most common ECG
manifestation of ARVD/C and is a major diagnostic criteria
(Table). TWI in leads V1 and V2 is a minor criterion. A com-
plete or incomplete right bundle branch block (RBBB) pattern
is a common finding in ARVD/C patients, especially in those
with severe structural disease, and its presence obscures the
interpretation of the known depolarization abnormalities.15 In
patients with incomplete RBBB, TWI through V3 still appears
to be the feature with optimal sensitivity and specificity. How-
ever, in patients with complete RBBB, an R/S ratio <1 in V1
seems to provide the optimal sensitivity and specificity in
diagnosing ARVD/C.15 TWI beyond V3 in patients with
complete RBBB is also a feature of ARVD/C. Epsilon waves,
which are distinct low-frequency deflections in the ECG that
occur following the QRS and before the T wave (Figure 1),
are uncommon and a marker of advanced ARVD/C. The new
diagnostic criteria for ARVD/C include terminal activation
908
delay, which is defined as a prolonged duration of time
(≥55 ms) from the S wave to the termination of the QRS com-
plex as a minor criterion for ARVD.11
The SAECG provides increased sensitivity in the detection
of activation delay. It is defined as abnormal if 1 or more of
the following criteria are present: (1) filtered QRS duration
(fQRS) >114 ms, (2) terminal low-amplitude (<40µV) signal
duration ≥38 ms, and (3) root-mean-square voltage of the ter-
minal 40 ms of the filtered QRS complex (RMS40) <20 µV.11
The likelihood of an abnormal result seems to correlate with
the degree of structural abnormalities. A positive SAECG is
now considered a minor criterion.11
Ambulatory Holter monitoring is a valuable test for the
evaluation of patients with suspected ARVD/C. The presence
of frequent ventricular ectopic beats or sustained/nonsustained
VT (NSVT), particularly of left bundle branch block (LBBB)
morphology, is consistent with the diagnosis of ARVD/C. It
is generally accepted that less than 200 PVCs per 24 h is within
normal limits. The presence of ≥500 PVCs per 24 h is com-
monly observed in patients with ARVD/C and is considered a
minor criterion.11 Recently, it was reported that the number of
PVCs on 24-hour Holter monitoring is directly proportional to
a patient’s chance of developing appropriate ICD therapy
among those with an ICD implanted for primary prevention.16,17
The day-to-day variability in PVC frequency observed in
patients with ARVD/C has also explored.18 Although some
degree of PVC variability was observed, the degree of vari-
ability was acceptable for risk stratification based on the num-
ber of PVCs per 24 h. Holter monitoring can also be done on
a yearly basis to assist in evaluating a patient’s arrhythmic
risk. If 24-h Holter monitoring does not capture any arrhyth-
mias, further options include extending the duration of Holter
monitoring, implanting a loop recorder or exercise testing to
induce VT.
Assessment of ventricular structure and function is critical
for the diagnosis. Echocardiography is the most widely avail-
able method of imaging. Findings on a transthoracic echocar-
diogram that are suggestive of ARVC/D include global or
segmental wall motion abnormalities with cavity dilation,
hypertrophic RV trabeculation and systolic dysfunction. RV
outlet tract (RVOT) dilation (diameter >30 mm) has been
reported to have the highest sensitivity and specificity of the
echocardiographic parameters in diagnosing ARVD.11 Table
lists the echocardiographic parameters that have been incor-
porated into the TFC.11 Representative MRI in a patient with
ARVD/C are shown in Figure 5. Cardiac MRI (CMR) is an
imaging modality that has the benefit of providing tissue char-
acterization and identification of intramyocardial fat and fibro-
sis in addition to assessment of ventricular structure and
function. MRI is the imaging modality of choice in evaluating
the RV in ARVD/C.5–7 The ability to provide multiplanar
images of the RV allows for accurate quantitative assessment
of RV global function and assessment of RV regional func-
tion. The noninvasive nature of MRI makes it ideal for the
evaluation and follow-up of asymptomatic first-degree rela-
tives. The major and minor criteria for ARVD/C on MRI are
listed in Table. However, It is important to recognize that
MRI is the most common reason for misdiagnosis of ARVD/C.11
Some common reasons for misdiagnosis of ARVD/C were
recently identified and include the presence of a myocardial
tether, a moderator band, and pectus excavatum.6 It is also
important to recognize that ARVD/C does not affect the RV
apex early in the course of the disease, which is a common
misconception resulting from an erroneous initial report of a
triangle of dysplasia.1 It was recently reported that the triangle
Circulation Journal  Vol.79, May 2015
CALKINS H
of dysplasia consists of the inflow tract, the outflow tract, and
the posterolateral LV.19
An endomyocardial biopsy may be obtained to demonstrate
the characteristic histopathology of ARVD/C if the diagnosis
is unclear or to rule out a competing diagnosis. However, the
test appears to have low diagnostic sensitivity for several
reasons, including patchy distribution of the disease. One
study reported that immunohistochemical analysis of desmo-
somal protein distribution in endomyocardial biopsy speci-
mens has diagnostic value.20 Although there was initial hope
that this test may prove to be invaluable in the evaluation of
patients, enthusiasm fell rapidly when it was recognized that
sarcoidosis and giant cell myocarditis can cause patterns sim-
ilar to that observed in ARVD/C.21 The diagnostic role of
immunohistochemical analysis of biopsy samples as a diag-
nostic tool in ARVD/C is no longer supported. Table shows
the pathological parameters that have been incorporated into
the revised TFC.11 Despite the potential value of endomyocar-
dial biopsy, biopsy is rarely performed today.
The role of genetic testing in the diagnosis of ARVD/C is
now well established and is considered a major diagnostic
criterion.11 More than 60% of ARVC/D probands are found to
have a mutation.2,3 Thus, lack of an identifiable mutation does
not exclude the disease. However, at present the most impor-
tant utility of this test is in the cascade screening of family
members. Asymptomatic gene carriers are likely to require
life-long monitoring because of age-dependent penetrance,
whereas non-carriers are unlikely to have the disease and
serial screening is generally not required. Exercise restriction
also needs to be considered, especially in those who harbor a
disease-causing mutation.
The diagnosis of ARVD/C should be considered in any
patient who does not have known heart disease and who pres-
ents with frequent PVCs or symptomatic VT, especially if
there is LBBB morphology with superior axis, the LBBB VT
ECG pattern is not typical of idiopathic RVOT VT, or if the
VT occurs in a patient with TWI in the right precordial leads.
The most common conditions that must be considered in the
differential diagnosis include idiopathic RVOT VT, VT aris-
ing from the aortic root, and cardiac sarcoidosis. Several stud-
ies have recently compared the morphology of VT or PVCs
with a LBBB inferior (LBI) axis morphology in patients with
idiopathic RVOT VT with that of patients with ARVC/D. A
recent study examining patients with PVCs or VT with a LBI
axis morphology confirmed that a QRSd >120 ms in lead V1
during VT or with PVCs favors the diagnosis of ARVD/C as
compared with idiopathic RVOT VT.22 Although it is impor-
tant to consider the diagnosis of ARVD/C in a patient with
LBI axis PVCs or VT, it is not recommended that these
patients undergo a complete evaluation for ARVD/C. If the
ECG and echocardiogram are normal and there is no family
history of sudden death, an exhaustive evaluation is not
advised. If the patient prefers a curative ablative strategy, an
EPS and ablation would be the next step. If at the time of EPS
multiple forms of VT are induced, the potential diagnosis of
ARVD/C would be reconsidered.
Another novel marker of ARVD/C that has been recently
reported is a characteristic response to high-dose isoproterenol
infusion.23,24 In a recent study, a total of 412 consecutive
patients referred for evaluation of PVCs or ARVD/C underwent
this test and 35 of them had been diagnosed with ARVD/C
based on the revised 2010 TFC. The isoproterenol infusion
consisted of intravenous administration of very high dose
(45 mcg/min) isoproterenol for 3 min. A continuous ECG was
recorded during and for up to 10 min following the infusion.
Arrhythmogenic RV Dysplasia
The test was interpreted as being “positive” if polymorphic
PVCs (>3 morphologies) and at least 1 couplet were observed
or if sustained or nonsustained monomorphic or polymorphic
VT with a predominantly LBBB morphology not typical of
RVOT VT was observed. The isoproterenol test was positive
in 74/412 (18%) patients, in 32/35 (91.4%) patients with an
established ARVD/C diagnosis and in 42/377 (11.1%) patients
without ARVD/C. The resultant sensitivity, specificity, posi-
tive and negative predictive values of isoproterenol testing to
identify patients diagnosed with ARVD/C based on the 2010
TFC were 91.4%, 88.9%, 43.2%, and 99.1%, respectively.
Monomorphic sustained or nonsustained RVOT VT were
observed in 0/35 ARVD/C patients vs. 27/377 (7.2%) of
patients without ARVD/C. During a median follow-up of 5
years, 6 of the initial non-ARVD/C group met the diagnostic
criteria for ARVD/C. Each of these individuals had had a
positive isoproterenol response. None of the patients who had
typical RVOT VT developed ARVD/C during follow-up.
Based on these data, it was determined that survival free from
a diagnosis of ARVD/C was lower in the negative isoproter-
enol group vs. the positive isoproterenol response group.
Genetic screening was performed in 30 of the 41 patients
eventually diagnosed with ARVD/C (with a pathogenic muta-
tion identified in 10) and in 24/371 non-ARVD/C patients.
The concept of using a high-dose isoproterenol test as a
screening/diagnostic test for ARVD/C is novel and potentially
of great importance. However, at this point I think it should
not be considered to be a diagnostic test. Whether in the long
run it will prove to be useful for diagnosis and/or risk stratifi-
cation will require further study.
Cardiac sarcoidosis should be suspected in patients who
have evidence of conduction system abnormalities, especially
in the presence of other extracardiac symptoms. In rare situa-
tions, an endomyocardial biopsy may become necessary to
differentiate between the 2 disorders. The infrequency with
which endomyocardial biopsy is required reflects the fact that
cardiac sarcoidosis can usually be suspected based on the
presence of conduction system abnormalities, mediastinal
lymphadenopathy, tissue diagnosis of extracardiac sarcoid-
osis, or the presence of septal scar.25
A minority of ARVD/C patients first present with symp-
toms of RV systolic HF. The differential diagnosis in such
patients includes RV infarction or pulmonary hypertension.
Dilated cardiomyopathy must be considered if there is evi-
dence of biventricular failure. Patients with dilated cardiomy-
opathy who have early significant ventricular ectopy should
be evaluated for possible biventricular arrhythmogenic cardio-
myopathy. Cardiac transplantation is rarely required in patients
with ARVD/C.26
Management of ARVD/C
Management of patients with ARVD/C has 4 components.
The first is getting the diagnosis correct. The second is accu-
rate risk stratification for SCD and deciding whether to place
an ICD. The third component of management is minimizing
ICD therapies. And the final component of management is
preventing progression of the disease. Each of these will be
examined in detail.
Establishing an Accurate Diagnosis
As noted, the first step in management is making the diagno-
sis. Misdiagnosis of ARVD/C is common because of lack of
awareness of the 2010 TFC and misinterpretation of MRI.
Circulation Journal  Vol.79, May 2015
909
Risk Stratification and Deciding When to Implant an ICD
Prevention of SCD is the primary goal of management. Sev-
eral studies of ARVD/C patients who received an ICD have
reported appropriate interventions during follow-up in more
than 50% of patients.17,27 Predictors of appropriate therapy
included a prior sustained VA, syncope, and the extent of
structural heart disease.
The incidence of appropriate ICD therapy among 84
patients who had an ICD implanted for primary prevention
was recently investigated.17 Over a mean follow-up of 4.7±3.4
years, appropriate ICD therapy was experienced by 40 (48%)
patients, of whom 16 (19%) received interventions for rapid
VT/VF. Proband status, inducibility at EPS, presence of
NSVT, and PVC count >1,000/24 h were identified as signifi-
cant predictors of appropriate ICD therapy (Figure 6). The
5-year survival free from appropriate ICD therapy for patients
with 1, 2, 3 and 4 risk factors was 100%, 83%, 21% and 15%,
respectively. Inducibility at EPS and NSVT remained as sig-
nificant predictors on multivariable analysis. These findings
are important because they demonstrate that nearly half of the
ARVD/C patients treated with an ICD for primary prevention
experienced appropriate ICD interventions. Inducibility at EPS
and NSVT are independent strong predictors of appropriate
ICD therapy. More frequent ventricular ectopy is associated
with progressively more common ICD therapy. Incremental
risk of VAs and ICD therapy was observed in the presence of
multiple risk factors.
At present ICD placement is recommended for all probands
who meet the TFC, especially if they have a history of sudden
death, sustained VT or arrhythmogenic syncope, or have a
high degree of ventricular ectopy and/or NSVT. Clinicians
should be more circumspect about recommending implanta-
tion of an ICD in a family member who has been diagnosed
with ARVD/C as a result of cascade screening. These indi-
viduals are being identified at a much earlier stage in their
disease than was possible previously. With exercise restriction
and the use of a β-blocker, their risk of SCD appears to be
reduced to a level below which placement of an ICD should
be routinely advised. If a decision is made not to implant an
ICD close monitoring and follow-up are emphasized.
Minimizing Symptoms and Preventing ICD Therapies
Pharmacologic Therapy  Pharmacologic therapy plays an
important role in the management of patients with ARVD/C.
This is the case despite the few studies done to define the
safety and efficacy of pharmacologic therapy. β-blockers are
recommended for almost all patients with ARVD/C, which
reflects several lines of evidence. First, β-blockers are the only
pharmacologic therapy that has been shown to reduce risk of
SCD in populations of patients without ARVD/C. Second, the
great majority of VAs and sudden death episodes are triggered
by exercise. And third, high-dose isoproterenol results in the
triggering of VT in patients with ARVD/C.23,24 Angiotensin-
converting enzyme (ACE) inhibitors are also advised for most
patients with ARVD/C and especially those with evidence of
significant disease. There are no published trials in patients
with ARVD/C, but there is a wealth of data supporting the role
of ACE in a broader population of patients with cardiomyopa-
thy. When it comes to membrane-active antiarrhythmic agents,
sotolol is used most commonly and if ineffective, amiodarone
is chosen. In rare cases, flecainide, propafenone, or dofetilide
is used. For most patients with ARVD/C and symptomatic
VAs and/or ICD therapies therapy with at least one antiar-
rhythmic medication will be attempted before considering VT
ablation. Some patients have a strong bias against antiarrhyth-
910 CALKINS H

Figure 6.  (A–D) Incidence of sustained ventricular arrhythmias in patients with ARVD/C receiving an implantable cardioverter
defibrillator (ICD) for primary prevention based on 4 variables: inducibility of ventricular tachycardia (VT) at electrophysiologic
study (EPS), frequency of premature ventricular contractions (PVC), nonsustained VT (NSVT), and proband status. (Adapted with
permission from Bhonsale A, et al.17)

mic drug therapy and move quickly to VT ablation. Whereas
others would much prefer more extensive attempts at antiar-
rhythmic drug therapy before considering VT ablation.
Catheter Ablation  Catheter ablation is another important
option for treatment of patients with ARVD/C who have VT.
It is important to recognize that unlike patients with idiopathic
VT in which catheter ablation is curative, the role of catheter
ablation in patients with ARVD/C is to improve quality of life
by decreasing the frequency of episodes of VT. The standard
approach at Johns Hopkins is to consider catheter ablation
following a trial of antiarrhythmic therapy.
Three studies have evaluated the outcomes of catheter abla-
tion of VT in patients with ARVD/C.28–30 The first study28
reported a cohort of 24 patients with ARVD/C who underwent
VT ablation. These 24 patients underwent 48 ablation proce-
dures at 29 different electrophysiology centers. The cumula-
tive VT-free survival was 75% at 1.5 months, 50% at 5
months, and 25% at 14 months. The immediate success of the
procedure had no bearing on recurrence nor did the use of
assisted mapping techniques, or repetition of the procedure.
The second study29 reported an expanded series of 87 patients
who underwent a total of 175 VT ablation procedures. Over a

Circulation Journal  Vol.79, May 2015

Arrhythmogenic RV Dysplasia 911

Figure 7.   Association of exercise history with the likelihood of a diagnosis of arrhythmogenic right ventricular dysplasia/cardio-
myopathy (ARVD/C). The likelihood of meeting the ARVD/C diagnostic criteria at last follow-up is associated with increasing hours
per year of exercise (P<0.001) and participation in endurance athletics (P<0.001). Hrs/yr, hours per year; TFC, 2010 Task Force
diagnostic Criteria. (Adapted with permission from James CA, et al.32)

follow-up of 88+66 months, the freedom from VT was 47%,
21%, and 15% at 1, 5, and 10 years, respectively. The cumula-
tive freedom from VT following epicardial VT ablation was
64% and 45% at 1 and 5 years, respectively. Importantly, the
burden of VT decreased following ablation from a median of
0.16 VT episodes per month pre-ablation to 0.08 episodes per
month post-ablation. Most recently, a single center experience
with epicardial VT ablation in patients with ARVD/C was
published.30 It included 30 ARVD/C patients who underwent
endo-/epicardial mapping and epicardial catheter ablation of
VT. ICD interrogations were evaluated for VT recurrence: 8
(27%) patients experienced VT recurrence after epicardial
RFA and the VT-free survival was 83%, 76%, and 70% at 6,
12 and 24 months, respectively. A significant reduction in the
VT burden was observed. No complications occurred. Most
VT recurrences were in the first year after RFA, during exer-
cise, had fast cycle lengths, and required ICD shock for termi-
nation. We consider this to be an important treatment modality.
For most patients it represents a second-line therapy but rarely
a patient prefers to proceed with VT ablation prior to antiar-
rhythmic drug therapy.
Exercise Restriction  An important recommendation for
patients with ARVD/C is exercise restriction. The association
of exercise stems from the observation that SCD in ARVD/C
patients often occurs during exertion. Kirchhof et al showed
that endurance training of transgenic plakoglobin-deficient
mice was associated with RV enlargement, RV conduction
slowing and VAs as compared to wild-type hearts.31 The
results of this and other studies support the hypothesis that
repeated strenuous exercise is an important factor increasing
the chance of development of ARVD/C, especially in patients
with a desmosomal mutation.
The first study evaluating the role of exercise in ARVD/C
patients inheriting a pathogenic desmosomal mutation was
performed by James et al (Figure 7).32 They studied 87 pro-
bands and family members from the Johns Hopkins ARVD/C
Registry who were identified as carrying a single copy of a
pathogenic mutation in a desmosomal gene. All patients par-
ticipated in an exercise interview detailing their exercise his-
tory for leisure/recreation, work, and transportation. Participants
were classified as an endurance athlete if they performed
≥50 h/year of vigorous intensity sports with a high dynamic
demand as defined by the 36th Bethesda Conference Classifi-
cation of Sports (Task Force 8).32 The study had several key
findings. First, ARVD/C patients who were endurance athletes
became symptomatic at an earlier age. Second, endurance
exercise and a higher duration of exercise participation were
both associated with increasing likelihood of developing man-
ifest ARVD/C. Third, endurance exercise was associated with
worse survival from VA and HF. Lastly, those individuals
who continued to participate in the top quartile for hours of
annual exercise after presentation had worse survival from
first VA compared with individuals who reduced their exer-
cise after presentation. The study thus confirmed the role of
exercise as a disease modifier in ARVD/C patients with a
desmosomal mutation.
The role of exercise in ARVD/C patients without a muta-
tion was subsequently studied.33 The role of duration and
intensity of exercise participation was examined among 43
probands without a desmosomal mutation (non-desmosomal)
and compared with 39 probands with desmosomal mutations
all of whom met the 2010 TFC. It was found that among non-
desmosomal patients, those participating in the highest quar-
tile of MET-Hrs/year exercise presented at a significantly
earlier age, had worse structural abnormalities on CMR and
significantly poorer survival from a VA during follow-up.
Next, exercise participation stratified by mutation status and
family history was compared and it was found that although
non-desmosomal ARVD/C patients had done a similar dura-
tion of annual exercise as desmosomal carriers; their exercise
was significantly more intense, with significantly higher par-
ticipation in endurance sports and expending greater MET-
Hrs/year of exercise as compared with the desmosomal
patients. Lastly, ARVD/C non-desmosomal patients with no

Circulation Journal  Vol.79, May 2015

912
family history performed the highest MET-Hrs/year exercise
compared with non-desmosomal patients with a family history
and being desmosomal mutation carriers. Because the non-
desmosomal patients without family history did the highest
intensity exercise, it was concluded that exercise may be the
key environmental factor driving disease pathogenesis in that
subgroup. Interestingly, when annual pre-presentation MET-
Hrs and endurance exercise participation during youth (age
≤25) were compared, it was found that higher intensity exer-
cise during youth was associated with earlier age of presenta-
tion in both desmosomal and non-desmosomal ARVD/C
patients.
The widely used “36th Bethesda Conference Eligibility
Recommendations for Competitive Athletes with Cardiovas-
cular Abnormalities” guidelines recommend avoidance of all
competitive activities for patients with probable or definite
diagnosis of ARVD/C, except for class I-A sports with a low
cardiovascular demand. The American Heart Association has
a grading system for recommendations regarding participation
in recreational sports, ranking them on a scale of 0 to 5.34 In
general, ARVD/C patients are prohibited from participating in
all competitive sports and recreational sports requiring ≥4
MET’s. Based on the growing body of literature described
here and the clinical experience at Johns Hopkins, there is a
strong belief that patients with ARVD/C or those at risk for
developing ARVD/C should limit exercise.
Preventing Progression
The final consideration in patients with ARVD/C is preventing
disease progression. It is important to note that no studies have
examined the extent and rate of progression of ARVD/C. In
my experience the rate of progression is slow, but it is impor-
tant to note that ARVD/C is a progressive disease. The most
important tool in preventing disease progression is restriction
of exercise and the considerable data supporting this relation-
ship have been described.
Cardiac Transplantation
It is rare that patients with ARVD require cardiac transplanta-
tion.25 Details of 18 ARVD/C patients who underwent cardiac
transplantation for ARVD/C were recently reported. The aver-
age age at first ARVD symptoms was 24±13 years and the
average age at cardiac transplant was 40±14 years. These
patients often had clinical onset of disease at a relatively
young age. At 1 year after transplantation, survival was 94%
and 88% were alive at an average post-transplant follow-up of
6.2±4.8 years.
Summary and Conclusion
ARVD/C is an inherited cardiomyopathy characterized clini-
cally by VA, SCD, and structural abnormalities of the RV.
Because of the significant heterogeneity in its manifestation,
the diagnosis of ARVD/C is challenging and requires a multi-
faceted approach to patient evaluation. The management of
ARVD/C is primarily aimed at reducing the burden of symp-
tomatic arrhythmias and decreasing the incidence of SCD.
ICDs significantly reduce mortality in patients with ARVD/C.
Antiarrhythmic drug therapy and VT ablation are used primar-
ily to decrease the frequency of episodes of VT. Exercise is a
very important environmental stimulus that triggers develop-
ment of the disease in susceptible individuals and affects the
clinical course. Restriction of exercise in patients with ARVD/C
is strongly recommended.
Circulation Journal  Vol.79, May 2015
CALKINS H
Acknowledgments
The Johns Hopkins ARVD/C Program is supported by the St. Jude Med-
ical Foundation and Medtronic Inc, Dr Francis P. Chiaramonte Private
Foundation Foundation, the Healing Hearts Foundation, the Campanella
family, the Patrick J. Harrison Family, the Peter French Memorial Foun-
dation, the Wilmerding Endowments, and the Dr Satish, Rupal, and Robin
Shah ARVD Fund at Johns Hopkins.
Disclosures
Research support was provided by St Jude Medical and Medtronic.
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