Arrhythmia/Electrophysiology

Arrhythmogenic Right Ventricular Dysplasia

A United States Experience
Darshan Dalal, MD, MPH; Khurram Nasir, MD, MPH; Chandra Bomma, MD; Kalpana Prakasa, MD;
Harikrishna Tandri, MD; Jonathan Piccini, MD; Ariel Roguin, MD; Crystal Tichnell, MGC;
Cynthia James, PhD, ScM; Stuart D. Russell, MD; Daniel P. Judge, MD; Theodore Abraham, MD;
Philip J. Spevak, MD; David A. Bluemke, MD, PhD; Hugh Calkins, MD

Background—Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by right

ventricular dysfunction and ventricular arrhythmias. The purpose of our study was to describe the presentation, clinical
features, survival, and natural history of ARVD in a large cohort of patients from the United States.
Methods and Results—The patient population included 100 ARVD patients (51 male; median age at presentation, 26
[interquartile range {IQR}, 18 to 38; range, 2 to 70] years). A familial pattern was observed in 32 patients. The most
common presenting symptoms were palpitations, syncope, and sudden cardiac death (SCD) in 27%, 26%, and 23% of
patients, respectively. Among those who were diagnosed while living (n⫽69), the median time between first
presentation and diagnosis was 1 (range, 0 to 37) year. During a median follow-up of 6 (IQR, 2 to 13; range, 0 to 37)
years, implantable cardioverter/defibrillators (ICD) were implanted in 47 patients, 29 of whom received an appropriate
ICD discharge, including 3 patients who received the ICD for primary prevention. At follow-up, 66 patients were alive,
of whom 44 had an ICD in place, 5 developed signs of heart failure, 2 had a heart transplant, and 18 were on drug
therapy. Thirty-four patients died either at presentation (n⫽23: 21 SCD, 2 noncardiac deaths) or during follow-up
(n⫽11: 10 SCD, 1 of biventricular heart failure), of whom only 3 were diagnosed while living and 1 had an ICD
implanted. On Kaplan-Meier analysis, the median survival in the entire population was 60 years.
Conclusions—ARVD patients present between the second and fifth decades of life either with symptoms of palpitations
and syncope associated with ventricular tachycardia or with SCD. Diagnosis is often delayed. Once diagnosed and
treated with an ICD, mortality is low. There is a wide variation in presentation and course of ARVD patients, which can
likely be explained by the genetic heterogeneity of the disease. (Circulation. 2005;112:3823-3832.)
Key Words: arrhythmia 䡲 cardiomyopathy 䡲 death, sudden 䡲 heart failure 䡲 tachycardia

A rrhythmogenic right ventricular dysplasia (ARVD) is an

inherited cardiomyopathy characterized by right ventric-
ular (RV) dysfunction and ventricular arrhythmias.1,2 On
pathological examination, patients with ARVD demonstrate
fibrofatty replacement of the myocardium of the RV.3 Studies
have shown that ARVD is present in up to 20% of individuals
who experience sudden cardiac death (SCD) and is even more
common among athletes who die suddenly.3– 6
ARVD was first described in 1977 by Fontaine et al.7 The
clinical features of 24 French patients with this condition
were first reported by Marcus et al in 1982.1 During the
ensuing 22 years, relatively few studies have been published
describing the clinical features and outcomes of patients with
ARVD.1,8 –21 The great majority of these studies have in-
volved European populations.1,8 –16 In fact, only 2 indepen-
dent series of ARVD patients from the United States, involv-
Clinical Perspective p 3832
ing 20 and 12 patients, respectively, have been reported in the
literature.17,18
The purpose of this study was to describe the clinical
characteristics and outcomes of a large cohort of ARVD
patients from the United States. Particular attention was
focused on defining the presenting symptoms, time to diag-
nosis, and long-term outcomes of these patients.
Methods
Patient Recruitment
Patients were identified from the Johns Hopkins ARVD registry.
This registry was initiated in 1998 and prospectively enrolls patients
referred to the Johns Hopkins ARVD Program with a possible
diagnosis of ARVD. The study protocol was approved by the Johns

Received February 15, 2005; revision received October 13, 2005; accepted October 17, 2005.
From the Division of Cardiology (D.D., K.N., C.B., K.P., H.T., J.P., A.R., C.T., C.J., S.D.R., D.P.J., T.A., D.A.B., H.C.), Department of Radiology
(D.A.B.), and Division of Pediatric Cardiology (P.J.S.), The Johns Hopkins University School of Medicine, Baltimore, Md.
The online-only Data Supplement, which contains Table I and Table II, can be found with this article at
http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.542266/DC1.
Correspondence to Hugh Calkins, MD, 600 N Wolfe St, Carnegie 530, Baltimore, MD 21287. E-mail hcalkins@jhmi.edu
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.542266

3823
3824 Circulation December 20/27, 2005

TABLE 1. Demographic Characteristics, Athletic Participation, and Presenting

Symptoms in the Entire Patient Population
Diagnosed While Alive Diagnosed on Autopsy Total
Characteristic (n⫽69) (n⫽31) (n⫽100)
Demographics
Age at presentation, mean⫾SD, y 30⫾12 29⫾15 29⫾13
Gender (male) 36 (52) 15 (48) 51 (51)
Race
White 65 (94) 30 (97) 95 (95)
Black 1 (1.5) 1 (3) 2 (2)
Hispanic 2 (3) 䡠䡠䡠 2 (2)
Middle Eastern 1 (1.5) 䡠䡠䡠 1 (1)
Actively involved in athletic activity 37 (54) 12 (39) 49 (49)
Presenting symptoms
Palpitations 25 (36) 2 (6) 27 (27)
Syncope 21 (30) 5 (16) 26 (26)
Dyspnea 9 (13) 䡠䡠䡠 9 (9)
Near syncope 8 (12) 1 (3) 9 (9)
Nausea, vomiting, and diaphoresis 6 (9) 䡠䡠䡠 6 (6)
Dizziness or lightheadedness 14 (20) 䡠䡠䡠 14 (14)
Peripheral edema 3 (4) 䡠䡠䡠 3 (3)
Chest pain 2 (3) 䡠䡠䡠 2 (2)
Death 䡠䡠䡠 23 (74) 23 (23)
Resuscitated from SCD 1 (1.5) 䡠䡠䡠 1 (1)
Asymptomatic 15 (22) 䡠䡠䡠 15 (15)
Data are represented as frequency (%) except for age at presentation, which is expressed as
mean⫾SD.

Hopkins Medicine institutional review board. Written, informed Diagnosis of ARVD

consent was obtained from each patient. All medical records were
obtained at enrollment. Subsequently, patients were contacted at
yearly intervals to determine the occurrence of events during that
period.
Patient Evaluation and Clinical Testing
The patient’s medical history was obtained both by review of
medical records and by patient interview. Information regarding the
presenting symptoms as well as major clinical events (including
syncope, sustained ventricular tachycardia [VT], implantable cardio-
verter/defibrillator [ICD] implantation, catheter ablation, appropriate
ICD discharge, heart failure, cardiac transplantation, SCD, and other
causes of death) was recorded by age. Patients and family members
were also interviewed to determine the family history.
The results of noninvasive testing, including ECG, signal-
averaged ECG (SAECG), Holter monitoring, echocardiogram, and
MRI, were obtained in those diagnosed while living. QRS duration
and the duration of the S-wave upstroke on a 12-lead ECG were
measured with the image analysis software SigmaScan Pro (version
5.0).22 The presence of epsilon waves and the distribution of T-wave
inversion on the ECG were also determined.22 SAECGs with the use
of time-domain analysis with a bandpass filter of 40 Hz were
evaluated in patients who did not have a preexisting complete or
incomplete right bundle branch block pattern. The SAECG was
considered positive for late potentials if any 2 of the following were
present: (1) filtered QRS duration ⬎114 ms; (2) low-amplitude
signal duration ⬎38 ms; or (3) root mean square voltage ⬍20 mV.23
The results of Holter monitoring, baseline ECG, and exercise stress
test were used to determine the presence of sustained or nonsustained
VT as well as the morphology of ventricular ectopy and/or VT. The
severity and extent of RV dysfunction were also determined.
The diagnosis of ARVD was established on the basis of the criteria
set by the Task Force of the Working Group of Myocardial and
Pericardial Disease of the European Society of Cardiology and of the
Scientific Council on Cardiomyopathies of the International Society
and Federation of Cardiology.24 Autopsy diagnosis was established
in patients whose first clinical presentation was death. Patients with
the recommended gross as well as histopathological evidence of
ARVD were considered to have been diagnosed with ARVD.3,21
Statistical Analyses
Categorical variables were expressed as frequency (percentage).
Continuous variables were expressed as mean⫾SD. Variables with
skewed distributions were expressed as median (interquartile range
[IQR], range). Kaplan-Meier survival analysis was used to examine
survival (from all cardiac causes of death) since first presentation.
Kaplan-Meier analysis was also used to examine the freedom from
the following events since birth (ie, by age): (1) any symptom, (2)
ventricular arrhythmia, (3) onset of heart failure, and (4) cardiac
death. These analyses were performed separately in those patients
who were diagnosed with ARVD while living and those in whom the
diagnosis was established on autopsy. All statistical analyses were
performed with STATA statistical software (version 8.2).
Results
Patient Population
The patient population was composed of 100 patients diag-
nosed with ARVD. The clinical features of the patients are
summarized in Tables 1 and 2 (and listed for individual
patients in the online-only Data Supplement Tables I and II).
Sixty-nine of the 100 patients were diagnosed with ARVD

TABLE 2. Clinical Data and International Task Force Criteria
in the 69 ARVD Patients Who Were Diagnosed While Living
Clinical Characteristic
Imaging and cine imaging studies
Severe dilatation and reduction of RVEF with no
LV impairment*
Localized ventricular aneurysms*
Severe segmental dilatation of the RV*
Mild dilatation and reduction of RVEF with no LV
impairment†
Mild segmental dilatation of RV†
Regional RV hypokinesis†
ECG abnormalities
Prolongation of QRS in leads V1 through V3*
Presence of epsilon waves*
Inverted T waves in leads V1 through V3 or
beyond†
S-wave upstroke ⱖ55 ms in leads V1 through V3
SAECG abnormalities
Late potentials on SAECG†
Arrhythmias
LBBB type VT documented†
Frequent ventricular extrasystoles†
Family history
Family history confirmed by biopsy or autopsy*
SCD in family at ⬍35 years of age†
Family members diagnosed by the present
criteria†
Histopathological study of biopsy/autopsy specimen
Infiltration of RV by fat with presence of
surviving strands or cardiomyocytes (n⫽25)*
Data are represented as frequency (%). EF indicates ejection fraction; LV, left
ventricle; and LBBB, left bundle branch block.
*Major criteria; †minor criteria.
while living (online-only Data Supplement Table I), and 31
patients were diagnosed with ARVD on autopsy (online-only
Data Supplement Table II). There were 51 men. The median
age at presentation was 26 (IQR, 18 to 38; range, 2 to 70)
years. Ninety-five were white, 2 were black, 2 were Hispanic,
and 1 was of Middle-Eastern origin. Forty-nine were rou-
tinely involved in sports or exercise. Thirty-two patients from
19 families had evidence for the familial form of ARVD,
including 19 (22%) of the 87 index cases in the study
population.
Presenting Symptoms
Table 1 summarizes the presenting symptoms among the 100
patients in this series. Palpitations, syncope, and death were
the most common presenting symptoms (27%, 26%, and
23%, respectively). Fifteen patients were asymptomatic at the
time of first presentation. ARVD was suspected in these
patients on the basis of family history suggestive of ARVD or
premature SCD or an abnormal ECG pattern at a routine
physical examination. Fatal ventricular arrhythmia leading to
SCD was the first manifestation of ARVD in 22 patients. Of
Dalal et al ARVD: A United States Experience 3825
these, 1 was resuscitated and survived the presenting episode
of SCD, and 21 died. Two additional patients presented with
n⫽69 death from noncardiac causes.
Characteristics of Patients Diagnosed With ARVD
21 (30) While Living
Summarized in Table 2 (and listed in the online-only Data
7 (10) Supplement Table I) are the results of clinical testing of the
7 (10) 69 ARVD patients who were diagnosed with ARVD while
36 (67) living. The diagnosis of ARVD was established on the basis
of the presence of (1) 2 major criteria (n⫽23); (2) 1 major
8 (12) plus 2 minor criteria (n⫽36); and (3) 4 minor criteria (n⫽10).
37 (54) It is notable that only 1 patient (patient 17) had a “structurally
normal” right ventricle. All patients demonstrated 1 or more
40 (58) ECG abnormalities characteristic of ARVD. The most com-
mon ECG abnormalities detected were delayed S-wave up-
20 (29)
stroke and T-wave inversions in 91% and 81% of the patients,
56 (81)
respectively.
53/58 (91) Clinical Course of Patients Diagnosed With ARVD
While Living
40/59 (67) Shown in Figure 1A and summarized in Figure 2 is the
clinical course of each of the 69 patients in this series who
51/66 (77) were diagnosed with ARVD while living. Each patient is
35/52 (67) represented as a straight line, and the major events in the
course of the disease are plotted by the age at which the event
took place.
12 (17)
The median age at presentation was 29 (IQR, 20 to 36;
4 (6) range, 2 to 63) years. All patients except 1 presented
6 (9) clinically after the onset of adolescence. This patient (patient
1) was a 2-year-old white girl who presented with a syncopal
episode. Her ECG demonstrated sustained monomorphic VT,
12/29 (41) which was terminated by cardioversion. She experienced
another syncopal episode at the age of 3 years. The patient
underwent MRI evaluation at the age of 6 years and was
eventually diagnosed with ARVD on the basis of the task
force criteria. An ICD was implanted at that time. The oldest
patient (patient 69) was a 63-year-old white man who
presented with palpitations associated with sustained VT,
which was cardioverted externally. Diagnosis was established
1 year later when he developed recurrent VT. An ICD was
implanted then. Neither of these patients received any ICD
discharge during follow-up.
The median age at diagnosis was 33 (IQR, 26 to 43; range,
6 to 72) years, and the median time between first presentation
and diagnosis was 1 (IQR, 0 to 6; range, 0 to 34) year. Among
the 69 patients who were diagnosed while living, the median
follow-up was 6 (IQR, 2 to 13; range, 0 to 37) years.
As shown in Figure 2, 26 patients presented with an
episode of symptomatic sustained VT. Nine patients who
initially presented with symptoms in the absence of docu-
mented VT subsequently developed sustained VT. After the
episode of VT, 31 of these 35 patients underwent placement
of an ICD, 11 of whom also underwent 1 or more catheter
ablation procedure. Four of these patients were treated with
drug therapy alone, 2 (patients 5 and 49) of whom experi-
enced SCD within 3 years of presentation. One patient
(patient 39) of the 22 who presented with ventricular fibril-
lation, was successfully resuscitated from cardiac arrest. He
3826 Circulation December 20/27, 2005

Figure 1. Clinical course of each of the 69 patients in this series who were diagnosed with ARVD while living (A) and 31 patients diag-
nosed on autopsy (B). Each patient is represented as a straight line, and the major events in the course of the disease are plotted by
the age at which the event took place. The initiation of each line represents the first clinical presentation, and the termination of the line
represents either a terminal event or the censoring due to the end of follow-up. The junction of the dotted line and the solid line repre-
sents the age at which the patient was diagnosed with ARVD. The following symbols represent different events that occurred in the his-
tory of the disease: 䉫, syncope; 췦, first documented VT; ⫻, termination of VT by external cardioversion; ‘, catheter ablation of VT; U,
ICD implantation; 䢇, appropriate ICD therapy; ▫, onset of heart failure; , heart transplant; and ⫹, death.

received both an ICD and catheter ablations during follow-up.
In addition to these 32 patients in whom an ICD was
implanted after an episode of sustained VT (n⫽31) or aborted
SCD (n⫽1), an ICD was implanted on a prophylactic basis in
15 patients, including 3 asymptomatic patients. Three of these
15 patients subsequently experienced appropriate ICD ther-
apy. Of the total 47 patients who had an ICD implanted,
29 (62%) received at least 1 appropriate ICD therapy during
a median of 4 (IQR, 2 to 6; range, 0 to 20) years after the ICD
implantation. Among the 69 patients, there were only 3
deaths (2 SCD [patients 5 and 49] and 1 due to heart failure
[patient 6]). All 3 patients had 1 or more episodes of syncope,
and only 1 (patient 6) had an ICD in place at the time of
death.
 Dalal et al
Clinical Characteristics of Patients Diagnosed
With ARVD on Autopsy
Summarized in Figure 2 (and listed in online-only Data
Supplement Table II) are the characteristics of 31 patients (15
male) who were diagnosed with ARVD for the first time at
autopsy. The median age was 24 (IQR, 16 to 39; range, 13 to
70) years. Twenty-nine of these patients experienced a
cardiac arrest. Eighteen patients (62%) were involved in
routine activity, 9 (31%) were involved in active exercise, 1
(3.5%) was pregnant, and 1 (3.5%) was in bed at the time of
death. The cardiac arrest was the first symptom of ARVD in
21 patients. Two patients died of a condition other than
ARVD but were diagnosed with ARVD on autopsy.
On gross examination, the mean heart weight was 357⫾68
(range, 250 to 500) g in women and 417⫾106 (range, 240 to
650) g in men (P⫽0.08). RV dilatation was moderate to
severe in 9 patients (29%) and mild in 20 patients (65%). The
mean RV wall thickness was 2.7⫾2.2 mm. On microscopic
examination, RV myocardial loss, either complete or with
few myocardial cells, was seen in all heart specimens. Fatty
infiltration of RV myocardium (except for a thin endomyo-
cardial layer and trabeculae) alone was seen in 9 hearts
(29%). Fibrofatty infiltration was seen in 22 hearts (71%).
Inflammatory infiltrates were seen in 7 (23%) of the heart
specimens.
Eight of these 31 patients had other symptoms before
death. Importantly, 5 of these 8 patients experienced 1 or
ARVD: A United States Experience 3827
Figure 2. Schematic outline and quantifi-
cation of the presentation, treatment, ar-
rhythmia, and outcome in the entire
patient population. Sx indicates symp-
toms; Asx, asymptomatic; VF, ventricular
fibrillation; Abl, catheter ablation of VT;
Rec VT, recurrent VT; HF, heart failure;
and w/o, without. *These patients died of
noncardiac causes of death; autopsy
revealed findings consistent with ARVD.
†These patients experienced fatal VF lead-
ing to SCD; they could not be resusci-
tated. ‡This patient died because of biven-
tricular heart failure at the age of 27 years;
she had an ICD in place at the time of
death and was awaiting a heart transplant.
more episodes of syncope. The median time between presen-
tation and death in these 8 patients was 1.5 (IQR 1 to 3, range
0 to 4) years. The age and the sequence of events that
occurred in each of the patients diagnosed on autopsy are
represented in Figure 1B.
Survival and Heart Failure in ARVD
As shown in Figure 2, 31 patients in the cohort of 100
experienced SCD. Six patients developed right-sided heart
failure, one of whom (patient 6) progressed to biventricular
heart failure and died at the age of 27 years while awaiting
heart transplant. Two patients died of causes other than
ARVD. Two patients (patients 37 and 62) underwent cardiac
transplantation after developing incessant VT. One of these
patients (patient 62) also had significant right-sided heart
failure. Sixty-six of the ARVD patients in this series were
alive at last follow-up, of whom 44 had an ICD in place, 20
were on medical therapy alone, and 2 had a transplanted
heart.
Figure 3 shows the Kaplan-Meier curve for survival free
from ARVD-related deaths in the 100 patients since their first
clinical presentation (causes of death other than ARVD were
excluded). In the entire patient population, there were 32
deaths from cardiac causes (31 SCD and 1 from biventricular
heart failure). In 24 of the 31 patients diagnosed on autopsy,
SCD was the first presenting symptom. The remaining 7
SCDs all occurred within 5 years of first presentation. None
3828 Circulation December 20/27, 2005
Figure 3. Kaplan-Meier survival analysis demonstrating proportion of patients surviving free from cardiac causes of death since first
clinical presentation.
of the 7 patients had an ICD implanted at the time of death.
Only 3 deaths occurred among the 69 patients who were
diagnosed with ARVD while living. Two of these deaths
were SCDs, which occurred within 5 years of first clinical
presentation in patients without an implanted ICD, and 1
death occurred as a result of biventricular heart failure and
occurred 14 years after the first clinical presentation. The
patient had an ICD implanted at the time of death and was
awaiting a heart transplant.
Figure 4 shows the results of Kaplan-Meier survival
analysis by age for the 100 patients in the study with the
following outcomes: (1) any symptom, (2) ventricular ar-
rhythmia, (3) heart failure, and (4) cardiac death. Shown in
Figure 4A are the results of this analysis in the 69 patients
diagnosed while living, and shown in Figure 4B are the
results of the analysis in the 31 patients who were diagnosed
on autopsy. The survival curves show that none of these
events are common before the onset of adolescence.
Among the 69 patients diagnosed while living, half of the
ARVD patients had their first clinical presentation (experi-
enced symptoms) by the age of 32 years. The development of
symptoms mirrors the development of ventricular arrhythmia,
and half the individuals develop VT by the age of 41 years.
Heart failure was a rare event, occurring in ⬇25% of patients
who survive up to the age of 56 years. Death also was
extremely rare among those diagnosed while living, and it is
notable that only 3 patients (described above) experienced
cardiac death during follow-up. The death-free survival time
in 94% of this group of patients was ⬎60 years.
The median age at first clinical presentation (24 years)
among the 31 patients diagnosed on autopsy was not signif-
icantly lower than that in those diagnosed while living
(P⫽0.16). However, the median age at cardiac death (25
years) in this group was significantly lower than that in the 69
patients diagnosed while living (P⬍0.001). The small differ-
ence between the age at presentation and the age at death
reflects the fact that the majority of these patients experienced
SCD as their first clinical presentation, and those who did not
experience SCD as their first presenting symptom experi-
enced it shortly after their first presentation.
When we performed Kaplan-Meier analysis after combin-
ing the entire patient population (n⫽100; results not shown),
the median age at first presentation was 30 years. By the age
of 60 years, nearly 50% of the patients experienced cardiac
death. Heart failure was experienced by ⬇25% of patients
who survived up to the age of 70 years.
Discussion
The results of this study describe in detail the presentation,
clinical characteristics, and follow-up of 100 ARVD patients
from the United States. This is the largest cohort of ARVD
patients from the United States, and the results of this study
allow us to compare the clinical features of these patients with
those of the previously described European populations of
ARVD patients. The results also provide important insights
into the natural history and treatment of this rare but poten-
tially life-threatening inherited cardiomyopathy.
Prior Studies
Since first described ⬎20 years ago,1,7 ARVD has fascinated
the cardiology community.20,25,26 The great majority of prior
studies have focused on particular aspects of ARVD such as
 Dalal et al ARVD: A United States Experience 3829

Figure 4. Kaplan-Meier survival analysis demonstrating proportion of patients free from (1) any symptom, (2) ventricular arrhythmia, (3)
cardiac death, and (4) onset of heart failure since birth among the 69 patients diagnosed while living (A) and from (1) any symptom and
(2) cardiac death among the 31 patients diagnosed on autopsy (B). The numbers below the graph represent the subjects at risk of the
event and those having the event in each decade of life. The numbers in parentheses represent the percentage of patients, among the
total number at risk, experiencing the event.
3830 Circulation December 20/27, 2005
diagnostic testing,22,27,28 ICD therapy,29 –31 and clinical fea-
tures of the disease.1,10,15 In contrast, few studies have
described the clinical course and natural history of patients
with ARVD. Five of the most prominent studies have
included 12, 15, 35, 45, and 130 European patients, respec-
tively.11–14,32 There have been only 2 independent studies
from the United States, involving 1218 and 2017 ARVD
patients.
Presentation of ARVD
The results of this study provide several important insights
into the clinical presentation of ARVD in the United States.
First, ARVD patients typically present between the second
and fifth decades of life. Although only 8 patients presented
before the onset of adolescence or after 50 years of age, the
age at presentation ranged widely between 2 and 70 years. On
Kaplan-Meier analysis, one half the patients remained symp-
tom free for 35 years of life. The marked variability in age of
presentation suggests that ARVD remains concealed for
varying periods of time in different individuals.
Second, the results of our study highlight the wide spec-
trum of presenting symptoms. The most common presenting
symptoms were palpitations, syncope, and death. This vari-
ability of clinical presentation in our study is consistent with
prior studies.1,2,10,33 The underlying basis for the wide vari-
ability of clinical presentation requires further research. It is
likely that genetic and other modifying factors such as
exercise and/or viral myocarditis may account for some of
this variability.3,5,34
Third, the results of this study highlight the close link
between ARVD and SCD. Our findings confirm the recent
findings of Tabib et al6 as well as those from the prior
landmark studies reported by Thiene et al,3 Corrado et al,4
and Basso et al35 that the incidence of SCD due to ARVD
decreases after the fourth decade of life. Our study also
confirms the findings that a large proportion of these patients
have SCD during routine activity.6,35 The 8 patients (26%)
experiencing SCD and subsequently diagnosed on autopsy,
who had prior symptoms, represent an important subset of
patients who may have benefited from earlier diagnosis and
ICD implantation. Furthermore, 8 of the 11 patients (diag-
nosed while living [n⫽3] or on autopsy [n⫽8]) who died of
cardiac causes had experienced a syncopal episode before
SCD. Our data support the importance of syncope as a
prognostic factor in ARVD, as suggested by Marcus et al.14
Clinical Characteristics of ARVD Patients
Our findings are consistent with the results of prior studies
that described the clinical characteristics of patients with
ARVD.1,9,10 Notably, in this study, among those diagnosed
with ARVD while living, ⬎95% of patients had 1 or more
ECG features of ARVD, ⬇70% had an abnormal SAECG,
and all patients except 1 had a structurally abnormal RV. The
marked similarity of clinical characteristics of ARVD be-
tween this and prior studies suggests the similarity between
patients from the United States and Europe and almost
certainly reflects the use of the task force criteria.
Family History
A familial pattern of inheritance of the disease was observed
in 32 patients in 19 families in our series. This likely
represents an underestimate of true prevalence of familial
pattern because systematic screening of all family members
was not performed. Furthermore, we relied on the task force
criteria to establish a diagnosis of ARVD while screening
family members. Hamid et al10 recently proposed that less
stringent criteria be used for the diagnosis when screening
family members who are likely to be evaluated at an earlier
stage of the disease. The incidence of familial pattern of
ARVD in our series fits within the wide range of 15% to 50%
described in the literature.36,37
Clinical Course and Natural History of ARVD
The results of our study call attention to the variable clinical
course experienced by patients with ARVD. First, it is
notable that one half of the patients with ARVD presented
with a malignant or potentially malignant ventricular arrhyth-
mia. This fact emphasizes the importance of screening family
members of patients with known ARVD. An additional 44%
of the remaining patients experienced a sustained ventricular
arrhythmia during the course of the disease. These findings
make it clear that arrhythmic events are the most important
manifestation of ARVD. This also helps explain why patients
with ARVD, once treated with an ICD, have an excellent
prognosis. Second, in our patient population, progression to
heart failure was uncommon, occurring in ⬍10% of patients.
Only 1 patient progressed from right heart failure to a
biventricular heart failure and subsequently died while await-
ing a heart transplant. Prior studies have reported up to 20%
incidence of heart failure among ARVD patients.13,14,32,38 The
recent study published by Hulot et al32 reported a much
higher incidence of death from heart failure. The difference in
incidence of and mortality as a result of heart failure is
probably due to the more advanced disease in the tertiary care
hospitals in which the studies were conducted as opposed to
the Web-based recruitment system used in our study. It is also
likely that the study samples included in different studies
represent different phenotypes of the disease. In fact, the
study reported by Marcus et al,14 which included patients
from both France and the United States, showed a high
incidence of heart failure among the series from France (8 of
22 patients) compared with a zero incidence among the
patients from the United States. Finally, the results of our
study further demonstrate that diagnosis and subsequent
treatment are associated with excellent survival. Among the
69 patients diagnosed while living, only 2 experienced SCD,
neither of whom had an ICD in place. Our findings differ
from those reported by Hulot et al,32 which indicate an overall
death rate of 21 of 130 patients. This is likely explained by
the lower use of ICD therapy. In fact, none of the 31 patients
from our patient population who died suddenly had an ICD in
place. Our data indicate that the median survival free from
cardiac death in ARVD patients is ⬇60 years. This type of
analysis has not been performed previously in ARVD
patients.
 Dalal et al
Study Limitations
The patients in our study population either were referred to us
because of clinical symptoms and diagnosis of ARVD or
were screened because of a diagnosis of ARVD in a family
member. This ascertainment bias as well as familial cluster-
ing (although the majority of the patients [87%] were unre-
lated probands) may have influenced the results of our study.
Accordingly, the findings of our study may not be directly
applicable to the entire population of ARVD patients, which
may comprise a large number of patients with a milder form
of the disease. The Kaplan-Meier analyses may therefore
have underestimated the true event-free survival time among
ARVD patients. However, because of the complexity of
establishing ARVD diagnosis, lack of a single sensitive
marker for the disease, and the rarity of the disease, it is
virtually impossible to avoid this ascertainment bias. Another
important limitation of our study lies in the fact that the study
population was composed of 2 different subsets of patients:
those diagnosed while living and followed prospectively
(n⫽69) and those diagnosed on autopsy (n⫽31). The burden
of SCD experienced by ARVD patients may have been
overestimated by this selection bias. Finally, among the
patients diagnosed on autopsy, although each of the his-
topathological specimens was evaluated by a pathologist,
precise information about the extent and the distribution of
the disease was not available for analysis.
Conclusion
In conclusion, the results of our study demonstrate that
patients with ARVD have highly variable ages and symptoms
at presentation and that most patients with ARVD experience
symptomatic, potentially life-threatening arrhythmias during
follow-up. Although SCD is a common presenting symptom,
once diagnosed, the incidence of SCD is rare, and the overall
prognosis of ARVD is excellent. This largely reflects the
widespread use of ICDs in the United States. Few patients
with ARVD progress to heart failure. These findings are
consistent with the previously described 4 possible phases of
ARVD: (1) the concealed phase; (2) an overt electric disor-
der; (3) RV failure; and (4) a biventricular pump failure.39
The onset and the duration of each of these phases vary
widely among individuals. Further research is needed to
identify which clinical and/or genetic factors account for the
differing clinical course of ARVD patients. It is likely that the
results from the North American ARVD Registry and the
international ARVD registry may provide important informa-
tion in the future.40,41
Acknowledgments
The Johns Hopkins ARVD Program is supported by the Bogle
Foundation, the Campanella family, the Wilmerding Endowment,
and National Institutes of Health grant 1 UO1 HL65594-01A1. This
work was also supported by a grant from the Donald W. Reynolds
Foundation.
Disclosure
Dr Judge receives support from the D.W. Reynolds Foundation for
the study of sudden cardiac death. Dr Calkins receives support from
Guidant, Medtronic, and St Jude.
ARVD: A United States Experience 3831
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CLINICAL PERSPECTIVE
Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by right ventricular
dysfunction and ventricular arrhythmias. The results of our study provide important insights into the presentation and
clinical course of patients with ARVD. From a clinical perspective, 3 findings of this report should be highlighted. First,
the results of this study demonstrate that ARVD typically presents between the second and fifth decades of life with
palpitations, syncope, or sudden death. Although most patients who experience sudden death have no prior warning
symptoms, an important subset of patients experience syncope before sudden death. These findings emphasize the
importance of screening family members and also being alert to the potential for ARVD among patients with syncope.
Second, the results of this study demonstrate that patients with ARVD, once treated with an implantable cardioverter/
defibrillator (ICD), have an excellent prognosis. None of the ARVD patients who died suddenly had undergone ICD
implantation. It is important to emphasize, however, that the patients in this series met the very strict task force criteria for
ARVD. We do not advocate routine ICD placement in patients with only borderline or suggestive evidence of ARVD.
Finally, the results of our study reveal that progression to right- or left-sided heart failure is rare, occurring in ⬍10% of
patients in this series. We are hopeful that advancements in the understanding of the genetic basis of ARVD will help to
unravel many of the remaining mysteries of this disease during the next 5 years.