REVIEWS

Pathophysiology of arrhythmogenic
cardiomyopathy
Cristina Basso, Barbara Bauce, Domenico Corrado and Gaetano Thiene
Abstract | Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous disorder of heart
muscle that is associated with ventricular arrhythmias and risk of sudden cardiac death, particularly in the
young and athletes. Mutations in five genes that encode major components of the desmosomes, namely
junction plakoglobin, desmoplakin, plakophilin2, desmoglein2, and desmocollin2, have been identified in
approximately half of affected probands. AC is, therefore, commonly considered a desmosomal disease.
No single test is sufficiently specific to establish a diagnosis of AC. The diagnostic criteria for AC were
revised in 2010 to improve sensitivity, but maintain specificity. Quantitative parameters were introduced and
identification of a pathogenic mutation in a first-degree relative has become a major diagnostic criterion.
Caution in the interpretation of screening results is highly recommended because a pathogenic mutation
is difficult to define. Experimental data confirm that this genetically determined cardiomyopathy develops
after birth because of progressive myocardial dystrophy, and is initiated by cardiomyocyte necrosis; cellular
and animal models are necessary to gain insight into the cascade of underlying molecular events. Crosstalk
from the desmosome to the nucleus, gap junctions, and ion channels is under investigation, to move from
symptomatic to targeted therapy, with the ultimate aim to stop disease onset and progression.
Basso, C. etal. Nat. Rev. Cardiol. 9, 223233 (2012); published online 29 November 2011; doi:10.1038/nrcardio.2011.173

Introduction

The evolving definition of AC

Arrhythmogenic cardiomyopathy 1 is a clinically and

genetically heterogeneous disorder of heart muscle that is
associated with ventricular arrhythmias and an increased
risk of sudden cardiac death, even as the first clinical
manifestation, particularly in the young and in athletes.24
Prevalence is estimated globally at between 1 in 2,000 and
1 in 5,000.2 Mutations in five genes that encode major
components of the desmosomes, namely junction plako
globin (JUP), desmoplakin (DSP), plakophilin2 (PKP2),
desmoglein2 (DSG2), and desmocollin2 (DSC2), have
been found to cause AC.2,5 Dysontogenetic (dysplasia),
inflammatory (myocarditis), and degenerative (myo
cardial dystrophy) theories have been proposed as the
mechanism of this conceptually evolving disease. 6,7
Despite major progress in human genetics and clinical
diagnosis of AC, risk stratification remains an impor
tant challenge and, because the pathophysiology of this
disease is mostly unknown, only symptomatic therapy
is available. In this Review, we discuss AC from both
the basic-science and clinical perspectives, and in the
context of the 2010 diagnostic criteria, the evidence for a
wide phenotypic spectrum that includes left ventricular
involvement, the increasing availability of genetic screen
ing in clinical practice, and the preliminary experimental
data on the pathobiology of the disease.

The change in nomenclature since the early 1980s reflects

the evolution in thinking about AC. The disease was
first called right ventricular (RV) dysplasia (dysplasie
ventriculaire droite), a name that was introduced by
Fontaine and colleagues who considered the condition
to be a developmental disorder (maldevelopment of the
RV wall).8,9 Thereafter, evidence from both morphological
and clinical studies showed that AC was not a structural
defect present at birth (like Uhl anomaly 10), but an
acquired and progressive disease of the myocardium. The
term dysplasia was replaced, and the condition became
known as RV cardiomyopathy.3 Over the same period,
ventricular arrhythmias were recognized as the pre
dominant clinical presentation of AC, and many reports
referred to arrhythmogenic RV dysplasia or arrhythmo
genic RV cardiomyopathy.11 The disease was eventually
listed, together with hypertrophic, restrictive, and dilated
variants, in the WHO classification of cardiomyopathies
in 1995.12
The discoveries of mutations in desmosome genes as
the primum movens of progressive myocardial injury
reinforced the idea that AC is a cardiomyopathic disease.
Moreover, genotypephenotype correlations and patho
logy reports have demonstrated that the spectrum of the
disease is wider than initially thought, with the identifi
cation of biventricular and even isolated left ventricular
(LV) forms in addition to the more-frequent RV manifesta
tion.13,14 The condition is, therefore, increasingly being
referred to simply as arrhythmogenic cardiomyopathy.

Competing interests
The authors declare no competing interests.

NATURE REVIEWS | CARDIOLOGY

Department of Medical
Diagnostic Sciences
and Special Therapies
(C. Basso, G. Thiene)
and Department of
Cardiac, Thoracic and
Vascular Sciences
(B.Bauce, D. Corrado),
University of Padua
Medical School,
Via A.Gabelli,
6135121Padova,
Italy.
Correspondence to:
C. Basso
cristina.basso@unipd.it

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Key points
Arrhythmogenic cardiomyopathy (AC) is a familial heart-muscle disease
that is usually inherited with an autosomal-dominant pattern; mutations
in desmosomal-protein genes are found in approximately 50% of probands
The 1994 diagnostic criteria were updated in 2010 to increase their sensitivity,
but maintain their specificity; differential diagnosis with AC phenocopies is
mandatory when dealing with sporadic forms of AC
Emerging tools offer the possibility to visualize the fibrofatty scar, as either
low-voltage myocardial areas using electroanatomical mapping, or areas
of delayed contrast-enhancement with cardiac MRI
Genotypephenotype studies show that the clinicomorphological spectrum
of AC is wider than originally thought, and includes variants with predominant
or even isolated left ventricular involvement within a single family
Animal and cellular models indicate that both abnormal biomechanical
properties and crosstalk from the desmosome to the nucleus, gap junctions,
and ion channels are implicated in the pathobiology of AC
Electrical instability is the main clinical manifestation of AC; in addition
to re-entry arrhythmias caused by fibrofatty replacement, current hypotheses
implicate acute cell death, gap-junction remodeling, and ion-channel crosstalk

The evolution of the name and perception of the disease is

well-documented in three monographs published between
1997 and 2011.1517

Clinical diagnosis of AC
Suspicion of classical AC usually arises when adolescents
or young adults present with heart palpitations, syncope,
or cardiac arrest. Ventricular tachycardia or premature
ventricular beats with left bundle branch morphology and
Twave inversion in the V1 to V3 leads on a 12lead electro
cardiogram (ECG) are common reasons to suspect AC.
Less-common presentations are RV or biventricular heart
failure, which can mimic dilated cardiomyopathy.2,18 The
major challenge is to distinguish AC from a normal heart
with physiological adaptation to hemodynamic overload,
such as occurs in athletes, and from so-called disease
phenocopies, which include myocarditis, sarcoidosis,
idiopathic RV outflow tract tachycardia, and congenital
heart disease with RV overload.
No single, gold-standard criterion is sufficiently speci
fic to establish reliably a diagnosis of AC. Multiple para
meters are needed, therefore, as included in the original
1994 Task Force diagnostic criteria,11 which combined
multiple sources of diagnostic information, such as
familial, electrocardiographic, arrhythmic, morpho
functional, and histopathological findings. Although they
provide an extremely useful common approach to clinical
diagnosis in index patients, the 1994 criteria have been
shown to lack sensitivity for the identification of early or
minor phenotypes, particularly in the setting of familial
disease.19 A limitation of the original Task Force criteria
was the lack of quantitative cut-off values for accurate
grading of RV dilatation and dysfunction, and fibrofatty
myocardial replacement.

2010 diagnostic criteria

Revised criteria were published in 2010 to improve diag
nostic sensitivity, but with the important prerequisite of
maintaining diagnostic specificity.19 These criteria provide
224 | APRIL 2012 | VOLUME 9

quantitative imaging cut-off points to define a normal

right ventricle, and to categorize the various degrees of
morphofunctional RV abnormality. Quantitative para
meters were also introduced for tissue characterization
by endomyocardial biopsy, ECG, and signal-averaged
ECG. Twave inversion in V1 to V3 leads, and ventricular
tachycardia with a left bundle branch block morphology
with superior or indeterminate QRS axis (either sus
tained or nonsustained), have become major diagnostic
criteria. Moreover, Twave inversion in V1 to V2 leads in
the absence of right bundle branch block (and in V1 to
V4 leads in the presence of complete right bundle branch
block), positivity for any one of the three signal-averaged
ECG parameters for late potentials, and >500 premature
ventricular beats in a 24h period on Holter monitoring
have been included among the minor criteria.
By contrast with the 1994 criteria, the family history
category of the 2010 criteria includes molecular genetic
information. In particular, the identification of a patho
genic mutation in a first-degree relative has become a
major criterion for the diagnosis of AC. Because of the
diagnostic implications, however, caution in the interpre
tation of genetic-screening results is highly recommended.
A pathogenic mutation is challenging to define and, even
if a desmosomal gene mutation is identified, the variable
disease penetrance means that determining whether the
individual will be affected is difficult.
Overall, according to the revised criteria for AC, ful
fillment of two major, one major and two minor, or four
minor criteria confirms a definite diagnosis; one major
and one minor, or three minor criteria indicates a border
-line diagnosis; and one major, or two minor criteria
from different categories suggests a possible diagnosis.
Meanwhile, a new diagnostic test for AC that is based
on immunohistochemical analysis of human myocardial
samples has been developed. This test has revealed a
reduced signal for junction plakoglobin at intercalated
discs in most affected patients.20 Compared with the 1994
clinical Task Force criteria, the immunohistochemical
test seems to be highly sensitive (91%) and specific (82%)
for the diagnosis of AC; however, this disease biomarker
remains a research tool because of the possibility of falsenegative and false-positive results, such as in sarcoidosis
and giant-cell myocarditis.21

Novel diagnostic imaging techniques

Novel clinical tools available for the diagnosis of AC
include contrast-enhanced cardiac MRI,2225 and electro
anatomical mapping.2628 Cardiac MRI is increasingly
used to provide noninvasive tissue characterization of
the ventricular myocardium. In addition to identification
of RV involvement, this technique can help to identify
even early or minor LV involvement, in the absence
of morphofunctional abnormalities detected by echo
cardiography.24,25 Electroanatomical mapping can be
used to identify the abnormal low-voltage areas, which
have been demonstrated consistently in endomyocardial
biopsies to correspond with the loss of electrically active
myocardium caused by fibrofatty scarring.26,27 Systematic
percutaneous catheter mapping of the epicardium in
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patients with AC in whom endocardial ablation failed con
firmed an observation made by pathologiststhat fibro
fatty replacement (electroanatomical scarring) is more
extensive on the epicardial than the endocardial side.28
However, electroanatomical mapping is invasive and per
formed only in selected patients with suspected AC and
ventricular arrhythmias of RV origin for differential diag
nosis with idiopathic RV outflow tract tachycardia, and to
guide catheter ablation of the arrhythmogenic substrate.

Left-dominant AC
Most of the information on AC comes from studies
of the usual form of the disease with predominant RV
involvement. However, recognition of a disease pattern
characterized by early and predominant LV involvement
has increased. The left-dominant AC (LDAC) pattern
should not be confused with the well-known LV involve
ment observed in the advanced stages of AC, as a result
of disease progression. Clinical markers of LDAC include
ECG abnormalities that suggest left-side involvement,
such as lateral or inferolateral Twave inversion (leads V5,
V6, LI, and aVL),24,29 and ventricular arrhythmias of right
bundle branch block morphology that suggests an LV
origin. True LDAC mirrors classic right-dominant AC,
with the left ventricle more-severely affected than the right
ventricle (an RV/LV volume ratio <1).
A far more-sensitive indicator of left-sided disease
is late gadolinium enhancement, which is frequently
detected in a segment without a concomitant wall-motion
abnormality, and thus precedes the onset of LV dysfunc
tion or dilatation. Typically, LV late gadolinium enhance
ment involves the inferolateral and inferoseptal regions,
and affects the subepicardial or midwall layers, similar to
the histological pattern of fibrofatty myocardial replace
ment observed at post-mortem examination.6,13,14,30 Septal
late gadolinium enhancement is present in >50% of cases
of LDAC,24 unlike the right-dominant classical pattern in
which septal involvement is unusual.
Differential diagnosis of dilated cardiomyopathy
in patients with suspected AC is mandatory for risk-
stratification and familial-evaluation purposes. The main
distinction in LDAC is a propensity to electrical instabil
ity that exceeds the degree of ventricular dysfunction,
compared with dilated cardiomyopathy, where ventricu
lar arrhythmias and sudden cardiac death occur in the
context of overt systolic dysfunction with symptoms of
heart failure. Moreover, regional involvement (by contrast
with the global involvement in dilated cardiomyopathy)
is suggestive of AC, particularly when RV abnormalities
are prominent.24
Importantly, patients with a moderate-to-severe
decrease in LV function were excluded from a diagnosis
of AC by the 1994 Task Force criteria,11 but this restriction
has been eliminated in the 2010 criteria.19 As recognized
by the Task Force, awareness is growing that classic AC
with RV involvement is the most well-recognized variant
of a broad spectrum of disease that includes LDAC and
biventricular subtypes. The lack of specific diagnos
tic guidelines contributes to the under-recognition of
these nonclassical variants of AC. Future revisions of the

Task Force criteria will need to address this disparity, by

incorporating features such as ventricular tachycardia of
right bundle branch block morphology, subepicardial
or midmyocardial late gadolinium enhancement of the
LV myocardium, and global or regional LV dysfunction
in patients who present with arrhythmia rather than
heartfailure.
The genetic association between LDAC and classical
RV AC is supported by data showing that one-third of
the genotyped LDAC cohort of the Heart Hospital ter
tiary center has pathogenic mutations in ACrelated des
mosomal genes.24 These AC variants often coexist within
the same family, and the histopathological features (myo
cardial loss, fibrofatty replacement, and inflammatory
infiltrates) of the left ventricle parallel the changes in the
right ventricle.24

The desmosomal genetic basis of AC

More than a decade elapsed between the recognition of
familial AC,31 and the identification of the first diseasecausing gene mutation.32 The difficulty in identifying
affected individuals in the families of patients with AC,
mostly because of the variable penetrance and the low
sensitivity of diagnostic criteria in the familial forms
of the disease, represented a major obstacle to early
linkage-mapping studies and subsequent candidategene evaluation. In 1994, a disease locus was identified
in chromos ome14 by linkage analysis in large fami
lies with dominant AC,33 but only in the year 2000 was
an AC-causing gene mutation identified in JUP in a
fully penetrant, autosomal-recessive form of the disease
with an easily recognizable cardiocutaneous phenotype
(Naxos disease).32 A recessive mutation in DSP was sub
sequently found to cause another cardiocutaneous syn
drome, Carvajal disease, which is characterized at the
cardiac level by biventricular involvement.34 Therefore,
after many years of linkage-analysis studies that led to the
identification of several disease loci, but no disease genes,
the molecular basis of AC was discovered by investiga
tion of cardiocutaneous syndromes.35 In particular, a
morphological study of the heart of a patient with Carvajal
disease, showed biventricular wall thinning with aneu
rysms, myocardial atrophy, and fibrosis,36 which immedi
ately suggested that the disease-causing gene mutations
involved in that cardiocutaneous syndrome might also be
ideal candidates for the autosomal-dominant form of AC.
Consequently, in 2002, mutations in the DSP gene were
identified37 in families that had been followed up since the
1980s in an outpatient clinic in Padua, Italy.38
Subsequently, a variety of mutations have been found
in other desmosomal genes, including PKP2, DSG2, and
DSC2.3941 Mutations in JUP have been reported even in
dominant forms of AC,42 and in DSC2 and PKP2 in reces
sive variants of the disease.43,44 With the exception of a
few genes unrelated to the cell-adhesion complex, such as
RYR2 (encoding the ryanodine receptor2), TGFB3 (trans
forming growth factor3), and TMEM43 (transmembrane
protein43, also known as protein LUMA),4547 the mostcommon disease-causing mutations occur in genes that
encode desmosomal proteins (Table1). Mutations in DES

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Table 1 | Genes associated with AC
Reference

Gene

Chromosome
locus

Protein

Mode of
inheritance

Comment

McKoy etal.31

JUP

17q21

Junction plakoglobin

AR*

Cardiocutaneous syndrome

Asimaki etal.

JUP

17q21

Junction plakoglobin

AD

None

Norgett etal.33

DSP

6p24

Desmoplakin

AR

Cardiocutaneous syndrome

Rampazzo etal.

DSP

6p24

Desmoplakin

AD

None

Gerull etal.38

PKP2

12p11

Plakophilin2

AD, AR

None

Pilichou etal.39

DSG2

18q12

Desmoglein2

AD

None

Syrris etal.

DSC2

18q12

Desmocollin2

AD, AR

None

Desmosomal genes

41

36

40

Extradesmosomal genes
Tiso etal.44

RYR2

1q42q43

Ryanodine receptor2

AD

CPVT (AC phenocopy)

Beffagna etal.45

TGFB3

14q23q24

Transforming growth
factor3

AD

Pathogenic or modifier?

Merner etal.46

TMEM43

3p25

Transmembrane
protein43 (protein LUMA)

AD

None

van Tintelen etal.47

DES

2q35

Desmin

AD

Overlap syndrome (DC and HC

phenotype, early conduction disease)

Taylor etal.48

TTN

2q31

Titin

AD

Overlap syndrome (early conduction

disease, AF)

*Naxos disease. Carvajal disease. Abbreviations: AC, arrhythmogenic cardiomyopathy; AD, autosomal dominant; AF, atrial fibrillation; AR, autosomal recessive;
CPVT, catecholaminergic polymorphic ventricular tachycardia; DC, dilated cardiomyopathy; HC, hypertrophic cardiomyopathy.

(desmin) and TTN (titin) have been proposed as novel

causes of AC.48,49
Results of genotypephenotype studies in which
large series of familial cases of AC were investigated
have shown that half of index cases present a causal or
possibly causal mutation in a desmosomal gene, which
reached a peak of 70% of probands with a desmosomal
gene mutation in a UK series.5052 The majority of muta
tions involve PKP2 and DSG2, followed by DSP and
DCS2. 5052 This prevalence is similar in the UK and Italy,
but DSP-mutation carriers represent only 1% of all pro
bands with AC in North America.52 In the Netherlands,
90% of pathogenic ACcausing mutations involve PKP2
and are mostly truncation mutations.53 These nonuniform
data might reflect the presence of founder mutations, the
use of inconsistent definitions for pathogenicity, and geo
graphic variations in either genetic or nongenetic factors.
Moreover, the strictness with which diagnostic criteria are
applied could have a role, given that LV involvement in the
clinical spectrum of AC was recognized only in the 2010
revision of the diagnostic criteria.19

Genetic screening for AC

Although molecular genetic studies have provided sub
stantial insights into the pathogenesis of AC, the role of
genotyping in clinical practice has not yet been confirmed.
The original idea of a monogenic disease has evolved over
the past decade with the discovery of a complex genetic
background, which explains the low penetrance and vari
able expression of the AC phenotype, and accounts for
our limited ability to identify truly genetically affected
individuals. AC is characterized by marked intrafamilial
and interfamilial phenotypic diversity. A number of the
226 | APRIL 2012 | VOLUME 9

alleles identified are of low pathogenicity and the major

challenge for clinical cardiologists working with inherited
cardiomyopathies is how to be sure that identified genetic
abnormalities are causal. Emerging evidence shows that
more than one genetic abnormality might be required for
clinical disease expression, because many individuals who
carry a single mutation within an AC proband family do
not meet the 2004 and 2010 Task Force diagnostic crite
ria.54,55 Compound heterozygous mutations in a single
desmosomal gene, or digenic mutations (gene variants in
two or more desmosomal genes) are often necessary to
develop the AC phenotype.54,55 Interestingly, genedose
effects are evident in recessive syndromes, such as Naxos
and Carvajal diseases, which show an earlier clinical onset
and higher penetrance of heart failure and life-threatening
ventricular arrhythmias than autosomal-dominant AC.50
Furthermore, common genetic-sequence variants could
act as modifiers in AC.
In a comprehensive study of genetic variation for AC
susceptibility genes, mutations were identified in 16% of
healthy individuals compared with 58% of index patients
with AC.56 Most of the mutations in the controls were
missense, which suggests that many of them were benign.
After assessment for only so-called radical mutations (inframe and frame-shift insertions and deletions, splice
junction, and nonsense mutations), the prevalence of AC
mutations dropped to 0.5% in controls compared with
43% in probands.56 On the basis of these findings, only
radical mutations are likely to be associated with AC.
Rare missense mutations should be considered with great
caution; factors that strengthen their pathogenicity could
include the specific amino-terminal regions of DSP and
DSG2 (hot spots), and PKP2 and DSG2 mutations that
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involve residues that are highly conserved across species.
Notably, mutations in nonwhite controls occurred at a
significantly higher frequency than in white controls,
suggesting an influence of ethnicity on the probability of
missense mutations truly being pathogenic.56
All these considerations explain why, despite increasing
accessibility to genetic-screening facilities for patients and
cardiologists, caution is needed before genetic testing can
be considered for routine clinical use. Although cascade
genetic screening of family members of gene-positive pro
bands remains a major indication, the clinical application
should be performed at referral centers with expertise in
inherited cardiovascular disorders, where the test can be
interpreted by qualified genetic counselors and discussed
with the patient.57 Genetic testing for AC is not a per
fectly binary test that yields a positive or negative result,
and should not override clinical judgment. An identified
genetic variant cannot be considered the Holy Grail of
diagnosis and, equally, relatives with border-line find
ings should not be discharged just because of a negative
screening for a mutation identified in the index patient
with AC. More importantly, a careful clinical and genetic
evaluation of the family members remains essential
because analysis of co-segregation is often crucial to help
assess the pathogenic relevance of a mutation.

Putative pathophysiological mechanisms

Desmosomes mediate cellcell adhesion through three
families of proteinsthe armadillo proteins (junction
plakoglobin and plakophilins), cadherins (desmocollins
and desmogleins), and plakins (desmoplakin). These
complex networks of proteins are found primarily in
tissues subjected to mechanical stress, such as the epider
mis and the heart.58,59 Mutations in desmosomal genes
with recessive and dominant patterns of inheritance are
associated with cutaneous disease, cardiac disease, or both,
which demonstrates the important role of the desmosome
in epithelial and cardiac structure and function. Moreover,
the components of the cell-adhesion apparatus are increas
ingly being shown to possess intracellular signaling
capabilities in addition to structural functions.58
Before the identification of the first AC-causing gene
mutation, many etiopathogenetic theories were proposed.
The disontogenetic theory (congenital dysplasia) has been
definitively abandoned, but the other original theories are
still applicable to the perspective of a genetically deter
mined cardiomyopathy predominantly caused by defective
desmosomal genes.2,6,7 The various disease mechanisms
described below are unlikely to be mutually exclusive, and
might all contribute to the pathogenesis of AC under the
final common pathway of impaired desmosomal function.

Myocardial dystrophy
The degenerative theory (myocardial dystrophy), 6
which was postulated in 1996, long before the discovery
of disease-causing gene mutations, remains the most-
comprehensive pathogenic theory of AC. The observa
tion of similar histopathological features in AC and
skeletal-muscle dystrophies, consisting of acquired and
progressive muscular atrophy with fatty and fibrous tissue

Figure 1 | The progression of the AC phenotype. Evidence from experimental animal

models recapitulates the disease phenotype of patients with AC. a | A structurally
normal heart develops and is present at birth. b | The disease process of
myocardial loss starts on the epicardial side, and c | extends as a wave-front from
the epicardium towards the endocardium. d | Wall thinning and biventricular
aneurysms develop at a later stage because of transmural fibrofatty tissue repair.
Abbreviation:AC, arrhythmogenic cardiomyopathy.

replacement, provided the original idea that genetically

determined cardiomyocyte death, by either apoptosis or
necrosis,6,60,61 could account for the progressive loss of the
ventricular myocardium. Experimental data have shown
that the key initiating phenomenon in the cascade of
events that lead to fibrofatty replacement of the normal
myocardium is myocyte necrosis.62,63 Over time, myo
cardial dystrophy progresses to the phenotype of AC with
biventricular involvement (Figure1).
The role of desmosomal gene mutations in the
pathophysiology of myocardial injury remains under
investigation. The desmosomes are crucial for cellular
mechanical strength, through both cell-to-cell adhe
sion and transmission of force to the intermediate fila
ments in the cytoskeleton.58 Whether cardiomyocyte
death with sarcolemmal disintegration is a result of cyto
skeletal impairment, abnormal intracellular homeostasis,
or both, remains to be elucidated. The molecular path
ways involved in cell death are also under investigation,
with the aim of developing targeted therapies. Mice that
overexpress a mutation in Dsp (R2834H) showed disrup
tion of the intercalated disc and reduced co-localization
of desmoplakin and desmin filaments at the desmo
some level, which indicates that desmosomal instabil
ity is the primum movens of cardiomyocyte damage.64
Similarly, ultrastructural investigation of endomyo
cardial biopsies in patients with AC and a desmosomal
gene mutation revealed intercalated-disc remodeling
with desmosomal abnormalities, including a decreased
number of desmosomes, desmosomal-gap widening, and

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Desmosome crosstalk

Ion channels

Gap junctions

Nucleus

Electrical heterogeneity

Conduction slowing

Loss of cardiomyocytes,
fibrogenesis, adipogenesis

Arrhythmogenic
cardiomyopathy

Ventricular arrhythmias

Figure 2 | Hypothesized intracellular desmosome crosstalk. Possible targets

include intercalated-disc proteins (ion channels or gap-junctional proteins) and
nuclear-signaling proteins.

abnormally located desmosomes, often with pale, internal

desmosomal plaques.65

Desmosomal interactions
Mutations in desmosomal genes can interfere with signal
ing pathways to the nucleus, gap-junctional proteins, and
ion channels. Interruption of these crosstalk pathways can
result in the phenotype of AC (Figure2).
Desmosomal crosstalk with the nucleus
In addition to mechanical factors, possible intracellular
signaling pathways that mediate desmosome-to-nucleus
crosstalk and regulation of gene expression have been
investigated in mouse models that recapitulate the pheno
type of AC. Data from cardiac-restricted Dsp+/ mice indi
cate that suppression of Dsp causes nuclear translocation
of junction plakoglobin, where it competes with catenin1
for transcription factor7-like2 (formerly known as Tcellspecific transcription factor4), which leads to inhibition
of the canonical Wntcatenin 1 signaling pathway.66
Activation of Wntcatenin1 signaling enhances myo
genesis, inhibits adipogenic transcription factors (such
as CCAAT/enhancer-binding protein, adiponectin,
and peroxisome proliferator-activated receptor), and
maintains preadipocytes in an undifferentiated state. By
contrast, suppression of Wntcatenin1 signaling initiates
adipogenesis and proliferation of adipocytes, and reduces
the expression levels of target genes (MYC, CCND1).66
In an inducible, cardiac-restricted Jup/ mouse with
altered desmosomal ultrastructure and diminished pres
ence of desmosomal proteins at the intercalated discs,
loss of junction plakoglobin caused increased stabiliza
tion of catenin 1, associated with activated RAC
serine/threonine-protein kinase (also known as AKT1
kinase) and inhibition of glycogen synthase kinase3.63
According to these data, catenin1transcription-factor
activity (transcription factor7, lymphoid enhanced-
binding factor1) might contribute to the hypertrophic
response in cardiac-restricted Jup/ mice.
A mouse model of cardiomyocyte-restricted loss of
junction plakoglobin was developed and recapitulated the
phenotype of AC with ultrastructural evidence of absent
desmosomes.67 Despite the increase in catenin1 at adhe
rens junctions in cardiomyocytes from Jup-mutant mice,
Wntcatenin1 signaling was not altered. By contrast,
228 | APRIL 2012 | VOLUME 9

transforming growth factor signaling was significantly

elevated in the early stages,67 which suggests an impor
tant pathogenic role in human JUP-related AC. On the
basis of these findings, the prevailing pathogenic hypo
thesis was that the disruption or absence of desmosomes
renders cardiomyocytes incompetent of handling high
mechanical stresses, which ultimately leads to myocyte
detachment and cell death, followed by inflammation and
fibrosis.67 The enhanced activity of transforming growth
factor in the hearts of Jup-mutant mice seemed to be
triggered by the increased myocardial wall stress because
of the compromised cellcell mechanical coupling. AC
progression in a homozygous Dsg2-mutant mouse has
been correlated with increased mRNA expression of
Myc, Hesx1, Chrdl2, Ctgf, and Gdf15, which are markers
of cardiac stress, remodeling, and heart failure.68
Desmosomegap-junction interaction
Immunohistochemical and electron-microscopy studies in
patients with Naxos or Carvajal disease revealed reduced
localization of mutant junction plakoglobin to cellcell
junctions, diminished expression of gapjunction 1
protein (also known as connexin43), and a decreased
number and size of gap junctions.36,69 Subsequently, the
signal for junction plakoglobin was found to be dimin
ished at intercalated discs consistently and specifically
in patients with AC.20 Redistribution of junction plako
globin from junctions to intracellular pools could be
part of a final common pathway in disease pathogenesis,
and impaired mechanical coupling might also account
for abnormal electrical coupling through gap-junction
remodeling. The reduction in the expression of gapjunc
tion1 protein and gap-junction remodeling might con
tribute to conduction slowing, and thereby predispose
the heart to electrical instability, even before myocyte
damage occurs. However, this hypothesis has not been
proven in either animal models or humans, and requires
furtherstudy.
Desmosomenonjunctional-protein interaction
The possible interaction between junctional and non
junctional proteins at the intercalated-disc level has also
been investigated. Molecules that are not involved in
providing a physical continuum between cells also popu
late the intercalated disc. In particular, sodium channel
protein type5 subunit and plakophilin2 coexist in
the same molecular complex, and loss of plakophilin2
expression affects the amplitude and kinetics of the
sodium-channel current and the propagation velocity
of action potentials in ventricular myocytes.70 Another
important component of the voltage-gated sodium
channel is the cytoskeletal adaptor protein ankyrin3,
which interacts with plakophilin2 and gapjunction1
protein.71 The intercalated disc should, therefore, be con
sidered as a functional unit when seeking to understand
the molecular pathology of AC. Desmosomes, gap junc
tions, and sodium channels are not independent, but act
as a functional triad in which changes in the composition
of one constituent can affect the function and integrity
of the others.
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Myocarditis
In addition to the inherited metabolic or ultrastructuraldefect (dystrophic) theory, cardiomyocyte necrosis could
be ascribed to myocarditis (the inflammatory theory).
This pathogenic theory remains under consideration
because inflammatory cells are a common observation
in pathology studies of hearts with AC, with a reported
prevalence of up to 75%.6,72 The inflammation might be
a reaction to proinflammatory cytokines induced by cell
death or apoptosis, or caused by a viral infection. The
well-known heredofamilial background of the disease
is not inconsistent with the viral-infection hypothesis,
because disease genes can influence both anti-infective
and autoimmune responses, as observed in dilated
cardiomyopathy.73 Cardiotropic viruses, such as entero
virus, adenovirus, hepatitisC virus, and parvovirusB19,
have been reported in the myocardium of some patients
with AC, and proposed as possible etiological agents in
support of an infective pathogenesis.74 Alternative expla
nations could be that the viral agent acts as a bystander
or, more likely, that the dystrophic myocardium favors
viral settlement (superimposed myocarditis), which
leads to progression of the disease phenotype. However,
the observation of extensive inflammation in the early
stages of disease onset in transgenic mouse models of
AC,62,63 and the frequent detection of myocarditis in the
absence of viral genome in both familial dilated cardio
myopathy and AC, are consistent with the hypothesis of
noninfective myocarditis.
A process of active necrosis with an accompanying
inflammatory response might underlie the clinical onset
or the periodical exacerbations of an otherwise chronic
disease, as demonstrated in both transgenic mice and
human samples.6,62,72 Accordingly, chest pain, ECG abnor
malities, and release of myocardial enzymes (mimicking
an acute myocardial infarction) are sometimes reported
in patients with AC, particularly during adolescence
(probably because of increased mechanical wall stress).29
Moreover, a higher level of Creactive protein has been
demonstrated in patients with AC soon after ventricular
tachycardia compared with idiopathic RV outflow tract
tachycardia.75 Consistent with the hypothesis that pro
inflammatory cytokines might be induced by cell death
or apoptosis, high plasma levels of IL1, IL6, and
tumor necrosis factor were found in a small series of
patients with AC.76 An altered distribution of junction
plakoglobin at the intercalated disc in cardiac sarcoidosis,
giant-cell myocarditis, and AC is consistent with a role
of cytokines in disruption of desmosomal proteins, and
arrhythmogenesis in patients with AC.21
The source of fibrofatty tissue
In both the dystrophic and inflammatory theories, the
fibrofatty replacement of ventricular myocardium has
been considered for many years to be a nonspecific, repar
ative response to myocardial injury, similar to the process
that occurs after ischemic death in an acute myocardial
infarction. A transdifferentiation theory has been pro
posed as an alternative explanation for progressive myo
cardial atrophy and fatty replacement, which suggests that

cardiac myocytes undergo a metamorphosis and switch

to the fate of adipocytes.77 However, this theory, which
was advanced on the basis of a single observation in an
explanted heart, seems questionable because of the limited
dedifferentiation capabilities of adult cardiomyocytes,
and requires further investigation.
Another theory is that adipocytes in AC derive from
progenitor cells of the second heart field, which give rise
to the bulbus cordis and pulmonary infundibulum (the
inlet, apex, and outlet of the right ventricle).78 According
to this hypothesis, the progenitor cells of the second heart
field switch to adipogenesis because of suppressed Wnt
catenin1 signaling as a result of the translocation of
junction plakoglobin to the nucleus.78 Because AC is now
considered to be a biventricular disease, subepicardial pro
genitor cells are more likely than those from the second
heart field to have a role in fibrofatty replacement.79 Indeed,
subepicardial progenitor cells spread into both ventricles,
and generate the myocardium and interstitial cells. The
wave-front extension of the fibrofatty tissue from the epi
cardium towards the endocardium (with relative sparing
of the ventricular septum, which is a nonsubepicardial
structure) supports this alternative theory of the origin of
the progenitor cells. Although data are limited, progenitor
cells of both adipocytes and fibroblasts are likely either to
express desmosomal proteins or to have the expression of
these proteins elicited by paracrine signaling.

AC and nondesmosomal genes

Autosomal-dominant AC has also been linked with
genes that are unrelated to the cell-adhesion complex.
Mutations in the gene encoding ryanodine receptor2
(RYR2), which mediates calcium release from the sarco
plasmic reticulum, have been identified in families with
an autosomal-dominant form of AC with segmental RV
cardiomyopathic changes, a normal 12lead ECG, effortinduced ventricular arrhythmias, and sudden cardiac
death.45 Myocardial structural changes were once thought
to result from altered intracellular calcium levels, but the
clinical phenotype is now recognized to be that of cat
echolaminergic polymorphic ventricular tachycardia
rather than AC, and is considered a disease phenocopy.
Similarly, mutations in the genes encoding desmin
(DES)48 and titin (TTN)49 account for clinical-overlap syn
dromes rather than typical AC, and can be listed among
AC phenocopies characterized by a high incidence of early
onset conduction-system disorders.
Mutations in TGFB3 are thought to induce myocardial
fibrosis by stimulating the proliferation of mesenchymal
cells and the production of extracellular-matrix compo
nents.46 Moreover, they might affect cell-to-cell junction
stability, because transforming growth factor3 modulates
the expression of genes that encode desmosomal proteins
in various cell types. However, whether this genetic variant
is truly causal of AC remains unclear.
Mutations in TMEM43 have been identified in a large
cohort of related patients in Newfoundland, Canada,
who exhibit a highly lethal and fully penetrant variant
of AC.47 Little is known about the function of TMEM43,
but it could be a part of an adipogenic pathway regulated

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REVIEWS
by peroxisome proliferator-activated receptor, whose
dysregulation might explain the fibrofatty replacement of
the myocardium in patients with AC. The gene product
of TMEM43 has been demonstrated to be the protein
previously known as protein LUMA, which is a binding
partner of emerin and the lamins, and has been associated
with EmeryDreifuss muscular dystrophy.80

Exogenous and endogenous modifiers of AC

Although AC-causing genes have been identified suc
cessfully in genetic studies in humans, a broad spectrum
of disease expression is observed in patients with AC,
even among members of the same family, or between
families with identical missense mutations. The precise
location of a desmosomal gene mutation and its impact
on protein structure and function might predict whether
it alters cellcell adhesion or intermediate-filament
binding. In particular, mutations that impair cell adhe
sion might explain a prevalent RV involvement because
of the compliance of the thin RV wall to the wide physio
logical changes in preload. By contrast, mutations that
truncate the Cterminus of desmoplakin might result in
predominant LV involvement because of its direct inter
action with desmin. However, because patients with AC
can present with a variable phenotype (right-dominant,
biventricular, and left-dominant forms) within the same
family, the primary mutation cannot be the sole cause of
these various manifestations, and a modifier effect must be
invoked. In addition to modifier genes and still-unknown
disease-causing genes, exogenous and endogenous factors
(such as age, sex, strenuous exercise, drugs, hormones,
infection or inflammation, and emotional stress) might
modulate the disease phenotype.81
Studies of AC have consistently demonstrated a male
predominance of the disease. Men are more often the
index cases within an affected family because of the onset
of severe ventricular arrhythmias and occurrence of
sudden cardiac death at a younger age than in women,
despite a similar prevalence of carrier status between the
sexes. Although merely speculative, possible roles for
deleterious effects of strenuous exercise in men, and pre
vention of myocyte death by estradiol in women have been
proposed.82,83 Studies in monozygotic twins are of great
value in the investigation of inherited cardiomyopathies
and, although limited by low numbers of patients, provide
preliminary evidence for environmental influences in AC.
Indeed, phenotypes of monozygotic twins with AC are not
identical and in the few available reports a role for strenu
ous physical effort as a factor to trigger arrhythmias in
patients with AC has been postulated.84,85
Human genetic studies are, however, intrinsically
limited by highly variable and unmeasurable environ
mental stimuli (such as exercise and inflammation), the
various genetic backgrounds, and the small number of
individuals carrying the same mutation. Knock-in animal
models that mimic the human phenotype of AC might be
valuable, because both the environmental influences and
the genetic background can be controlled.86 The role of
external factors in modifying the phenotype of AC was
addressed in heterozygous Jup+/ mice, where reduced
230 | APRIL 2012 | VOLUME 9

expression of junctional plakoglobin altered RV contractil

ity and electrophysiological function, without an effect on
myocardial structure, desmosome integrity, or the expres
sion of gapjunction1 protein.87 The desmosomal model
of AC suggests that lifestyle measures and therapies that
reduce mechanical stress on the heart would be beneficial.
Accordingly, the cardiac phenotype was exacerbated in
mice by daily swimming,87 which supports the hypothesis
that endurance training accelerates disease progression in
patients with AC.88 Furthermore, load-reducing therapy
(furosemide and nitrates) can prevent training-induced
development of AC in Jup+/ mice.89 Long-term follow-up
and intervention studies in large cohorts are needed to
confirm these preliminary observations. These data might
support the use of drugs such as blockers (with benefits
beyond those of arrhythmia suppression) or inhibitors of
angiotensin-converting enzyme to prevent the progres
sion, or even onset, of disease in border-line or healthy
gene-mutation carriers.

Implications for treatment of AC

Physical exercise and participation in competitive athletics
have been associated with a propensity for life-threatening
ventricular arrhythmias and an increased risk of sudden
cardiac death in patients with AC.4,88,90,91 The identifica
tion of affected individuals by preparticipation screening
has proven to be life-saving, with a substantial reduction
in the mortality of young athletes.90 Furthermore, physi
cal activity is considered to be a factor that accelerates
progression of the disease phenotype.87,89 As a corol
lary, asymptomatic and healthy gene-carriers should be
advised to refrain from intense physical exercise, not only
to reduce the risk of ventricular arrhythmias, but also to
prevent diseaseprogression.
Antiarrhythmic drugs are the first-line therapy for
patients with an arrhythmic presentation. The classIII
agent sotalol has emerged as the preferred agent for initial
treatment; amiodarone is a second-line antiarrhythmic
agent in patients with refractory ventricular arrhythmias.
Whether prophylactic therapy with blockers lowers
the rate of arrhythmic complications and slows disease
progression by reducing mechanical stress on the heart
remains to be proven. By contrast, the role of pharmaco
logical therapy to prevent inappropriate shocks from an
implantable cardioverterdefibrillator (ICD) because of
sinus tachycardia, supraventricular tachycardias, or atrial
fibrillation with rapid ventricular response has been clearly
demonstrated.92,93 Anticoagulation is indicated in patients
with atrial fibrillation but, although reports of pulmonary
or systemic embolism exist, studies do not support the
prophylactic use of anticoagulants in patients with RV
aneurysms or left-dominant or biventricular forms of AC.
Catheter ablation of the fibrofatty scar has evolved
from a palliative procedure in patients with end-stage
AC and incessant ventricular tachycardia, frequent ICD
shocks, or adverse effects from antiarrhythmic drugs, to
an early option for the management of ventricular tachy
cardia,94,95 with good results particularly when the epi
cardial approach is used.28 Although ICDs confer optimal
protection against sudden cardiac death in patients with
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2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
AC, the high rate of inappropriate interventions and
complications, and the psychological effects in young
patients, argue strongly against indiscriminate device
implantation.96,97 Cardiac transplantation is unusual in
patients with AC, but has been performed for both inces
sant ventricular tachycardia and end-stage heart failure
that is refractory to conventional treatment.
Risk stratification remains the major challenge for
clinicians treating patients with AC. The available data,
which are still derived from retrospective clinical studies,
suggest that young age, previous cardiac arrest, fast and
poorly tolerated ventricular tachycardia with various
morphologies, syncope, severe RV dysfunction, and LV
involvement are potential predictors of poor prognosis
and sudden cardiac death. A malignant family history
alone is not considered a predictor of increased risk of
AC and does not justify an ICD.97 Data are too limited
to allow speculation on the potential role of genotyping
for risk stratification and therapy in patients with AC.
However, the available evidence suggests that, although
asymptomatic patients with AC and healthy gene-carriers
do not require prophylactic treatment, these individuals
should have a regular cardiac follow-up.

Conclusions
Much progress has been made at both the bench and
the bedside since the discovery of the first AC-causing
gene mutations.32 The 1994 diagnostic criteria11 were
updated in 201019 to increase their sensitivity in famil
ial cases of AC, and differential diagnosis with so-called
phenocopies is always pursued in sporadic cases. Novel
diagnostic tools for tissue characterization are increas
ingly used and include electroanatomical mapping 26 and
contrast-enhanced cardiac MRI.22,23 The latter is a unique
tool to detect early LV involvement, even in the setting
of preserved LV morphology and function.23 Genotype
phenotype correlative studies have shown that LV involve
ment is part of the disease phenotype,25 which justifies the
more-inclusive name arrhythmogenic cardiomyopathy.
Risk stratification remains the main clinical challenge

1.

2.

3.

4.

5.

6.

Online Medical Inheritance in Man. 107970

Arrhythmogenic right ventricular dysplasia,
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Basso, C., Corrado, D., Marcus, F.I., Nava, A.
& Thiene, G. Arrhythmogenic right ventricular
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and parameters for ICD use in primary prevention have

beenproposed.96,97
Understanding the cascade of cellular and molecular
events leading from a gene defect to myocardial dystrophy
is crucial for the transition from symptomatic treatments
to disease-targeted therapies. Cellular and animal-model
experiments are being performed to identify curative
targets along the final common pathway involved in
cardiac-muscle necrosis and failure of myocyte regenera
tion. Drugs that target cellular pathways, as well as genebased and cell-based therapies are being investigated for
skeletal muscular dystrophies. For instance, on the basis
of the hypothesis that sarcolemmal defects lead to calcium
overload with mitochondrial damage and subsequent cell
necrosis, drug protection of the mitochondria has been
demonstrated to improve pathological changes in mouse
models of muscular dystrophy.98 The frequent observa
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bursts underlie disease onset and progression2,6,72 suggest
a possible role for anti-inflammatory drugs.
Finally, the genetic, epigenetic, and environmental
factors that intervene as disease modifiers by interaction
with mutations in desmosomal genes need to be investi
gated. The scientific community anticipates a time when
lifestyle modification, antiarrhythmic drugs, and ICDs
are not the only approaches to manage the symptoms of
AC, and we are able to modulate the pathways that lead
to progressive myocardial dystrophy.
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Acknowledgments
The authors are supported by Telethon, Rome;
CARIPARO Foundation, Padova; and Veneto Region,
Venice, Italy.
Author contributions
C. Basso researched the data, and all the authors
contributed substantially to discussion of the content
of the article. C. Basso wrote the manuscript, and all
the authors were involved in reviewing and editing it
before submission.

VOLUME 9 | APRIL 2012 | 233

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