Arrhythmogenic right ventricular cardiomyopathy/dysplasia
Orphanet Journal of Rare Diseases
Arrhythmogenic right ventricular cardiomyopathy/dysplasia
Gaetano Thiene 0
Domenico Corrado 0
Cristina Basso 0
0 Address: Pathological Anatomy, Department of Medical-Diagnostic Sciences and Special Therapies, University of Padua Medical School , Padua , Italy
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias. Its prevalence has been estimated to vary from 1:2,500 to 1:5,000. ARVC/D is a major cause of sudden death in the young and athletes. The pathology consists of a genetically determined dystrophy of the right ventricular myocardium with fibro-fatty replacement to such an extent that it leads to right ventricular aneurysms. The clinical picture may include: a subclinical phase without symptoms and with ventricular fibrillation being the first presentation; an electrical disorder with palpitations and syncope, due to tachyarrhythmias of right ventricular origin; right ventricular or biventricular pump failure, so severe as to require transplantation. The causative genes encode proteins of mechanical cell junctions (plakoglobin, plakophilin, desmoglein, desmocollin, desmoplakin) and account for intercalated disk remodeling. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance has been proven. Recessive variants associated with palmoplantar keratoderma and woolly hair have been also reported. Clinical diagnosis may be achieved by demonstrating functional and structural alterations of the right ventricle, depolarization and repolarization abnormalities, arrhythmias with the left bundle branch block morphology and fibro-fatty replacement through endomyocardial biopsy. Two dimensional echo, angiography and magnetic resonance are the imaging tools for visualizing structural-functional abnormalities. Electroanatomic mapping is able to detect areas of low voltage corresponding to myocardial atrophy with fibro-fatty replacement. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, dialted cardiomyopathy and sarcoidosis. Only palliative therapy is available and consists of antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator. Young age, family history of juvenile sudden death, QRS dispersion 40 ms, T-wave inversion, left ventricular involvement, ventricular tachycardia, syncope and previous cardiac arrest are the major risk factors for adverse prognosis. Preparticipation screening for sport eligibility has been proven to be effective in detecting asymptomatic patients and sport disqualification has been life-saving, substantially declining sudden death in young athletes.
Diseases name and synonyms
Arrhythmogenic right ventricular
Arrhythmogenic right ventricular
cardiomyopathy/dysplasia (ARVC/D) is a unique heart muscle disease,
clinically characterized by non-ischemic ventricular
arrhythmias originating from the right ventricle (RV), at
risk of cardiac arrest. It is one of the major causes of
sudden death in the young and in the athletes. The pathology
consists of progressive dystrophy of the RV myocardium
with fibro-fatty replacement.
In the last 25 years, it was possible to identify the disease
, to realize its heredo-familiar character  and the risk
of sudden death , to report the pathology , to put
forward clinical diagnostic criteria , to find therapeutic
measures  and, finally, to discover the genetic
The prevalence of approximately 1 in 5,000 people has
been estimated . The exact prevalence of ARVC/D,
however, is unknown and could be higher than the estimated
because of the existence of many non-diagnosed or
In the Veneto Region, Italy, the prevalence of the disease
has been estimated to vary from 1:2,000 to 1:5,000 .
The disease was first described by Giovanni Maria Lancisi
in 1736, who in his book De Motu Cordis et Aneurysmatibus
reported a family with disease recurrence in four
generations: the affected members presented with palpitations,
heart failure, dilation and aneurysms of the RV and
sudden death .
Dalla Volta et al. in 1961 reported a patient with
"auricularization" of the RV pressure curve, emphasizing the
peculiar hemodynamic picture of this non-ischemic heart
muscle disease with RV behaving like an atrium .
However, we had to wait until the 80's to find the first
clinical and pathologic series of patients with ARVC/D
reported by Drs Marcus, Nava and Thiene [1-3].
Marcus et al. in 1982 reported the disease in adults, first
emphasizing the origin of arrhythmias from the RV and
the histopathological substrate consisting of fibro-fatty
replacement of the RV free wall, accounting for epsilon
wave and ventricular arrhythmias of RV origin with left
bundle branch block (LBBB) morphology .
Familiar occurrence with an autosomal dominant pattern
of inheritance and variable penetrance was first proven by
Nava et al. in 19871988 [2,11].
In 1988, Thiene et al. observed an impressive series of
sudden deaths in the young (35 years), with pathology
consisting of ARVC/D, mostly occurring during effort, and
all characterized by inverted T-waves in the right
precordial leads at electrocardiogram (ECG) and apparently
benign ventricular arrhythmias of LBBB morphology .
They accounted for 20% of all sudden deaths in the young
and for the first time it was acknowledged that ARVC/D is
another important cause of sudden death in the
The diagnostic imaging was then implemented to
visualize the RV, either non-invasively through echocardiogram
 or invasively through angiography .
Signal averaged ECG proved to be a sensitive tool to detect
delay in the electric impulse transmission in the RV
myocardium . Improvements in the diagnostic procedures
led the proposal of diagnostic criteria, whether major or
minor, based upon RV dysfunction or structural
alterations at imaging, tissue characterization at biopsy,
repolarization or depolarization abnormalities and
arrhythmias at the ECG, and family history of sudden
The first gene locus (ARVD1) was found by Rampazzo et
al. in 1994 at chromosome 14q23 . The pathological
profile was described in detail by Basso et al. in 1996,
emphasizing the frequent left ventricular (LV)
involvement and an inflammatory component .
In 1995, ARVC/D was included among cardiomyopathies
in the revised World Health Organization (WHO)
classification  and progressive cell death (apoptosis) in
myocyte was proven [18,19].
The need of an International Registry of the disease was
raised  and two research programs were implemented
in both sides of the Atlantic Ocean [21,22].
Meanwhile, spontaneous occurrence of ARVC/D have
been observed in cats  and dogs .
The first gene defect was discovered in the recessive variant
of the disease (identified since 1985) from the Naxos
island and consisting of a cardiocutaneous syndrome
(ARVC/D, palmoplantar keratosis and woolly hair) .
A deletion was detected in the gene encoding plakoglobin,
a cell junction protein .
Thereafter, other genes encoding cell junction proteins
were found defective in the dominant, classical form of
ARVC/D: desmoplakin , plakophilin-2 ,
desmoglein-2 , desmocollin-2 . These mutations were
found to account for intercalated disk remodeling at the
ultrastructural level . Other variants of the disease
were explained by mutation of the ryanodyne 2 receptor
 and transforming growth factor 3 genes .
The discovery of these gene mutations allowed
preliminary genotype-phenotype correlations to be made
The implantable cardioverter defibrillator (ICD)
represented a major advance in therapy .
Finally, electroanatomic mapping proved to be a sensitive
tool for identifying areas of fibro-fatty replacement with
low amplitude electrical activity .
Study of ARVC/D in transgenic mice [40,41] models may
help elucidate the pathogenesis of the disease and
elaborate therapeutic strategies.
Clinical features and natural history
The onset occurs usually after childhood, with
palpitations and/or syncope.
1) Subclinical phase with concealed structural abnor
malities, during which the affected patient presents no
symptoms, and cardiac arrest may be the first and last
dFGiiargacupdrheeicat1shhoinwNinogrtheavsatrIitoaulys causes of juvenile sudden
carGraphic showing the various causes of juvenile sudden
cardiac death in Northeast Italy. ARVC/D ranks second (13%)
after atherosclerotic coronary artery disease. ARVC =
arrhythmogenic right ventricular cardiomyopathy; ATS CAD
= atherosclerotic coronary artery disease; DMC = dilated
cardiomyopathy; HCM = hypertrophic cardiomyopathy;
NonATS CAD = non-atherosclerotic coronary artery
disease; Postop CHD = postoperative congenital heart disease.
manifestation of the disease. ARVC/D has been reported
as the second cause of sudden death in the young 
(Figs. 1, 2, 3) and the main cause of sudden death in
competitive athletes in the Veneto Region, Italy . A subtle
substrate exists, although does not yet manifest as an overt
2) Overt electrical disorder, with palpitations and syn
cope. The most typical clinical presentation of the disease
is symptomatic ventricular arrhythmias of RV origin,
usually triggered by effort. Arrhythmias range from isolated
premature ventricular beat to sustained ventricular
tachycardia (VT) with LBBB morphology (Figs. 2, 4) up to
ventricular fibrillation leading to cardiac arrest. The QRS
morphology and axis during VT reflect its site of origin. A
LBBB with inferior axis suggests an origin from the RV
outflow tract (RVOT), while a LBBB with superior axis
suggests an origin from the RV inferior wall. However, VTs
with LBBB morphology are not specific for ARVC/D. Basal
ECG may disclose inverted T waves in the right precordial
leads (a T wave inverted beyond V1 after 14 years of age is
almost pathognomonic of ARVC/D)  (Fig. 2). QRS
enlargement of more than 110 ms and epsilon wave are
strongly indicative of intraventricular impulse conduction
delay . Signal average ECG (wide amplitude
superficial ECG) may help to disclose fragmented low amplitude
late potentials at the end of the QRS complex  (Fig. 5).
They correspond to the epsilon wave on surface ECG and
reflect areas of slow intraventricular conduction due to
islands of surviving myocardium interspersed with fatty
and fibrous tissue, accounting for fragmentation of the
electrical activation within the residual ventricular
dFAuig1riu7nrgyeeaa2srooclcdearsgyammpetomatic male athlete who died suddenly
A 17 year old asymptomatic male athlete who died suddenly
during a soccer game. 12 lead ECG showing inverted T
waves up to V4 (a) and isolated premature ventricular beats
(b). In vitro MRI (c) and corresponding cross section of the
heart (d) show RV dilatation with anterior and posterior
SFaigmuercea3se of fig. 2
Same case of fig. 2. Note the biventricular involvement at
long axis in vitro MRI (a), with transmural fibro-fatty
replacement in the RV free wall (b) and focal subepicardial in the LV
free wall (c).
(1FL2iBglBueBarde) mE4CoGrphreocloogryding of VT with left bundle branch block
12 lead ECG recording of VT with left bundle branch block
myocardium. VT/fibrillation may be easily triggered at the
intracavitary electrophysiologic testing.
3) RV failure. The progressive loss of the RV myocardium
may impair the mechanical function of the RV and
account for severe pump failure.
4) Biventricular failure. When the disease involves the
ventricular septum and the LV, congestive heart failure
occurs, mimicking dilated cardiomyopathy. Endocavitary
mural thrombosis may occur, especially within
aneurysms or in the atrial appendages when heart failure is
complicated by atrial fibrillation, as to account for
thromboembolism. In such conditions, contractile dysfunction
may be so severe as to require cardiac transplantation
(Fig. 6). Clearly, when the LV is affected, ventricular
raEFivCigeghGrutarpgreeredc5coeorldredicnitagrl:ol(ceaa)rdpdsoi;os(gbtr-)eapxohciystiat(tiSvioAenElaCetpeGsp)ilotnewntaiavles (aatrsriogwnasl)- in
ECG recording: (a) post-excitation epsilon wave (arrows) in
right precordial leads; (b) positive late potentials at
signalaveraged electrocardiography (SAECG).
arrhythmias may appear polymorphic, originating from
different cardiac regions. The occurrence of fatal outcome,
mostly sudden death, varies between 0.13% per year in
adults with diagnosed and treated ARVC/D, but it is
unknown and may be higher in adolescents and young
adults, in whom the disease is concealed and the first
manifestation can be sudden death.
Pathology and pathogenesis
The disease consists of a replacement of the myocardium
of the RV by fibro-fatty tissue [3,4]. The phenomenon is
progressive with time, starts from the epicardium and
eventually extends down to reach the endocardium as to
become transmural. This implies a weakness of the free
wall resulting in RV dilatation and aneurysms, typically
located at the inferior, apical and infundibular walls (the
so-called triangle of dysplasia) . The fibro-fatty
replacement of the myocardium interferes with intraventricular
conduction of the electric impulse accounting for delay
(late potentials, epsilon wave, parietal right bundle
branch block) and onset of re-entrant phenomena which
are the mechanism of ventricular arrhythmias. Fatty
infiltration of the RV has not to be considered "per se" a
sufficient morphologic hallmark of ARVC/D. A certain
amount of intramyocardial fat is present in the RV
anterolateral and apical region even in the normal heart and
increases with age and body size. Moreover, ARVC/D
should be kept distinct from adipositas cordis. Presence of
replacement-type fibrosis and myocyte degenerative
changes are essential to provide a clear-cut diagnosis,
besides remarkable fat replacement  (Fig. 7).
The myocardial atrophy is progressive with time and by no
way is present at birth, as seen in Uhl's disease, a congenital
heart defect in which the RV myocardium failed to develop
FHiegaurrtesp6ecimen coming from heart transplantation
Heart specimen coming from heart transplantation. Note the
biventricular involvement both at gross examination (a, b)
and histology (c, d).
TFiygpuicrael h7istologic features of ARVC/D
Typical histologic features of ARVC/D. Ongoing myocyte
death (a) with early fibrosis and adipocytes infiltration (b).
during embryonic life . Instead, the myocardial loss is
the consequence of cell death occurring after birth, usually
during childhood . An apoptotic mechanisms of
myocyte death has been proven, either at post-mortem 
or in vivo in endomyocardial biopsy specimens .
More than half of the hearts studied at post-mortem
disclosed LV involvement, usually limited to the
subepicardium of the postero-lateral free wall . The
involvement of the ventricular septum is rare, probably because it
is not a subepicardial structure. In the most severe cases
requiring transplantation, aneurysms may be seen also in
the LV .
Histology of the RV myocardium discloses severe atrophy
of the myocardium, replaced by fibro-fatty tissue, which
should be regarded as an healing phenomenon following
myocyte deaths . Fibrous tissue, present in variable
amounts, is an essential part of the healing process and
plays a fundamental role in the intraventricular
conduction delay of the electrical impulse, which is at the basis of
onset of the life-threatening arrhythmias.
Death of single or multiple myocytes may be seen at
histology, as proof of the acquired nature of myocardial
atrophy, and may be associated with inflammatory
Myocardial inflammation may be seen in up to 75% of
hearts at autopsy, and probably it plays a role in triggering
ventricular tachyarrhythmias . Nobody knows
whether inflammation is a reactive phenomenon to cell
death, or whether it is the consequence of an infection or
immune mechanism. Viruses have been detected in the
myocardium of some ARVC/D patients and have been
claimed to support an infective etiology of the disease
. Others say that the viruses are innocent bystanders
or that spontaneous cell degeneration may serve as a
milieu favoring viral settlement in the myocardium .
Transvenous endomyocardial biopsy may be of great help
for an in vivo morphological demonstration of fibro-fatty
myocardial replacement  (Fig. 8). Samples should be
retrieved from the RV free wall, since the fibro-fatty
replacement is usually transmural and thus detectable
from the endocardial approach and the ventricular
septum is usually spared. A residual amount of myocardium
<45%, due to fibrous or fibro-fatty replacement, has been
proven to have a high diagnostic accuracy .
Histomorphometric criteria of endomyocardial biopsy from
different sites of the RV are currently under evaluation.
Clinical and differential diagnosis
In vivo diagnosis may be achieved by demonstrating
alterations of the RV function and structure, typical
lItFwinireoiagvlntiluhv;sorevcfe)tntnifseh8iobseurdeohste-jcofuaahrgtpatureylsarhcrfoetaerpwprmlaipnzcrtageohtmtiaeohcenabhntiobtotyphofseetfyhntseawdetpobotmihuobeympiotleopcisvtamierscedlps;oiaabrflme)tbdhpcioerlteopRssVuysn:sfadre)ecer-In vivo tissue characterization by endomyocardial biopsy: a)
transvenous jugular approach of the bioptome; b) cross
section of the heart showing that the septum is spared to
underlie the need to perform the biopsy at the level of the RV free
wall; c) fibro-fatty replacement of two bioptic samples.
depolarization and repolarization abnormalities,
arrhythmias of the LBBB morphology, fibro-fatty replacement of
the myocardium and existence of a family history.
Diagnostic criteria have been put forward  and divided
into major and minor (Table 1). The diagnosis of ARVC/
D would be fulfilled by the presence of two major, or one
major plus two minor or four minor criteria from different
Morphologic changes accounting for global and/or
regional dysfunction are detectable by echocardiography,
angiography, cardiac magnetic resonance imaging (MRI),
or radionuclide scintigraphy. Major criteria consist of
severe dilatation and reduction in systolic function of the
RV with no (or only mild) impairment of the LV; localized
RV aneurysms (akinesia or diskinetic areas with diastolic
bulgings); and severe segmental dilatation of the RV.
Minor criteria are mild global RV dilatation and/or
reduction in ejection fraction with normal LV, mild
segmental dilatation of the RV free wall and regional RV
infundibular, apical and subtricuspid region has a high
diagnostic specificity (>90%) .
Echocardiography is a non-invasive and widely used
technique, and represents the first-line imaging approach for
evaluating patients with suspected ARVC/D or for
screening of family members (Fig. 10). Echocardiography also
allows serial examinations aimed to assess the disease
onset and progression during the follow-up of affected
patients and family members. Both functional and
structural abnormalities are detectable and, in the presence of
typical echocardiographic features, contrast angiography
or MRI may be avoided.
MRI is an attractive imaging tool because it is
non-invasive and has the ability to characterize tissue by
distinguishing fat from muscle (Fig. 11). However, recent
studies have shown a high degree of interobserved
variability in assessing fatty deposition, which may be
observed even in normal hearts. Cine-MRI may be of
value in estimating RV volume and wall motion
abnormalities with akinesia, dyskinesia and aneurysms.
Radionuclide angiography is also an accurate
non-invasive imaging technique for detection of global RV
dysfunction and regional wall motion abnormalities. Its
diagnostic concordance with RV angiography is nearly
Tissue characterization of the RV free wall with fibro-fatty
replacement of the myocardium, as demonstrated on
endomyocardial biopsy (Fig. 8) or surgical resection, is
considered a major criterion.
In contrast, repolarization abnormalities consisting of
inverted T-waves in right precordial leads (V2 and V3) in
the absence of RBBB, in individuals older than 12 years of
age, are considered a minor criterion (Fig. 2).
As far as depolarization/conduction abnormalities,
epsilon wave or localized prolongation of the QRS complex
>110 ms in V1-V3 is a major criterion, whereas the
presence of late potentials on signal averaged ECG has to be
considered minor (Fig. 5).
Also arrhythmias, like sustained or non-sustained VT with
LBBB morphology (Fig. 6), on basal ECG, Holter or
exercise testing and frequent premature ventricular
beats, >1000 over 24 hour Holter monitoring, are
RV angiography is usually reported as the gold standard
for the diagnosis of ARVC/D (Fig. 9). Angiographic
evidence of akinetic/diskinetic bulgings localized in
Finally, family history is a major criterion when familial
disease is confirmed at necropsy or surgery, whereas it is
minor in case of family history of premature sudden death
1. Family history Major Familial disease confirmed at necropsy or surgery. Minor
2. ECG depolarization/conduction abnormalities
3. ECG repolarization abnormalities Minor
5. Global or regional dysfunction and structural alterations*
6. Tissue characteristics of walls
* Detected by echocardiography, angiography, magnetic resonance
imaging, or radionuclide scintigraphy.
Modified from McKenna et al. 
(<35 years) or a family history of clinical diagnosis based
on the present criteria.
A modification of Task Force Criteria for the diagnosis of
ARVC/D has been proposed in case of family members for
early detection of the disease . In first degree relatives
of a patient, confirmed to be affected by ARVC/D, the
presence of right precordial T-wave inversion (V2 and V3),
or late potentials on signal-averaged ECG, or VT with
LBBB morphology, or mild functional or morphological
changes of the RV on imaging, should be considered
diagnostic for familial ARVC/D. In addition, the threshold of
premature ventricular beats has been reduced from 1000
to 200 over 24 hour Holter monitoring to appear
indicative of familial disease expression (Table 2).
New tools for improving diagnostic accuracy have been
introduced in recent years. Among non-invasive
investigations, MRI with gadolinium late enhancement has been
demonstrated to be able to detect fibrosis in the RV and LV
myocardium . Among invasive procedures, three
dimensional electroanatomic mapping shows
lowvoltage areas which correspond to fibro-fatty myocardial
replacement  (Fig. 12). It is able to differentiate
ARVC/D from inflammatory cardiomyopathy mimicking
ARVC/D, which shows a preserved electrogram voltage
and has a better arrhythmic outcome. Moreover, this
procedure is useful to distinguish early-minor forms of
ARVC/D from idiopathic RVOT tachycardia, a
nonfamilial benign arrhythmic disorder without substrate
and a preserved electrogram voltage .
Of course, mutational analysis will help to establish with
certainty who are the gene carriers, although
asymptomatic. However, since these patients may not have the
phenotypic expression of the disease, the Task Force
criteria are critical to this assessment.
ARVC/D is heredo-familial in nearly 50% of cases, thus
the ongoing myocardial atrophy may be genetically
determined. The classical form is an autosomal dominant
disease with variable penetrance [2,11]. In the 90's, gene loci
have been mapped to various chromosomes, the first
(ARVD1) by Rampazzo et al. to chromosome 14q23 .
The candidate genes were first searched for in those
coding cytoskeleton or sarcomeric proteins, however
ARVC/D revealed to be neither a cytoskeleton disease, like
dilated cardiomyopathy, nor a sarcomeric disease, like
hypertrophic cardiomyopathy. The key for interpretation
came from a recessive form of ARVC/D, the so-called
Naxos disease, a cardiocutaneous syndrome featured by
palmoplantar keratosis, woolly hair and heart muscle
disease [25,62]. Noteworthy, epidermic cells and myocytes
share similar mechanical junctional apparatus, i.e.
desmosomes and fascia adherens, which provides continuous
cell-to-cell connection. This explains why genes coding
proteins of the intercellular junction became candidate
genes. Intercalated discs contain three types of cell-cell
connection: gap junction (or nexus), adherens junction,
and desmosome. Gap junctions mediate ion transfer
between cells and each gap junction channel is a
composite of two hemi-channels, or connexons, located within
the cytoplasmic membrane of adjacent cells. The
connexon, in turn, is formed by an assembly of six connexin
subunits, of which connexin 43 (Cx 43) is the principal
subtype in the human heart, but also connexins 40 and 45
are expressed at lower levels.
Synchronous contraction requires transmission of force
between cells, which is accomplished via adheren
RV angiocardiography features of ARVC/D: RV dilatation
with deep horizontal fissures in trabecular hypertrophy ("pile
d'assiettes" profile) as well as subtricuspid aneurysm.
Two dimensional echocardiography findings in ARVC/D:
note the presence of a typical inferior subtricuspid bulging
(TV= tricuspid valve, parasternal long axis view of the RV).
junctions. The transmembrane component of an
adherens junction, which establishes intercellular contact, is a
cadherin, i.e. Ca2+-dependent glycoprotein. N-cadherin is
the predominant isoform expressed in the human heart.
trdFMhiiigaReghlIutRairtnvVreeoanf1rptpe1hraeiyctilwen)ai:tllhnaooffnatetectsytpehirndeeepbtcrlyaahcAnoesRmmTV1euCnr(ta/Dl)(bdd()iulfofeunstgeoabmxriisagshvstiievsweigmnoafylotihncearMRI in a patient affected by ARVC/D (long axis view of the
right ventricle): note the transmural diffuse bright signal in
the RV free wall on spin echo T1 (a) due to massive
myocardial atrophy with fatty replacement (b).
Attached to the cytoplasmic tail of N-cadherin are
-catenin and plakoglobin ( -catenin), both of which bind to
-catenin, which in turn, interacts directly with actin
filaments within the sarcomere.
Finally, desmosomes, together with adheren junctions,
provide mechanical attachment between cells. However,
in contrast to adheren junctions, desmosomes are not
linked to the actin network, but with intermediate
filaments, namely desmin in the heart and keratin in the skin.
Proteins from three separate families assemble to form
desmosomes: the desmosomal cadherins, armadillo
proteins, and plakins (Fig. 13).
The genes encoding the desmosomal cadherins are
clustered on chromosome 18q12.1 and four desmogleins
(DSG1-4) and three desmocollins (DSC1-3) are
recognized. The desmosomal cadherins comprise the
transmembrane component of the desmosomal complex.
Their extracellular domains interface directly with their
counterparts on neighboring cells. Besides their role in
cell adhesion, the desmosomal cadherins may function as
regulators of morphogenesis. The intracellular portions of
the desmosomal cadherins interact with proteins of the
armadillo family, i.e. plakoglobin and plakophilin.
Noteworthy, plakoglobin is also found in adhering junctions
together with its homologue -catenin. -catenin,
conversely, is not a constituent of desmosomes as it binds
specifically to the classical cadherins. However, -catenin
has an additional nonadhesive function as a regulator of
transcription, and a similar role has been postulated for
plakoglobin. The plakophilins are found in the nucleus as
well as the desmosome, although their function therein
ARVC/D in First-Degree Relative Plus One of the Following:
4. Structural or functional abnormality of the RV
ECG = electrocardiogram; EF = ejection fraction; LBBB = left bundle branch block; RV = right ventricle; SAECG = signal-averaged
electrocardiography; VT = ventricular tachycardia. *Previously >1,000/24-h period in Task Force criteria. Modified from Hamid et al. 
IFnivgausirvee 1e2lectro-anatomic mapping by CARTO
Invasive electro-anatomic mapping by CARTO. a) 12 lead ECG with inverted T waves up to V4 and LBBB premature
ventricular beat; b) four chamber 2D echo showing RV dilatation and apical aneurysm; c) low voltages RV areas (red) by Carto
mapping; d, e) extensive fibro-fatty replacement of the RV myocardium at endomyocardial biopsy (modified from Corrado et al.,
SdFceighfeeucmrteieve1o3fptrhoeteminosleincuAlaRrVsCtr/uDcture of the desmosome, site of
Scheme of the molecular structure of the desmosome, site of
defective proteins in ARVC/D. PG = plakoglobin, DSP =
desmoplakin, PP = plakophilin, DSG = desmoglein, DSC =
remains speculative. Binding sites for both plakoglobin
and plakophilin are situated in the N-terminal domain of
desmoplakin. At its C-terminal, desmoplakin anchors
desmin intermediate filaments to the cardiomocyte
A deletion in plakoglobin was first found in Naxos disease
in 2000 , followed by mutation of demoplakin in
2002 , plakophilin-2 in 2004 , desmoglein-2 in
2006  and desmocollin-2 also in 2006  (Table 3).
Thus, ARVC/D was found to be a cell junction disease also
in the dominant form, with the plakophilin-2 as the most
frequent disease gene [62-66]. Genotype-phenotype
correlations revealed that the desmoplakin mutation is
associated with a high occurrence of sudden death and
frequent LV involvement , sometimes so pronounced
as to deserve the term arrhythmogenic LV
cardiomyopathy . In contrast, the plakophilin mutation results in a
more extensive disease manifestation with
life-threatening ventricular arrhythmias . Plakoglobin and
plakophilin mutations leads to similar cardiac phenotypes with
RV preponderance .
Ultrastructural investigation in endomyocardial biopsy of
patients with ARVC/D and cell junction gene mutations
revealed intercalated disk remodeling with a decrease in
the number and length of desmosomes and intercellular
gap widening  (Fig. 14).
Cell junction protein mutations may account for a final
common pathway, namely disruption of intercellular
junction, myocyte death and structural changes, which are
the substrate of life-threatening ventricular
A recessive mutation of desmoplakin has been proven to
explain another cardiocutaneous syndrome, i.e. Carvajal
disease , characterized by keratoderma, woolly hair
and a biventricular form of ARVC/D , with distinct
ultrastructural abnormalities of intercalated discs and
decreased immunoreactive signals for desmoplakin,
plakoglobin and Cx 43.
Moreover, remodeling of intercalated disc may lead to
widening of myocyte gap junction, which may also
contribute to the arrhythmogenicity of the disease and
enhance the risk of sudden death .
Two other gene defects have been reported to explain the
disease so far. One is the gene encoding for the cardiac
ryanodine receptor 2, which is located in the smooth
sarcoplasmic reticulum and mediates calcium release for
electroanatomical coupling (ARVD2 with polymorphic
ventricular arrhythmias) . Similar mutations have
been shown to account for cathecolaminergic VT, a
peculiar malignant arrhythmic disease in normal hearts .
Mild pathologic substrates have been described in ARVD2
, but clearly this disease is different from the classical
form of ARVC/D and most probably we are dealing with
the same nosographic entity as cathecolaminergic VT.
Another form of ARVC/D was found to be associated with
regulatory mutations in the TGF gene . The gene
defect may account for increased propensity for
extracellular matrix production and adipogenesis. However, the
report has been anedoctical and needs to be confirmed.
With gene mutations available, transgenic mice are now
being developed to gain an insight into the
etiopathogenetic mechanisms of the disease, with possible
therapeutic implications [40,41].
Risk stratification and therapy
Young age, "malignant" family history, QRS dispersion
40 ms, T-wave inversion beyond V1, LV involvement,
VT, syncope or previous cardiac arrest are considered the
major determinants for adverse prognosis and impending
sudden death .
Different antiarrhythmic drugs have been employed:
sodium blockers, -blockers, sotalol, amiodarone,
verapamil alone or combinations. Wichter et al. reported the
various efficacy rates by demonstrating that sotalol is
Author, year [References]
FTirgaunsrmei1ss4ion electron microscopy of the intercellular junction between two adjacent myocytes in ARVC/D
Transmission electron microscopy of the intercellular junction between two adjacent myocytes in ARVC/D. Note the
presence of abnormal desmosomes, either long (arrows) or short-repeated structures (insert) (modified from Basso et al.,
superior with a complete or partial efficacy in 68% of
patients vs 26% for amiodarone  (Fig. 15).
Catheter ablation has been accomplished in VT refractory
to drug treatment . Although the treatment may be
effective in the short term, the procedure is associated
with high rate of recurrence (40% freedom from
recurrence at 3 years), clearly indicating its palliative nature.
Nonetheless, in terms of survival, the outcome is quite
good (Fig. 16).
ICD has been proven to be life-saving. Corrado et al. 
found a freedom from electric shock, delivered in case of
ventricular flutter/fibrillation, in 76% of patients at 48
months after implantation, whereas the survival curve was
excellent with 96% of patients alive at the same time
period. Considering that each episode followed by electric
shock would have been fatal, 20% of patients were saved
by ICD (Fig. 17).
In refractory congestive heart failure, cardiac
transplantation is the only therapeutic option .
An algorithm for management of ARVC/D has been
proposed (Fig. 18). In symptomatic patients, if an aborted
sudden death occurred, ICD is imperative. In case of
sustained VT and/or syncope, ICD is also indicated in the
presence of risk factors (extensive RV dysfunction, LV
Efficacy rates of different antiarrhythmic drugs for treatment
of ventricular tachycardia in ARVC/D (modified from
Wichter et al., 2005) .
involvement, polymorphic VT, late potentials and epsilon
wave, family history) . If sustained VT as well as
palpitations occurred in low risk patients (none of the
previous risk factors), antiarrhythmic therapy and/or ablation
are indicated. Syncope is reported as a distinct high risk
factor, particularly in the young [36,75].
In asymptomatic patients without a family history and a
mild form of ARVC/D, -blockers are recommended with
follow-up control. If the form of ARVC/D is severe,
electrophysiology-intracavitary testing is recommended. If
negative, -blockers and serial follow-up should be
undertaken. If positive, ICD should be considered, as well
as -blockers and other antiarrhythmic drugs.
In the absence of symptoms and a family history, it is
controversial whether electrophysiologic testing should be
carried out even in patients at low risk. Finally, it should
be underlined that, at present, no curative therapy has
been postulated and clearly the aforementioned
treatments are palliative. Gene therapy is still far from being
established  and no treatment to limit disease
progression has been conceived so far. Some drug interventions
targeting the cascade of events leading to apoptosis and
cell death, such as anticaspase agents, might be
hypothesized. Corticosteroid treatment may be considered for
myocardial inflammation, which is so frequently
observed and probably aggravates the arrhythmogenicity:
it is a hypothesis that needs to be investigated.
(LFmoignougdritfeeier1dm6frfolmlowW-uicphtaeftreertcaalt.,h2e0te0r5)ab[7la7t]ion in ARVC/D
Long term follow-up after catheter ablation in ARVC/D
(modified from Wichter et al., 2005) .
Long term follow-up after ICD implantation in ARVC/D
patients for secondary prevention (modified from Corrado et
al., 2003) .
Prevention of sudden death
Cardiac arrest in ARVC/D is the consequence of a
combination of various factors (substrate, trigger, arrhythmias)
and measures for prevention should focus on these
various steps (Fig. 19).
ICD aims to convert ventricular flutter/fibrillation into
sinus rhythm for resuscitation from cardiac arrest. The
device may be implanted in selected patients at risk or
may be external, used on the spot in case of sudden
cardiac arrest occurring in public sites, like sports courts,
fPFrriogomuporWese1idc8hatlegorreithaml., f2o0r0m5)a[n7a6g]ement of ARVC/D (modified
Proposed algorithm for management of ARVC/D (modified
from Wichter et al., 2005) .
airports, schools, etc. The availability of this tool even at
home for families at risk, should be considered, provided
it is accompanied by a life-support training.
Drug therapy and ablation plays a fundamental role in the
arrhythmic mechanism to prevent onset of
life-threatening arrhythmias. The efficacy is, however, limited and the
recurrence of arrhythmias quite high.
Effort, by volume overload and stretching of the RV
myocardium, is considered a major trigger. Sport activity
increases 5 fold the risk of sudden death in the young 
(Fig. 20). Thus, identification of the asymptomatic ARVC/
D carriers is crucial to avoid effort. Preparticipation
screening and sport disqualification, with a choice of life
style without strenuous efforts, has been shown to be
quite effective in preventing sudden death in athletes .
In the Veneto Region, following implementation of
obligatory preparticipation screening there was a sharp decline
in sudden death in athletes from 1:28,000 per year in the
pre-screening period to 1/250,000/year in the late
screening period, mostly due to identification and
disqualification of patients affected by ARVC/D  (Fig. 21).
A different life style may be safe "per se", regardless of the
need of antiarrhythmic/ablation therapy or ICD. These
are palliative, empiric treatments.
Curative therapy of the disease, the radical form of
prevention of sudden death, may be accomplished in various ways:
a) Heart replacement, in case of refractory congestive heart failure and/or arrhythmias, with cardiac transplantation.
b) Some therapy to prevent myocyte death and inflammation, to block onset and progression of the disease at the
dFDeiigangudrraeemat1hi9lliunstAraRtVinCg/tDhe different levels for prevention of
sudDiagram illustrating the different levels for prevention of
sudden death in ARVC/D.
(FRmiegloaudtrivfeiee2dr0isfrkoomf sCpoorrrta-rdeolaettedal.s,u2d0d0e3n) d[7e9a]th in ARVC/D
Relative risk of sport-related sudden death in ARVC/D
(modified from Corrado et al., 2003) .
pathobiological level. Nothing is available so far and
transgenic animal models are ideal to investigate the
pathogenesis of the diseases and to figure out curative
c) Repair of the defective genes at somatic level (gene
therapy), a controversial and yet inconclusive approach.
d) Genetic counseling and birth control.
It must be underscored that the phenotypic expression of
the gene defect, with the exception of cardiocutaneous
syndromes, is only at the cardiac level and nowadays a
series of effective measures are available to ensure normal
life, with very low risk of premature death in affected
adFTteirhgcelurneetdreaesseo,2Vf1(mseunodeddtioefineRdceagfriodinmacoCfdoIetrartlyha,di1on9ce7idt9eanl2.c,0e200i2n0:6an)toh[tl8e0tt]ehsevshnaornpTrends of sudden cardiac death incidence in athletes vs
nonathletes, Veneto Region of Italy, 19792002: note the sharp
decrease (modified from Corrado et al., 2006) .
This work has been supported by the European Commission 5th
Framework Program ARVC/D Contract QLG1-CT-2000-01091
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