Professional Documents
Culture Documents
ARVC 2015 Carte
ARVC 2015 Carte
ARVC 2015 Carte
Arrhythmogenic
Current Thinking on
Right Ventricular
Cardiomyopathy/Dysplasia
Editors
CORINNA BRUNCKHORST l FIRAT DURU
Associate Editor
ARDAN M. SAGUNER
Foreword by
A. JOHN CAMM
Current Concepts in Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia
Current Concepts in Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia
Editors:
Associate Editor:
Minneapolis, Minnesota
© 2014 Corinna Brunckhorst, Firat Duru
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ISBN: 978-1-935395-92-8
eISBN: 978-1-935395-19-5
v
Table of Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Chapter 8 The Role of Implantable Defibrillators and Catheter Ablation in the Management of
Patients with Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia . . . . . . . . 93
Florence Porterfield, Hugh Calkins
vii
viii Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Contributors
Editors
Prof. Dr. Corinna Brunckhorst, MD
Co-Director Arrhythmia Service, University Heart Center, Zurich, Switzerland
Associate Editor
Ardan M. Saguner, MD
Fellow Arrhythmia Service, University Heart Center, Zurich, Switzerland
Contributors
Esperanza Agullo-Pascual, PhD Mario Delmar, MD, PhD
Leon H. Charney Division of Cardiology, New Professor of Medicine/Cardiology, Leon H.
York University School of Medicine, New York, Charney Division of Cardiology, New York
New York, USA University School of Medicine, New York,
New York, USA
Hugh Calkins, MD
Professor of Medicine, Nicholas J. Fortuin Paul Erne, MD
Professor of Cardiology, Johns Hopkins Medical CardioVasc Schweiz, Klinik St. Anna, Lucerne,
Institutions, Johns Hopkins, Baltimore, Switzerland; Department of Cardiology,
Maryland, USA University Heart Center, Zurich, Switzerland
ix
x Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
xi
Preface
Since the late 1970s, when Guy Fontaine and Frank Marcus first reported their pioneering obser-
vations on a previously undescribed disease of the right heart, our knowledge on arrhythmogenic
cardiomyopathies has increased remarkably. As challenging as its diagnosis and treatment, even
naming the disease has been a matter of controversy. In the early years, the disease was termed
right ventricular dysplasia, but now the expression arrhythmogenic right ventricular cardiomyopa-
thy/dysplasia (ARVC/D) is commonly used, as in the 2010 modified Task Force Criteria.
For clinicians in the field of cardiac arrhythmias, ARVC/D remains a matter of concern
because (a) the disease may cause sudden death in an otherwise healthy young individual, par-
ticularly during strenuous physical activity; (b) right ventricular outflow tract arrhythmias, which
are generally thought to be benign in nature, may be the initial manifestation of an underlying
structural disorder; (c) the disease may proceed to varying degrees of right or biventricular heart
failure; (d) despite the identification of genetic mutations in about half of the cases, there is
significant variation in the phenotypic expression of the disease; and finally, (e) there is not a
single diagnostic tool to either diagnose or exclude the presence of this clinical entity. Today,
there is a vast amount of evidence suggesting ARVC/D to be a disease of the intercellular junc-
tion. Nevertheless, other pathogenetic mechanisms, such as inflammation and apoptosis, may
also play a role.
In 2011, we established the Zurich ARVC Program in an attempt to increase awareness for
this challenging disease. This program, which is supported by the Georg and Bertha Schwyzer-
Winiker Foundation, focuses on providing clinical excellence for the care of these patients and
promoting in-depth basic and clinical research for this condition. In this context, we organized
the first ARVC/D symposium in May 2012 in Zurich, where international key opinion leaders
and national experts participated. This symposium created a platform for exchange of knowledge
and initiated various collaborations between different research groups. It was the collective mis-
sion of the ARVC/D experts to bring together the cutting-edge information on this disease and
print it for distribution to a wider public. The result is a new comprehensive book on ARVC/D
with each of the authors contributing a dedicated chapter on their particular area of expertise.
Because the Zurich ARVC/D symposia are planned to be held every 2 years, this book will
be regularly updated in an electronic format so that our interested readers can stay abreast of the
most recent developments on this challenging disease.
This book includes various chapters on basic and clinical science of ARVC/D. The first
chapter describes the fascinating discovery of the disease in detail. Pathophysiology, molecu-
lar mechanisms, and genetic background of ARVC/D are presented concisely. Moreover, the
mechanisms of disease progression leading to a diversity of disease phenotypes and the chal-
lenges in the clinical setting with respect to diagnosis, risk stratification, and therapy of the
disease are elucidated.
xiii
xiv Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
The ultimate goal of this book is to offer novel insights in all major aspects of this unique
disease and to serve as a valuable guide to help readers provide the best possible care for their
ARVC/D patients. We hope the book fulfills this purpose and thank the authors for their valu-
able contributions.
1
septum separating the two cavities. This was an obvious anatomical reality leading to the
contrary to the dogma at that time that physi- understanding of the physiology rather than
ologic direct communication existed between making a purely artistic design.
the two ventricles in the adult. If we focus on
the walls of the heart where the epicardium William Harvey (1578–1657)
and endocardium are carefully drawn, we can
see the configuration of the right ventricle as In Leonardo’s time, the mechanism of blood
compared to the left ventricle. The right ven- flow was not yet elucidated. Since the heart was
tricle is blatantly dilated. The right ventricu- known to contract forcefully, it was suspected
lar wall is much thinner and shows segmental to drive the blood through the body, and it was
abnormalities. In this anatomical description, known that these contractions were essential to
it is possible that the patient had arrhythmo- life. However, it was not until William Harvey,
genic right ventricular dysplasia (ARVD) that a physician from England who resided for sev-
could have led to sudden death. eral years at the University of Padua, Italy, at
This anatomical projection by Leonardo the turn of the 17th century, demonstrated the
can be currently obtained by 4-chamber echo- pulmonary and systemic circulation including
cardiography. An echocardiographer who is the arteries, veins, and cardiac chambers so
aware of this disease would assume the diag- that the human circulation was defined. The
nosis by looking at the sketch of the master of French philosopher René Descartes had sys-
Milan. The epicardial fat, which is a charac- tematically criticized Harvey’s findings based
teristic of dysplasia, is absent on this drawing. on pure, logical reasoning.1 Descartes’s com-
It may have been intentionally removed in ments were disturbing to Harvey, and he was
order to simplify the drawing, similar to the forced to make new experiments that resulted
absence of fat in all the other organs in this in information to the complete satisfaction of
picture. Leonardo interpreted the anatomy Descartes.2 The result was that the mechanism
more as a scientist than as an artist. He sought of blood flow was finally elucidated.
Discovery of Right Ventricular Cardiomyopathies 3
Giovanni Maria Lancisi (1654–1720) of 110. The patient was discharged from the
hospital after 3 months, and for the next 14
The first clinical description of ARVD was months, she was confined to her home and
made by the Italian physician Giovanni Maria had many cardiac consultations. She was
Lancisi, who was interested in heart aneu- treated with cardiotonics, procainamide, and
rysms and reported typical familial cases stud- diuretics. During the last few months of her
ied over four generations and one additional life, she had 2 episodes of palpitations asso-
family member with autopsy.* ciated with nausea and chest pain. An x-ray
taken 3 months before her death showed a
Twentieth Century right pleural effusion as well as considerable
enlargement of the cardiac silhouette. She
Massachusetts General died at home.
Clinicopathological Exercises (1952) The case discussion was conducted by
Dr. Sprague. He stressed the difficulty of
In the modern era, a comparison of clinical diagnosis in this young woman, who had
and pathological data as a cause of ARVD was edema in her legs for 11 months, fever, dys-
discussed at the Massachusetts General Hos- pnea, and cough. She died suddenly, but had
pital in 1952. The discussion’s chairmen were severe heart failure. Rheumatic fever was
Dr. Benjamin Castleman, pathologist, and Dr. excluded, and the possibility of a common
Howard B. Sprague, clinician.3 Another partic- congenital disease could not be confirmed.
ipant was Dr. Paul Dudley White. The meet- In the discussion, a systemic disease such as
ing concerned a 24-year-old woman admitted von Gierke’s was considered. There was no
for abdominal swelling and fever. Ten years evidence for a collagen vascular disease. The
earlier, her brother died at the age of 17, one possibility of amyloidosis or granulomatous
year after the onset of heart failure. myocarditis was considered. The most likely
At the age of 20, the patient had expe- diagnosis was myocarditis of unknown etiol-
rienced 4- to 5-minute episodes of rapid ogy, complicated by ventricular tachycardia
heartbeat associated with discomfort. Clini- and possibly pulmonary embolism. However,
cal examination suggested a dilated heart this did not explain the history of her brother,
extending to the anterior axillary line. The who died at age 17 due to heart failure. The
rhythm was regular with some extrasystoles clinical diagnosis proposed by Dr. Sprague
and episodes of bigeminy. A week after dis- was that of myocarditis of unknown etiology
charge from Massachusetts General Hos- associated with a ventricular ectopic rhythm.
pital, she was admitted to Good Samaritan The pathological analysis by Dr. Castleman
Hospital with acute heart failure. The ECG indicated that the patient had extreme dila-
revealed low voltage with inverted T waves tion of the right side of the heart. This ven-
in leads I, II, and III, and in the precordial tricle, and the right atrium as well, were huge
leads. In addition, she had frequent ventricu- and thin, “the thinnest in [his] personal expe-
lar extrasystoles. An esophageal lead showed rience.” In some areas, the thickness of the
that she had atrial tachycardia at a rate of ventricular myocardium was no more than a
220 beats per minute with a ventricular rate millimeter. Dr. White then asked if there was
fibrous tissue, but Dr. Castleman had seen
*Note: A more comprehensive description is
very little, and only around the vessels. The
reported in Dr. Fontaine’s book (in French). It
is cited as the last bibliographic reference of this volume of the right ventricle was estimated to
chapter. be five times that of the left ventricle. In both
4 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
showed obvious prolongation of the QRS com- Facquet, who indicated that I should not con-
plexes in leads V1 and V2, an Epsilon wave in tinue to pass the examinations in academic
V1, and T-wave inversions in the right precor- medicine since my accomplishments in the
dial leads in a young woman, who is the only field of cardiac pacemakers were already sig-
one of the four cases to have presented with nificant. He suggested that I pursue inves-
palpitations (Figure 1.2). tigations of “these new techniques that the
Americans have and that we do not have.”
The First Epicardial Mapping in Since I was trained in electrical engineer-
Europe (1971) ing before studying medicine, and I was
convinced that the surgical treatment of the
In 1968, an abstract reported the first surgical WPW syndrome needed extensive electronic
treatment of tachycardia in Wolff-Parkinson- participation during surgery to guide this
White (WPW) syndrome that was performed surgical approach, I discussed this approach
at Duke University. I was convinced that this with Professor Facquet, who suggested that I
method could be used to treat the most severe meet with the chief of the cardiovascular sur-
cases of ventricular tachycardia resistant to gical department, Professor Cabrol, and with
all other forms of treatment including anti- his assistant, Professor Gérard Guiraudon.
arrhythmic drugs and pacemakers. I recalled After an interview with Gérard, we decided
a statement of my mentor, Professor Jean to work together on this project one afternoon
FIGURE 1.2 Twelve-lead ECG from Dalla Volta Case Number 4 . The comment of the last sentence (in French) is
“Transeptal sub-epicardial ischemia .”
6 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
every week in the department of experimen- dilated, hypokinetic, and covered by a promi-
tal heart surgery. nent layer of fat.
After six months, the technique of epi- The first epicardial map during sinus
cardial mapping was perfected in dogs with rhythm was almost normal (Figure 1.3). The
a special stimulator that I designed in order anterior aspect of the right ventricle was acti-
to activate the heart and to mimic the various vated normally, but with a 10-ms delay. The
forms of abnormal epicardial activation in the VT was easily induced by electrical stimula-
WPW syndrome. We performed the first suc- tion. Mapping was completed in less than 20
cessful European surgical procedure for the minutes and revealed that the “site of origin”
treatment of WPW syndrome in 1971, and a was in the mid-right ventricular free wall as
report of this case was published in 1972.6,7 suspected by the electrocardiographic mor-
It was then that I decided that the same phology. It was decided to perform a “simple
technique of epicardial mapping could be ventriculotomy” along the border of the RV
applied to other forms of life-threatening from apex to base. This large incision facili-
arrhythmias such as ventricular tachycardia tated an extensive view of the right ventricular
(VT). Four patients with VT due to remote cavity, which appeared normal. The histology
myocardial infarction or idiopathic dilated of the fragment taken from the free wall, stud-
cardiomyopathy were operated on with the ied several years later, was essentially normal
same success before we attempted this proce- with no signs of inflammation. When the ven-
dure on the first patient with ARVD. tricle was closed and the extracorporeal circu-
lation was withdrawn, it became clear that the
The First Successful Surgical tachycardia was no longer inducible. Subse-
Treatment of ARVD (1973) quently, he had no further arrhythmias and no
longer needed antiarrhythmic drugs.
The first patient, a 65-year-old man, did not This case was initially considered as “idio-
have coronary artery disease but had had pathic tachycardia,” and the case report was
recurring episodes of ventricular tachycardia one of four published in a book chapter after
for 10 years. These episodes were resistant presentation of these cases in 1975 during a
to treatment with all antiarrhythmic drugs. scientific meeting in Amsterdam.8 It was the
These tachycardias seemed to originate from first time that this innovative surgical treat-
the right ventricle as judged by the morphol- ment for VT was described. Our team was
ogy of the ECG during VT. This was of convinced we had discovered a new method
great interest, since VT originated from the of surgical treatment of resistant VT. The
left ventricle in the four preceding patients. patient died at the age of 86 from heart failure
In addition, the left ventricular contractility without any new episodes of VT.
was normal, with the exception of a slight
anomaly on the anterior wall near the apex. Left Ventricular Involvement in Right
Since the rate of tachycardia was decreased Ventricular Dysplasia (1975)
by drug therapy, it could be studied by epicar-
dial mapping. All the documented episodes One of the first ARVD patients operated on for
of VT had the same morphology, suggest- the treatment of VT had a significant delayed
ing a single area of origin. The surgical pro- electrical activation in the left ventricular epi-
cedure took place on October 30, 1973. As cardium in addition to that in the right ven-
soon as the heart was exposed, the surgeon tricle. This was a 42-year-old man referred for
noted that the right ventricle was moderately VT resistant to all antiarrhythmic drugs. The
Discovery of Right Ventricular Cardiomyopathies 7
A B
FIGURE 1.3 Epicardial mapping of the first ARVD patient . Panel A: Map in sinus rhythm . Panel B: Map during ventricular
tachycardia .
VTs occurred each month and led to a loss firmed that there was a markedly delayed area
of consciousness. These VTs had the same of electrical activity located on the left ven-
left bundle branch block morphology, except tricle. In addition, this location was consistent
for some short episodes of nonsustained VT with the morphology of some bursts of extra-
with right bundle branch block observed only systoles induced by electrical stimulation.
after induction by stimulation. Angiography However, during the intervention, map-
showed akinesia of the left ventricular apex ping was focused on the origin of right VT,
with a discrete area of dyskinesia. The anterior triggered by stimulation, and sufficiently sta-
interventricular artery was short, suggesting a ble so that it could be mapped properly. A left
probable old thrombosis of this vessel, which ventriculotomy was done as a precaution. It
could explain the akinesia at the apex of the was performed at the critical point observed
left ventricle. It could also be due to narrow- in the left ventricle based on the informa-
ing of the vessel caused by hypertrophy of the tion provided by the mapping during sinus
leiomyocytes of this vessel (a well-known fea- rhythm. Although there was a possibility of
ture of ARVD). Surgical therapy for VT was recurrence, the patient did not have any recur-
performed on January 7, 1975. rent VT. After the procedure, the patient’s car-
Mapping during sinus rhythm recorded diologist stated that the patient showed signs
many areas of late potentials at the pulmonary of left ventricular failure without recurrence
infundibulum and the diaphragmatic surface of the arrhythmias. The patient died 7 years
of the right ventricle, especially at the anterior after VT surgery. An autopsy was performed
portion near the apex, but also on the anterior and documented that it was a typical case of
aspect of the left ventricular wall.9 This was an biventricular dysplasia.
unexpected finding. It was so unexpected that
I rechecked the computer mapping two years Naming the Disease:
later from the saved recordings. I wondered if I Arrhythmogenic Right Ventricular
had made an error in measurement. However, Dysplasia (1977)
not only was there no obvious abnormality in
any single measurement, but adjacent points In September 1976, an international meeting
followed the same general pattern. This con- was organized in Liège, Belgium. I reported
8 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
the results of the surgical treatment of VT ous, since all patients were referred for the
in 13 patients, of whom 3 had VT originat- same type of ventricular arrhythmia. Right
ing in the right ventricle. We also saw other ventricular involvement was also the salient
patients with VT compatible with an origin feature of this group. The last term, “dyspla-
from the right ventricle but who did not sia,” was more difficult to select. At that time,
require surgery. I attempted to classify the I had no access to histologic material. The
patients in different subgroups and found only hint of the etiology was the consistently
that the patients with VT from the RV had increased amount of fat and decrease in the
a consistent profile. They were male, young, thickness of the surviving myocardial wall
and had good left ventricular function. They visible when the right ventricle was opened
also had VT that could be induced and ter- at the time of antiarrhythmic surgery. I con-
minated by electrical stimulation. During cluded that this strange disease could only
sinus rhythm, the ECG showed inversion be the result of a problem in development,
of T waves in the precordial leads V1–V3. In and therefore the term “dystrophy” or “dys-
addition, late activation potentials (Epsilon plasia” appeared to be appropriate. However,
waves) were observed on the epicardium of because of the young age of the patients, it
the three operated cases. At that time, histo- was probable that the disease started early in
logical data was not available and the electro- life, and therefore the term “dysplasia” was
genesis of late potentials and Epsilon waves finally chosen.
was unknown. However, these were readily It was also shown that in some patients,
explained when the first histologic document Epsilon waves could be recorded on the sur-
became available (Figure 1.4). face ECG (Figure 1.5). Finally, the termi-
I was convinced that a new clinical entity nology “Arrhythmogenic Right Ventricular
was discovered because these patients did not Dysplasia” was proposed in 1977.9
fit into the description of classical diseases At that time, I stated, “By an analysis
causing VT. I decided to choose a name for of the data obtained from the operated and
this disease that included its prominent fea- non-operated cases, we think it is possible to
tures. The term “arrhythmogenic” was obvi- postulate a syndrome which we would like to
ventricles, and explained one cause 11. Description of the typical pattern of an
of progression to global heart failure epithelioid granuloma of cardiac sar-
as mentioned above. This was called coidosis associated with ARVD, which
“biventricular dysplasia.”14 has been now explained by desmosomal
6. In the late stage of the disease, whitish participation in the two diseases.
plaques of hyaline fibrosis independent 12. Report of bacterial myocarditis in a typi-
of the dysplastic areas were visible corre- cal case of a young adult ARVD patient
sponding to an organized mural thrombus. who died suddenly (while playing soc-
This stressed the need for anticoagulant cer). Abscess involving the full thick-
therapy at an end stage of the disease.15 ness of the left ventricle, suggesting that
7. Presence of small vessel disease due to myocardium of ARVD patients is more
increase in the thickness of leiomyo- susceptible to both viral and bacterial
cytes—similar to that seen in hypertro- infection.
phic cardiomyopathy—was visible in 13. Major fatty involvement of RV free wall
some areas independently of the dysplas- without fibrosis was an independent
tic phenomenon.15 This could possibly abnormal entity called “Fat Dissociation
explain the atypical chest pain observed Syndrome.”18,19 It could be a possible
in 17% of patients, as observed by Dr. cause of irreversible heart failure after
Hugh Calkins on my request (personal cardiac transplantation and has been
communication). also reported under the name of “adi-
8. Areas of major (replacement) fibrosis positas cordis.”20
suggesting sequelae of a severe form of 14. Clear understanding of the pathogen-
myocarditis. This suggested the possible esis of Uhl’s anomaly, first reported at
involvement of cardiotropic viruses.16 Johns Hopkins, with total absence of
9. General overall spectrum of myocarditis the RV myocardium and apposition of
ranging from the fulminant form to com- epicardium against endocardium with
plete healing with a spectrum of inter- a small layer of fat in between and the
mediate forms of acute, chronic-active, presence of “small vessel disease” in
and chronic with multifocal presenta- one of my specimens.11 This disease
tions. Involvement of both ventricles by was suspected by Dr. Thomas James to
lymphocytic infiltrations and biventricu- be representative of an early and severe
lar failure due to possible cardiotropic form of apoptosis as opposed to ARVD
viruses explain why two-thirds of these due to a more delayed and progressive
patients die due to congestive heart fail- phenomenon.21,22 Apoptosis was finally
ure or require heart transplantation.16 demonstrated by our group for the first
10. Presence of lymphocytes more fre- time in the human heart.23 Preservation
quently observed on the epicardial lay- of a flat layer of myocardium, which
ers with increased thickness embedding explained the impressive delayed poten-
lymphocytes. This infiltration by lym- tials observed on the infundibulum of
phocytes decreased in intensity toward our patient and permitted an almost per-
the endocardium, suggesting the clas- fect delineation of the pathway of VT.9
sical pattern of pericarditis-myocarditis, 15. Discovery of Naxos disease based on
again stressing the role of an environ- typical histologic findings in patients
mental factor, probably due to superim- with ventricular arrhythmias originat-
posed cardiotropic viruses.17 ing in the RV with an ECG pattern
12 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
the disease showing its progression to irrevers- spoke of ARVD, ignoring the terms used by
ible heart failure in a considerable proportion others, sometimes because it was simply easier
of patients,34 the value of contrast angio,35 and to say, and some speakers used both terms in
the remodelling of gap junctions as a result of the same speech.
distorted desmosomes.36 In several of these Task Force meetings,
the question of terminology was raised again.
Dysplasia Controversy and An ad hoc session was organized to present
Subsequent Terminology (2005) arguments for each terminology, followed
by a vote. I was the first to speak. After pre-
Nevertheless, the controversy on terminology senting my arguments, for which I had not
did not stop, and is still ongoing. On April enough time to prepare, and the comments
15, 2005, in a meeting conducted by email, by the other group members, the final vote
Rampazzo (a molecular biologist from Padua, was made, giving a slight advantage to the
Italy) wrote: “Finally, the name ‘dysplasia’ was term ARV “cardiomyopathy.” At that time, it
adopted because alterations of myocardial seemed that the term ARV “dysplasia” was
tissue were assumed to occur due to devel- banished forever.
opmental defects. On the contrary, now it is However, when I had to review the final
clear that such alterations are the end-stage version of a manuscript ready to be sent to
of a slow degenerative process: therefore the Circulation, which was in the hands of Dr.
term ‘cardiomyopathy’ appears more appro- Frank Marcus, I stressed again that I defi-
priate.” Later, the group from Padua adopted nitely wanted to keep the term of the original
the concept of myocardial inflammation and description made by Dr. McKenna et al in
healing as the basis for the disease. For me, a the British Heart Journal.37 Dr. Marcus tried
degenerative process or healed inflammation a last time to convince me to accept the term
should have produced a right bundle branch of “cardiomyopathy” and forget “dysplasia.”
block on the surface ECG with reduced However, after reviewing multiple papers for
amplitudes of the QRS complexes, and not Circulation, I had been selected by Dr. Jim
the very small, long-lasting bleeps (called Willerson to become a member of the edito-
Epsilon waves) seen after a normal QRS com- rial board for a period of 5 years. Therefore, I
plex as has been ascertained in a large propor- was in such a position to say to Frank that if
tion of ARVD patients (Figure 1.5). dysplasia was “ablated,” I would ask the pub-
lisher to withdraw my name from the author
The International Task Force and the list of the revised criteria. In the end, the orig-
Revised Criteria (2010) inal term was retained in the Revised 2010
International Task Force Criteria for identi-
A new period of discomfort came up during fication of ARV Cardiomyopathy/Dysplasia
the following ARVD meetings, organized to (published in Circulation and the European
write the new criteria. These new criteria were Heart Journal in 2010).
developed in order to increase diagnostic sen- Please note that the original terminol-
sitivity and to identify the disease in family ogy used for the first description in the British
members, in whom the phenotype is gener- Heart Journal in 1994 was ARVD/C,37 which
ally less severe than in the proband (the first is the term that I personally always use, but
patient identified in a given family). The lack I accepted the term ARVC/D when the con-
of consistency in terminology was apparent. cept of multiple facets of ARVCs was my final
Each time I had to present my work, I always terminology.
14 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Addendum 1 Abbreviations
Since the first draft of this chapter, I have iPSC induced pluripotent stem cells
been surprised by the current problems VT ventricular tachycardia
observed in the proper classification of
ARVC patients. Each month we have in La References
1. Hurst W, Conti CR, Fye WB. Profiles in Car-
Salpêtriére Hospital a staff meeting present-
diology. Mahwah, NJ: Foundation for the
ing all cases observed during the preceding
Advances in Medicine and Science; 2003.
30-day interval. Between 12 and 20 people
2. Wright T. Circulation: William Harvey’s Revolu-
of different expertise give their views, until a tionary Idea. London: Chatto & Windus; 2012.
diagnosis is obtained after final presentation 3. Massachusetts General Hospital. Weekly clin-
of the contrast angiography, which, at least in icopathological exercises: case 38201 cardiac
our center, remains the gold standard in the dilatation of right heart, extreme, congenital.
identification of different forms of ARVCs.35 N Engl J Med. 1952;246:785-790.
After suspecting the disease based on ven- 4. Dalla Volta S, Battaglia G, Zerbini E. “Auricu-
tricular arrhythmias, nowadays patients are larization” of right ventricular pressure curve.
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ber, and on the other side because of the clinical and hemodynamic syndrome of auric-
ularisation of the right ventricle. A propos
wide spectrum of ECG abnormalities such as
de 4 cas personnels. Arch Mal Coeur. 1965;
Epsilon waves or Brugada-like ECG patterns.
58:1129-1143.
However, in most of these questionable cases 6. Fontaine G, Guiraudon G, Vachon JM, et al.
with some structural abnormalities seen by Section d’un faisceau de Kent dans un cas
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a clear diagnosis, and therefore the patients type AB. I-Explorations électrophysiologiques
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especially for advanced research, to be strict Section d’un faisceau de Kent dans un cas
and clear with terminology, and not to put in de syndrome de Wolff-Parkinson-White. II-
the same basket patients with different forms Cartographies épicardiques. Arch Mal Coeur
of ARVCs, ARVD, and unclear cases of right Vaiss. 1972;65:925-934.
8. Fontaine G, Guiraudon G, Frank R, Coutte
ventricular cardiomyopathies.10,42
R, Dragodanne C. Epicardial mapping and
surgical treatment in 6 cases of resistant ven-
Addendum 2 tricular tachycardia not related to coronary
Since the final version of this book manu- artery disease. In: Wellens HJJ, Lie KI, Janse
script, I authored an important editorial with MJ, eds. The Conduction System of the Heart.
Leiden: Stenfert Kroese Pub.; 1976:545-563.
HS Chen published in the American Journal
9. Fontaine G, Guiraudon G, Frank R, et al.
of Cardiology.
Stimulation studies and epicardial mapping in
Fontaine G, Chen HS. Arrhythmogenic right
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P, Tonet J, Frank R. Arrhythmogenic right Comparisons between Naxos disease and
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Gajdos P. Catastrophic global heart failure in in arrhythmogenic right ventricular cardio-
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Am Coll Cardiol. 2002;39:892-895. ventricular cardiomyopathy. Nat Genet.
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species? Acta Cardiol. 1999;54:189-194. in desmoglein-2 gene are associated with
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1998;97:1571-1580. opathy associated with mutations in the
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quences of apoptosis in the human heart. tion. 1996;93:841-842.
Discovery of Right Ventricular Cardiomyopathies 17
31. Fontaine G, Fornes P, Hebert JL, et al. Ven- ples of arrhythmogenic right ventricular dys-
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Meyer DM. Some previously neglected exam- 2010:270-271.
2
Disease Mechanisms in Arrhythmogenic
Right Ventricular Cardiomyopathy/Dysplasia:
From the Macro- to the Nanoscale
may lead to deadly arrhythmias even if the derived cardiomyocytes (iPSC-CMs). These
molecular deficiencies are not sufficient to authors proposed that induction of adult-like
cause major structural damage. metabolic energetics and abnormal PPAR-
gamma (PPARγ) activation underline the
Mechanisms of Fibrofatty pathogenesis of ARVC/D. However, this study,
although highly relevant to the field, should
Infiltration
be taken within the limitations of the sys-
The mechanisms of fibrofatty infiltration are tem. Indeed, lipid droplets were found inside
poorly understood. The discovery that many myocytes, a feature distinct from the pres-
cases of ARVC/D are consequent to muta- ence of actual adipocytes, which is the com-
tions in desmosomal molecules led to specu- mon observation in the heart with ARVC/D.
lation as to the possible relationship between Similarly, no excessive presence of fibroblasts
junctional molecules and the regulation of or collagen deposits was documented in this
cell transcription. The early studies of the study (these two points suggest that the fibro-
Saffitz group provided evidence of reduced adiposis process is myocyte independent).
presence of plakoglobin at the intercalated Moreover, several chemicals (some with
disc.3-5 Follow-up studies from the Marian lab potential alternative effects) were necessary to
suggested that the loss of plakoglobin from induce the phenotype. The authors observed
the intercellular junction may be associated that a chemically induced metabolic chal-
with increased plakoglobin in the nucleus, lenge caused human PKP2-deficient cells
with concomitant reduction in canonical derived in vitro toward the cardiac lineage to
Wnt/beta-catenin signaling through Tcf/Lef1 accumulate lipids, have increased apoptosis,
transcription factors and consequent expres- and present other molecular and functional
sion of adipogenic and fibrogenic genes.6 A anomalies consistent with the ARVC/D phe-
subsequent publication from the same group notype. These results are of great importance
concluded that adipocytes in ARVC/D may and potentially revealing to fundamental
originate from second heart field cardiac molecular mechanisms of disease. The data
progenitors that switch to an adipogenic fate open the door to future experiments where
because of suppressed canonical Wnt signal- investigators can assess whether the pathog-
ing by nuclear plakoglobin.7 nomonic features of the disease can be reca-
While these papers represented a major pitulated in an experimental system.
advance in the field, some questions remained A third, much-less-studied hypothesis
unanswered. Indeed, the cardiac phenotype regarding the origins of the fibrofatty infiltra-
of the mice, though consistent with a car- tion stems from studies on epicardium-derived
diomyopathy, did not completely emulate cells in vitro. Matthes et al9 observed that epi-
the anatomical and histological features of cardial and epicardium-derived cell cultures
ARVC/D. Furthermore, studies in mice lack- obtained from neonatal hearts and lacking
ing plakoglobin show that loss of expression PKP2 revealed increased abundance of alpha
of this protein also causes a cardiomyopathic smooth muscle-actin positive cells, increased
phenotype. Yet in this case, there is no plako- abundance of lipid markers, enhanced cell
globin (nuclear or otherwise) that can lead to migration velocity, and increased cell prolifer-
suppression of the canonical Wnt pathway. ation. These studies led to the hypothesis that
An alternative hypothesis has recently desmosomal dysfunction in the epicardial cell
been proposed,8 born out of experiments in layer can lead to increased migration, prolifera-
patient-specific induced pluripotent stem cell– tion, and differentiation of epicardium-derived
Disease Mechanisms in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 21
cells, with a consequent increase in the abun- microstructure (interstitial fibrosis; loss of cell–
dance of fibroblasts and adipocytes infiltrating cell mechanical and electrical coupling), or
(and in fact replacing) the myocardium. The nanostructure (dysfunction of macromolecu-
possible involvement of the epicardial layer of lar complexes responsible for cellular electrical
cells is consistent with the common observa- activity). We state at the outset that these three
tion that the fibrofatty infiltration progresses components are not mutually exclusive, and
from epicardium toward endocardium. Yet in fact are likely to coexist in every ARVC/D-
the experiments described above are very pre- affected heart. We make these distinctions as
liminary, have been done in vitro only, and are a way of cataloging the various factors that
still short of validation, at least in an animal can precipitate the arrhythmic behavior of the
model of the disease. On the other hand, the patient with ARVC/D.
possible involvement of the epicardial layer
poses the interesting—if futuristic—hypoth- Macrostructure: Ventricular
esis that gene therapy could be targeted to the Arrhythmias in the Presence of
epicardium (delivered locally), and in doing Overt Structural Disease
so, a local modification of the behavior of the
culprit cells could be accomplished. Progressive structural anomalies in ARVC/D,
Overall, there have been major advances such as regional wall motion anomalies,
in the understanding of the molecular mecha- appearance of ventricular aneurysms, and
nisms of the fibrofatty infiltration characteris- increased trabeculation, initially localize to the
tic of ARVC/D. The availability of genetically right ventricle (RV) in the majority of cases.10
modified animal models, patient-specific Macroreentry related to anatomical obstacles
iPSCs derived toward the cardiac lineage and (fibroid and adipose tissue) is the likely mecha-
potentially toward other cell types (epicardial nism that underlies the arrhythmias detected
cells?), and the development of novel molecu- in this phase of the disease, with similarities to
lar tools places the field on the verge of excit- the arrhythmias observed in the postinfarction
ing new discoveries that hopefully will bring setting. Indeed, it is generally accepted that
us closer to a cure. the inhomogeneous distribution of fibrofatty
tissue and residual myocytes can provide the
Mechanisms of Arrhythmias substrate for slow conduction and nonuniform
The mechanisms that cause ventricular anisotropy, thus favoring re-excitation.11 The
arrhythmias in patients with ARVC/D are progressive nature of ARVC/D could explain
likely multifactorial, and the substrate varies the existence of multiple reentrant pathways,
depending on disease stage. As such, it is rea- which predispose patients to recurrences and
sonable to speculate that the causes of ventric- frequent incessant episodes of arrhythmias,
ular arrhythmias in the presence of an overt notwithstanding therapeutic interventions.
clinical phenotype and structural disease Arrhythmias manifest as episodes of sustained
are different from the ones causing ventricu- ventricular tachycardia (VT) of RV origin (left
lar fibrillation and sudden death in the con- bundle branch block with inferior or superior
cealed phase, when structural anomalies are axis morphology), usually tolerated for a long
not yet detectable. As a gross generalization, time by the patients, because left ventricular
one can divide the arrhythmogenic mecha- function is still preserved.11,12
nisms as those resulting from alterations in The anatomical substrate of arrhythmias
macrostructure (anatomical obstacles, most was recently studied using endocardial voltage
likely involving areas of fibrofatty infiltration), mapping, a technique that allows the physi-
22 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
cian to detect the presence and extension of subsequent myocyte death and fibrofatty
the electroanatomic scar by identifying myo- replacement.15 Initial studies by the Saffitz
cardial replaced tissue as a low-amplitude sig- group3-5 showed a consistent decrease in the
nal. In their study, Migliore et al13 showed that immunoreactive levels of plakoglobin at the
in a population of 69 consecutive ARVC/D intercalated disc region of heart sections
patients, the arrhythmic risk was proportional from ARVC/D-affected patients. Interest-
to the extent of RV low-voltage areas detected ingly, the adhesion molecule N-cadherin
by endocardial voltage mapping. The authors was not altered, while there was a marked
concluded that the extent of bipolar RV reduction in the gap junction protein Con-
endocardial low-voltage areas was a powerful nexin43 (Cx43). Similar results have been
predictor of arrhythmic outcome, whereas a also described in an animal model of sponta-
normal bipolar endocardial voltage map char- neous ARVC/D. Indeed, familial ARVC/D
acterized the low-risk subgroup. and sudden death is a common occurrence
The existence of an anatomical substrate in Boxer dogs, which show similar clinical
provides the basis for a therapeutic approach and pathological features as those of the
based on catheter ablation. A recent large human condition.16 The characterization of
study from the investigators of the ARVD the intercalated disc in this animal model by
Registry14 evaluated the efficacy of radiofre- immunochemistry techniques also showed
quency catheter ablation in ARVC/D, with loss of the gap junction signal among other
particular focus on novel modalities, includ- proteins of the intercalated disc.17 All these
ing epicardial catheter ablation. The authors observations suggest that ARVC/D is asso-
concluded that, even though recurrences ciated with a significant remodeling of
were common, radiofrequency ablation sig- the structures involved in cell–cell com-
nificantly decreased the burden of VT in munication. In fact, the remodeling of the
ARVC/D patients, with epicardial ablation intercalated disc has been also confirmed
strategies being associated with longer sur- by transmission electron microscopy. Endo-
vival free of VT. Overall, arrhythmias result- myocardial biopsies from ARVC/D patients
ing from alterations in the macrostructure exhibit a decreased number of desmosomes,
represent a group more amenable to diagnosis increased length of desmosomes, and wid-
and treatment, as modern methods of map- ening of the intercellular gap.18 Similar
ping and ablation become available. results were also obtained in boxer dogs
afflicted with ARVC/D. Decreased number
Microstructure: Loss of Cell– of desmosomes, gap junctions, and adherens
Cell Continuity, Gap Junctions, junctions suggested changes in the macro-
and Propagation through the molecular components of the intercalated
disc. Moreover, electron microscopy images
Intercellular Space
also showed loss of cytoskeletal organiza-
tion in the subsarcolemmal space, suggest-
ARVC/D and Gap Junctions. Since the dis- ing a loss of attachment of the cytoskeletal
covery that mutations on genes coding for apparatus to points of cell–cell apposition.19
cardiac desmosomal proteins can be respon- Mutations in desmosomal proteins such as
sible for ARVC/D, it has been proposed that desmocollin-2 or desmoglein-2 have also
defective desmosomes could favor detach- shown a reduction in the content of desmo-
ment of myocytes at the intercalated discs, somal proteins and Cx4320 and decreased
especially under mechanical stress, with number of desmosomes, while the des-
Disease Mechanisms in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 23
mosome gap is increased.21 Other animal in the absence of gap junctions, provided
models of desmosomal (or area composita) there are (1) a large INa at the intercalated
deficiency have consistently observed changes disc and (2) a narrow intercellular cleft sepa-
in the abundance of Cx43 immunoreactive rating the two apposing cells. According to
plaques at the cardiac intercalated disc.22,23 this model, propagation failure in ARVC/D-
affected hearts may be consequent not only
The Intercellular Cleft as a Part of the Elec- to the loss of gap junction–mediated coupling
trical Circuitry at the Intercalated Disc. but also to the impaired electric field transmis-
Together with changes in the abundance of sion resulting from the widening of the inter-
Cx43 immunoreactive protein at the interca- cellular cleft. Experimental and numerical
lated disc, various investigators have observed simulations will be necessary to further assess
a widening of the intercellular gap in both the latter hypothesis.
human hearts18 and the hearts of animals
with a desmosomal deficiency.24 This effect The Nanostructure: ARVC/D as a Disease of
may have an important yet unrecognized the Cardiac Connexome. It is well accepted
importance in arrhythmogenesis. Indeed, that disruption of the cardiac structure, or of
new studies have revamped an old idea: that the cardiac histology, can be arrhythmogenic.
cell–cell propagation of electrical charge does Yet, lethal arrhythmias often occur during the
not occur only through gap junctions, but concealed stage of the disease, prior to overt
instead, an electric field–mediated transfer structural damage.10 We therefore postulated
of charge can occur between cells. According that mutations in proteins of the desmosome
to this model, the intercellular cleft (and its may actually affect the integrity of other
dimension) is a key component of the cell– molecular complexes, resident in the cardiac
cell propagation circuitry. A more detailed intercalated disc, that are relevant for elec-
explanation of this model is provided below. trical synchrony. Our work has focused pri-
Most mathematical models of cardiac marily on the gap junctions, and the sodium
action potential propagation assume that gap channel complex.
junctions are the only path for transfer of charge
between cells. Accordingly, these models pre- Relationship Between Desmosomal Mole-
dict that decreases in junctional conductance cules and Cx43. Based on the elegant studies
bring about decreases in conduction velocity. from the Saffitz laboratory demonstrating loss
This notion contrasts sharply with actual data of gap junction plaques in ARVC/D-affected
showing that only extreme reductions in Cx43 hearts,5 we utilized in vitro cell systems to
abundance (and electrical coupling) lead to assess the molecular crosstalk between the des-
significant changes in conduction velocity.25-27 mosomal protein PKP2 and the gap junction
These results have given new impetus to the protein Cx43.32 Loss of PKP2 expression was
notion that, under poor gap junction–medi- achieved by using small interfering (siRNA)
ated coupling, propagation can be maintained technology in neonatal rat ventricular myo-
via a separate “electric field mechanism.”28-31 cytes and epicardium-derived cells. Loss of
This alternative postulates that the large INa PKP2 led to a redistribution of Cx43 inside the
in the proximal side of an intercellular cleft cell and loss of gap junction plaques, detected
generates a negative extracellular potential by immunofluorescence and also by reduced
within the cleft, which depolarizes the distal dye transfer (Lucifer Yellow) between cells.
membrane and activates its sodium channels. Moreover, pull-down experiments showed
Thus, propagation can continue downstream that these two proteins form part of a com-
24 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
mon macromolecular complex that might thus emphasizing the fact that PKP2-depen-
be relevant to understand the molecular dent arrhythmias can occur without changes
mechanism of ARVC/D. This observation in either macro- or microstructure.39 More
has been confirmed by other following stud- recently, these observations have been further
ies looking at the effect of ARVC/D-related supported by studies in an animal model of
PKP2 mutations.33,34 Furthermore, this com- PKP2 haplosufficiency.24 Mice with only 50%
plex has been also described to be important content in PKP2 showed ultrastructural abnor-
in the regulation of the blood-testis barrier.35 malities (reduced number of desmosomes and
increased intercellular space) but not histo-
Desmosomal Molecules and the Sodium logical or anatomical differences compared
Channel Complex: Experimental Systems. to control mice. Furthermore, no changes in
A number of experiments have demonstrated the content or localization of proteins such
that a 50% to 80% loss of Cx43 expression as Cx43, N-cadherin, plakoglobin, or NaV1.5
in the heart decreases electrical coupling were seen. However, patch-clamp experiments
between cells36 but does not lead to significant showed changes indicative of impaired sodium
changes in conduction velocity.25,27 These current. Moreover, flecainide challenge in iso-
observations led us to speculate that desmo- lated myocytes, Langendorff-perfused hearts,
somes and gap junctions might interact with and anesthetized animals showed sodium cur-
other molecules that, although not classically rent reduction, decreased propagation velocity,
considered junctional, also localize to the and altered electrocardiographic parameters
cell end. In particular, we explored the rela- larger than in controls. The pharmacological
tionship between PKP2 and the voltage-gated challenge also provoked ventricular arrhyth-
sodium channel (VGSC) complex. Pull-down mias and death in PKP2 heterozygous animals,
and coimmunoprecipitation experiments but not in wild-type controls. Separate studies
indicated that there is a physical interaction have also shown sodium current deficiency
(direct or indirect) between PKP2 and the in cells from mice expressing a desmoglein-2
alpha subunit of the main cardiac sodium mutation.40 Overall, experimental cell and
channel, NaV1.5. Patch-clamp experiments animal models strongly support the notion of
in isolated adult cardiomyocytes showed that cross-talk between desmosomal molecules,
knockdown of PKP2 expression reduced the and the sodium channel complex.
total sodium current amplitude and caused a
negative shift in its steady-state inactivation. Relationship Between Desmosomal Mol-
Optical mapping in PKP2-deficient NRVMs ecules and the Sodium Channel in the
showed a decreased conduction velocity and Human Heart. Demonstration of an interac-
a propensity to reentry, in the absence of ana- tion between the desmosomes and the sodium
tomical obstacles.37 In a follow-up study, the channel complex in the human heart is more
cytoskeletal adaptor protein ankyrin-G was challenging, given the obvious complexities
proposed to partner with desmosomes and of human research. Unpublished studies from
gap junction molecules and exert a functional our laboratory, though, strongly support this
effect on intercellular communication in the interaction. Furthermore, immunochemistry
heart.38 Further studies, using mathematical studies in samples from ARVC/D patients have
models of cell–cell propagation, revealed also shown that although N-cadherin remains
that the PKP2-dependent changes in ionic at the membrane, a reduction of NaV1.5 at the
currents were sufficient to induce arrhyth- intercalated disc can be observed.41 Separately,
mias in a continuous model of cardiac cells, Gomes et al reported decreased NaV1.5 at the
Disease Mechanisms in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 25
intercalated disc in samples from patients with vicinity.45 In a follow-up study, these authors
desmoplakin mutations.42 Studies currently in proposed that one of the proteins resident in
progress are likely to yield new light on these the perinexus is NaV1.5.46 Separately, our labo-
interesting questions. ratory has used super-resolution microscopy
methods (direct stochastic optical reconstruc- die laboratory46 indicate that PKP2, Cx43, and
tion microscopy, or dSTORM) for the first NaV1.5 populate the perinexus, and that this
time to define the proximity between immu- domain represents the physical space holding
noreactive junctional proteins.47 Our results the connexome, a protein-interacting network
show that PKP2 often shares a physical space where multiple molecules work together to
with Cx43, thus indicating that these proteins coordinate excitability, cell coupling, and cell
are able to directly interact and likely regulate adhesion in the heart.
the function of the other. The effects of PKP2
mutations on gap junctions and on sodium Conclusion
channel function may result not from a dis- In summary, we have reviewed current con-
tant effect, but from the loss of direct protein cepts on the possible mechanisms of fibrofatty
interactions that occur in the perinexal space. infiltration and arrhythmias in ARVC/D. Not
The results described here support the surprisingly, the global picture is that of a
notion that the intercalated disc is the host multifactorial disease, where changes in
of multiple molecular complexes capable of all three scales (macro-, micro-, and nano-
interacting with each other. Images of the structure) are likely to be present, providing
intercalated disc obtained by modern electron multiple substrates for the generation and
microscopy methods (see Figure 2.1, Panel A) maintenance of abnormal rhythms. While
reveal the proximity of these structures and, as ablation strategies have advanced the therapeu-
such, the likelihood of their mutual interac- tic approach to patients with macrostructure-
tions. The model of an interacting intercalated based reentry, methods to intervene at the
disc (Figure 2.1, Panels B and C) is consistent level of the microstructure, or at the level of
with our results demonstrating PKP2 within molecular complexes, remain mostly unavail-
the Cx43 plaque (Figure 2.2). Therefore, our able. Also critical is the development of strate-
dSTORM results47 and the data from the Gour- gies to assess arrhythmia risk. ARVC/D is a
low penetrance disease and therefore much with patient-specific iPSCs. Nature. 2013;494:
work is needed to improve risk stratifica- 105-110.
tion and better define the criteria that guide 9. Matthes SA, Taffet S, Delmar M. Pla-
the implantation of defibrillation devices. kophilin-2 and the migration, differentiation
Improved understanding of mechanisms will and transformation of cells derived from the
epicardium of neonatal rat hearts. Cell Com-
hopefully improve novel strategies for assess-
mun Adhes. 2011;18:73-84.
ment of risk.
10. Delmar M, McKenna WJ. The cardiac desmo-
some and arrhythmogenic cardiomyopathies:
Abbreviations from gene to disease. Circ Res. 2010;107: 700-714.
NRVM neonatal rat ventricular myocyte
11. Corrado D, Basso C, Pilichou K, Thiene G.
RV right ventricle, right ventricular
Molecular biology and clinical management
VT ventricular tachycardia
of arrhythmogenic right ventricular cardiomy-
opathy/dysplasia. Heart. 2011;97:530-539.
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3
Genetic Background of
Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia
sodium channels (Nav1.5).22-24 These altera- coplasmic reticulum.35 Affected subjects had
tions give rise to electrical cell–cell uncoupling exercise-induced polymorphic VT. Generally,
and slow conduction, respectively, thereby pro- RYR2 mutations lead to catecholaminergic
viding a substrate for early activation delay, polymorphic VT without structural abnor-
resulting in ventricular tachyarrhythmia, a malities. The RYR2 mutation associated with
hallmark of ARVC/D.25-29 Presumably, at a later ARVC/D has been advocated to act differ-
stage, myocyte loss and fibrofatty replacement ently from those in familial polymorphic VT
will have a major effect on tissue architecture, without ARVC/D.36
giving rise to zig-zag conduction pathways Transforming growth factors β (TGF-βs)
and load mismatch, further contributing to regulate the production of extracellular
enhanced activation delay.30-32 matrix components and modulates expression
Although the function of the desmosome of genes encoding desmosomal proteins. The
and other components of the intercalated disk gene TGFβ3 has been mapped to chromo-
seem clear, the exact mechanism by which a some 14. A mutation in the 5' UTR promoter
gene mutation results in the disease remains to region of TGFβ3, with a predicted inhibitory
be elucidated. Furthermore, not every subject effect, was found in clinically affected mem-
with a mutation and thus a predisposition for bers of one large ARVC/D family. In the
ARVC/D develops signs and symptoms of the same study, an additional 3' UTR mutation
disease. Additional genetic factors, for exam- in TGFβ3 was found in an unrelated indi-
ple, compound or digenic heterozygosity, or vidual with ARVC/D.37 These observations
environmental factors such as exercise or viral implicated that regulatory mutations resulting
infection, may explain differences in severity of in overexpression and enhanced activity of
disease evolution in mutation carriers.33,34 TGFβ3 may lead to fibrosis and thereby con-
tribute to the development of ARVC/D.
Nondesmosomal Genes A missense mutation in the transmem-
In a minority of patients, a nondesmosomal brane protein 43 (TMEM43) gene was found
gene mutation is associated with the ARVC/D in 15 unrelated ARVC/D families from a
phenotype. This was first described in an Ital- genetically isolated population in New-
ian family with a mutation in the cardiac foundland and caused a fully penetrant,
ryanodin receptor (RYR2) gene, which is sex-influenced, high-risk form of ARVC/D.38
responsible for calcium release from the sar- The TMEM43 gene contains the response
element for PPARγ, an adipogenic transcrip- the absence of mutations in the 5 desmosomal
tion factor. The mutation is thought to cause genes.43 Patients with this c.40_42delAGA
dysregulation of an adipogenic pathway regu- mutation displayed classic ARVC/D with RV
lated by PPARγ, which may explain the fibro- and additional LV involvement and low volt-
fatty replacement in these ARVC/D patients. ages (< 0.5 mV in standard leads) on their
Mutations in the desmine (DES) gene, ECG (Figure 3.3). Evidence of pathogenicity
encoding an intermediate filament protein, was strongly supported by cosegregation analy-
have been described to underlie a heteroge- sis in a large family with ARVC/D.44
neous disease spectrum with an occasional
ARVC/D phenotype. In a family with signs ARVC/D Without Identified
and symptoms of ARVC/D but without muta- Genetic Mutations
tions in the PKP2, DSP, JUP, DSG2, and
DSC2 genes, the DES mutation c.1360C > T Not all forms of ARVC/D are proven genetic.
was identified. This mutation has been dem- Recent preliminary data indicate that in
onstrated to affect the localization of DSP approximately 30% of Dutch index patients,
and PKP2 in the intercalated disk, suggesting no mutation can be found by screening of the
a link between desmosomal and DES associ- desmosomal and nondesmosomal candidate
ated cardiomyopathies.39,40 genes. In other cohorts, this percentage of
The cardiomyopathy gene titin (TTN) proven ARVC/D patients, diagnosed accord-
was evaluated as a candidate gene because of ing to internationally consensus-based Task
its proximity to an ARVC/D locus at position Force Criteria for diagnosis yet without muta-
2q32 and the connection of TTN to the tran- tions in the known ARVC/D-related genes, is
sitional junction at intercalated disks. Muta- even higher.16,17,19 These ARVC/D cases may
tions in the desmosomal genes PKP2, DSP, be explained by mutations in genes as yet
DSG2, and DSC2 were excluded. Of the 8 unknown or by the contribution of genetic
missense TTN variants identified in 7 fami- variants of unknown significance (VUS) in the
lies, 1 (p.Thr2896Ile) showed complete cose- known genes. Accordingly, a similar prevalence
gregation with the ARVC/D phenotype in a of familial involvement in probands with and
single large family.41 without a mutation in one of the implicated
Lamin A/C (LMNA) gene mutations desmosomal genes was found in a study by
were found in 4% of patients (4/108) with Quarta et al.17 However, in the study reported
borderline or definite ARVC/D diagnosis in a by Cox et al,18 mutation-carrying relatives have
cohort from the United Kingdom, with exclu- a sixfold increased risk of ARVC/D diagnosis
sion of mutations in PKP2, DSP, JUP, DSG2, compared to relatives of index patients without
and DSC2.42 These patients mostly had severe identified mutation. The evaluation of a family
structural abnormalities and conduction history of ARVC/D, suggesting an unknown
abnormalities on their ECG. In addition, 2 of genetic factor, is crucial in ARVC/D patients
4 patients had classic fibrofatty replacement without identifiable genetic predisposition.
with endomyocardial biopsy.42 Alternatively, these cases may be due to
A founder mutation in the nondesmo- environmental factors, for example, exercise or
somal phospholamban (PLN) gene, involved myocardial infection. Sports activity, particu-
in calcium homeostasis by interaction with the larly endurance sports, cause volume overload
SERCA-pump, was identified in 15% of Dutch of the right ventricle (RV) and mechanical
patients diagnosed with dilated cardiomyopa- stress on the cardiomyocytes, especially in the
thy and in 12% of ARVC/D index patients, in thin-walled RV. In a mouse model with JUP
Genetic Background of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 35
FIGURE 3.3 ECG of a phospholamban mutation carrier (while off medication) . The ECG shows low voltages (< 0 .5 mV
in standard leads) and negative T waves in leads V4 through V6 (minor criterion in the 2010 Task Force Criteria for ARVC/D
diagnosis) . Two premature ventricular complexes are observed, one with left bundle branch block morphology and one with
right bundle branch block morphology . This patient fulfilled the Task Force Criteria for ARVC/D . The phospholamban mutation
was not taken into account for the diagnostic criteria .
haploinsufficiency, daily performance of exer- animal model and athlete studies suggest that
cise (swimming) was a trigger for ventricular exercise is an important contributor to the
arrhythmias and an accelerator for structural ARVC/D phenotype, also in the absence of an
RV abnormalities when compared to mice identifiable genetic predisposition.
with the same predisposition by JUP haploin-
sufficiency but with a resting lifestyle.45,46 In Role of Genetic Screening
addition, in a cohort of 47 athletes (subjects It is important to realize that the clinical
engaged ≥ 3 hours per week in sports with diagnosis of ARVC/D is based exclusively
moderate-intense dynamic component, recre- on fulfilment of the diagnostic 2010 Task
ationally or competitive, for > 5 years) with RV Force Criteria.49 Mutations underlying the
arrhythmias, excluding idiopathic RV outflow disease show incomplete penetrance and vari-
tract VT, the prevalence of desmosomal muta- able clinical expression.4,5 Some genetically
tions was relatively low.47 By screening of all 5 affected patients may have no signs or symp-
genes—PKP2, DSP, JUP, DSG2, and DSC2— toms whatsoever, whereas no mutations can
pathogenic desmosomal mutations were be identified in a large minority of clinically
identified in 13% of the total cohort. Of the diagnosed patients. Therefore, genetic analy-
24 athletes who fulfilled the 1994 Task Force sis alone cannot be of any critical diagnostic
Criteria for ARVC/D diagnosis,48 only 4 had value for the index patient who meets the Task
a pathogenic desmosomal mutation (17%), Force Criteria; however, it can be used to
which is a lower prevalence when viewed from identify family members who are predisposed
the perspective of previous reports.16-20,47 These to disease development.
36 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
The current strategy for genetic testing One of those new techniques is analysis by
in ARVC/D (in the Netherlands) is as fol- next-generation sequencing. With this tech-
lows: Individuals with a clinical diagnosis nique, the analysis is faster and it permits
of ARVC/D are the first to be tested, that is, analysis of larger numbers of genes compared
index patients (probands). The detection of to the candidate gene approach. This might
a pathogenic mutation contributes as major result in the discovery of new ARVC/D-
criterion in the Task Force Criteria for diag- related genes. On the other hand, the findings
nosis of ARVC/D. However, identification of of associated large numbers of genetic VUS
a pathogenic mutation is not sufficient in the will also result in more uncertainty for the
absence of phenotypic criteria. In contrast, patient, family members, and the physician.
if no mutation can be identified in a patient
diagnosed with ARVC/D, the clinical diag- Interpretation of Genetic
nosis is still applicable. Screening
If a pathogenic mutation is identified in
the index patient, the parents, siblings, and The interpretation of the outcome of molec-
children of this patient can be tested for the ular genetic screening in ARVC/D index
mutation via the cascade method. When patients can be challenging. Screening might
an asymptomatic relative is found to carry a result in the finding of (1) proven pathogenic
pathogenic mutation, periodic cardiologic mutations, (2) most likely pathogenic muta-
screening is required. DNA analysis by direct tions, (3) VUS, (4) polymorphisms, or (5) no
sequencing of the desmosomal genes PKP2, abnormalities compared to control popula-
DSG2, DSC2, DSP, and JUP is recommended tions. An overview of the proven pathogenic
in ARVC/D patients with an appropriate indi- and most likely pathogenic mutations iden-
cation for this analysis. When no mutation tified in Dutch ARVC/D index patients is
is found, this analysis can be extended with shown in Table 3.1.
gene dosage analysis (MLPA) to detect larger The pathogenicity of radical mutations—
deletion or insertion mutations and with the that is, truncating or splice site mutations
screening of nondesmosomal genes (RYR2, (mutations affecting the invariant AG splice-
TGFβ3, TMEM43, DES, TTN, LMNA, acceptor and GU splice-donor sites of exons)
and PLN). Nondesmosomal genes can be resulting in truncation or absence of the
screened according to their geographical protein product from the mutated allele—is
prevalence or according to the observed phe- widely accepted (proven pathogenic). How-
notype. For example, in the presence of low ever, the pathogenicity of missense variants
voltages on the ECG, PLN screening can be (also known as nonsynonymous single nucle-
performed, while conduction disorders could otide variants) resulting in a single amino acid
be suggestive of LMNA mutations. substitution is more difficult to delineate. As
Genetic analysis in ARVC/D at present is with other clinical tests, understanding of the
performed with the candidate gene approach. extent and spectrum of genetic variation in
However, the development of new techniques the healthy population is necessary for correct
for genetic screening is rapidly progressing. interpretation.
Genetic Background of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 37
Proven pathogenic mutations, that is, truncating (deletion, frameshift, nonsense) and splice site mutations, and most likely pathogenic
mutations identified in ARVC/D index patients in the Netherlands . Missense mutations were considered most likely pathogenic
mutations when (1) predictive algorithms SIFT and PolyPhen-2 predicted pathogenicity (SIFT < 0 .02, PolyPhen-2 > 0 .900) and
(2) mutations were rare in the general population (minor allele frequency ≤ 0 .05% in ESP exome dataset) . #: RNA experiments
by our group showed that this nucleotide substitution leads to the use of a cryptic splice site and results in a frameshift
(c .1378G > A r .1333_1378del p .(Val445fs)), (c .2146-1G > C r .2146_2299del p .(Met716fs)), and (c .2489+4A > C r .2300
_2489del p .(Lys768fs)), manuscript in preparation .
In the study by Kapplinger et al,50 the tion, genetic analysis results should be viewed
results of molecular genetic analysis were com- as probabilistic and as part of the overall clini-
pared between 175 proven ARVC/D cases and cal assessment.
a control population of 427 unrelated, ostensi-
bly healthy individuals. Of the ARVC/D cases, Genotype–Phenotype
58% hosted a genetic variation that met criteria Correlation Analysis
of a mutation (variation predicted to alter the
protein) versus 16% of healthy controls. Radi- The identification of a pathogenic mutation
cal mutations were significantly more prevalent distinguishes individuals with a predisposi-
in the proven ARVC/D cases than in controls tion for ARVC/D. This is a first step in risk
(49.9% versus 0.47%, P < 9.8 × 10-44), confirm- stratification of ARVC/D index patients and
ing the accepted assumption of pathogenicity.50 family members. Nevertheless, one of the
However, missense variants were found at simi- primary therapeutic goals is timely diagnosis
lar rates in cases and controls. Three associa- of the “concealed phase,” when individuals
tions were identified, which might strengthen are at risk for arrhythmias despite absence of
the pathogenicity of missense variants found: symptoms. Genotype–phenotype correlation
(1) a rare missense variant identified in a Cau- analysis can provide more insight in risk pro-
casian patient is more likely to be pathogenic files of index patients and family members.
than in a non-Caucasian patient; (2) specific Most genotype–phenotype correlation stud-
amino-terminal regions in DSP and DSG2 ies focused on overt index patients.4,5,16,19,20,51-53
contain mutation “hot-spots”; and (3) missense Yet, index patients are by definition affected
variants that involve a highly conserved residue by the disease. Therefore, the effect of the
in PKP2 and DSG2 are more likely to be patho- genotype can be more objectively assessed in
genic.50 Most likely pathogenicity of specific family members who provide the opportunity
missense mutations is supported by predictive of prospective follow-up from a young age.
algorithms, such as SIFT and PolyPhen-2. In a genotype–phenotype study by
When properly interpreted, molecular Quarta et al17 including both ARVC/D index
genetic analysis allows ultimately the early patients and family members, it was shown
detection of presymptomatic disease, iden- that SCD was the presenting symptom in half
tification of individuals at risk, and genetic of the index patients. SCD occurred in 31% at
counseling for this sudden death-predisposing young age, between 14 and 20 years, confirm-
disease. Nonetheless, regardless of the sugges- ing that adolescence is a vulnerable period for
tion of pathogenicity of an identified muta- fatal ventricular arrhythmias in ARVC/D. In
Genetic Background of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 39
contrast to index patients, mutation-positive are also needed to assess variability of disease
family members had a better prognosis, with expression within a family by genetic modi-
signs and symptoms of ARVC/D present in fiers or environmental factors. Future studies
50% of relatives in their fifth decade of life.17 will be required to elaborate further on risk
The differences between index patients who stratification by genotype–phenotype correla-
presented with SCD and relatives with milder tion analysis.
disease expression may be explained by the
presence of multiple versus single genetic vari- Acknowledgments
ants. Accordingly, family members with more We thank Dr. Dennis Dooijes for critical
than one genetic variant had a significant review of this chapter.
(fivefold) increase in risk of disease expres-
sion, providing further evidence of gene–gene Abbreviations
interactions and gene–dose effects.17 LV left ventricle, left ventricular
A genotype–phenotype follow-up study of RV right ventricle, right ventricular
ARVC/D index patients and family members SCD sudden cardiac death
by our group showed that a pathogenic muta- VT ventricular tachycardia
tion in an index patient predicts outcome in
family members.18 Pathogenic desmosomal References
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patients, predominantly truncating PKP2 al. Right ventricular dysplasia: a report of 24
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and most likely pathogenic mutations. Com- Identification of a deletion in plakoglobin
in arrhythmogenic right ventricular cardio-
pared to relatives of index patients without
myopathy with palmoplantar keratoderma
mutations, mutation-carrying family members
and woolly hair (Naxos disease). Lancet.
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(2) a markedly enhanced risk for ventricular 3. Norgett EE, Hatsell SJ, Carvajal-Huerta L,
arrhythmias, and (3) earlier onset of ARVC/D et al. Recessive mutation in desmoplakin
signs and symptoms.18 In young relatives disrupts desmoplakin-intermediate filament
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mutations in plakophilin-2. Circulation.
nosis found in the study by Quarta et al.17,18
2006;113:1641-1649.
Although of great importance for risk strat-
5. van Tintelen JP, Entius MM, Bhuiyan ZA,
ification in ARVC/D, genotype–phenotype
et al. Plakophilin-2 mutations are the major
correlation studies are generally hampered by determinant of familial arrhythmogenic right
the small number of patients and family mem- ventricular dysplasia/cardiomyopathy. Circu-
bers. Rare genetic variants are found infre- lation. 2006;113:1650-1658.
quently. Therefore, large numbers of patients 6. Rampazzo A, Nava A, Danieli GA, et al. The
and relatives per specific variant are needed gene for arrhythmogenic right ventricular
to assess its contribution to the ARVC/D phe- cardiomyopathy maps to chromosome 14q23-
notype. Large numbers of family members q24. Hum Mol Genet. 1994;3:959-962.
40 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
7. Rampazzo A, Nava A, Miorin M, et al. 17. Quarta G, Muir A, Pantazis A, et al. Famil-
ARVD4, a new locus for arrhythmogenic right ial evaluation in arrhythmogenic right ven-
ventricular cardiomyopathy, maps to chromo- tricular cardiomyopathy: impact of genetics
some 2 long arm. Genomics. 1997;45:259-263. and revised Task Force Criteria. Circulation.
8. Ahmad F, Li D, Karibe A, et al. Localization 2011;123:2701-2709.
of a gene responsible for arrhythmogenic 18. Cox MG, van der Zwaag PA, van der Werf C,
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3p23. Circulation. 1998;98: 2791-2795. sia/cardiomyopathy: pathogenic desmosome
9. Li D, Ahmad F, Gardner MJ, et al. The locus mutations in index-patients predict outcome
of a novel gene responsible for arrhythmo- of family screening: Dutch arrhythmogenic
genic right-ventricular dysplasia character- right ventricular dysplasia/cardiomyopathy
ized by early onset and high penetrance maps genotype–phenotype follow-up study. Circu-
to chromosome 10p12-p14. Am J Hum Genet. lation. 2011;123:2690-2700.
2000;66:148-156. 19. Fressart V, Duthoit G, Donal E, et al. Des-
10. Melberg A, Oldfors A, Blomstrom-Lundqvist mosomal gene analysis in arrhythmogenic
C, et al. Autosomal dominant myofibrillar right ventricular dysplasia/cardiomyopathy:
myopathy with arrhythmogenic right ventric- spectrum of mutations and clinical impact in
ular cardiomyopathy linked to chromosome practice. Europace. 2010;12:861-868.
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11. Severini GM, Krajinovic M, Pinamonti B, et mutations in desmosomal proteins encoding
al. A new locus for arrhythmogenic right ven- genes in arrhythmogenic right ventricular
tricular dysplasia on the long arm of chromo- cardiomyopathy/dysplasia. Heart Rhythm.
some 14. Genomics. 1996;31:193-200. 2010;7:22-29.
12. Rampazzo A, Nava A, Malacrida S, et al. Muta- 21. Kaplan SR, Gard JJ, Carvajal-Huerta L, Ruiz-
tion in human desmoplakin domain binding Cabezas JC, Thiene G, Saffitz JE. Struc-
to plakoglobin causes a dominant form of tural and molecular pathology of the heart
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13. Gerull B, Heuser A, Wichter T, et al. 22. Oxford EM, Musa H, Maass K, Coombs W,
Mutations in the desmosomal protein pla- Taffet SM, Delmar M. Connexin43 remodel-
kophilin-2 are common in arrhythmogenic ing caused by inhibition of plakophilin-2 expres-
right ventricular cardiomyopathy. Nat Genet. sion in cardiac cells. Circ Res. 2007;101:703-711.
2004;36:1162-1164. 23. Sato PY, Musa H, Coombs W, et al. Loss of
14. Pilichou K, Nava A, Basso C, et al. Muta- plakophilin-2 expression leads to decreased
tions in desmoglein-2 gene are associated with sodium current and slower conduction veloc-
arrhythmogenic right ventricular cardiomy- ity in cultured cardiac myocytes. Circ Res.
opathy. Circulation. 2006;113:1171-1179. 2009;105:523-526.
15. Syrris P, Ward D, Evans A, et al. Arrhyth- 24. Noorman M, van der Heyden MA, van Veen
mogenic right ventricular dysplasia/cardio- TA, et al. Cardiac cell-cell junctions in health
myopathy associated with mutations in the and disease: electrical versus mechanical
desmosomal gene desmocollin-2. Am J Hum coupling. J Mol Cell Cardiol. 2009;47:23-31.
Genet. 2006;79:978-984. 25. Saffitz JE. Dependence of electrical coupling
16. den Haan AD, Tan BY, Zikusoka MN, et al. on mechanical coupling in cardiac myocytes:
Comprehensive desmosome mutation analy- insights gained from cardiomyopathies caused
sis in North Americans with arrhythmogenic by defects in cell-cell connections. Ann NY
right ventricular dysplasia/cardiomyopathy. Acad Sci. 2005;1047:336-344.
Circ Cardiovasc Genet. 2009;2:428-435. 26. Garcia-Gras E, Lombardi R, Giocondo MJ,
et al. Suppression of canonical Wnt/beta-
Genetic Background of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 41
catenin signaling by nuclear plakoglobin reca- opathy type 2 (ARVD2). Hum Mol Genet.
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ventricular cardiomyopathy. J Clin Invest. 36. Tiso N, Salamon M, Bagattin A, Danieli GA,
2006;116:2012-2021. Argenton F, Bortolussi M. The binding of the
27. Basso C, Czarnowska E, Della Barbera M, RyR2 calcium channel to its gating protein
et al. Ultrastructural evidence of intercalated FKBP12.6 is oppositely affected by ARVD2
disc remodelling in arrhythmogenic right and VTSIP mutations. Biochem Biophys Res
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microscopy investigation on endomyocardial 37. Beffagna G, Occhi G, Nava A, et al. Regu-
biopsies. Eur Heart J. 2006;27:1847-1854. latory mutations in transforming growth
28. Asimaki A, Tandri H, Huang H, et al. A factor-beta3 gene cause arrhythmogenic right
new diagnostic test for arrhythmogenic right ventricular cardiomyopathy type 1. Cardio-
ventricular cardiomyopathy. N Engl J Med. vasc Res. 2005;65:366-373.
2009;360:1075-1084. 38. Merner ND, Hodgkinson KA, Haywood AF,
29. Cerrone M, Noorman M, Lin X, et al. et al. Arrhythmogenic right ventricular car-
Sodium current deficit and arrhythmogenesis diomyopathy type 5 is a fully penetrant, lethal
in a murine model of plakophilin-2 haploin- arrhythmic disorder caused by a missense
sufficiency. Cardiovasc Res. 2012;95:460-468. mutation in the TMEM43 gene. Am J Hum
30. de Bakker JM, van Capelle FJ, Janse MJ, et Genet. 2008;82:809-821.
al. Slow conduction in the infarcted human 39. van Tintelen JP, Van Gelder IC, Asimaki A,
heart. “Zigzag” course of activation. Circula- et al. Severe cardiac phenotype with right
tion. 1993;88:915-926. ventricular predominance in a large cohort of
31. Cabo C, Pertsov AM, Baxter WT, Davidenko patients with a single missense mutation in the
JM, Gray RA, Jalife J. Wave-front curvature as a DES gene. Heart Rhythm. 2009;6:1574-1583.
cause of slow conduction and block in isolated 40. Otten E, Asimaki A, Maass A, et al. Desmin
cardiac muscle. Circ Res. 1994;75:1014-1028. mutations as a cause of right ventricular heart
32. Ellison KE, Friedman PL, Ganz LI, Steven- failure affect the intercalated disks. Heart
son WG. Entrainment mapping and radio- Rhythm. 2010;7:1058-1064.
frequency catheter ablation of ventricular 41. Taylor M, Graw S, Sinagra G, et al. Genetic
tachycardia in right ventricular dysplasia. J Am variation in titin in arrhythmogenic right ven-
Coll Cardiol. 1998;32:724-728. tricular cardiomyopathy-overlap syndromes.
33. Xu T, Yang Z, Vatta M, et al, Multidisci- Circulation. 2011;124:876-885.
plinary Study of Right Ventricular Dysplasia 42. Quarta G, Syrris P, Ashworth M, et al. Muta-
Investigators. Compound and digenic hetero- tions in the Lamin A/C gene mimic arrhyth-
zygosity contributes to arrhythmogenic right mogenic right ventricular cardiomyopathy.
ventricular cardiomyopathy. J Am Coll Car- Eur Heart J. 2012;33:1128-1136.
diol. 2010;55:587-597. 43. van der Zwaag PA, van Rijsingen IA, Asimaki
34. Sen-Chowdhry S, Syrris P, Pantazis A, Quarta A, et al. Phospholamban R14del mutation in
G, McKenna WJ, Chambers JC. Mutational patients diagnosed with dilated cardiomyopa-
heterogeneity, modifier genes, and environ- thy or arrhythmogenic right ventricular cardio-
mental influences contribute to phenotypic myopathy: evidence supporting the concept of
diversity of arrhythmogenic cardiomyopathy. arrhythmogenic cardiomyopathy. Eur J Heart
Circ Cardiovasc Genet. 2010;3:323-330. Fail. 2012;14:1199-1207.
35. Tiso N, Stephan DA, Nava A, et al. Identi- 44. Groeneweg JA, van der Zwaag PA, Jongbloed
fication of mutations in the cardiac ryano- JD, et al. Left-dominant arrhythmogenic car-
dine receptor gene in families affected with diomyopathy in a large family: associated des-
arrhythmogenic right ventricular cardiomy- mosomal or nondesmosomal genotype? Heart
Rhythm. 2013;10:548-559.
42 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
45. Kirchhof P, Fabritz L, Zwiener M, et al. 49. Marcus FI, McKenna WJ, Sherrill D, et al.
Age- and training-dependent development of Diagnosis of arrhythmogenic right ventricular
arrhythmogenic right ventricular cardiomy- cardiomyopathy/dysplasia: proposed modifi-
opathy in heterozygous plakoglobin-deficient cation of the Task Force Criteria. Circulation.
mice. Circulation. 2006;114:1799-1806. 2010;121:1533-1541.
46. Fabritz L, Hoogendijk MG, Scicluna BP, et al. 50. Kapplinger JD, Landstrom AP, Salisbury BA,
Load-reducing therapy prevents development et al. Distinguishing arrhythmogenic right
of arrhythmogenic right ventricular cardio- ventricular cardiomyopathy/dysplasia-asso-
myopathy in plakoglobin-deficient mice. J Am ciated mutations from background genetic
Coll Cardiol. 2011;57:740-750. noise. J Am Coll Cardiol. 2011;57:2317-2327.
47. La Gerche A, Robberecht C, Kuiperi C, 51. Hamid MS, Norman M, Quraishi A, et al.
et al. Lower than expected desmosomal Prospective evaluation of relatives for familial
gene mutation prevalence in endurance arrhythmogenic right ventricular cardiomy-
athletes with complex ventricular arrhyth- opathy/dysplasia reveals a need to broaden
mias of right ventricular origin. Heart. diagnostic criteria. J Am Coll Cardiol. 2002;
2010;96:1268-1274. 40:1445-1450.
48. McKenna WJ, Thiene G, Nava A, et al. Diag- 52. Syrris P, Ward D, Asimaki A, et al. Clincal
nosis of arrhythmogenic right ventricular expression of plakophilin-2 mutations in famil-
dysplasia/cardiomyopathy. Task Force of the ial arrhythmogenic right ventricular cardiomy-
Working Group Myocardial and Pericardial opathy. Circulation. 2006;113:356-364.
Disease of the European Society of Cardi- 53. Bhuiyan ZA, Jongbloed JD, van der Smagt J,
ology and of the Scientific Council on Car- et al. Desmoglein-2 and desmocollin-2 muta-
diomyopathies of the International Society tions in dutch arrhythmogenic right ventricu-
and Federation of Cardiology. Br Heart J. lar dysplasia/cardiomypathy patients: results
1994;71:215-218. from a multicenter study. Circ Cardiovasc
Genet. 2009;2:418-427.
4
child, for example, a positive genetic test could several ARVC/D genetic tests available,
be useful if in vitro fertilization methods are in research or commercial settings. These
being considered, since a preimplantation usually include the coding regions of the 5
genetic diagnosis could be performed. principal desmosomal genes associated to
The ARVC/D genetic test is also useful in the disease: PKP2 (plakophilin-2), DSG2
the context of sudden cardiac death syndrome (desmoglein-2), DSP (desmoplakin), DSC2
victims in whom ARVC/D is suspected. (desmocollin-2), and JUP (plakoglobin)
Detection of a pathogenic mutation could be (Figure 4.1). Less often, ARVC/D genetic
of crucial value for other relatives at risk.7 tests include other novel genes like DES
The expert consensus statement on the (desmin), TTN (titin), TMEM43 (trans-
state of genetic testing for channelopathies membrane protein 43), LMNA (lamin
and cardiomyopathies states that in patients A/C), PLN (phospholamban), and TGF- β3
satisfying the 2010 Task Force Diagnostic (transforming growth factor-β3). If a genetic
Criteria for ARVC/D, genetic testing is test result is “negative,” the patient should
indicated. They recommend considering have an explanation of the meaning of this
genetic testing in patients with possible negative result; the mutation might be pres-
ARVC/D according to the 2010 Task Force ent in a gene still not known or in a minor
Criteria, but do not recommended it for gene not scanned by the selected test.
patients with only a single minor criterion.
Mutation-specific genetic testing is also rec-
ommended for family members following
the identification of the ARVC/D-causative
mutation in an index case.8 Moreover, in
the 2010 Task Force Criteria, the identifica-
tion of a pathogenic mutation categorized
as associated or probably associated with
ARVC/D is considered a major criterion in
the diagnosis of the disease.9
in sequence alignments derived from closely mate the subject’s probability of developing
related species. Commercial and research the disease.
tests have developed different classifications Performing the ARVC/D genetic test on
to assign the risk of the ARVC/D variant or subjects under the age of 12 is controversial,18
variants reported. Generally speaking, vari- because even an individual who tests positive
ants could be classified as: is unlikely to develop the disease during child-
hood.19,20 An ARVC/D genetic test done too
1. Pathogenic, when a variant has been early could label a child as “sick” and impair
proved or is predicted to be deleterious. his quality of life, particularly if only variants
2. Variants of uncertain significance, when of uncertain significance have been found in
the variant is suspected to be deleterious. the affected relative. Nevertheless, if a radical
3. No known pathogenicity, if a variant is pathogenic mutation has been detected with a
not expected to cause disease. high-penetrance pattern and early presentation
of the disease or a recessive pattern is suspected,
Screening of family members is recom- genetic testing might be useful to predict the
mended when a Class I variant has been risk to develop the disease and could poten-
found. When a Class II variant is present, fam- tially be used for prenatal counseling.
ily members may benefit of genetic screening. There is no early treatment proven to be
For Class III variants, family screening is not useful in asymptomatic carriers; however, it
recommended.8 has been suggested that vasodilator drugs may
ARVC/D is a disease with incomplete decrease the progression of the ventricular
penetrance. Genetic carriers of one particu- damage,21 and excessive exercise appears to
lar mutation might not develop the disease.16 exacerbate the manifestation of the disease.22
When a family member does not exhibit For relatives of an ARVC/D case with variants
the phenotype yet carries the mutation, it is of uncertain significance or potential com-
important to consider the following factors: pound heterozygosity, clinical evaluation for
ARVC/D continues to be the most important
1. Age: the majority of cases will develop tool in disease detection23,24 and still-imper-
the disease after age 30. fect risk stratification.
2. Gender: males are more often affected
than females. Nonetheless, gender does ARVC/D Genotype–
not have a clear effect on outcome.17 Phenotype Correlation
It is advisable to plan carefully what infor- To date, the ARVC/D genetic tests do not
mation should be provided to asymptomatic provide a clear genotype–phenotype cor-
carriers. Before delivering any genetic test relation and have limited value-predicting
result, it is important to consider potential outcome. Reported series are small; nev-
psychological consequences. The physician ertheless, they show interesting data to be
should evaluate the particular clinical sce- confirmed in larger series. The most obvious
nario; the approach will differ if, for example, genotype–phenotype correlation in ARVC/D
the physician is providing genetic coun- is the extreme phenotype given by the auto-
seling to a family member who lost a close somal recessive forms, the cardiocutaneous
relative versus to a family member of a rela- syndromes known as Naxos and Carvajal syn-
tive with mild disease. Consider the type of dromes. The first is characterized by woolly
mutation(s), age, and gender in order to esti- hair and palmoplantar keratoderma with
Genetic Counseling for Patients and Relatives 47
early development of ARVC/D, while the sec- 5. Marcus FI, Edson S, Towbin JA. Genetics of
ond has the same skin phenotype along with arrhythmogenic right ventricular cardiomy-
left ventricular involvement, commonly with opathy: a practical guide for physicians. J Am
ventricular aneurysms in certain areas, and Coll Cardiol. 2013;61:1945-1948.
finally dilated cardiomyopathy. These pheno- 6. Wlodarska EK, Konka M, Zaleska T, et al.
types are given by homozygous mutations in Arrhythmogenic right ventricular cardiomy-
opathy in two pairs of monozygotic twins. Int J
plakoglobin (JUP) or desmoplakin (DSP).25,26
Cardiol. 2005;105:126-133.
Fressart et al reported recently that desmo-
7. Elger BS, Michaud K, Fellmann F, Man-
somal mutations are associated with younger gin P. Sudden death: ethical and legal prob-
age of disease presentation, multiple muta- lems of post-mortem forensic genetic testing
tions with sudden death,27 and DSG2 muta- for hereditary cardiac diseases. Clin Genet.
tions with left ventricular involvement. Patients 2010;77:287-292.
with left ventricular involvement are known 8. Ackerman MJ, Priori SG, Willems S, et al.
to have worse outcomes than those without.28 HRS/EHRA expert consensus statement on
Cox et al reported recently that young, asymp- the state of genetic testing for the channelo-
tomatic mutation-carriers frequently exhibit pathies and cardiomyopathies; this document
prolonged terminal activation duration as a was developed as a partnership between the
first or early sign of ARVC/D.29 Families with Heart Rhythm Society (HRS) and the Euro-
pean Heart Rhythm Association (EHRA).
DSP mutations have been reported to have a
Heart Rhythm. 2011;8:1308-1339.
high occurrence of sudden death as first clini-
9. Marcus FI, McKenna WJ, Sherrill D, et al.
cal manifestation.30
Diagnosis of arrhythmogenic right ventricular
Many research projects are running cur- cardiomyopathy/dysplasia: proposed modifi-
rently with the goal of finding other prognostic cation of the Task Force Criteria. Circulation.
applications of the ARVC/D genetic test, and in 2010;121:1533-1541.
the near future, the genetic test could potentially 10. Roberts J, Herkert J, Rutberg J, et al. Detection
be used for risk stratification of the disease. of genomic deletions of PKP2 in arrhythmo-
genic right ventricular cardiomyopathy. Clin
References Genet. 2013;83:452-456.
1. Harris A, Kelly SE, Wyatt S. Counseling cus- 11. Medlock MM, Tester DJ, Will ML, Bos JM,
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2. Ingles J, Yeates L, Hunt L, et al. Health sta- Heart Rhythm. 2012;9:1977-1982.
tus of cardiac genetic disease patients and 12. Kapplinger JD, Landstrom AP, Salisbury BA,
their at-risk relatives. Int J Cardiol. 2013;165: et al. Distinguishing arrhythmogenic right
448-453. ventricular cardiomyopathy/dysplasia-associ-
3. Campuzano O, Alcalde M, Allegue C, et al. ated mutations from background genetic noise.
Genetics of arrhythmogenic right ventricu- J Am Coll Cardiol. 2011;57:2317-2327.
lar cardiomyopathy. J Med Genet. 2013;50: 13. Quarta G, Muir A, Pantazis A, et al. Famil-
280-289. ial evaluation in arrhythmogenic right ven-
4. Bauce B, Nava A, Beffagna G, et al. Multiple tricular cardiomyopathy: impact of genetics
mutations in desmosomal proteins encoding and revised Task Force Criteria. Circulation.
genes in arrhythmogenic right ventricular 2011;123:2701-2709.
cardiomyopathy/dysplasia. Heart Rhythm. 14. Nakajima T, Kaneko Y, Irie T, et al. Com-
2010;7:22-29. pound and digenic heterozygosity in desmo-
some genes as a cause of arrhythmogenic
48 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
right ventricular cardiomyopathy in Japanese 23. Marcus FI, Abidov A. Arrhythmogenic right
patients. Circ J. 2012;76:737-743. ventricular cardiomyopathy 2012: diagnostic
15. van der Zwaag PA, Jongbloed JD, van den challenges and treatment. J Cardiovasc Elec-
Berg MP, et al. A genetic variants database trophysiol. 2012;23:1149-1153.
for arrhythmogenic right ventricular dyspla- 24. Smith W. Guidelines for the diagnosis and
sia/cardiomyopathy. Hum Mutat. 2009;30: management of arrhythmogenic right ven-
1278-1283. tricular cardiomyopathy. Heart Lung Circ.
16. Aneq MA, Fluur C, Rehnberg M, et al. Novel 2011;20:757-760.
plakophilin2 mutation: three-generation fam- 25. Alcalai R, Metzger S, Rosenheck S, Meiner
ily with arrhythmogenic right ventricular car- V, Chajek-Shaul T. A recessive mutation in
diomyopathy. Scand Cardiovasc J. 2012;46: desmoplakin causes arrhythmogenic right
72-75. ventricular dysplasia, skin disorder, and woolly
17. Bauce B, Frigo G, Marcus FI, et al. Com- hair. J Am Coll Cardiol. 2003;42:319-327.
parison of clinical features of arrhythmogenic 26. Protonotarios N, Tsatsopoulou A. Naxos dis-
right ventricular cardiomyopathy in men ver- ease and Carvajal syndrome: cardiocutane-
sus women. Am J Cardiol. 2008;102:1252-1257. ous disorders that highlight the pathogenesis
18. Bauce B, Rampazzo A, Basso C, et al. Clinical and broaden the spectrum of arrhythmogenic
phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy. Cardiovasc
right ventricular cardiomyopathy in pediatric Pathol. 2004;13:185-194.
patients carrying desmosomal gene muta- 27. Fressart V, Duthoit G, Donal E, et al. Des-
tions. Heart Rhythm. 2011;8:1686-1695. mosomal gene analysis in arrhythmogenic
19. Ohno S, Nagaoka I, Fukuyama M, et al. Age- right ventricular dysplasia/cardiomyopathy:
dependent clinical and genetic characteristics spectrum of mutations and clinical impact in
in Japanese patients with arrhythmogenic practice. Europace. 2010;12:861-868.
right ventricular cardiomyopathy/dysplasia. 28. Pinamonti B, Dragos AM, Pyxaras SA, et
Circ J. 2013;77(6):1534-1542. al. Prognostic predictors in arrhythmogenic
20. Corrado D, Basso C, Thiene G, et al. Spec- right ventricular cardiomyopathy: results
trum of clinicopathologic manifestations of from a 10-year registry. Eur Heart J. 2011;32:
arrhythmogenic right ventricular cardiomyop- 1105-1113.
athy/dysplasia: a multicenter study. J Am Coll 29. Cox MG, van der Zwaag PA, van der Werf C,
Cardiol. 1997;30:1512-1520. et al. Arrhythmogenic right ventricular dyspla-
21. Fabritz L, Fortmuller L, Yu TY, Paul M, Kirch- sia/cardiomyopathy: pathogenic desmosome
hof P. Can preload-reducing therapy prevent mutations in index-patients predict outcome
disease progression in arrhythmogenic right of family screening: Dutch arrhythmogenic
ventricular cardiomyopathy? Experimental right ventricular dysplasia/cardiomyopathy
evidence and concept for a clinical trial. Prog genotype–phenotype follow-up study. Circu-
Biophys Mol Biol. 2012;110:340-346. lation. 2011;123:2690-2700.
22. Heidbuchel H, La Gerche A. The right heart 30. Bauce B, Basso C, Rampazzo A, et al. Clinical
in athletes. Evidence for exercise-induced profile of four families with arrhythmogenic
arrhythmogenic right ventricular cardiomy- right ventricular cardiomyopathy caused by
opathy. Herzschrittmacherther Elektrophysiol. dominant desmoplakin mutations. Eur Heart
2012;23:82-86. J. 2005;26:1666-1675.
5
Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia:
Clinical Presentation, Differential Diagnosis,
and Diagnostic Challenges
V. ARRHYTHMIAS
MAJOR Nonsustained or sustained ventricular tachycardia of left bundle branch morphology with superior axis
(negative or indeterminate QRS in leads II, III, and aVF and positive in lead aVL)
MINOR Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block
morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis
> 500 ventricular extrasystoles per 24 hours (Holter)
VI. FAMILY HISTORY
MAJOR ARVC/D confirmed in a first-degree relative who meets current Task Force Criteria
ARVC/D confirmed pathologically at autopsy or surgery in a first-degree relative
†
Identification of a pathogenic mutation categorized as associated or probably associated with ARVC/D in
the patient under evaluation
MINOR History of ARVC/D in a first-degree relative in whom it is not possible or practical to determine whether the
family member meets current Task Force Criteria
Premature sudden death (< 35 years of age) due to suspected ARVC/D in a first-degree relative
ARVC/D confirmed pathologically or by current Task Force Criteria in second-degree relative
PLAX indicates parasternal long-axis view; RVOT, RV outflow tract; BSA, body surface area; PSAX, parasternal short-axis view; aVF,
augmented voltage unipolar left foot lead; and aVL, augmented voltage unipolar left arm lead .
*Hypokinesis is not included in this or subsequent definitions of RV regional wall motion abnormalities for the modified criteria .
†
A pathogenic mutation is a DNA alteration associated with ARVC/D that alters or is expected to alter the encoded protein, is
unobserved or rare in a large non-ARVC/D control population, and either alters or is predicted to alter the structure or function of the
protein or has demonstrated linkage to the disease phenotype in a conclusive pedigree .
Diagnostic terminology for revised criteria: DEFINITE DIAGNOSIS: 2 major or 1 major and 2 minor criteria or 4 minor from different
categories; BORDERLINE: 1 major and 1 minor or 3 minor criteria from different categories; POSSIBLE: 1 major or 2 minor criteria
from different categories .
often asymptomatic but may nonetheless be stage (“concealed phase”) in the absence of
at risk for SCD, particularly during exertion.2 overt structural changes.
In the overt “electrical phase,” individuals In endurance athletes, training can lead
present with symptomatic arrhythmias, and to RV enlargement, ECG abnormalities, and
RV morphologic abnormalities are readily dis- arrhythmias, reflecting the increased hemo-
cernible by conventional imaging. Later, dif- dynamic load during exercise.9 Global RV
fuse disease may result in RV or biventricular systolic dysfunction or regional wall motion
heart failure. The ultimate phenotype may abnormalities can indicate ARVC/D rather
resemble dilated cardiomyopathy (end-stage than physiologic ventricular enlargement.
disease). In the past, left ventricular (LV) The pathologic diagnosis of ARVC/D is
involvement was considered an expression based on histologic demonstration of fibrofatty
of the advanced disease phase. However, the replacement of RV myocardium on biopsy,
disease can start with isolated or predominant necropsy, or surgery.10 RV endomyocardial
LV involvement in the early stages, even in biopsy has limited sensitivity because the
the absence of systolic dysfunction.6 segmental nature of the disease may cause
false-negative results. Use of electroanatomic
Diagnosis of Familial ARVC/D voltage mapping to identify pathologic areas
In the setting of a positive family history, even for biopsy sampling may improve the yield.11
minor ECG and echocardiographic abnor- The recognition of myocyte loss with fibrous
malities are important and often diagnostic or fibrofatty replacement can be valuable diag-
(Table 5.2).7,8 Details of the genetic abnor- nostically. RV free wall biopsy carries a slight
malities and their implications are addressed risk of perforation, but the more accessible
in another chapter. interventricular septum rarely exhibits histo-
logic changes.12 Nevertheless, septal biopsy
Differential Diagnosis may identify other conditions such as sarcoid-
osis, myocarditis, and endomyocardial fibrosis.
The diagnosis of ARVC/D relies on the dem- The differential diagnosis of ARVC/D
onstration of structural, functional, and elec- includes idiopathic RV outflow tachycardia,
trophysiologic abnormalities that are caused sarcoidosis, myocarditis, dilated cardiomy-
by the underlying histologic changes. The opathy, Chagas disease, RV infarction, and
diagnosis can be challenging in the early Brugada syndrome. Congenital heart disease
with right chamber overload, such as Ebstein
In the context of ARVC/D in a first-degree relative, the diagnosis of familial ARVC/D is based on the documentation of ONE of
the following in a family member:
ECG T-wave inversion in right precordial leads V1, V2, and V3 in individuals > 14 years
SAECG Presence of late potentials on SAECG
Arrhythmias Ventricular tachycardia of LBBB morphology on ECG, Holter monitor, or during exercise
testing or > 200 PVCs in 24 hours
Structural or functional Either mild global dilatation or reduction in RV ejection fraction with normal LV or mild
abnormalities of the RV segmental dilatation of the RV or regional RV hypokinesis
anomaly, atrial septal defect, Uhl anomaly, carditis, which could lead to a decrease in
and pulmonary hypertension, are other clini- cardiac function and accelerate disease
cal phenocopies.1 Catecholaminergic poly- progression.19 The presence of a pathologic
morphic ventricular tachycardia is considered mutation and the addition of myocarditis or
a disorder distinct from ARVC/D.13 volume loading may trigger overt manifesta-
Idiopathic RV outflow tachycardia, a tions of ARVC/D, a phenomenon that has
benign nonfamilial condition, is an important been seen in some animal models.20 The
and challenging differential diagnosis. The link between ARVC/D and myocarditis is
absence of ECG repolarization/depolariza- still undefined.
tion abnormalities and RV structural changes,
as well as the recording of a single VT mor- Diagnostic Challenges
phology and noninducibility at programmed
ventricular stimulation with a normal volt- Electrocardiography. Inverted T waves in
age map, provides evidence for the idiopathic right precordial leads (V1–V3) may be a nor-
nature of the VT.14 A scoring system15 that can mal finding in children under 14 years of
distinguish RV outflow tract tachycardia in age. It may also be present in less than 1%
patients with ARVC/D from that in patients of older normal individuals.21 In individuals
with idiopathic VT consists of the follow- over 14 years of age (in the absence of com-
ing: During sinus rhythm in patients with plete RBBB with QRS complex duration
ARVC/D, there may be T-wave inversions ≥ 120 ms), the presence of inverted T waves
in leads V1–V3. During VT in patients with in right precordial leads (V1–V3 or beyond)
ARVC/D, the QRS duration in lead 1 is ≥ 120 is a major criterion in the revised Task Force
ms. There is QRS notching and the precor- Criteria.3 Its prevalence in ARVC/D has been
dial transition is present in lead V5 or later. reported as 55% to 94% in different series.22
Myocardial involvement in sarcoidosis The extent of right precordial T-wave inver-
can mimic the clinical and structural abnor- sion relates to the degree of RV involvement.
malities of ARVC/D.16 In a prospective study of Arrhythmias of RV origin with LBBB
consecutive patients with suspected ARVC/D morphology is a cardinal feature of ARVC/D
evaluated by a standard protocol including but can occur in other diseases, particularly
biopsy, a surprisingly high incidence (15%) of in idiopathic RV outflow tract tachycardia.
cardiac sarcoid was found.17 The similarity in The presence of LBBB VT with an infe-
clinical presentation and cardiovascular mag- rior axis (R-wave positive in leads II and III
netic resonance imaging (MRI) findings can and negative in lead aVL) is typical of focal
pose a challenge in differentiating between RV outflow tract tachycardia.23 Similar fea-
the 2 conditions in the absence of histologic tures may be seen in patients with ARVC/D
diagnosis. The current diagnostic ARVC/D but usually coexist with anterior T-wave
guidelines do not reliably exclude patients with inversion and ventricular arrhythmias of
cardiac sarcoidosis. Clinical and electrophysi- varying morphologies.
ologic parameters in cardiac sarcoid that may Depolarization delay in right precor-
help include reduced LV ejection fraction, a dial leads is also common in ARVC/D.
significantly wider QRS complex, right-sided Evaluation of the duration of terminal QRS
apical VT, and more inducible forms of mono- complex activation incorporates slurring of
morphic VT.18 the S wave, as well as the R', into a single
It has been suggested that patients with measure of terminal activation duration.24
ARVC/D may be susceptible to viral myo- However, T-wave inversion in leads V1, V2, and
54 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
V3 extending to V4 is uncommon in patients of the thin wall of the RV and possible confu-
with RBBB who do not have ARVC/D and sion with fat.30
is seen frequently in those who do have the Pathologies causing RV volume over-
disease. load such as intracardiac shunts (eg, atrial
septal defects, anomalous pulmonary venous
Imaging. Technical advances in cardiac drainage) can be misinterpreted as possible
MRI and echocardiography have improved ARVC/D on standard echocardiography.31 A
the ability to image the RV with reproducible clue to the correct diagnosis may be the pres-
measurements of volume and systolic func- ence of a dilated RV with normal or supernor-
tion, and permit classification of severity and mal function and without regional wall motion
differentiation from normals.25 Cardiac MRI abnormalities in these other conditions.
is commonly used in patients with suspected Cardiac MRI can define the diagnostic
ARVC/D. Previous diagnostic reliance on features of ARVC/D, but it may also detect
subjective assessment of RV wall thinning, other diseases that can mimic ARVC/D.
wall motion abnormalities, and fatty infiltra- Quarta et al31 analyzed 657 CMR referrals
tion of the myocardium by CMR are probably suspicious for ARVC/D in a single tertiary
not reliable.26,27 referral center. Potential ARVC/D mimics
During the initial experiences with car- were grouped into 3 categories: (1) displace-
diac MRI in ARVC/D, the focus was on the ment of the heart, (2) RV overload, and
ability of MRI to detect fatty tissue in the RV (3) ARVC/D-like cardiac scarring. For each, a
free wall. It soon became evident that this judgment of clinical impact was made. They
finding is of limited diagnostic specificity found 20 patients (3.0%) who fulfilled imag-
in the absence of concomitant wall motion ing criteria for a diagnosis of ARVC/D. Thirty
abnormalities. In addition, there was also a other patients (4.6%) had a potential ARVC/D
high degree of interobserver variability.26 The mimic, of which 25 (3.8%) were considered
amount of subepicardial fat increases with clinically important. These results have
body weight and age.28 The presence of exten- important consequences for both patients
sive fatty infiltration of the RV has not been and their families. Clinical assessment of the
found to be familial and is not associated with patients is, therefore, critical in the diagnosis
arrhythmic death during exercise.29 There- of ARVC/D in addition to the detection of
fore, recognition of significant fatty involve- major and minor imaging criteria.
ment without concomitant fibrosis of the RV
in normal individuals renders this unique Genetic Testing. Individuals who have the
capability of MRI to be of limited value. Incor- familial genetic defect may not have any clini-
rect interpretation of the MRI study is often a cal manifestations and may have a normal life
frequent cause of misdiagnosis of ARVC/D.27 expectancy without developing the disease.
To a large extent, this has been mitigated Thus the genetic–phenotypic relationship is
with the revised Task Force Criteria,3 which quite variable.32 It must be noted that 5% to
includes specific imaging guidelines. 20% of patients with the diagnosis of ARVC/D
Late gadolinium enhancement on car- may have 2 genetic abnormalities located
diac MRI permits myocardial tissue charac- either on the same protein, such as plakophilin,
terization in the LV. It can be difficult to be or on another desmosomal protein (compound
certain of late gadolinium enhancement for and digenic heterozygosity).33 Individuals with
characterization of RV myocardium because 2 desmosomal genetic defects have a greater
ARVC/D: Clinical Presentation, Differential Diagnosis, and Diagnostic Challenges 55
chance of having phenotypic expression of the 3. Marcus FI, McKenna WJ, Sherrill D, et al.
disease and are often more severely affected.34 Diagnosis of arrhythmogenic right ventricular
Interpretation of genetic abnormalities is com- cardiomyopathy/dysplasia: proposed modifi-
plicated by the fact that up to 16% of normal cation of the Task Force Criteria. Circulation.
controls may have a desmosomal genetic 2010;121:1533-1541.
4. Kaplan SR, Gard JJ, Protonotarios N, et al.
abnormality. Therefore, a genetic abnormal-
Remodeling of myocyte gap junctions in
ity must be interpreted with great caution, and
arrhythmogenic right ventricular cardiomyop-
genetic counseling is recommended.32 athy due to a deletion in plakoglobin (Naxos
disease). Heart Rhythm. 2004;1:3-11.
Conclusion 5. Sen-Chowdhry S, Syrris P, Ward D, Asimaki
The accurate diagnosis of ARVC/D is criti- A, Sevdalis E, McKenna WJ. Clinical and
cally important because the diagnosis carries genetic characterization of families with
a risk of sudden cardiac death. An incorrect arrhythmogenic right ventricular dysplasia/
diagnosis can lead to unnecessary insertion cardiomyopathy provides novel insights into
of an implantable cardioverter-defibrillator, patterns of disease expression. Circulation.
2007;115:1710-1720.
elevate the patient’s psychosocial burden, and
6. Basso C, Corrado D, Bauce B, Thiene G.
initiate costly and extensive screening of fam-
Arrhythmogenic right ventricular cardio-
ily members, with the possibility of overdiag- myopathy. Circ Arrhythm Electrophysiol.
nosis due to inaccurate interpretation of tests 2012;5:1233-1246.
performed during screening.35 The modifica- 7. Hamid MS, Norman M, Quraishi A, et
tions3 of the original Task Force Criteria repre- al. Prospective evaluation of relatives for
sent a framework to improve the diagnosis and familial arrhythmogenic right ventricular
management of ARVC/D. The revised Task cardiomyopathy/dysplasia reveals a need to
Force Criteria have increased diagnostic sen- broaden diagnostic criteria. J Am Coll Cardiol.
sitivity, particularly in dominant ARVC/D.36 2002;40:1445-1450.
8. Nava A, Bauce B, Basso C, et al. Clinical
profile and long-term follow-up of 37 fami-
Abbreviations lies with arrhythmogenic right ventricular
LBBB left bundle branch block
cardiomyopathy. J Am Coll Cardiol. 2000;36:
LV left ventricle, left ventricular
2226-2233.
MRI magnetic resonance imaging
9. Bauce B, Frigo G, Benini G, et al. Differ-
PVC premature ventricular contraction
ences and similarities between arrhythmo-
RBBB right bundle branch block
genic right ventricular cardiomyopathy and
SCD sudden cardiac death
athlete’s heart adaptations. Br J Sports Med.
VF ventricular fibrillation 2010;44:148-154.
VT ventricular tachycardia 10. Basso C, Burke M, Fornes P, et al. Guidelines
for autopsy investigation of sudden cardiac
References death. Virchows Arch. 2008;452:11-18.
1. Basso C, Corrado D, Marcus FI, Nava A, 11. Avella A, d’Amati G, Pappalardo A, et al.
Thiene G. Arrhythmogenic right ventricu- Diagnostic value of endomyocardial biopsy
lar cardiomyopathy. Lancet. 2009;373: guided by electroanatomic voltage mapping
1289-1300. in arrhythmogenic right ventricular cardiomy-
2. Thiene G, Nava A, Corrado D, Rossi L, Pen- opathy/dysplasia. J Cardiovasc Electrophysiol.
nelli N. Right ventricular cardiomyopathy 2008;19:1127-1134.
and sudden death in young people. N Engl J 12. Basso C, Ronco F, Marcus F, et al. Quanti-
Med. 1988;318:129-133. tative assessment of endomyocardial biopsy
56 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
netic resonance imaging. J Am Coll Cardiol. 34. Quarta G, Muir A, Pantazis A, et al. Famil-
2005;45:98-103. ial evaluation in arrhythmogenic right ven-
31. Quarta G, Husain SI, Flett AS, et al. tricular cardiomyopathy: impact of genetics
Arrhythmogenic right ventricular cardiomy- and revised Task Force Criteria. Circulation.
opathy mimics: role of cardiovascular mag- 2011;123:2701-2709.
netic resonance. J Cardiovasc Magn Reson. 35. Marcus F, Basso C, Gear K, Sorrell VL. Pit-
2013;15:16. falls in the diagnosis of arrhythmogenic right
32. Marcus FI, Abidov A. Arrhythmogenic right ventricular cardiomyopathy/dysplasia. Am J
ventricular cardiomyopathy 2012: diagnostic Cardiol. 2010;105:1036-1039.
challenges and treatment. J Cardiovasc Elec- 36. Protonotarios N, Anastasakis A, Antoniades
trophysiol. 2012;23:1149-1153. L, et al. Arrhythmogenic right ventricular
33. Xu T, Yang Z, Vatta M, et al. Multidis- cardiomyopathy/dysplasia on the basis of the
ciplinary Study of Right Ventricular revised diagnostic criteria in affected fami-
Dysplasia I. Compound and digenic hetero- lies with desmosomal mutations. Eur Heart J.
zygosity contributes to arrhythmogenic right 2011;32:1097-1104.
ventricular cardiomyopathy. J Am Coll Car-
diol. 2010;55:587-597.
6A
The Role of Echocardiography in
Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia
myocytes and their replacement by fibrofatty fulfilled with regional RV akinesia, dyskinesia,
tissue induces (1) wall motion abnormali- or aneurysm and one of the following: paraster-
ties such as akinesia or dyskinesia, (2) wall nal long axis (PLAX) RV outflow tract (RVOT)
thinning and formation of aneurysms, and ≥ 32 mm (corrected for body size [PLAX/BSA]
(3) ventricular dilatation and reduced ejection ≥ 19 mm/m2), or parasternal short axis RVOT
fraction (Figure 6A.1). Such features are first (PSAX) ≥ 36 mm (corrected for body size
detected as focal changes, at later stages typi- [PSAX/BSA] ≥ 21 mm/m2), or fractional area
cally in the triangle of dysplasia, and finally change ≤ 33%. A minor echocardiographic cri-
in a diffuse manner.5-7 Echocardiography has terion is fulfilled with regional right ventricular
been a valuable tool for detection of these akinesia or dyskinesia and PLAX RVOT from
changes for decades.8-10 ≥ 29 mm to < 32 mm (corrected for body size
[PLAX/BSA] ≥ 16 mm/m2 to < 19 mm/m2) or
PSAX RVOT from ≥ 32 mm to < 36 mm (cor-
rected for body size [PSAX/BSA] ≥ 18 mm/
m2 to < 21 mm/m2), or fractional area change
from > 33% to ≤ 40%.4
Echocardiographic
Assessment of the Right
Ventricle in ARVC/D
Right Ventricular Anatomy
FIGURE 6A.1 Pathology specimen of a human heart
affected by ARVC/D . Focal areas with degeneration of Although the Task Force Criteria are clearly
cardiac myocytes lead to replacement of the myocardium
defined, evaluation of RV size and function by
by fibrofatty tissue . These changes progress from an
standard 2D transthoracic echocardiography
initially epicardial to finally transmural involvement . As a
result, progressive thinning of the RV wall with aneurysm
is difficult due to the complex geometry of the
formation and ventricular dilatation occurs . The affected right ventricle. In contrast to the symmetrical
myocardial areas show wall motion abnormalities with and almost conical shape of the LV, the RV is
hypokinesia, akinesia, or dyskinesia depending on the more triangular in shape, curves over the LV,
severity of myocardial involvement . and appears like a crescent on cross-section. It
is composed of 3 distinct portions—the inflow
The structural alterations induced by tract, the apical trabeculated part, and the out-
ARVC/D constitute the basis for 1 major and flow tract—and its blood supply is mainly pro-
1 minor imaging criteria in the modified Task vided by the right coronary artery.11,12 Because
Force Criteria.4 These imaging criteria are of this complex shape, quantification of RV
based on global or regional ventricular dysfunc- volume and function is challenging, as many
tion as well as structural alterations, and are assumptions are required. Hence, the accurate
applied for different imaging modalities (echo- assessment of RV morphology and function
cardiography, cardiac magnetic resonance requires integration of multiple echocardio-
imaging, or RV angiography). The extent of graphic views, including parasternal long axis,
the functional impairment or structural altera- parasternal short axis, apical 4-chamber,
tions determines whether a major or a minor and subcostal views (Figures 6A.2–6A.4).13
criterion is fulfilled in a given patient (Table Although different methods for quantitative
6A.1). A major echocardiographic criterion is echocardiographic assessment of the RV have
The Role of Echocardiography in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 61
TABLE 6A.1 The role of echocardiography in the revised Task Force Criteria for ARVC/D
The combination of a regional RV wall motion abnormality such as akinesia or dyskinesia or the presence of a RV aneurysm with either
a dilatation of RVOT or a reduction of RV fractional area change is required for a major criterion. When similar but less pronounced
alterations are present, a minor criterion is identified. Source: Modified from Marcus FI, McKenna WJ, Sherrill D, et al.4
segments, which show thickening and inward leading to overestimation of RVOT size.
movement during systole. In contrast to the Moreover, the endocardial definition of the
original criteria, hypokinesia is no longer part anterior wall is often suboptimal.4 In addition
of the revised Task Force Criteria. As the myo- to these technical pitfalls, limited normative
cardium of the RV is thinner than that of the data are available, and the window for RVOT
LV and the direction of systolic movement is size has not been standardized. It is particu-
known to be affected by the complex ventricu- larly important to realize that the current
lar shape, it may be more difficult to distinguish guidelines for the echocardiographic assess-
hypokinesia from other forms of contraction in ment of the right heart recommend measur-
the RV.15 Therefore, it is certainly reasonable ing the distal diameter of the RVOT, because
to exclude hypokinesia from the list of criteria this diameter shows the best reproducibil-
applied for the diagnosis of ARVC/D. ity.4 Unfortunately, the distal diameter is not
A ventricular aneurysm is defined as a identical with the diameters included in the
localized, outward bulging of the ventricu- revised Task Force Criteria. Finally, the upper
lar wall without any discontinuity of the limit of the normal range for the RVOT diam-
latter.16 Diagnosis of an aneurysm is usually eters in parasternal long and short axes are not
straightforward; however, in some instances, identical in the current guidelines and the
it may be difficult to evaluate it in the RV api- revised Task Force Criteria. Certainly, more
cal region depending on whether the view research is required to solve these important
has been foreshortened. In ARVC/D, mul- issues.
tiple ventricular aneurysms can frequently be
observed (Figures 6A.2–6A.4). Right Ventricular Systolic Function
tion.28,29 Therefore, at present, fractional area more accurately than any other echocardio-
change seems to be an excellent parameter for graphic method.35,36 Indeed, 3D measurements
assessing RV function in patients with ARVC/D. of RV size are less prone to underestimation of
Another widely used parameter for RV the true size than 2D assessment.37 Boundary
systolic function is tricuspid annulus plane tracing errors remain the largest source of error;
systolic excursion (TAPSE). This parameter in addition, it may be difficult to acquire a 3D
reflects the systolic movement of the basal dataset of the RV that includes its outflow tract,
and adjacent segments of the RV wall in the since the latter is located in an anterior position
apical 4-chamber view and thus measures and is often obscured by near-field artifacts.
the longitudinal systolic function of the RV. While there are limited normative data available
The movement of the right ventricle under- at this time, and the data were only obtained in
lying TAPSE is visibly obvious, can easily be small series with different methods,4 3D mea-
measured, and is very reproducible.30-32 How- surement of RV size will certainly become an
ever, it reflects RV systolic function in an indispensible tool for the echocardiographic
even more restricted manner than fractional evaluation of ARVC/D in the near future.
area change, and one intuitively assumes
that it may therefore be of lower value in Right Ventricular Function
diseases like ARVC/D, which induces focal
myocardial alterations in many patients. A Tissue Doppler imaging allows measurement of
recent study indeed confirmed that the prog- RV systolic and diastolic function by determin-
nostic value of TAPSE is clearly lower than ing myocardial velocities.38 Instead of TAPSE,
that of fractional area change in patients longitudinal function of the RV can be deter-
with ARVC/D.26 mined by tissue Doppler imaging of the tricus-
pid annulus. A retrospective study in a small
Future Developments patient group demonstrated a decline of systolic
tissue velocity in the RV lateral wall in patients
in Echocardiographic with ARVC/D over time,39 while another study
Assessment of ARVC/D observed a wide variation of tissue velocity mea-
surements in such patients.40
Right Ventricular Size The myocardial performance index (also
called Tei index) is a quantitative method for
The size of the RV would represent a meaning- assessing RV function, which is also feasible
ful parameter in the evaluation of ARVC/D. in many patients with poor image quality.41
Although RV size is often compared with that It is calculated as the sum of the isovolumic
of the LV for a qualitative evaluation,33 this contraction time and the isovolumic relax-
approach is not sufficient in the context of ation time divided by the RV ejection time.42
ARVC/D. A 2D assessment of RV size, as it is It has been established that this index is more
performed with different RVOT diameters and or less unaffected by heart rate, loading con-
with fractional area change, has its limitations as ditions, or tricuspid regurgitation. The value
well. Indeed, many parameters of RV size have of the Tei index in patients with ARVC/D is
only recently been evaluated in a large, normal yet unknown.
population assessed according to gender and Strain is defined as the degree of defor-
indexed to body surface area.34 The best assess- mation of an object, whereas strain rate rep-
ment of RV size is 3D echocardiography, which resents the speed at which strain occurs.43
allows determination of the volume of the RV Both parameters can be determined by tissue
The Role of Echocardiography in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 65
Doppler imaging. RV longitudinal strain can important role for the diagnosis of ARVC/D in
easily be assessed from the apical view in rou- the next decade. Indeed, physicians have just
tine echocardiography.44 In normal subjects, started to apply the new technologies men-
RV longitudinal velocities are higher than tioned above, in particular 3D imaging of the
those of the LV and show a baso-apical gra- RV, in clinical routine.
dient with higher velocities at the base.45 This
can be explained by the differences in loading Abbreviations
conditions with a lower afterload in the right
ICD implantable cardioverter-defibrillator
ventricle and by the dominance of longitudi-
LV left ventricle, left ventricular
nal and oblique myocardial fibers in the RV
RV right ventricle
free wall. Moreover, compared to the homog- RVOT right ventricular outflow tract
enous distribution of LV deformation proper- TAPSE tricuspid annulus plane systolic
ties, RV strain and strain rate values have an excursion
inhomogeneous distribution, which is related
to the complex geometry of the thin-walled, References
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Group Myocardial and Pericardial Disease
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nary embolism. Am J Cardiol. 1999;83:804-806. real-time three-dimensional echocardiogra-
28. Zornoff LA, Skali H, Pfeffer MA, et al. Right phy: comparison with cardiac MRI. Chest.
ventricular dysfunction and risk of heart fail- 2007;131:1844-1851.
ure and mortality after myocardial infarction. 38. Kukulski T, Hübbert L, Arnold M, Wranne
J Am Coll Cardiol. 2002;39:1450-1445. B, Hatle L, Sutherland GR. Normal regional
29. Anavekar NS, Skali H, Bourgoun M, et al. right ventricular function and its change with
Usefulness of right ventricular fractional area age: a Doppler myocardial imaging study. J
change to predict death, heart failure, and Am Soc Echocardiogr. 2000;13:194-204.
stroke following myocardial infarction (from 39. Aneq MÅ, Lindström L, Fluur C, Nylander
the VALIANT ECHO study). Am J Cardiol. E. Long-term follow-up in arrhythmogenic
2008;101:607-612. right ventricular cardiomyopathy using tis-
30. Kaul S, Tei C, Hopkins JM, Shah PM. Assess- sue Doppler imaging. Scand Cardiovasc J.
ment of right ventricular function using two- 2008;42:368-374.
dimensional echocardiography. Am Heart J. 40. Kjaergaard J, Hastrup Svendsen J, Sogaard P,
1984;107:526-531. et al. Advanced quantitative echocardiography
31. Lopez-Candales A, Dohi K, Rajagopalan in arrhythmogenic right ventricular cardiomy-
N, Edelman K, Gulyasy B, Bazaz R. Defin- opathy. J Am Soc Echocardiogr. 2007;20:27-35.
ing normal variables of right ventricular size 41. Tei C, Dujardin KS, Hodge DO, et al. Dop-
and function in pulmonary hypertension: pler echocardiographic index for assessment
an echocardiographic study. Postgrad Med J. of global right ventricular function. J Am Soc
2008;84:40-45. Echocardiogr. 1996;9:838-847.
32. Miller D, Farah MG, Liner A, Fox K, 42. Burgess MI, Bright-Thomas RJ, Ray SG. Echo-
Schluchter M, Hoit BD. The relation between cardiographic evaluation of right ventricular
quantitative right ventricular ejection fraction function. Eur J Echocardiogr. 2002;3:252-262.
and indices of tricuspid annular motion and 43. Kowalski M, Kukulski T, Jamal F, et al.
myocardial performance. J Am Soc Echocar- Can natural strain and strain rate quantify
diogr. 2004;17:443-447. regional myocardial deformation? A study
33. Vitarelli A, Terzano C. Do we have two in healthy subjects. Ultrasound Med Biol.
hearts? New insights in right ventricular func- 2001;27:1087-1097.
tion supported by myocardial imaging echo- 44. Pettersen E, Helle-Valle T, Edvardsen T, et
cardiography. Heart Fail Rev. 2010;15:39-61. al. Contraction pattern of the systemic right
34. D’Oronzio U, Senn O, Biaggi P, et al. Right ventricle shift from longitudinal to circum-
heart assessment by echocardiography: gender ferential shortening and absent global ven-
and body size matters. J Am Soc Echocardiogr. tricular torsion. J Am Coll Cardiol. 2007;49:
2012;25:1251-1258. 2450-2456.
68 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
45. Gondi S, Dokainish H. Right ventricular 47. Atsumi A, Ishizu T, Kameda Y, et al. Applica-
tissue Doppler and strain imaging: ready tion of 3-dimensional speckle tracking imaging
for clinical use? Echocardiography. 2007;24: to the assessment of right ventricular regional
522-532. deformation. Circ J. 2013;77:1760-1768.
46. Aneq MÅ, Engvall J, Brudin L, Nylander 48. Sarvari SI, Haugaa KH, Anfinsen OG, et al.
E. Evaluation of right and left ventricular Right ventricular mechanical dispersion is
function using speckle tracking echocar- related to malignant arrhythmias: a study of
diography in patients with arrhythmogenic patients with arrhythmogenic right ventricu-
right ventricular cardiomyopathy and their lar cardiomyopathy and subclinical right
first degree relatives. Cardiovasc Ultrasound. ventricular dysfunction. Eur Heart J. 2011;32:
2012;10:37. 1089-1096.
6B
The Role of Cardiac Magnetic Resonance
Imaging in Arrhythmogenic Right
Ventricular Cardiomyopathy/Dysplasia
ation times, leading to hyperenhancement ventricular (LV) wall, which promotes mis-
in T1-weighted images. While initial ex vivo delineation of the borders of myocardial tis-
studies used a signal intensity of 2–3 standard sue. Moreover, the so-called Look-Locker
deviations above the normal-appearing myo- sequences (nulling of the myocardium to
cardium in order to detect LGE, newer studies detect LGE) is done using the LV, which
have used up to 6 standard deviations in vivo might result in wrong timing for the RV.
(due to motion and blurring) and alternatively
a threshold > 50% of the maximal signal inten- Power and Benefit of CMR
sity within the scar.26-29 In a study by Tandri et
al, there was an excellent correlation between
Imaging in ARVC/D
CMR, LGE findings, and histopathology in CMR can reveal information about func-
their ARVC/D cohort.17 The regions of fibro- tional and morphological alterations in
sis should match with the hypo- and akinetic patients with ARVC/D, which is facilitated
regions on cine images. Moreover, a differen- by advances in CMR technology in recent
tiation between ARVC/D and idiopathic ven- years, including better and faster imaging
tricular tachycardia from the RVOT might be acquisition methods (steady-state free-pre-
supported by LGE imaging, because patients cession [SSFP] imaging, black blood imag-
with idiopathic RVOT tachycardia should not ing). In contrast to echocardiography, CMR
show fibrosis on CMR—although this is not a can also visualize the tissue surrounding
sine qua non criterion (Figure 6B.2). the heart, revealing pathologies that might
ARVC/D patients with fibrosis show a mimic ARVC/D, such as thoracic abnor-
higher susceptibility to arrhythmias than malities (eg, pectus excavatum) or abnormal
patients without LGE. Although this sug- heart positions with concomitant distortion
gests that inducibility of malignant ventricu- of RV shape (eg, partially absent pericar-
lar tachycardias correlates with regions of dium).21 Special ARVC/D CMR protocols
LGE, there are no studies directly investigat- exist, which are mainly based on SSFP-
ing the arrhythmogenic substrate in patients cine, T1-weighted black blood, T1-weighted
with ARVC/D.26 This might be because of black blood with fat suppression, and LGE
the thinner RV wall compared to the left imaging.
FIGURE 6B.2 Cardiac magnetic resonance (CMR) imaging in a 60-year-old female patient with arrhythmogenic right
ventricular cardiomyopathy (ARVC/D) and extensive left ventricular involvement . Panel A: End-systolic short-axis cine image
shows abnormalities of regional and global right ventricular (RV) and left ventricular (LV) function (white arrow heads) .
Panel B: Late enhancement images confirm extensive fibrosis of the RV and LV walls (white arrows) .
The Role of Cardiac Magnetic Resonance Imaging in ARVC/D 73
mapping using endocardial activation dura- al reported a 23-year-old male patient with
tion,38 which was significantly prolonged in biventricular involvement where the post-
patients with ARVC/D.38 Moreover, patients mortem specimen revealed fatty infiltrations
with idiopathic RVOT tachycardia do not in the RV and LV. This was also shown on
display prolonged signal duration and areas postmortem CMR images. In a small study of
of low voltage. A special cardiomyopathy 6 ARVC/D patients, 2 presented LGE in the
called Uhl’s anomaly is characterized by a LV.41 LV involvement in different ARVC/D
paper-thin RV, caused by an almost complete cohorts seems to vary quite remarkably, from
absence of myocardial fibers; thus, ARVC/D 16% to 76%.42,43 Even a left-dominant type
might be misdiagnosed in some cases.39,40 of arrhythmogenic cardiomyopathy is being
discussed. Most commonly, the posterolat-
Left-Sided Arrhythmogenic eral region of the LV is affected; a nicely
illustrative case was reported by Paetsch et
Cardiomyopathy al.44 This might lead to the conclusion that
In the 1994 Task Force Criteria, it was stated neither predominant RV or LV involvement
that only mild LV dysfunction should be pres- represents distinct cardiomyopathies, but
ent in patients with ARVC/D, and that LV patterns of a generalized arrhythmogenic
involvement should preferably occur at late cardiomyopathy.43 This is supported by the
stages of the disease. However, more recent fact that ARVC/D is mostly a desmosomal
reports have described advanced biventricu- disease, and desmosomes are expressed in
lar and early LV involvement. Pinamonti et both ventricles (Figure 6B.3).
FIGURE 6B.3 Cardiac magnetic resonance (CMR) imaging in a 32-year-old female patient with arrhythmogenic right
ventricular cardiomyopathy (ARVC/D) . Endsystolic cine 4-chamber (Panel A) and axial (Panel B) images show regional wall
motion abnormalities (white arrowheads) . Panels C and D: Late enhancement images confirm extensive fibrosis of the RV
wall (white arrow) .
The Role of Cardiac Magnetic Resonance Imaging in ARVC/D 75
type relations, diagnostic features and progno- ing Task Force Criteria for arrhythmogenic
sis. Eur Heart J. 2006;27(18):2208-2216. right ventricular dysplasia. J Cardiovasc Elec-
16. Bomma C, Rutberg J, Tandri H, et al. Misdi- trophysiol. 2003;14(5):476-482.
agnosis of arrhythmogenic right ventricular 26. Yokokawa M, Mueller G, Bogun F. Role of
dysplasia/cardiomyopathy. J Cardiovasc Elec- imaging in ablation therapy of ventricular
trophysiol. 2004;15(3):300-306. arrhythmias. Focus on cardiac magnetic reso-
17. Tandri H, Saranathan M, Rodriguez ER, et al. nance imaging. Circ J. 2012;76(6):1292-1298.
Noninvasive detection of myocardial fibrosis 27. Kim RJ, Fieno DS, Parrish TB, et al. Relation-
in arrhythmogenic right ventricular cardio- ship of MRI delayed contrast enhancement to
myopathy using delayed-enhancement mag- irreversible injury, infarct age, and contractile
netic resonance imaging. J Am Coll Cardiol. function. Circulation 1999;100:1992-2002.
2005;45(1):98-103. 28. Simonetti OP, Kim RJ, Fieno DS, et al. An
18. Kirsch J, Johansen CK, Araoz PA, Brady PA, improved MR imaging technique for the visu-
Williamson EE, Glockner JF. Prevalence alization of myocardial infarction. Radiology.
of fat deposition within the right ventricular 2001;218(1):215-223.
myocardium in asymptomatic young patients 29. Amado LC, Gerber BL, Gupta SN, et al.
without ventricular arrhythmias. J Thorac Accurate and objective infarct sizing by con-
Imaging. 2010;25(2):173-178. trast-enhanced magnetic resonance imaging
19. O’Connor S, Recavarren R, Nichols LC, in a canine myocardial infarction model. J Am
Parwani AV. Lipomatous hypertrophy of the Coll Cardiol. 2004;44(12):2383-2389.
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Lab Med. 2006;130(3):397-399. lucci M, Splendiani A, Masciocchi C. Car-
20. Kellman P, Hernando D, Arai AE. Myocardial diac MRI: comparison between single-shot
fat imaging. Curr Cardiovasc Imaging Rep. fast spin echo and conventional spin echo
2010;3(2):83-91. sequences in the morphological evalua-
21. Quarta G, Sado DM, Moon JC. Cardiomy- tion of the ventricles. Radiol Med. 2002;
opathies: focus on cardiovascular magnetic 103(1-2):34-44.
resonance. Br J Radiol. 2011;84(Spec No 31. Schick F, Miller S, Hahn U. Fat- and water-
3):S296-S305. selective MR cine imaging of the human
22. Naito H, Arisawa J, Harada K, Yamagami H, heart: assessment of right ventricular dyspla-
Kozuka T, Tamura S. Assessment of right ven- sia. Invest Radiol. 2000;35(5):311-318.
tricular regional contraction and comparison 32. Thiene G, Basso C, Corrado D. May active
with the left ventricle in normal humans: myocarditis mimic arrhythmogenic right
a cine magnetic resonance study with pre- ventricular cardiomyopathy phenotype by
saturation myocardial tagging. Br Heart J. electroanatomic mapping? J Am Coll Cardiol.
1995;74(2):186-191. 2009;54(13):1190.
23. Ma N, Cheng H, Lu M, Jiang S, Yin G, Zhao 33. Pieroni M, Dello Russo A, Marzo F, et al.
S. Cardiac magnetic resonance imaging in High prevalence of myocarditis mimicking
arrhythmogenic right ventricular cardiomyop- arrhythmogenic right ventricular cardiomyop-
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25. Tandri H, Calkins H, Nasir K, et al. Magnetic 35. Catalano O, Antonaci S, Moro G, et al.
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The Role of Cardiac Magnetic Resonance Imaging in ARVC/D 77
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nelli N. Sudden death in young competitive mogenic right ventricular cardiomyopathy? J
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malformation of the heart: almost total absence
Drug Therapy in ARVC/D
7
Drug Therapy in Arrhythmogenic Right
Ventricular Cardiomyopathy/Dysplasia:
When and How to Use Which Drugs
Thomas Wichter, MD
Clinical signs of heart failure are usually TABLE 7.1 Risk factors for ventricular tachyarrhythmias
limited to patients with advanced right ven- and sudden arrhythmic death in ARVC/D
tricular dysfunction and/or left ventricular
involvement, both occurring mostly in later MAJOR RISK FACTORS
stages of ARVC/D and in patients with a long • Survived cardiac arrest or ventricular fibrillation (VF)
history of ventricular arrhythmias. • Sustained VT with hemodynamic compromise
Diagnostic criteria for ARVC/D were pro- (unstable VT)
• Unexplained syncope
posed and updated by an international study
group.7,8 The catalogue includes morpho- INTERMEDIATE RISK FACTORS
mias. Moreover, beta-blockers are essential as current knowledge and recommendations fol-
an adjunct treatment to reduce appropriate low an empiric approach and are based on retro-
ICD interventions (VT burden) and to pre- spective analyses, registry data, expert opinion
vent inappropriate ICD shocks resulting from and consensus, and individual decisions. Add-
exercise-induced sinus tachycardia, supraven- ing further to the complexity of evaluating
tricular tachycardia, or atrial fibrillation with antiarrhythmic treatment efficacy during long-
rapid ventricular conduction. term follow-up, recurrent arrhythmic events in
ARVC/D patients result in frequent changes
Antiarrhythmic Drug Therapy of antiarrhythmic drugs and dosages as well as
In ARVC/D patients, treatment to improve modifications of antiarrhythmic strategies and
symptoms and prognosis is mainly directed modalities (drugs, ablation, ICD) to treat and
toward the prevention and management of prevent ventricular tachyarrhythmias.
the clinically dominant problem of ventricu- In ARVC/D, antiarrhythmic drug ther-
lar arrhythmias, whereas the treatment of apy may be used to:
symptomatic heart failure is relevant for only • prevent VT recurrence and arrhyth-
a minority of ARVC/D patients. Antiarrhyth- mia worsening as a first-line therapy in
mic treatment options in ARVC/D include patients at low or intermediate risk
anti-arrhythmic drugs, catheter ablation, and • reduce VT burden and ICD discharges
ICD therapy (Figure 7.1). as an adjunct therapy to ICD implanta-
Experience with the use of antiarrhythmic tion or catheter ablation in patients at
drugs in patients with coronary artery disease intermediate and high risk
or cardiomyopathies are not transferable to • reduce emergency hospital admissions
patients with ARVC/D. Prospective random- and improve quality of life
ized studies to compare antiarrhythmic modali- • prevent sudden arrhythmic death (ques-
ties have not been conducted so far. Therefore, tionable and unproven)
FIGURE 7.1 Stepwise treatment for ventricular tachycardia in patients with ARVC/D . See text for details . Source: Adapted
from Wichter T, Corrado D, Paul M35 with kind permission from Springer Science and Business Media .
84 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
all efficacy rates for different antiarrhythmic strated overall efficacy rates of 25% and 44%,
agents. Multivariate analysis identified exten- respectively. However, they were not likely to
sive right ventricular dysfunction as an indepen- be successful in reentrant arrhythmias.37
dent predictor of antiarrhythmic drug failure. Drug combinations of class-1 drugs with
Sotalol in a relatively high dosage of amiodarone or sotalol were effective in a
320–480 mg/day (releasing its class-III anti- minority of patients with ARVC/D in whom
arrhythmic potential) was identified as the the individual drugs had previously failed.
most effective drug with a 68% overall acute Combinations of 2 class-1 drugs and class-1
success rate. Of the patients with inducible drugs with beta-blockers were not effective in
VT who did not respond to oral sotalol, all any of these patients.37
but one proved refractory to all other anti- Long-Term Antiarrhythmic Drug Efficacy.
arrhythmic agents tested (including amio- Long-term antiarrhythmic drug efficacy
darone). Side effects requiring withdrawal of (mean follow-up, 53 ± 32 months) was assessed
sotalol treatment were rare (5.5%) and mostly in all 143 ARVC/D patients discharged on an
occurred within the first days of therapy.36 antiarrhythmic drug. The incidence of sud-
Amiodarone alone was reported with simi- den death was low (4 of 143 patients = 2.8%,
lar or less favorable results when compared with or 0.6% per year) and the overall rate of nonfa-
sotalol. Of 12 patients receiving both drugs suc- tal VT recurrence was acceptable (25% after 5
cessively, 1 of 8 sotalol nonresponders was effec- years). Patients who were discharged on a drug
tively treated with amiodarone, whereas 2 of 9 that was tested to be effective had a favorable
amiodarone nonresponders were effectively prognosis. In contrast, in patients with unsuc-
treated with sotalol.36 The combination of ami- cessful serial drug testing, noncompliant drug
odarone with beta-blockers was more effective intake, or inadequate dosage, the ventricular
than amiodarone alone.37 However, given the tachyarrhythmia recurrence rate approached
high incidence of serious side effects of amio- 60% after 3 years37 (Figure 7.3).
darone during long-term treatment, amioda-
rone should not be recommended as a first-line
drug in a young patient with ARVC/D. There-
fore, sotalol or nonpharmacological treatment
options should be considered prior to initiation
of long-term amiodarone therapy.
Class-1 antiarrhythmic drugs proved
effective in only a minority of patients with
ARVC (18%), although some patients received
3 or more different class-1 drugs successively
without satisfactory antiarrhythmic efficacy.
Class-1c agents appeared to be slightly more
effective than class-1a and class-1b drugs.36,37 FIGURE 7.3 Long-term outcome (mean follow-up,
Beta-blockers and verapamil were tested in 53 ± 32 months) of 143 patients with ARVC/D and low
only a small proportion of ARVC/D patients or intermediate risk of sudden death discharged on
with noninducible, nonreentrant VT and pre- antiarrhythmic drugs after serial drug testing . See text for
details . Source: Adapted from Wichter T, Paul M, Eckardt
sumed mechanisms of triggered activity or
L, et al,37 with kind permission from Springer Science and
abnormal automaticity. In this particular sub-
Business Media .
group, beta-blockers and verapamil demon-
86 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
The North American Experience (Multi- al36,37 mainly relate to the efficacy of antiar-
center Study). Marcus et al39 recently pub- rhythmic drugs for the suppression of VT in
lished the results of empiric antiarrhythmic general and to the efficacy of sotalol in particu-
drug therapy in an observational study of 108 lar. The 2 studies differ with respect to study
patients derived from the Multicenter Study populations (high-risk patients with an ICD vs
on ARVC/D conducted in North America.20 low- or intermediate-risk patients), sotalol dos-
The ARVC/D patients enrolled were at ages (160–320 vs 320–480 mg/day), treatment
high risk of sudden death, reflected by high guidance (empiric vs guided by electrophysi-
rates of ICD implantation (88%) and beta- ological study or Holter and exercise tests), and
blocking agents (61%) at baseline. Patients follow-up duration (16 ± 13 vs 53 ± 32 months).
were treated with additional antiarrhythmic
drugs at the discretion of the treating physi- Other Clinical Studies and Expert Opinions.
cian on an empiric basis with no systematic Other data on antiarrhythmic drug therapy
approach to test drug efficacy. in ARVC/D are weaker and of less clinical
During a mean follow-up period of 16 ± importance than those from the 2 major stud-
13 months, 235 ventricular arrhythmic events ies discussed above.
were observed in 32 patients (30%). Beta- The European multicenter ICD study
blockers provided no clinical benefit with published by Corrado et al40 reported on 132
regard to prevention of VT or ventricular patients with ARVC/D and implantable ICDs.
fibrillation when compared with patients not In patients with an index episode of hemody-
taking beta-blockers or antiarrhythmic drugs. namically unstable VT, syncope, or survived
However, there was a trend (not statistically cardiac arrest, the majority of potentially life-
significant) toward a reduction of ICD shocks. saving ICD interventions occurred despite an
Low-dose sotalol with a mean dose of 240 mg adjunct empiric antiarrhythmic drug therapy.
per day was administered on an empiric basis It was concluded that in high-risk patients
in 38 patients. The incidence of clinically rel- with ARVC/D, such empiric antiarrhythmic
evant ventricular arrhythmias or ICD shocks treatment does not protect against sudden
was not affected; therefore, no arrhythmic death but may reduce the number of VT epi-
protection was observed in patients treated sodes (VT burden) and ICD interventions
with sotalol. However, the cycle length of (shock delivery in particular). Of the 132 total
recurrent VT was prolonged, resulting in study patients, 104 (79%) received antiar-
slower heart rate during VT. Only the small rhythmic drugs in addition to the implanted
subgroup of 10 patients receiving amiodarone ICD. Sotalol (36%), amiodarone alone (8%)
showed a reduction of ventricular tachycardia or combined with beta-blockers (13%), beta-
recurrences and appropriate ICD interven- blockers alone (20%), and flecainide (2%)
tions when compared with all other patients were used as antiarrhythmic agents. During
in this study. These data, however, should be follow-up of 39 ± 25 months, 53 of 64 patients
interpreted with caution because of the small (83%) with appropriate ICD therapies (48%)
numbers of patients treated and the potential were on an antiarrhythmic drug at the time
selection bias involved.39 of the first ICD intervention. Compared with
the 51 of 68 patients (75%) with no or inap-
Comparison of Major Antiarrhythmic Drug propriate ICD interventions, there was no
Studies. Discrepancies between the North difference in antiarrhythmic drug efficacy.
American study by Marcus et al39 and the The incidence of ventricular flutter or fibrilla-
European experience reported by Wichter et tion as a surrogate for “hypothetical sudden
Drug Therapy in ARVC/D 87
death” did not differ in the groups with and a triggering factor for ventricular arrhythmia
without antiarrhythmic drug therapy, nor in many of these patients. However, whether
was a difference found in incidence of flut- these antiarrhythmic drug strategies improve
ter/fibrillation among patients on different prognosis by the prevention of sudden death
antiarrhythmic drugs.40 remains unproven.
On the other hand, a subgroup analysis
from the same study40 indicated that patients Monitoring of Antiarrhythmic Drug Efficacy.
with an index episode of VT without hemody- The available data indicate and confirm that
namic compromise had a favorable long-term adequate monitoring of drug efficacy is a
course without life-threatening ventricular mandatory prerequisite for long-term antiar-
tachyarrhythmia recurrences (ventricular flut- rhythmic drug therapy in ARVC/D. Empiric
ter or fibrillation) requiring ICD interventions. antiarrhythmic drug treatment without evi-
This indicates the potential role for antiar- dence for appropriate suppression of the clini-
rhythmic drug therapy in the intermediate risk cal arrhythmia cannot be recommended due
cohort with hemodynamically stable VT as an to a high incidence of VT recurrences and a
index event. significant mortality from sudden death dur-
The German single-center experience ing long-term follow-up.10-14,39 In contrast, the
from Münster reported similar results in high- assessment of antiarrhythmic drug efficacy
risk patients after ICD implantation41 and in by serial electrophysiologic studies (induc-
intermediate- or low-risk patients treated by ible VT) or Holter monitoring combined with
antiarrhythmic drugs or catheter ablation.37 exercise testing and/or provocation with intra-
Also, the Johns Hopkins experience from Bal- venous catecholamines (noninducible VT)
timore reported comparable data on ICD ther- provided better long-term outcomes when
apy and drug treatment in a cohort of ARVC/D compared with empiric drug treatment.36,37,43
patients with implanted defibrillators.42 In this context, it is important to stress the
Pezawas et al43 also confirmed these role of follow-up visits at regular and sched-
results and reported a low risk if the clini- uled intervals during the long-term course of
cal index VT or the induced VT was slower ARVC/D, not only to detect disease progres-
and hemodynamically well tolerated. In sion, but also to improve and optimize drug
such patients, a conservative approach with therapy and patient compliance. During rou-
antiarrhythmic drug therapy guided by pro- tine follow-up visits on antiarrhythmic drug
grammed ventricular stimulation was selected therapy, particular attention should be given
and resulted in good long-term outcomes. to arrhythmias and the QRS width (class-1
Several small studies confirmed the effi- drugs) and the QT interval (class-3 and class-
cacy of high-dose sotalol and amiodarone 1a drugs) in 12-lead resting ECG, exercise
with adjunct beta-blockade, both provid- test, and Holter monitoring. In addition, elec-
ing similar results in suppressing VT recur- trolyte disturbances (especially hypokalemia)
rences.13,14 The combination of amiodarone should be avoided, and attention should be
with beta-blockers may be more effective given to potential drug interactions (particu-
than the individual drugs alone. Both thera- larly those with QT prolongation) in order
peutic regimens consist of a combination of to prevent proarrhythmic drug effects. Serial
class-3 antiarrhythmic properties plus beta- echocardiography and/or MRI is useful for
blockade, which appears to act synergistically the early detection of disease progression and
in patients with ARVC/D. This may be due development of right and/or left ventricular
to the strong catecholamine dependence as dysfunction and heart failure.
88 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
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5. Marcus FI, Edson S, Towbin JA. Genetics of 15. Hulot S, Jouven X, Empana JP, Frank R,
arrhythmogenic right ventricular cardiomy- Fontaine G. Natural history and risk strati-
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trum of clinicopathologic manifestations of 16. Lemola K, Brunckhorst C, Helfenstein U,
arrhythmogenic right ventricular cardiomyop- Oechslin E, Jenni R, Duru F. Predictors of
athy/dysplasia: a multicenter study. J Am Coll adverse outcome in patients with arrhythmo-
Cardiol. 1997;30:1512-1520. genic right ventricular dysplasia/cardiomyop-
7. McKenna WJ, Thiene G, Nava A, et al. athy: long term experience of a tertiary care
Diagnosis of arrhythmogenic right ventricu- centre. Heart. 2005;91:1167-1172.
lar dysplasia/cardiomyopathy. Task Force of 17. Kiès P, Bootsma M, Bax J, Schalij MJ, van der
the Working Group Myocardial and Peri- Wall EE. Arrhythmogenic right ventricular
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Cardiology and of the Scientific Council on nosis, and treatment. Heart Rhythm. 2006;3:
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ety and Federation of Cardiology. Br Heart J. 18. Schuler PK, Haegeli LM, Saguner AM, et
1994;71:215-218. al. Predictors of appropriate ICD therapy in
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Diagnosis of arrhythmogenic right ventricular cardiomyopathy: long term experience of a ter-
cardiomyopathy/dysplasia: proposed modifi- tiary care center. PLoS ONE. 2012;7(9):e39584.
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2010;31:806-814. 19. Basso C, Wichter T, Danieli GA, et al.
9. Corrado D, Basso C, Thiene G. Pathological Arrhythmogenic right ventricular cardiomy-
findings in victims of sport-related sudden car- opathy: clinical registry and database, evalu-
diac death. Sports Exerc Injury. 1996;2:78-86. ation of therapies, pathology registry, DNA
10. Blomström-Lundqvist C, Sabel KG, Olsson banking. Eur Heart J. 2004;25:531-534.
SB. A long-term follow up of 15 patients with 20. Marcus F, Towbin JA, Zareba W, et al. ARVD/C
arrhythmogenic right ventricular dysplasia. Br Investigators. Arrhythmogenic right ventricular
Heart J. 1987;58:477-488. dysplasia/cardiomyopathy (ARVD/C): a multi-
11. Marcus FI, Fontaine GH, Frank R, Gallagher disciplinary study–design and protocol. Circu-
JJ, Reiter MJ. Long-term follow-up in patients lation. 2003;107:2975-2978.
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ease. Eur Heart J. 1989;10(Suppl. D):68-73. mogenic right ventricular cardiomyopathy/
12. Canu G, Atallah G, Claudel JP, et al. Prog- dysplasia clinical presentation and diagnostic
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39. Marcus GM, Glidden DV, Polonsky B, et al. tachycardia in arrhythmogenic right ven-
Efficacy of antiarrhythmic drugs in arrhyth- tricular dysplasia/cardiomyopathy: clinical
mogenic right ventricular cardiomyopathy. J presentation, risk stratification and results
Am Coll Cardiol. 2009;54:609-615. of long-term follow-up. Int J Cardiol.
40. Corrado D, Leoni L, Link MS, et al. Implant- 2006;107:360-368.
able cardioverter-defibrillator therapy for 44. Buja G, Estes NA III, Wichter T, Corrado D,
prevention of sudden death in patients with Marcus F, Thiene G. Arrhythmogenic right
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41. Wichter T, Paul M, Wollmann C, et al. 45. Corrado D, Calkins H, Link MS, et al.
Implantable cardioverter/defibrillator therapy Prophylactic implantable defibrillator in
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opathy: single-center experience of long-term ular cardiomyopathy/dysplasia and no prior
follow-up and complications in 60 patients. ventricular fibrillation or sustained ven-
Circulation. 2004;109:1503-1508. tricular tachycardia. Circulation. 2010;122:
42. Roguin A, Bomma CS, Nasir K, et al. Implant- 1144-1152.
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2004;43:1843-1852. incidence of appropriate and inappropri-
43. Pezawas T, Stix G, Kastner J, Schneider ate interventions, and complications. Circ
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8
The Role of Implantable Defibrillators
and Catheter Ablation in the Management
of Patients with Arrhythmogenic Right
Ventricular Cardiomyopathy/Dysplasia
for secondary prevention, experienced appro- ventricular tachycardia (NSVT) (P < 0.001),
priate ICD therapies (P = 0.001). EP testing and Holter PVC count > 1,000/24 hours
did not predict appropriate ICD interventions (P = 0.024) were identified as significant
in those who received an ICD for primary predictors of appropriate ICD therapy. The
prevention. Fourteen patients (21%) received 5-year survival free from appropriate ICD
ICD therapy for life-threatening (VT/VF therapy for patients with 1, 2, 3, and 4 risk fac-
> 240 bpm) arrhythmias. There was no dif- tors was 100%, 83%, 21%, and 15%, respec-
ference in the incidence of life-threatening tively. Inducibility at EP study (HR 4.5, 95%
arrhythmias in the primary and secondary CI 1.4–15, P = 0.013) and NSVT (HR 10.5,
prevention groups (P = 0.29). The results of 95% CI 2.4–46.2, P = 0.002) remained as sig-
this study revealed that patients who meet the nificant predictors on multivariable analysis.
2010 Task Force Criteria for ARVC/D8 are at These findings are important as they demon-
high risk for SCD and should undergo ICD strate that nearly half of the ARVC/D patients
implantation for primary and secondary pre- treated with an ICD for primary prevention
vention, regardless of EP testing results. experienced appropriate ICD interventions.
A more recent study19 focused on the Inducibility at EP study and NSVT are both
important issue of the role of ICDs for pri- independent, strong predictors of appropriate
mary prevention. This study reported the ICD therapy. In addition, ventricular ectopy
outcomes of 84 patients enrolled in the Johns is associated with progressively more common
Hopkins ARVC/D registry who had an ICD ICD therapy. Incremental risk of ventricular
implanted for primary prevention of VT or arrhythmias and ICD therapy was observed in
VF. Seventy (83%) patients were diagnosed the presence of multiple risk factors. In con-
with definite ARVC/D and 14 (17%) were sidering these results, it is important to recog-
diagnosed with probable ARVC/D based on nize that the use of appropriate ICD therapy
the 2010 Task Force Criteria.8 Thirty (36%) due to rapid VT/VF as a surrogate for SCD
patients had familial ARVC/D, whereas 54 results in an overestimation of this endpoint.
(64%) patients were probands with no family Our most recent study20 explored the
history of the disease. The pathogenic desmo- relationship between phenotypic charac-
somal mutation was discovered in 36 (43%) teristics and the proposed risk prediction
individuals after genetic testing. Seventy-two of sustained ventricular arrhythmias in 215
(86%) patients had inducible sustained VT/ patients with a desmosomal mutation identi-
VF (VT or VF lasting > 30 seconds or that fied through our Johns Hopkins ARVC/D reg-
needed to be stopped due to the development istry. Clinical, electrocardiographic (ECG),
of hemodynamic compromise) in a controlled and arrhythmic outcome (composite measure
EP study prior to the ICD intervention. The of first occurrence of sustained VT/resusci-
induced VT/VF had a mean cycle length of tated SCD/SCD/appropriate ICD therapy)
257 ± 54 ms. After Holter monitoring in 65 data was obtained for 215 patients (104 fami-
patients, 39 (60%) were determined to have lies; 85% with pathogenic PKP-2 mutations).
> 1,000 premature ventricular complexes Over a mean follow-up of 7 years, 86 (40%)
(PVCs)/24 hours. Over a mean follow-up of patients experienced the arrhythmic outcome.
4.7 ± 3.4 years, appropriate ICD therapy was Event-free survival was significantly lower
seen in 40 (48%) patients, of which 16 (19%) among probands (P < 0.001) and symptom-
received interventions for rapid VT/VF. Pro- atic (P < 0.001) patients. Integration of ECG
band status (P < 0.001), inducibility at EP repolarization and depolarization abnormali-
study (P = 0.005), presence of nonsustained ties allowed for differential risk categorization.
96 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Event-free survival at 5 years for the low-risk with ARVC/D associated mutations. Shown
ECG group (0–1 T inversions or minor depo- in Figure 8.1 is the risk-stratification scheme
larization changes) was 97% versus 81% for the we developed based on these variables.20
intermediate-risk ECG group (2 T inversions As shown in Figure 8.1,20 the high-risk group
+ minor depolarization changes) versus 33% (≥ 50%) was composed of (1) probands with
for the high-risk ECG group (≥ 3 T inversions high-risk ECG; (2) probands with an interme-
± major or minor depolarization changes) diate-risk ECG and PVC count > 760/24 hours
(P < 0.001). Incremental arrhythmic risk was on a Holter monitor; or (3) family members
seen in patients with increasing PVCs on a with a high-risk ECG and PVC count > 760/24
Holter (P < 0.001). Proband status (HR 7.7; hours on a Holter monitor. The intermediate-
95% CI 2.8–22.5; P < 0.001), ≥ 3 T-wave inver- risk group (15%–50%) included (1) probands
sions (HR 4.2; 95% CI 1.2–14.5; P = 0.035), with low-risk ECG; (2) family members with
and male gender (HR 1.8; 95% CI 1.2–2.8; high-risk ECG and PVC count between 11
P = 0.004) were independent predictors of the and 760 on a Holter monitor; and (3) probands
first arrhythmic event on multivariable analy- with intermediate-risk ECG and PVC count
sis. Overall, the results of this study revealed < 760 on a Holter monitor. The low-risk group
that pedigree evaluation, an ECG, and a (< 15%) was made up of (1) family members
Holter examination provide for comprehen- with a high-risk ECG and < 10 PVC on a
sive arrhythmic risk stratification in patients Holter monitor and (2) family members with
FIGURE 8.1 Proposed risk-prediction scheme based on pedigree, ECG risk categories, and ventricular ectopy . Source:
Bhonsale A et al .20
The Role of Implantable Defibrillators and Catheter Ablation in the Management of Patients 97
a low- or intermediate-risk ECG. Our scheme particular patient (1) demonstrates the pres-
is the first attempt to standardize the risk ence or absence of high-risk features such as
level of fatal arrhythmias for individuals with frequent PVCs, NSVT, cardiac syncope, and
the most common ARVC/D gene mutation. severe structural heart disease; (2) whether
Even more important is the fact that these risk the patient is willing to give up competitive
stratifications are determined by fundamental athletics (ie, participation on a competitive
clinical tests that can be easily performed. By sports team or participation in competitive
establishing concrete guidelines, we are help- individual events like marathon running); and
ing ARVC/D patients to make the appropriate (3) the patient’s values and preferences. We
choice on ICD implantation for the primary use a higher threshold for ICD implantation
prevention of SCD. in family members. This reflects the fact that
our studies have consistently revealed that fam-
Current Indications for ICD ily members are at lower risk of experiencing
Implantation in Patients with a sustained arrhythmia, are diagnosed earlier
ARVC/D in the course of the disease, and, once diag-
nosed, are encouraged to give up competitive
According to the ACC/AHA/HRS 2008 Guide- athletics.
lines for Device-Based Therapy of Cardiac
Rhythm Abnormalities,21 ICD implantation is Catheter Ablation in ARVC/D
indicated in patients with structural heart dis-
ease who have experienced a sustained ventric- Introduction
ular arrhythmia (secondary prevention, Class
I indication). These guidelines also state that Catheter ablation plays an important role in
ICD implantation is reasonable in ARVC/D the management of ARVC/D patients who
patients who have one or more risk factors for have experienced recurrent symptomatic epi-
SCD (IIA indication, level of evidence C). sodes of sustained VT. It is important to recog-
We are supportive of these recommen- nize that, unlike patients with idiopathic VT,
dations but have applied them with a slightly in which catheter ablation is curative, the role
different perspective. We recommend ICD of catheter ablation in patients with ARVC/D
implantation for all ARVC/D patients who is to improve quality of life by decreasing
have experienced a sustained ventricular the frequency of episodes of sustained VT,
arrhythmia (secondary prevention). We also symptomatic NSVT, and frequent ventricular
carefully consider ICD implantation for pri- ectopy. Our standard approach is to consider
mary prevention in probands who meet the catheter ablation following a trial of beta-
2010 Task Force Criteria for ARVC/D.8 To blocker therapy and antiarrhythmic therapy
meet the diagnosis of definite ARVC/D using (often sotalol or amiodarone). In selected
these diagnostic criteria requires (1) the pres- patients who prefer not to be treated with long-
ence of any 2 of the major criteria; (2) the pres- term antiarrhythmic drug therapy, we may
ence of any combination of 1 major and 2 minor consider catheter ablation as first-line therapy
criteria; or (3) the presence of 4 minor criteria. after a careful discussion of the risks and ben-
When discussing the risks and ben- efits of catheter ablation versus pharmacologic
efits of ICD implantation in this subgroup therapy. Many patients elect to pursue catheter
of patients, we carefully consider whether a ablation prior to a trial of amiodarone.
98 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
and > 1.5 mV were respectively classified VT). Twenty-three percent of the RF abla-
as “dense scar,” “abnormal,” and “normal” tions were acute failures with persistent induc-
myocardium. As a result, areas of scar could ibility of the clinical VT. The cumulative
be identified in all patients. Based on the VT-free survival was 75% at 1.5 months, 50%
detailed maps developed by the 3D CARTO at 5 months, and 25% at 14 months. Surpris-
catheter navigation system, linear ablation ingly, the acute success of the procedure did
techniques were used either to encircle the not predict the likelihood of VT recurrence.
scar or abnormal region or to connect the In 40 (85%) of the procedures, patients expe-
scar or abnormal tissues to other scar or valve rienced VT recurrence at an average of 8 ±
continuity. The results of the substrate-map- 10 months after the procedure. In total, the
ping ablative procedure showed success in incidence of VT was 64%, 75%, and 91% at
18 (82%) patients. During the first, second, 1, 2, and 3 years, respectively, after a single
and third years of follow-up, VT recurred in procedure.
23%, 27%, and 47% of patients, respectively. We more recently reported on the out-
Both of these studies prove that substrate- comes of a larger series of patients with
based catheter ablation can be successful at ARVC/D who underwent an endocardial
controlling VT, especially in patients with or epicardial VT ablation procedure. In this
complicated forms of ARVC/D. recent study,30 we report the outcomes of 87
patients. Twenty-three patients, 19 of whom
The Johns Hopkins Experience with had experienced at least 1 previously failed
VT Ablation in Patients with ARVC/D endocardial catheter ablation, completed 26
epicardial catheter ablations. Ten of those
Although many studies have reported the procedures were solely epicardial ablations,
safety and efficacy of RF catheter ablation of whereas 16 were both epicardial and endocar-
VT in patients with ARVC/D, we will focus dial procedures. Over a mean follow-up of 88
our review on the studies that have been pub- ± 66 months, the overall freedom from VT
lished based on data obtained from the Johns was 47%, 21%, and 15% at 1, 5, and 10 years,
Hopkins ARVC/D registry, which tracks respectively. The cumulative freedom from
the outcomes of hundreds of patients with VT following epicardial VT ablation was 64%
ARVC/D across the United States. Our first at 1 year and 45% at 5 years. Importantly, the
study,29 which examined the outcomes of VT burden of VT decreased following ablation
ablation in patients with ARVC/D, was pub- from a median of 0.16 VT episodes per month
lished in 2007. In this study, we reported the preablation to 0.08 episodes per month post-
outcomes of 48 ablation procedures performed ablation. The results of this study were signifi-
in 24 patients with ARVC/D. In particular, cant as they demonstrated for the first time
we explored the long-term success rates of that VT ablation reduces the frequency of VT
RF catheter ablation in 24 ARVC/D patients. episodes in ARVC/D and also showed that
These 24 patients underwent 48 RF ablation outcomes are improved when an epicardial
procedures using 4 mm tipped deflectable approach is employed.
catheters at 29 different electrophysiology cen- Our most recent report31 focused on the
ters in the United States. The results of our value of catecholamine infusions in triggering
study revealed that 46% of procedures were VT in patients with ARVC/D. In this study,
acutely successful and 31% were partially suc- we looked at the relationship between the
cessful (defined as elimination of the clinical morphology of ventricular ectopy and the
VT but persistent inducibility of a nonclinical morphology of induced, sustained VT in 16
100 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
ARVC/D patients. The mean baseline PVC 74.5% VT-free survival after 2 years. This
frequency was 7,275 (range, 1,353–19,084) reduction in VT recurrence also was associ-
per 24 hours. Our approach involved per- ated with a decrease in PVC count among
forming a diagnostic EP study at baseline the ARVC/D patients.
both prior to and following a very high-dose
(30 mcg/kg/min) infusion of isoproterenol Current Indications and
(Figure 8.2). We recorded 12-lead ECG Techniques for VT Ablation in
morphologies of all baseline PVCs preferably Patients with ARVC/D
at baseline and during a high-dose isoproter-
enol infusion. Following this EP study, RF Catheter ablation now plays an important
catheter ablation (endo or endo/epi) was per- role in the management of our patients with
formed under sedation along with adminis- definite or suspected ARVC/D. We gener-
tration of high-dose isoproterenol. In a series ally recommend that a diagnostic EP study
of 16 ARVC/D patients, sustained VT was and endocardial VT ablation procedure be
induced in 11 of the 16 patients (68%) dur- performed in patients who present with sus-
ing isoproterenol infusion, either spontane- tained VT with a left bundle block morphol-
ously or by burst pacing. Furthermore, the ogy and also in patients with a high frequency
morphology of the induced VT was similar of PVCs (> 30,000 per 24 hours). For these
to the baseline PVCs in 59% of the induced patients, the EP study and endocardial map-
VTs. Based on the PVC/VT morphology, we ping procedure is of value in confirming the
performed a detailed map to identify regions diagnosis of suspected ARVC/D and also for
of scarred myocardium demonstrating low risk stratification. If a single PVC or VT mor-
voltage and multiple fragmented and delayed phology is identified arising from the right
electrograms. The ablation strategy we ventricular outflow tract without evidence of
employed was ablation of all of these areas. endocardial scar, the diagnosis of idiopathic
The endpoint of the procedure was nonin- VT is supported. For these patients, a VT or
ducibility of VT and/or PVCs, and the iso- PVC ablation procedure is often curative.
proterenol challenge was repeated at the end On the other hand, if multiple morphologies
of the ablation. Our results showed 85.2% of VT are found with evidence of endocar-
cumulative VT-free survival after 1 year and dial scar, the diagnosis of ARVC/D is more
A B
FIGURE 8.2 Complex ventricular ectopy during high-dose isoproterenol infusion (Panel A) that organizes into sustained
monomorphic ventricular tachycardia (Panel B) in a patient with ARVC/D . Source: Philips B et al .31
The Role of Implantable Defibrillators and Catheter Ablation in the Management of Patients 101
likely. It is important to recognize that areas tative epicardial voltage map obtained from a
of low voltage may reflect scar but also may be patient with ARVC/D undergoing an epicar-
due to poor tissue contact. The hallmark of dial ablation procedure. The endocardial volt-
ARVC/D is the identification of areas demon- age map in this patient was normal.
strating low voltage as well as multiple sharp The epicardial ablation strategy, although
components of an electrogram (thereby also associated with better outcomes, is not without
demonstrating slow conduction and areas of potential for complications. Epicardial access
conduction block). technique requires considerable understand-
For most patients with a history of VT ing of the cardiac and thoracic anatomy and, in
who are given a diagnosis of ARVC/D, we our experience, preprocedural imaging to plan
recommend placement of an ICD and drug the access is crucial in avoiding complications.
therapy with a beta-blocker or with sotalol. If Structures that are at risk for injury are the liver,
these medications are not tolerated or if recur- the stomach, the left internal mammary artery,
rent VT develops, patients have the option of the left lung, right ventricle, and the blood ves-
proceeding with a VT ablation procedure or sels in the interventricular groove. Laceration of
being started on amiodarone. For those inter- vascular structures and perforation of the right
ested in VT ablation, a decision must be made ventricle often result in the need for urgent tho-
as to whether their initial ablation procedure is racotomy to achieve hemostasis.
endocardial only or if they prefer to undergo a We perform a contrast CT that is used to
combined endocardial/epicardial ablation pro- visualize pericardial fluid and for image integra-
cedure. Increasingly, we encourage patients tion to facilitate electroanatomic mapping. In
with established ARVC/D who require a VT the supine position, the pericardial fluid accu-
ablation procedure to undergo a combined mulates anteriorly and the heart sinks to the
endocardial/epicardial substrate-based abla- bottom of the pericardial sac. A shallow anterior
tion procedure. In more than 30 patients, our approach targeting the mid-anterior RV wall is
success rate has exceeded 85% with no serious optimal for RV mapping and ablation. Axial and
complications.30 Figure 8.3 shows a represen- sagittal CT images will outline the pericardial
space to be accessed, both providing the extent of patients with ARVC/D. We recommend
of the fluid and a visual guide to the depth and EP testing and a limited ablation procedure
the distance from the midline. We perform our early in the course of the disease, especially
epicardial access under biplane fluoroscopy in patients suspected of having possible idio-
using anteroposterior and lateral views to emu- pathic VT or PVCs. We also recommend EP
late the axial and sagittal CT views. Using this testing and VT ablation using an endocardial/
technique, we have successfully performed epi- epicardial approach in patients with definite
cardial access in 25 ARVC/D patients with no ARVC/D who have recurrent VT and have
major complications except for mild pericarditis failed or been intolerant of antiarrhythmic
that resolved within 24 hours of the ablation.30 drug therapy. A decision whether to undergo
After aspirating all the pericardial fluid, we rou- VT ablation is highly dependent on the experi-
tinely administer 125 mg of methylprednisone ence of the operator and ablation center as well
into the pericardial cavity before withdrawing as the values and preferences of the patient
the pericardial sheath. who is contemplating the therapeutic options.
We use a deflectable epicardial sheath in
order to aid mapping of the RV and the LV Conclusion
epicardial surface. Using a 4 mm irrigated ICD therapy and catheter ablation are com-
catheter, detailed mapping of the RV is per- plementary strategies used for treatment of
formed while frequently aspirating the irrigat- patients with ARVC/D. ICD implantation
ing fluid in order to ensure proper contact of plays an important role for secondary preven-
the mapping catheter. Interpretation of low tion. It is also of value in ARVC/D patients felt
voltage in the epicardium can be challenging, to be at increased risk of sudden death based
especially close to the atrioventricular groove on careful risk stratification. Catheter ablation
and the apex, as the epicardial fat significantly of VT in the setting of ARVC/D is an impor-
attenuates the myocardial signal. Cut-off val- tant palliative procedure, the goal of which is
ues for abnormal RV voltage that have been to decrease the frequency of VT episodes. As
published, however, have not been extensively with all treatment strategies, a careful discus-
validated. For this reason, we rely on fraction- sion with the patient is important in deciding
ated potentials that are distinctly later than the on an optimal treatment strategy.
surface QRS, rather than low-voltage but early-
activated regions. Fractionated late potentials Acknowledgments
are frequently observed in the perivalvular
region, especially in the anterobasal and infero- The authors wish to acknowledge financial
basal RV. Both of these regions are affected support received by Dr. Calkins from the St.
in the majority of ARVC/D patients. We per- Jude Medical Foundation and Medtronic,
form pacemapping to identify the exit sites of Inc. The Johns Hopkins ARVC/D Program
the induced VT, which often localizes to the (ARVD.com) is supported by the Bogle Foun-
region of late potentials. Systematic ablation of dation, the Healing Hearts Foundation, the
all the late potentials eliminates the PVCs and Campanella family, and Wilmerding Endow-
renders the VT noninducible. ments, and the Dr. Francis P. Chiaramonte
Private Foundation.
Summary
Abbreviations
In summary, catheter ablation of VT now EP electrophysiologic, electrophysiology
plays an important role in the management FFRW far-field R wave
The Role of Implantable Defibrillators and Catheter Ablation in the Management of Patients 103
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therapies in patients with arrhythmogenic frequency catheter ablation of ventricular
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lar dysplasia: experience of 15 patients with a 31. Philips B, Madhavan S, James C, et al. High
mean follow-up of 45 months. Heart Vessels. prevalence of catecholamine-facilitated focal
1990;5(3):172-187. ventricular tachycardia in patients with
23. Fontaine G, Tonet J, Gallais Y, et al. Ventricular arrhythmogenic right ventricular dysplasia/
tachycardia catheter ablation in arrhythmogenic cardiomyopathy. Circ Arrhythm Electro-
right ventricular dysplasia: a 16-year experience. physiol. 2013;6(1):160-166.
Curr Cardiol Rep. 2000;2(6):498-506.
9
center and followed for 8.1 ± 7.8 years. There ventricular conduction predisposing to lethal
were 21 deaths, which accounted for an annual arrhythmias even in the prephenotypic phase
mortality rate of 3% due to either progressive of the disease, that is, before the appearance
heart failure in approximately two-thirds of of histological fibrofatty substitution.10-12 How-
patients or SCD in one-third of patients. ever, the clinical relevance of these findings
The mechanism of SCD in ARVC/D is remains to be proven.
cardiac arrest due to VF, which frequently
occurs as a first and definitive manifestation of Risk Stratification
the disease in young people without previous SCD in ARVC/D patients is often an unpre-
symptoms. In the early disease phase, VF may dictable event that occurs without alarming
reflect acute ventricular electrical instability symptoms, and the only reliable strategy
related to “hot phases” of the disease, with for SCD prevention is the implantation of
acute myocyte death and reactive inflamma- an implantable cardioverter-defibrillator
tion, often characterized by dynamic T-wave (ICD).1,2 In recent years, a number of studies
inversion, ST segment elevation, and myocar- tried to identify the clinical variable associ-
dial enzyme release. Older patients with a ated with an unfavorable arrhythmic course.
long-lasting disease more often experience These studies suggested that symptomatic
scar-related, hemodynamically stable VT.1,2 ARVC/D patients with prior cardiac arrest
It should be emphasized that ARVC/D due to VF, a history of syncopal episodes,
shows a propensity for life-threatening ventricu- and sustained ventricular tachycardia (VT)
lar arrhythmias during physical exercise, and benefit the most from ICD implantation. In
participation in competitive athletics has been contrast, the role of prophylactic ICD ther-
associated with an increased risk for SCD.3,4,8 apy in asymptomatic patients or relatives pre-
Identification of affected athletes by prepar- senting with traditional risk factors such as
ticipation screening has proven to result in a a family history of SCD, severe RV dysfunc-
substantial reduction of mortality of young tion, and inducibility of sustained VT/VF at
competitive athletes.4 In addition, physical programmed ventricular stimulation (PVS)
sports activity has been implicated as a factor remains controversial.13-41
promoting acceleration of disease progression.
There is experimental evidence that in hetero- Previous Major Arrhythmic Events
zygous plakoglobin-deficient mice, endurance
training accelerated the development of right In the series reported by Canu et al,13 a prior
ventricular (RV) dysfunction and arrhythmias.9 history of aborted SCD from VF was docu-
It has been advocated that impairment of myo- mented in 2 of the 3 patients who died sud-
cyte cell-to-cell adhesion may lead to tissue denly. In the DARVIN 1 study, Corrado et
and organ fragility that is sufficient to promote al reported that prior cardiac arrest due to
myocyte death, especially under conditions of VF and hemodynamically unstable VT are
mechanical stress, like that occurring during independent risk factors for life-saving ICD
competitive sports activity.2 interventions in a large series of ARVC/D
More recently, experimental animal patients, while patients implanted because of
models have suggested that gap junction VT without hemodynamic compromise had
remodeling and ion channel interference by a statistically significantly better outcome,
the diseased desmosomes may be alternative with a negligible incidence of VF episodes
substrates for anisotropic and delayed intra- during follow-up (Figure 9.1).14
Risk Stratification and Prognosis 107
Syncope has been proven to be the nonarrhythmic syncope, which makes dif-
strongest predictor of appropriate and life-sav- ferential diagnosis difficult and its prognos-
ing device interventions in patients with tic value elusive. For instance, in patients
ARVC/D who received an ICD for primary with hypertrophic cardiomyopathy, several
prevention (DARVIN 2). The 9% annual nonarrhythmic mechanisms such as reflex-
incidence of appropriate device discharges mediated change in vascular tone or heart
among patients with prior syncope is compar- rate, left ventricular outflow tract obstruction,
able to that observed in patients who under- and supraventricular tachyarrhythmia may
went device implantation because of a history cause syncope. On the contrary, in ARVC/D
of cardiac arrest or sustained VT (Figure 9.2).18 patients, most episodes of syncope are second-
Young individuals with genetic cardio- ary due to ventricular tachyarrhythmias and,
myopathies and/or ion channel disorders thus, associated with a poor prognosis similar
may suffer from vasovagal or, more widely, to previous sustained VT or VF.18
FIGURE 9.2 DARVIN II study, including ARVC/D patients who received an ICD for primary prevention only . Panel A: Kaplan-
Meier analysis of cumulative survival from any appropriate ICD interventions . Panel B: Kaplan-Meier analysis of survival free
of ventricular fibrillation/flutter (VF/Vfl) compared with actual patient survival . The estimated mortality reduction at 48 months
of follow-up is 23% (ie, the difference between the actual patient survival rate of 100% and VF/Vfl-free survival rate of 77%) .
Panels C and D: Kaplan-Meier analysis of freedom from any appropriate ICD interventions (Panel C) and shock therapies on
VF/Vfl (Panel D), stratified by syncope . Source: Modified from Corrado et al .18
Risk Stratification and Prognosis 109
arrhythmias had abnormal SAECG. Likewise, rence of major arrhythmic events during
the study of Nava et al30 failed to show any cor- follow-up (Figure 9.3).34
relation between SAECG and the risk of life-
threatening ventricular arrhythmias. Right Ventricular Dysfunction and Left Ven-
tricular Involvement. A ventricular dilata-
ECG Repolarization Abnormalities. Sev- tion/dysfunction is a well-established clinical
eral studies demonstrated that T waves in marker of a worse prognosis. In the study by
ARVC/D typically become negative as the Hulot et al6 that tracked the long-term follow-
disease worsens, and that a greater extent of up of 130 patients with ARVC/D, right heart
negative T waves across the 12-lead ECG is failure and LV dysfunction were identified as
associated with more severe RV dilation and independent risk factors predicting cardiovascu-
dysfunction.31-34 Turrini et al found that the lar death. Peters et al37 confirmed these results
incidence of negative T waves is higher among in 121 ARVC/D patients, in whom advanced
ARVC/D patients with a history of previous RV dilatation/dysfunction and LV involvement
cardiac arrest or sustained ventricular tachy- were major clinical variables associated with an
cardia compared to those with a less severe increase risk of SCD. Turrini et al28 reported a
arrhythmic burden.20 Three recent studies significant association between a reduced RV
extended this previous observation. First, ejection fraction (≤ 50%) determined by RV
Te Riele et al found that 88% of ARVC/D angiography and sustained ventricular arrhyth-
patients with documented, sustained ven- mias. A number of ICD studies indicated exten-
tricular arrhythmias within the last 6 months sive RV dysfunction as an independent risk
had an abnormal ECG. In particular, 122/145 factor for appropriate device discharges.38,39
(84%) subjects exhibited T-wave inversion
in precordial leads (in 97 of them, extend- Inducibility at Programmed
ing to lead V3 or beyond), while depolariza- Ventricular Stimulation
tion abnormalities such as Epsilon waves or
terminal activation duration > 55 ms were The electrophysiological study with programmed
present only in a minority of subjects.35 Sec- ventricular simulation (PVS) appears to be of
ond, Bhonsale et al, focusing on desmosomal limited value in identifying ARVC/D patients at
gene mutation carriers, found that the pres- risk of lethal ventricular arrhythmias due to a low
ence of T-wave inversion in ≥ 3 ECG leads predictive accuracy. The results of the DARVIN
was a powerful and independent noninvasive studies demonstrate that the incidence of appro-
predictor of events during follow-up.36 Third, priate and life-saving ICD discharges did not
Zorzi et al demonstrated that the extent of differ among patients who were and were not
negative T waves was the only independent inducible at PVS, regardless of their indication
ECG predictor of the degree of fibrofatty for ICD implant.14,18 Moreover, the type of ven-
substitution, as assessed by the endocardial tricular tachyarrhythmia inducible at the time
voltage mapping (see below), and it prevailed of electrophysiological study did not appear to
over RV dilation and dysfunction in predict- predict the occurrence of VF during follow-
ing the extent of the RV scar. In this study, up. These findings are in agreement with the
the link between repolarization abnormalities limitation of PVS for arrhythmic risk stratifica-
and the underlying scar substrate was further tion in other nonischemic heart diseases such
substantiated by the association between the as hypertrophic and dilated cardiomyopathy.
extent of negative T waves and the occur- In the study of Wichter et al,38 VT/VF induc-
ibility at preimplant electrophysiologic study
Risk Stratification and Prognosis 111
FIGURE 9.3 Panel A: Correlation between the extent of negative T waves (NTW) and amount of right ventricular
electroanatomical scar size (EAS% area) . Panel B: Kaplan-Meier analysis of survival free from major arrhythmic events
according to presence and the extent of negative T waves . Source: From Zorzi et al .34
in ARVC/D patients with a previous history of values of PVS inducibility were 65% and
cardiac arrest or sustained VT demonstrated 75%, respectively, and a sizable proportion
just a trend toward statistical significance for of patients experienced ICD interventions
subsequent appropriate device interventions. In during follow-up despite a negative test.
addition, in 2 recent studies assessing the prog- Discrepancies between study results may be
nostic value of endocardial voltage mapping explained by differences in arrhythmic end-
(see below), inducibility at PVS was a poor pre- points (ie, life-saving interventions versus
dictor of arrhythmic events during follow-up.40,41 any appropriate ICD discharges), population
At variance, inducibility at PVS was characteristics, and stimulation protocols. In
the most significant independent predictor this regard, the predictive role of PVS induc-
of appropriate ICD firing in the ARVC/D ibility as either a univariate or multivariate
cohort reported by the Johns Hopkins stud- predictor of life-saving ICD discharges for
ies.39,42 However, in the study by Bhonsale VF/ventricular flutter was not demonstrated
et al, the positive and negative predictive in the Johns Hopkins series.42
112 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
phenotypic expression and follow a benign stratification. These findings imply that other
course. On the other hand, patients may suffer environmental or genetic factors, such as the
arrhythmic events without warning symptoms presence of genetic modifiers or compound
and/or signs, in the setting of an unpredictable heterozygous mutations, may influence the
and abrupt acceleration of disease progression severity of disease clinical expression.
(“hot phases”).1,2
Furthermore, genotype–phenotype corre- Prevention of Sudden Death
lation studies have failed to detect malignant
ARVC/D mutations, which are specifically Implantation of an ICD is the most logical
associated with an increased susceptibility to therapeutic strategy for patients with ARVC/D,
life-threatening arrhythmic events as to require whose natural history is primarily character-
prophylactic ICD therapy.45 An exception is ized by the risk of arrhythmic cardiac arrest.
the study by Merner et al,46 which reported a Figure 9.5 shows the “pyramid” of arrhyth-
very malignant variant of ARVC/D linked to mic risk stratification and indications for ICD
a transmembrane TMEM43 gene mutation. implantation in ARVC/D patients, based on
No significant differences have been reported the annual rate of appropriate ICD interven-
with regard to a series of clinical, ECG, and tions for life-threatening ventricular arrhyth-
arrhythmic variables between ARVC/D muta- mias derived from observational studies.
tion carriers and noncarriers. In addition, the There is general agreement that patients
proportion of patients who received an ICD who survived an episode of VF or sustained VT
and the incidence of appropriate discharges most benefit from ICD implantation because of
during follow-up did not differ between gene- their high incidence of malignant arrhythmia
positive and gene-negative probands, sug- recurrences.14 On the other hand, asymptom-
gesting that genetic screening for ARVC/D atic patients had a favorable long-term outcome
gene mutations is unlikely to contribute sig- regardless of familial SCD and electrophysi-
nificantly to arrhythmic risk assessment and ologic study findings.18 These results are par-
Lowest < 1%/year Probands or relatives fulfilling Task Force Criteria for ARVC/D, Unjustified
regardless of family history of SD or inducibility at PVS (in the
absence of syncope, VT, or severe ventricular dysfunction)
FIGURE 9.5 Pyramid of arrhythmic risk stratification and current indications for ICD implantation in ARVC/D patients,
based on the annual rate of appropriate ICD interventions for life-threatening ventricular arrhythmias (ie, episodes of VF/Vfl)
derived from observational studies . Source: Modified from Corrado et al .47
114 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
12. Rizzo S, Lodder EM, Verkerk AO, et al. Interca- according to disease severity. Circulation.
lated disc abnormalities, reduced Na(+) current 2004;110:1527-1534.
density, and conduction slowing in desmo- 22. Marcus FI, Fontaine GH, Guiraudon G, et al.
glein-2 mutant mice prior to cardiomyopathic Right ventricular dysplasia: a report of 24 adult
changes. Cardiovasc Res. 2012;95:409-418. cases. Circulation. 1982;65:384-398.
13. Canu G, Atallah G, Claudel JP, et al. Pro- 23. Blomström-Lundqvist C, Hirsch I, Olsson
nostic et “evolution” a long term de la dys- SB, et al. Quantitative analysis of the signal
plasie arythmogène du ventricule droit. Arch averaged QRS in patients with arrhythmo-
Mal Coeur Vaiss. 1993;86:41-48. genic right ventricular dysplasia. Eur Heart J.
14. Corrado D, Leoni L, Link MS, et al. Implant- 1988;9:301-312.
able cardioverter defibrillator therapy for 24. Wichter T, Hindricks G, Lerch H, et al.
prevention of sudden death in patients with Regional myocardial sympathetic dysinner-
arrhythmogenic right ventricular cardio- vation in arrhythmogenic right ventricular
myopathy/dysplasia. Circulation. 2003;108: cardiomyopathy: an analysis using 123I-meta-
3084-3091. odobenzylguanidine scintigraphy. Circula-
15. Marcus FI, Fontaine GH, Frank R, et al. tion. 1994;89:667-683.
Long-term followup in patients with arrhyth- 25. Mehta D, Goldman M, David O, et al.
mogenic right ventricular disease. Eur Heart J. Value of quantitative measurements of signal
1989;10(Suppl. D):68-73. averaged electrocardiographic variables in
16. Turrini P, Corrado D, Basso C, et al. Disper- arrhythmogenic right ventricular dysplasia:
sion of ventricular depolarization-repolariza- correlation with echocardiographic right ven-
tion: a noninvasive marker for risk stratification tricular cavity dimensions. J Am Coll Cardiol.
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17. Blomström-Lundqvist C, Sabel KG, Olsson arrhythmogenic right ventricular dysplasia.
SB. A long term follow-up of 15 patients with Prevalence, diagnostic and prognostic values
arrhythmogenic right ventricular dysplasia. Br Eur Heart J. 1993;14:80-83.
Heart J. 1987;58:477-488. 27. Blomström-Lundqvist C, Olsson SB, Edvards-
18. Corrado D, Calkins H, Link M, et al. Pro- son N. Follow-up by repeated signal-averaged
phylactic implantable defibrillator in patients surface QRS in patients with the syndrome of
with arrhythmogenic right ventricular cardio- arrhythmogenic right ventricular dysplasia.
myopathy/dysplasia and no prior ventricular Eur Heart J. 1989;10(Suppl D):54-60.
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dia. Circulation. 2010;122;1144-1152. potentials and ventricular arrhythmias in
19. Fontaine G, Umemura J, Di Donna P, et al. arrhythmogenic right ventricular cardiomy-
La duree des complexes QRS dans la dysplasie opathy. Am J Cardiol. 1999;83:1214-1219.
ventriculaire droite arythmogene: un noveau 29. Oselladore L, Nava A, Buja G, et al. Signal-
marqueur diagnostique non invasif. Ann Car- averaged electrocardiography in familial form of
diol Angeiol. 1993;42:399-405. arrhythmogenic right ventricular cardiomyopa-
20. Turrini P, Corrado D, Basso C, et al. Disper- thy. Am J Cardiol. 1995;75(Suppl E):1038-1041.
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thy. Circulation. 2001;103:3075-3080. athy and ventricular arrhythmias. Eur Heart J.
21. Nasir K, Bomma C, Tandri H, et al. Elec- 2000;21:58-65.
trocardiographic features of arrhythmogenic 31. Steriotis AK, Bauce B, Daliento L, et al. Elec-
right ventricular dysplasia/cardiomyopathy trocardiographic pattern in arrhythmogenic
116 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
right ventricular cardiomyopathy. Am J Car- 40. Migliore F, Zorzi A, Silvano M, et al. Prognos-
diol. 2009;103:1302-1308. tic value of endocardial voltage mapping in
32. Marcus FI, Zareba W. The electrocardiogram patients with arrhythmogenic right ventricu-
in right ventricular cardiomyopathy/dyspla- lar cardiomyopathy/dysplasia. Circ Arrhythm
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understanding the pathologic and functional 41. Santangeli P, Dello Russo A, Pieroni M, et
changes of the heart in this disease? J Electro- al. Fragmented and delayed electrograms
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33. Nava A, Martini B, Thiene G, et al. Arrhyth- events in arrhythmogenic right ventricular
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ventricular cardiomyopathy: implications genic right ventricular dysplasia/cardiomyopathy
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37. Peters S, Peters H, Thierfelder L. Risk stratifi- 45. Corrado D, Thiene G. Arrhythmogenic right
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2004;43:1843-1852.
10
Ardan M . Saguner, MD
in the Veneto region from 3.5/100,000 in sian families. This has been explained as a
1979 to 0.5/100,000 in 2003.12,13 In 2003, the founder gene effect, attributed to one of the
DARVIN I study recruited 132 patients with early Dutch settlers arriving in South Africa.
ARVC/D from 22 institutions in northern The genotypic profile of the SA ARVC cohort
Italy and 1 in the United States and found was in concordance with the genotypic pro-
that almost 50% of the patients were saved file of the Dutch cohort, published in 2006
by appropriate ICD therapy during the study and updated in 2011, in which PKP2 gene
period of 39 months.14 In 2009, researchers mutations were found in more than half of
from the U.K. found that cardiomyopathies all Dutch patients with ARVC/D.18,19 Similar
are the most common cause of SCD in findings from separate cohorts from 2 differ-
young British athletes, with ARVC/D attrib- ent continents highlight the importance of
uted to 14% of these deaths.15 historic, ethnic, and sociologic factors when
Besides Europe, other continents have investigating a genetically determined dis-
also made important contributions to our ease. A large ARVC/D registry from Johns
understanding of ARVC/D. The South Hopkins (Baltimore, MD) was established
African ARVC (SA ARVC) registry was set in the 1980s and has published numerous
up in 2004, and published its first results in landmark papers since then.20-26 In 2009, the
2009 on the clinical course of its cohort.16,17 Multidisciplinary Study of Right Ventricular
Although the characteristics of ARVC/D in Dysplasia Investigators, also from the United
South Africa are similar to the French cohort, States, showed that amiodarone had superior
the SA ARVC registry was able to identify 5 efficacy in preventing ventricular arrhythmias
new PKP2 gene mutations, with 1 gene muta- compared to beta-blockers and sotalol in their
tion found in 4 different, unrelated Cauca- North American cohort of 95 patients.27 In
FIGURE 10.1 ARVC/D registries worldwide: For more than 15 years, ARVC/D has been studied in national and international
networks in order to gather capacities and knowledge, and to increase patient numbers . Source: Adapted from Elmaghawry M,
Alhashemi M, Zorzi A, Yacoub MH . Global Cardiol Sci Pract. 2012:26 (http://dx .doi .org/10 .5339 gcsp .2012 .26) .
TABLE 10.1 ARVC/D registries worldwide
The Johns Hopkins ARVC/D 1,226 226 Retrospective Active H . Calkins, MD arvd .com ctichne1@jhmi .edu
Program & Prospective
Dutch ARVC Registry 491 93 Retrospective Active R . Hauer, MD — R .N .W .Hauer@umcutrecht .nl
& prospective
Münster ARVC Registry 360 — Retrospective Active M . Paul, MD matthias .paul@ukmuenster .de
& Prospective T . Wichter, MD
Nordic ARVC Registry 317 268 Retrospective Active J .H . Svendsen, MD arvc .dk anders@kanten .dk
& Prospective
Zurich ARVC Registry 183 158 Retrospective Active F . Duru, MD arvc .ch arvc@usz .ch
& Prospective C . Brunckhorst, MD
A . Saguner, MD
Trieste ARVC Registry, Italy 129 — Retrospective Active B . Pinamonti, MD — dragosandreea82@yahoo .com
& Prospective
South African ARVC Registry 130 — Prospective Active B . Mayosi, MD www .paceafrica .org .za arvc .sa@uct .ac .za
North American 101 — Prospective Inactive F . Marcus, MD arvd .org fmarcus@shc .arizona .edu
Multidisciplinary Study
Australian Heart Registry 87 40 Prospective Active C . Semsarian, MD heartregistry .org .au j .ingles@centenary .org .au
J . Ingles, MD
Total 3,024
The Zurich ARVC Program
119
120 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Australia, a major national registry on cardio- lar Division of the University Heart Center,
myopathies was initiated in 2008.28 ARVC/D Zurich, Switzerland. The principal inves-
has also been observed in Japan, China, and tigators are Firat Duru, MD, Corinna B.
South America.29-31 In 1998, investigators from Brunckhorst, MD, and Ardan M. Saguner,
Ecuador published a case series of 12 patients MD, cardiologists with a special expertise in
presenting with cardiocutaneous syndrome of cardiac electrophysiology. The original idea
palmoplantar keratosis and dilated cardiomy- for such a registry derives from the fact that
opathy resembling Naxos disease.32 This syn- the University Heart Center, Zurich—with
drome is called Carvajal syndrome and has initially more than 100 patients and family
been attributed to severe desmoplakin muta- members—is caring for the largest number
tions.33 It is noteworthy that there have been of ARVC/D patients in Switzerland, and
case reports of patients with Carvajal syn- thus shares a considerable expertise in this
drome from Turkey, Greece, and the Arabian field. Yet, an important coincidence finally
Peninsula, demonstrating that cardiac genetic enabled the realization of this project. A
cardiomyopathies are not restricted to certain young athlete and medical student from the
geographic areas.34-37 As ARVC/D is present University of Zurich experienced an episode
worldwide and does not have a specific racial of arrhythmogenic syncope while playing
or geographical predilection, international football at the age of 19. He was immediately
collaborations are of paramount importance referred to the university’s hospital and diag-
to improve our understanding of this complex nosed with ARVC/D, after he had been eval-
disease. To accommodate this issue, a multi- uated by several physicians in the previous
disciplinary collaborative international regis- years without a clear diagnosis being made.
try has been established by the Study Group Subsequently, an ICD was implanted. As
on ARVC/D of the Working Groups on Myo- this young man’s father was a leading mem-
cardial and Pericardial Disease and Arrhyth- ber of the oldest and one of the largest Swiss
mias of the European Society of Cardiology private foundations, the Georg und Bertha
and the Scientific Council on Cardiomyopa- Schwyzer-Winiker Foundation—an organi-
thies of the World Heart Federation in 2001, zation that supports social, cultural, environ-
coordinated from Padua, Italy.3 At the same mental, veterinarian, and medical research
time, the Multidisciplinary Study of Right projects, particularly at the University of
Ventricular Dysplasia Investigators in North Zurich—the foundation provided generous
America was coordinated by Dr. Frank Mar- financial funding for the hospital’s ARVC/D
cus.4 The comprehensive research of these project, which gave birth to the Zurich
large registries has laid the groundwork for the ARVC Program. This program aims to char-
Revised 2010 Task Force Criteria for the diag- acterize the Swiss ARVC/D cohort, based
nosis of ARVC/D.38 Although our understand- on various clinical and basic research proto-
ing of ARVC/D has significantly improved cols, in order to improve our understanding
during recent years, numerous unresolved of this complex disease, but also to provide
issues remain. expert care for patients with ARVC/D in
Switzerland. A nationwide registry is nec-
Establishment of a essary to have an adequate sample size and
Swiss Registry prospectively evaluate the accuracy of clini-
cal diagnosis, long-term clinical outcome,
The Zurich ARVC Program was established and efficacy of therapy. This registry has the
in July 2011 and is based at the Cardiovascu- potential to facilitate genetic and molecular
The Zurich ARVC Program 121
research on the causes and pathophysiol- 2011. Physicians and other hospitals refer sus-
ogy of ARVC/D. Furthermore, availability pected cases to our local panel of ARVC/D
of a national database will enhance aware- experts, consisting of electrophysiologists,
ness of this underrecognized but important cardiac genetic specialists, cardiac imagers,
disease among local cardiologists. Particular heart failure specialists, and cardiac sur-
attention is drawn to genetic and molecu- geons, for further evaluation. In addition,
lar heterogeneity and joint genetic traits in we have a very close collaboration with our
comparison to other ARVC/D cohorts. To cardiac pathology specialists and the forensic
quote Guy Fontaine, the first describer of institute of the University of Zurich. More-
ARVC/D, “Switzerland is an interesting over, members of the local ARVC/D team
country with all its mountains and valleys, regularly visit participating study sites to col-
and it is worth investigating local genetic lect and manage patient data. All patients
peculiarities of ARVC/D, possibly related with suspected or confirmed ARVC/D are
to the fact that with this geographical and encouraged to participate in our registry.
ethnical background, certain outstanding Written informed consent is obtained for
genetic variations may be found, similar to DNA and RNA analyses from whole blood
the Greek island of Naxos.” and tissue samples; release to the electronic
The Swiss people are usually physically registry, which is based on the internet plat-
active and many are engaged in sports activi- form secuTrial® ; and storage of any biopsy
ties; therefore, expression of the ARVC/D material obtained during diagnostic workup.
phenotype may result in more severe out- The functional organization of the registry
comes than in other cohorts around the has been formalized (Figure 10.2).39 We have
globe. Ethical approval was obtained from created our own homepage (www.arvc.ch), as
the local ethical committee and prospective well as our own logo (Figure 10.3), to increase
enrollment has been performed since July the visibility of our registry.
FIGURE 10.2 Organigram of the Zurich ARVC Program . Source: Adapted from SA Heart . 2008;5(4):148-154 .
122 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
genetic screening, we will establish a systematic fied in recent years but are still incomplete—eg,
epidemiological database of ARVC/D in Swit- the role of electrophysiologic study (EPS) for
zerland. Although a rare event, we are informed predicting future adverse events in ARVC/D is
in case of an explanted heart due to ARVC/D still controversial. We have recently published
obtained at cardiac transplantation, which con- manuscripts demonstrating that inducibility of
stitutes a very valuable and informative source sustained monomorphic ventricular tachycar-
for experimental and clinical research. dia, but also a history of heart failure and left
ventricular involvement, may be helpful to
Diagnostic Validation identify patients who may need an ICD.40-42
Although these were preliminary, rather small,
With our registry, we aim to prospectively and retrospective studies, we believe that EPS
validate the 2010 Revised Task Force Criteria helps in risk stratification, and we hope to con-
for clinical diagnosis of ARVC/D, specifically firm these results in our prospective cohort with
applied to our Swiss cohort. Detection of famil- a larger sample size and less advanced disease.
ial disease, particularly in young family mem- Based on future findings, we may identify anti-
bers with less advanced disease, is a key task arrhythmic drugs, heart failure therapies, and
for all physicians who are involved in the care catheter-based therapeutic strategies to improve
of patients with ARVC/D. Furthermore, devel- long-term outcome, while potentially reducing
opment of improved quantitative methods to the number of ICD implantations in ARVC/D.
assess right ventricular but also left ventricular
function and dimensions can help to enhance Conclusion
the specificity and sensitivity of ARVC/D diag- The Zurich ARVC Program represents the
nosis. Our recent and detailed echocardiogra- largest cohort of ARVC/D patients from Swit-
phy protocols include strain imaging, speckle zerland. It is our privilege that all 5 Swiss
tracking, and 3D echocardiography, and our University Hospitals (Basel, Bern, Geneva,
modern MRI protocols include tissue deforma- Lausanne, and Zurich) and many non-
tion and evaluation of diastolic dysfunction for academic Swiss centers already participate in
quantifying regional myocardial strain. Our our registry. Thus, we have been able to col-
recent voltage mapping protocol with the newly lect data from 183 patients with ARVC/D in
developed contact force catheter was applied to the last 3 years. Despite the relatively short exis-
15 patients so far. With these newer tools we tence of our registry, considerable progress has
hope to improve earlier disease detection, par- been made with respect to patient recruitment
ticularly in families without pathogenic muta- and data collection. Our registry compares
tions, and to add important data for a future favorably with other ARVC/D registries.16,25
version of the Task Force Criteria. Preliminary The mean age of our cohort is 50.2 years with
analyses of these data have shown that frac- 128 male patients (70%), while 108 patients
tional area change (FAC) may be an important (59%) have an ICD implanted. Fifty-five per-
parameter of right ventricular function to pre- cent of our patients have a “definite” diagnosis
dict adverse future events in ARVC/D. of ARVC/D according to the Revised 2010 Task
Force Criteria (Figure 10.4), while the majority
Risk Stratification and Progress consists of index patients (n = 149, 81%). We
in Therapies have a large commitment for scientific collabo-
rations. Cardiologists are requested to coop-
Important clinical markers of sudden cardiac erate with us by referring index patients with
death and a poor prognosis have been identi- confirmed or suspected ARVC/D for a second
1
report from the North American ARVC reg- lar cardiomyopathy caused by deletions in
istry. J Am Coll Cardiol. 2009;54:609-615. plakophilin-2 and plakoglobin (Naxos dis-
28. Ingles J, McGaughran J, Vohra J, et al. Estab- ease) in families from Greece and Cyprus:
lishment of an Australian national genetic genotype–phenotype relations, diagnos-
heart disease registry. Heart Lung Circ. tic features and prognosis. Eur Heart J.
2008;17:463-467. 2006;27:2208-2216.
29. Ma KJ, Li N, Wang HT, et al. Clinical study 37. Ortac R, Tavli V, Diniz G, Yilmazer MM,
of 39 Chinese patients with arrhythmogenic Demirpence S. Naxos-Carvajal disease: a rare
right ventricular dysplasia/cardiomyopathy. cause of cardiomyopathy with woolly hair and
Chinese Med J. 2009;122:1133-1138. palmoplantar hyperkeratosis. Anadolu Kardi-
30. Nakajima T, Kaneko Y, Irie T, et al. Com- yol Derg. 2011;11:E17-18.
pound and digenic heterozygosity in desmo- 38. Marcus FI, McKenna WJ, Sherrill D, et al.
some genes as a cause of arrhythmogenic Diagnosis of arrhythmogenic right ventricular
right ventricular cardiomyopathy in Japanese cardiomyopathy/dysplasia: proposed modifi-
patients. Circ J. 2012;76:737-743. cation of the Task Force Criteria. Eur Heart J.
31. Ohno S, Nagaoka I, Fukuyama M, et al. Age- 2010;31:806-814.
dependent clinical and genetic characteristics 39. Hendricks N, Mayosi BM, Okreglicki A. The
in Japanese patients with arrhythmogenic South African Arrhythmogenic Right Ven-
right ventricular cardiomyopathy/dysplasia. tricular Cardiomyopathy Registry: a brief
Circ J. 2013;77(6):1534-1542. report and a status report. SA Heart. 2008;
32. Carvajal-Huerta L. Epidermolytic palmo- 5(4):148-154.
plantar keratoderma with woolly hair and 40. Lemola K, Brunckhorst C, Helfenstein U,
dilated cardiomyopathy. J Am Acad Dermatol. Oechslin E, Jenni R, Duru F. Predictors of
1998;39:418-421. adverse outcome in patients with arrhyth-
33. Norgett EE, Hatsell SJ, Carvajal-Huerta L, mogenic right ventricular dysplasia/cardio-
et al. Recessive mutation in desmoplakin myopathy: long term experience of a tertiary
disrupts desmoplakin-intermediate filament care centre. Heart. 2005;91:1167-1172.
interactions and causes dilated cardiomyopa- 41. Schuler PK, Haegeli LM, Saguner AM, et
thy, woolly hair and keratoderma. Hum Mol al. Predictors of appropriate ICD therapy
Genet. 2000;9:2761-2766. in patients with arrhythmogenic right ven-
34. Narin N, Akcakus M, Gunes T, et al. Arrhyth- tricular cardiomyopathy: long term experi-
mogenic right ventricular cardiomyopathy ence of a tertiary care center. PLoS One.
(Naxos disease): report of a Turkish boy. Pacing 2012;7(9):e39584.
Clin Electrophysiol. 2003;26:2326-2329. 42. Saguner AM, Medeiros-Domingo A,
35. Bukhari I, Juma’a N. Naxos disease in Saudi Schwyzer MA, et al. Usefulness of inducible
Arabia. J Eur Acad Dermatol Venereol. ventricular tachycardia to predict long-term
2004;18:614-616. adverse outcomes in arrhythmogenic right
36. Antoniades L, Tsatsopoulou A, Anastasakis ventricular cardiomyopathy. Am J Cardiol.
A, et al. Arrhythmogenic right ventricu- 2013;111(2):250-257.
Case 1
FIGURE C1.1 ECG showing terminal negative T waves in leads V1 and V2 and a slurred S upstroke in V1 .
point, the diagnosis of ARVC/D was made, block morphology, with a slightly different
and the initial symptom of sweating with nau- axis than the previous VTs.
sea was interpreted as VT; thus, 1 major crite- After the second ablation, no medical
rion and 4 minor criteria from different groups treatment was administered, and the patient
of the International Task Force Criteria for the remained asymptomatic for more than 1 year.
clinical diagnosis of ARVC/D were fulfilled.2 However, in December 1994, recurrence
Treatment with sotalol (320 mg/day) was ini- of VT was documented, and sotalol (80 mg
tiated. A follow-up 24-hour Holter monitoring twice daily) was initiated. The patient experi-
under this medication showed no reduction of enced another 2 episodes of syncope that were
PVC load. During a repeat electrophysiologic both associated with insufficient medical pro-
study, a sustained VT with 240 bpm was again tection due to irregular sotalol intake while
inducible under this treatment. The morphol- traveling. In a follow-up TTE, an important
ogy of the induced VT corresponded to the VT progression of the disease was observed. The
found during the first electrophysiologic study. right ventricle was dilated, showing reduced
Therefore, 1 month after occurrence of systolic function, and additionally, mild
the first symptoms, the patient was referred left ventricular involvement was observed.
a third time for electrophysiologic study; Repeated Holter monitoring revealed 15 to 25
the PVCs were pacemapped and eliminated PVCs per minute.
by radiofrequency ablation. Consecutively, As the ventricular arrhythmias could not
sotalol was stopped. However, the patient be suppressed medically, the decision was
reported 2 episodes of vertigo during follow- made to initiate implantable cardioverter-
up that corresponded to sustained VT, and a defibrillator (ICD) therapy. The device, a
second ablation procedure was performed 6 Medtronic Jewel II 7219 (Medtronic, St. Paul,
weeks after the first procedure. The VT tar- MN), was implanted under general anesthe-
geted at that time showed a left bundle branch sia in June 1995. After ICD implantation, the
Difficult-to-Treat Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 129
patient reported an uneventful course and bisoprolol. Dosage of bisoprolol was increased
well-being under treatment with sotalol (40 stepwise up to 10 mg twice daily.
mg twice daily) until October 1996. At that In September 2003, ICD replacement
time, one appropriate ICD shock due to VT and upgrade to a DDD system was performed
was noted. The VT occurred after the patient as the patient presented with progressive heart
had stopped sotalol for 2 weeks without con- failure, chronotropic incompetence under beta-
sulting his physician; therefore, medical treat- blockade, and ICD battery depletion. The course
ment was reinitiated. from September 2003 to June 2005 was unevent-
In 1999, ICD battery replacement was ful; the patient presented with stable dyspnea
performed due to battery depletion (CPI/ NYHA II without any tachycardia.
Guidant Ventak Mini 1793). In 2000, recur- In July 2005, recurrence of symptomatic
rent VTs were terminated by the ICD appro- VTs at a heart rate of 136 bpm (Figure C1.3)
priately. An echocardiography at that time was observed. During tachycardia, the patient
again showed a relevant progression of the felt dizzy und unwell. The tachycardias were
cardiomyopathy. Both right ventricular and self-limiting, and occurrence was triggered by
left ventricular systolic function were severely alcohol intake. However, in March 2006, this
impaired. Medical treatment for heart failure slow VT did not terminate spontaneously, and
was initiated, and the dosage of sotalol was the patient had to be hospitalized. The tachy-
increased to 320 mg per day. Under treatment cardia remained incessant, despite initiation
with an ACE inhibitor, left ventricular ejec- of treatment with amiodarone. Therefore, the
tion fraction increased from 35% to 48%. patient was referred for repeat radiofrequency
In June 2001, an episode of strong malaise ablation. In the electrophysiology lab, a VT at
occurred such that the patient had to lie down a heart rate of 120 bpm was documented (Fig-
and make an emergency call for an ambu- ure C1.4). After activation and voltage map-
lance. The patient registered a VT with a heart ping (Figure C1.5), radiofrequency ablation
rate of 150 bpm (Figure C1.2) that was below was performed with an irrigated tip catheter.
the VT detection zone of the ICD. As the After successful ablation treatment with a beta-
patient became hemodynamically instable, an blocker, amiodarone and an ACE inhibitor was
emergency cardioversion was performed. continued. An echocardiogram performed in
Interrogation of the ICD revealed 557 VTs that May 2007 showed severely impaired right and
had occurred since the battery replacement in left ventricular systolic function and signifi-
1999. Of those 557 VTs, 75 had been treated cant inter- and intraventricular dyssynchrony.
successfully by the ICD. Consequently, the Therefore, the decision to perform an upgrade
detection zone of the ICD was lowered and to a biventricular ICD (CRT-D) was made in
medical treatment was changed from sotalol to October 2007. The implantation of the left
FIGURE C1.2 ECG strip showing ventricular tachycardia at a heart rate of 150 bpm with one fusion beat .
130 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Conclusion
This case illustrates the nature of ARVC/D as
a progressive disease with hereditary transmis-
sion. Often, aggressive treatment is needed,
including long-acting beta-blockers, sotalol
or amiodarone, and heart failure medication.
With optimal medical treatment, devices, and
radiofrequency ablation, a favorable course
with a good quality of life may be achieved,
even in severe, progressive forms with biven-
tricular involvement, as presented in this case.
Abbreviations
ICD implantable cardioverter-defibrillator
PVC premature ventricular contraction
VT ventricular tachycardia
Christian M . Schmied, MD
(V1 to V3) (Figure C2.2). The findings offered The young athlete rapidly recovered
a strong suspicion of first manifestation of and subsequently underwent implantation
arrhythmogenic right ventricular cardiomyop- of a dual-chamber ICD. Thereafter, she was
athy/dysplasia (ARVC/D), so a transthoracic restricted from competitive sports, with the
echocardiography was performed (Figure possible exception of low dynamic/low static
C2.3). The echocardiogram showed RV dila- sports (such as billiards, bowling, or golf).1,2
tation and aneurysmatic changes in segments
of the RV wall. Thus, the diagnosis of definite Discussion
ARVC/D was confirmed by the presence of 4 This case report exemplifies some of the cru-
criteria: 1 major arrhythmia criterion, 1 major cial issues in the spectrum of ARVC/D in
repolarization criterion, 1 major imaging cri- sports. When Corrado and colleagues pub-
terion, and 1 minor depolarization criterion. lished their landmark and groundbreaking
assessment of 269 young competitive athletes
FIGURE C2.2 Resting ECG after cessation of ventricular tachycardia . Deeply inverted T waves and a widened QRS
complex with a slurred S upstroke appear in the right precordial leads (V1–V3) .
Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia in Sports 135
A B
FIGURE C2.3 Parasternal long (A) and short axis (B) views showing massive right ventricular (RV) dilatation .
who suddenly died during sports,3,4 ARVC/D Nevertheless, use of the 12-lead ECG has
immediately gained closer scrutiny among considerably improved the accuracy of detec-
sports cardiologists because 22.4% of sudden tion of this fatal disease in athletes.8,11-18 With a
cardiac deaths (SCD) in this cohort of young high diagnostic sensitivity and specificity (up
athletes were due to ARVC/D, making it the to 71% and 96%, respectively), it has become
most common cause.3,4 This was surprising, the major diagnostic tool in primary screen-
as the disease was not of relevant prevalence ing of young athletes.19,20
in former surveys that examined these tragic There are only few differential diagnoses
sports-related events in competitive North of this ECG pattern in athletes. Particularly,
American athletes.5-7 Yet the reasons for the so called “Afro-Caribbean” early repo-
this unexpectedly high rate of SCD due to larization pattern—a mostly benign finding
ARVC/D in the Italian survey are a matter with T-wave inversions in the anterior leads
of ongoing debate: It is a well-recognized that are characteristically associated with a
fact that in a normal population, ARVC/D preceding convex “domed” ST-segment ele-
has been underdiagnosed in recent reports vation—has recently gained growing atten-
and, consequently, must be a relevant issue tion (Figure C2.4).13,16,21-23
in competitive athletes as well.3,4,8,9 Since SCA and SCD became a major
Frequently, the first overt clinical mani- public issue—not only in young competi-
festation of the disease in athletes is sud- tive athletes but in the general population as
den cardiac arrest (SCA) during intensive well—ambitious strategies were established to
activity, as preceding and suggestive symp- prevent these fatal events in athletes.11,12,24 Cur-
toms are mostly unspecific.3,10 Corrado et al rently, the feasibility and accuracy of 2 main
demonstrated that syncope and palpitations strategies are the matter of debate: First, pri-
on exertion appeared in about half of the marily in North America, expert panels rec-
affected athletes with underlying ARVC/D ommend a baseline screening integrating a
prior to a fatal cardiac event.3 For example, focused physical examination in combination
the young female floorball player in this case with a questionnaire assessing the athletes’ per-
retrospectively mentioned only nonspecific sonal and family history.12 Second, the Euro-
symptoms as transient fatigue and mild diz- pean approach, based on mainly Italian data
ziness at times. and incorporated by the European Society of
Cardiology (ESC), the International Olympic
136 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
The current case report outlines another SCD sudden cardiac death
important issue: So-called “amateur” competi- VT ventricular tachycardia
tive athletes are mostly outside the focus regard-
ing an adequate precompetition screening to References
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survey observing more than 1,000 Swiss com- Recommendations for competitive sports par-
ticipation in athletes with cardiovascular dis-
petitive athletes who are not associated with
ease. Eur Heart J. 2005;26:1422-1445.
one of the big sports associations, only a strik-
2. Maron BJ, Zipes DP. 36th Bethesda Confer-
ing 9% underwent adequate cardiac screen-
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Particularly, female gender, younger age, and J Am Coll Cardiol. 2005;45:2-64.
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greater in men,5-7,30 these subgroups of athletes 4. Corrado D, Thiene G, Nava A, Rossi L, Pen-
need to be targeted with particular attention. nelli N. Sudden death in young competitive
While a yearly incidence of about 0.7 athletes: clinico-pathologic correlations in 22
to 3 SCD per 100,000 young athletes (age cases. Am J Med. 1990;89:588-596.
5. Thompson PD, Funk EJ, Carleton RA, Stur-
< 35 years) is an established estimate in lit-
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as 1:3,000.31 Schiavon M, Thiene G. Trends in sudden
cardiovascular death in young competi-
tive athletes after implementation of a pre-
Conclusion
participation screening program. JAMA.
In conclusion, it should once more be high-
2006;296:1593-1601.
lighted that ARVC/D has become a major
9. Fontaine G, Marcus FI, McKenna WJ,
issue in sports cardiology. However, due Nava A, Thiene G, Wichter T. Arrhyth-
to continuous improvement of screening mogenic right ventricular dysplasia/car-
methods to prevent sudden cardiac death in diomyopathy: need for an international
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in the vast majority of affected, yet asymp- Right Ventricular Dysplasia/Cardiomyopa-
tomatic athletes. thy of the Working Groups on Myocardial
and Pericardial Disease and Arrhythmias of
Abbreviations the European Society of Cardiology and of
ICD implantable cardioverter-defibrillator the Scientific Council on Cardiomyopathies
RV right ventricle, right ventricular of the World Heart Federation. Circulation.
2000;101(11):E101-E106.
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Impressions from the
First Zurich ARVC/D Symposium
IMPRESSIONS FROM THE FIRST ZURICH ARVC/D SYMPOSIUM, LAKE ZURICH, MAY 2012.
141
142 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
RICHARD HAUER (left) and DOMENICO CORRADO (right) RICHARD HAUER (left), FRANK I. MARCUS (center), and
GUY H. FONTAINE (right)
(From left) HUGH CALKINS, RICHARD HAUER, DOMENICO CORRADO (left) and
FRANK I. MARCUS, GUY H. FONTAINE, LUKAS KAPPENBERGER (right)
THOMAS WICHTER, and DOMENICO CORRADO
DOMENICO CORRADO SPEAKING IN FRONT OF FRANK I. MARCUS (left) and
THE AUDIENCE LUKAS KAPPENBERGER (right)
From left to right: HUGH CALKINS, RICHARD HAUER, GROUP PHOTO IN RÜSCHLIKON, WHERE THE
FRANK I. MARCUS, GUY H. FONTAINE, and SYMPOSIUM TOOK PLACE
THOMAS WICHTER
Index
arrhythmogenic right ventricular dysplasia (ARVD)
A characteristics of, 9
ablation. See catheter ablation; radiofrequency naming of, 7–10, 14
ablation arrhythmogenic right ventricular tachycardia
action potential, 23 syndrome, 9–10
adipositas cordis, 11 ARVC. See arrhythmogenic right ventricular
adolescents, 133–137 cardiomyopathy
“Afro-Caribbean” early repolarization pattern, 135 ARVC/D. See arrhythmogenic right ventricular
age of onset, 31–32, 79 cardiomyopathy/dysplasia
amiodarone, 85–88, 118 athletes
aneurysms, ventricular, 51, 62–63, 82 amateur, 137
angiography, 9 case study of, 133–137
antiarrhythmic drug therapy endurance, 52
acute efficacy of, 84–85 heart in, 73
Class-I, 85 screening of, 135–137
efficacy of, 84–85, 87 sudden cardiac death in, 135, 137
European studies of, 84–85, 87 auricularisation of the pressure curves of the right
expert opinions about, 86–87 ventricle, 4
failure of, 85 Australia, 118–119
long-term efficacy of, 85
monitoring of, 87
North American studies of, 86 B
studies of, 84–87 bacterial myocarditis, 11
uses of, 83 beta-blockers, 82–85, 87, 114
anticoagulation, 82 biventricular dysplasia, 11
antithrombotic therapy, 82 black blood imaging, T1-weighted, 73
apoptosis, 11 blood flow, 2
arrhythmias British Heart Journal, 13
beta-blockers for, 82–84
description of, 51 C
fibrosis and, 72 Calkins, Hugh, 12
mechanisms of, 21–26 cardiac magnetic resonance (CMR) imaging
risk stratification for, 113 description of, 54
arrhythmogenic right ventricular cardiomyopathy diagnostic criteria using, 69–71
(ARVC), 10–11 power and benefit of, 72–73
arrhythmogenic right ventricular cardiomyopathy/ QRS dispersion and, 71
dysplasia (ARVC/D) cardiomyocytes, 59–60, 93, 106
characteristics of, 31, 59, 93 cardiomyopathies
controversy regarding, 13 left-sided arrhythmogenic, 74–75
definition of, 19, 49, 59, 105 World Health Organization’s new classification
new criteria for, 13 of, 12
in 21st century, 12–15 Carvajal syndrome, 31, 46, 120
Task Force Criteria for. See Task Force Criteria case studies, 127–131, 133–137
without genetic mutations, 34–35 Castleman, Benjamin, 3–4
145
146 Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
transmembrane protein 43. See TMEM43 of left bundle branch block morphology, 49, 53, 79
transthoracic echocardiography, 130 monomorphic, 79, 105
treatment nonsustained, 114
antiarrhythmic drugs. See antiarrhythmic drug QRS complex during, 9
therapy radiofrequency ablation of, 99–102
antithrombotic, 82 sustained, 113
drug therapy. See drug therapy treatment of, 83
heart failure, 82 verapamil, 85
preload-reducing, 81, 88 VF. See ventricular fibrillation
targets and options for, 80–81 viral myocarditis, 53
triangle of dysplasia, 10, 59 voltage-gated sodium channels, 24
tricuspid annulus plane systolic excursion (TAPSE), VT. See ventricular tachycardia
64
Trieste ARVC registry, 119
TTN, 34, 36, 44
W
wall motion abnormalities, 71
T-wave inversions, 49, 53, 96, 106, 110, 135–136
wall thinning, 71
T1-weighted black blood imaging, 73
White, Paul Dudley, 3
Willerson, Jim, 13
U wnt pathway, 20
Uhl’s anomaly, 11 wnt/beta-catenin signaling, 20
Wolff-Parkinson-White (WPW) syndrome, 5–6
World Health Organization (WHO) cardiomyopathy
V classification, 12
ventricular aneurysms, 51, 62–63, 82
WPW. See Wolff-Parkinson-White syndrome
ventricular arrhythmias
anatomical substrate of, 21
in exercise, 106 Z
mechanisms of, 21–26 Zurich ARVC Program
overt structural disease and, 21–22 diagnostic validation, 123
ventricular dilatation, 110 DNA/tissue banking, 122
ventricular ectopy, 95, 99–100 epidemiology studies, 122–123
ventricular fibrillation (VF), 105–106 establishment of, 120
ventricular tachyarrhythmias, 79–80, 85 goals of, 120
ventricular tachycardia (VT) introduction of, 117–120
case study of, 128–129 investigators involved in, 120
catecholamine infusions as trigger for, 99–100 organigram of, 121
catheter ablation of, 99–102 patient cohort classification, 124
electrocardiographic findings, 129–130, 134 risk stratification goals, 123
implantable cardioverter-defibrillator for, 101 summary of, 123–124
Current Concepts in Arrhythmogenic Right
Ventricular Cardiomyopathy/Dysplasia
Edited and written by internationally recognized authorities, Current Concepts in Arrhythmogenic
Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) presents important insights to all aspects
of this unique disease and will serve as a valuable guide to help readers provide the best possible
care for their patients.
“The editors have enlisted as authors those who first recognized and named
the disease, and most of those responsible for the recent advances in this
fascinating area. The result is an excellent and comprehensive but very
readable text dealing with this increasingly important spectrum of diseases. It
is a unique book that should be found on the shelves of everyone who seeks
to manage patients with cardiac arrhythmia, because among those who seek
advice, there are sure to be patients with this challenging disease.”
- From the Foreword by A. John Camm, MD