Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype
Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype
Jose Mar´ıa Lo´ pez-Ayala 2
Ivan Go´ mez-Milane´ s 1
Juan Jose´ Sa´ nchez Mun˜ oz 2
Francisco Ruiz-Espejo 1
Mart´ın Ort´ız 0
Josefa Gonza´ lez-Carrillo 2
David L o´pez-Cuenca 2
M. J. Oliva-Sandoval 2
Lorenzo Monserrat 0
Mariano Valde´ s 2
Juan R. Gimeno 2
0 A Corun ̃a University Hospital, A Corun ̃a Biomedical Research Institute , A Corun ̃a , Spain
1 Department of Clinical Analysis, Virgen de la Arrixaca University Hospital , Murcia , Spain
2 Department of Cardiology, University of Murcia, Virgen de la Arrixaca University Hospital , Murcia , Spain
Aims Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype - phenotype correlations in patients carrying a novel DSP c.1339C.T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC and results (n ¼ 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n ¼ 23) (aged 40 + 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C.T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C.T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion DSP c.1339C.T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a
primary myocardial disorder clinically characterized by ventricular
arrhythmias, sudden cardiac death (SCD), and end-stage heart
failure. It is a common cause of SCD among young people and
athletes,1 and fatal arrhythmia may even occur in the absence of
significant ventricular remodelling.
Arrhythmogenic right ventricular cardiomyopathy was thought
to primarily affect the right ventricle (RV) although in a proportion
of cases, the disease has been shown to affect the left ventricle (LV)
not only at the end stage but also as a primary target. In this scenario,
isolated arrhythmogenic left ventricular cardiomyopathy (ALVC)
is frequently misdiagnosed as dilated cardiomyopathy (DCM) or
† We identified a new desmoplakin mutation (DSP c.1339C.T)
associated with a severe phenotype of arrhythmogenic
cardiomyopathy and a high burden of ventricular arrhythmia.
† Left ventricular non-compaction with high personal and
familiar arrhythmic burden should arouse suspicion towards
† Vast majority of desmoplakin truncated mutations reported in
the literature are associated with severe phenotypes.
Mutations in genes encoding desmosomal proteins (desmoplakin,
plakophilin-2, plakoglobin, desmocollin-2, and desmoglein-2)4 were
first identified in classical ARVC and were later found in left dominant
forms.5,6 Other non-desmosomal genes have recently been
associated with arrhythmogenic cardiomyopathy (ACM).7
The aim of this study was to investigate genotype – phenotype
correlations in patients carrying a novel DSP c.1339C.T, and to review
the literature on the clinical expression and the outcomes in patients
with DSP truncating mutations.
The study was approved by the Ethics Committee of our hospital (Virgen
de la Arrixaca University Hospital, Murcia) and it complied with the
ethical principles of the Declaration of Helsinki. All participants gave
their written consent. A genealogical pedigree of each family was
obtained. Clinical assessment consisted of a 12-lead digital
electrocardiogram (ECG), a signal-averaged ECG (SA-ECG), a 2D-Doppler
echocardiogram, cardiac magnetic resonance (CMR), an exercise test, and 24 h
Holter monitoring. In addition, an electrophysiological study (EPS) was
performed in three patients. Patients were followed up annually
[median 26 (
13 – 87
The population studied included 47 unrelated patients [29 (62%) males,
aged 40 + 19 years]. Twenty three (49%) met the criteria for ARVC and
24 for DCM, showing either sustained ventricular tachycardia (S-VT) or a
history of SCD in a first- or second-degree relative under 35 years of age.
We chose a DCM population with such a particular aggressive arrhythmic
burden that arouse the suspicion of arrhythmogenic left ventricular
cardiomyopathy as the first diagnosis to be considered.
A genetic study of the five desmosomal genes (DSP, DSG2, DSC2, PKP2,
PKG), PLN, and LDB3 was performed in the 47 patients. A novel DSP
c.1339C.T mutation was identified in three unrelated probands.
Firstdegree relatives from these three families were invited to participate in
a clinical and genetic investigation. Fifteen relatives were found to carry
DSP c.1339C.T. Two additional patients previously diagnosed with
DCM, mild systolic dysfunction, and ventricular arrhythmia died before
the study started and in light of their family history, they were considered
to be obligatory carriers.
A LV end-diastolic diameter (LVEDd) of .117% from normal and/or
LV systolic impairment (,45%) was used for the diagnosis of DCM in
probands. Familial criteria were applied in the remaining carriers.8
Arrhythmogenic right ventricular cardiomyopathy diagnosis was made
according to the revised Task Force Criteria (TFC).9 Jenni et al.10 criteria
were employed for the definition of left ventricular non-compaction
Deoxyribonucleic acid was extracted from peripheral blood samples
using the Maxwell 16 Blood Purification kit. Previously published DSP,
DSC2, DSG2, PKP2, PKG, PLN primer sequences were used for
amplification. Results were compared with the sequences available in Gen Bank
(RefSeq: NC_000006.11) and analysed by SeqScape software
(AppliedBiosystem).11 MYBPC3 and MYH7 were studied in two selected
individuals from families with DSP c.1339C.T with LVNC phenotype. DSP
c.1339C.T variant was absent in 500 Spanish control samples and was
not present in the 5000 exome project [Exome Variant Server, NHLBI
GO Exome Sequencing Project (ESP) (URL: http://evs.gs.washington.
edu/EVS/) [1/12/2013].] Four published markers that flank the DSP
gene were used to investigate the presence of a potential founder
effect in carriers of DSP c.1339C.T. All of them are located within the
DSP gene. Microsatellite 1 (Des.mic.1) is located in intron 1 and
Microsatellite 2 (Des.mic.23) is located in intron 23 of the DSP gene. Both of them
were indentified in a sequence of a BAC clone mapping to 6p23-p24
(GeneBank accession no. AL031058). The primer sequences for
Des.mic 1 and 3 are as follows:
Des.mic.1 forward, 5′-CCCATCTATGCATAATGCAACC-3′;
Des.mic.23 forward, 5′-CGCTTTTGATCATGGCCCTAGTG-3′;
We analysed endomyocardial biopsy (EMB) samples from right
ventricular (RV) septum in one case (C.III.12). They were formalin fixed, paraffin
embedded, cut at a thickness of 4 mm, and mounted on slides. We
incubated the slides with a primary antibody [monoclonal mouse
anti-Ncadherin (1 : 400) (Sigma); monoclonal mouse anti-plakoglobin (1 :
1000) (Sigma); monoclonal rabbit anti-connexin 43 (1 : 400) (Sigma)
and monoclonal rabbit anti-desmin (1 : 200)(Abcam)]. The slides were
incubated with secondary goat anti-mouse or goat anti-rabbit (1 : 400)
(Jackson ImmunoResearch). Stained slides were checked using a confocal
microscope (LSM510, Meta Zeiss). Findings were compared with a
control sample from a patient deceased for no cardiovascular reason in
which necropsy did not show any evidence of cardiac disease. Case and
control samples were fixed and embedded according to the same
protocol and stained under similar conditions.
Electrocardiogram monitoring tests
One or more abnormal parameters in SA-ECG were considered as
pathological (MAC 5500 ECG Diagnosis System—GE Healthcare).
Patients with right bundle branch block (RBBB) or left bundle branch
block (LBBB) were excluded from the SA-ECG analysis. Tracings from
ambulatory 24 h Holter monitoring (Marquette Electronics and
Synetec, ELA Medical) and treadmill exercise tests (Marquette
Electronics, Inc. and General Electric T-2100) were reviewed. Non-sustained
ventricular tachycardia (NS-VT) was defined as the presence of three or
more ventricular beats at a rate of .100 b.p.m. Sustained ventricular
tachycardia was defined as VT lasting .30 s or lasting less if it was
All participants underwent 2D-Doppler echocardiogram
(HewlettPackard Sonos 7500, Hewlett-Packard). The standard analysis of the LV
included the measurement of end systolic and end diastolic diameters
and volumes, ejection fraction, wall motion abnormalities, and
pathological valvular flows. Right ventricle analysis consisted of outflow
tract diameter calculations (measured on both the long and short axis)
and in order to assess RV performance, TAPSE, Doppler tissue imaging
(DTI) and the fractional shortening ratios were both measured.
Cardiac magnetic resonance
Cardiac magnetic resonance was performed on 10 DSP c.1339C.T
carriers using a 1.5T magnet (Achieva CV, Philips Medical Systems). SSFP
end-expiratory breath-hold cine imaging was acquired. After a bolus
injection of Gadobutrol (0.1 mmol/kg, Gadovist; Bayer Shering Pharma,
Berlin, Germany) the T1 measurement was calculated using standard
late gadolinium enhancement (LGE) sequences. The analysis was
performed using a personal computer and semi-automated software
(Philips, Software work space 22.214.171.124). Five patients were excluded
from this analysis [three already carried an implantable
cardioverterdefibrilator (ICD) and two rejected the test].
A novel heterozygous DSP variant (c.1339C.T) inherited in an
autosomal dominant manner with high penetrance (83%) was identified in
3 patients. The mutation was a C to T transition at exon 11 in the DSP
gene leading to a premature stop codon. This change occurred at the
N-terminal region, and it is thought to generate a truncated peptide
(85% in length). The affected amino acid at position c.1339C.T is
located in one of the globular head domains of desmoplakin. This
domain is shown to mediate the interaction of desmoplakin with
two catenin proteins: plakoglobin and plakophilin-212 (Figure 1).
The microsatellite study suggested a founder effect in the three
families and the presence of a common ancestor.
The 37-year-old proband (A.III.5) (Figure 2) was diagnosed after an
episode of S-VT at rest. An echocardiogram demonstrated severe
LV dilatation and systolic impairment. The patient had a history of
longstanding alcohol drinking, smoking, and occasional cocaine use.
The angiogram excluded coronary lesions and an ICD was implanted.
His mother (A.II.3) had died suddenly at 67 years of age. She had
been diagnosed with DCM after ruling out coronary disease. The
maternal grandfather suffered from heart failure and died in his sleep at
the age of 37 years (A.I.1). A maternal aunt had previously died of
heart failure (A.II.2).
Prior to the proband’s admission, a cousin aged 55 years (A.III.1)
who presented with recurrent S-VT and a structurally normal
heart underwent ICD implantation. Familial cascade screening led
to a new diagnosis of four asymptomatic, though affected, individuals
(A.III.4, A.III.6, A.IV.6, and A.IV.7). It should be noted that the
diagnoses of A.III.4 and A.III.6 were LVNC. A severely increased LGE pattern
was observed in A.IV.6 and A.IV.7 alongside mild systolic dysfunction.
During the follow-up period, both siblings have suffered multiple
episodes of chest pains with troponin rise. Coronary artery disease was
ruled out in both cases. They had an ICD implanted for primary
prevention in the view of progressive systolic dysfunction.
The proband (B.II.1), a 42-year-old woman, was admitted after a
presyncopal S-VT episode. Echocardiography revealed global left
ventricular hypokinesia and a moderately impaired systolic function.
The mother (B.I.1), aged 72 years, had a history of presyncopal
episodes associated with S-VT. An echocardiogram showed severe
systolic impairment and angiography ruled out coronary disease. She
underwent an EPS where poorly tolerated S-VT of a different
morphology was induced. Both patients received an ICD.
A maternal aunt had previously died suddenly at the age of
40 years. Family genetic screening led to diagnosis of an asymptomatic
non-affected carrier: a sister (B.II.2) aged 50 years. The
echocardiogram was normal and the patient rejected CMR due to claustrophobia.
Four maternal aunts, one maternal uncle, and a nephew refused a
cardiac and genetic study.
A A C A A G T C T A A G A A G A T T G T A A G C T G A A G C C T C G T A A C C C A G
64 165 166167168 169 170 171 172 173 174 175 176 177 178 179180 181 182183184185186 187 188 189 190 191 192 193 194 195 196 197 198199 200 201 202 203 204205206 2
The 62-year-old female proband was admitted to hospital after a first
episode of acute heart failure (C.II.1). Echocardiography
demonstrated moderately impaired systolic function and MRI results led
to the diagnosis of LVNC.
His daughter (C.III.1) had suffered an episode of acute myocarditis
at the age of 32 years.
Six years after the diagnosis of the proband, a 45-year-old nephew
(C.III.5) presented with cardiac arrest while walking. He was diagnosed
with LVNC and moderate systolic dysfunction. One month after having
an ICD implanted, he received four shocks due to S-VT during mild
exertion (Figure 5). Both his 13-year old son (C.IV.1) and his
17-year-old daughter (C.IV.2) were asymptomatic and they were
diagnosed with LVNC in familial screening. The latter was found to have
frequent ventricular ectopics and couplets on holter monitoring.
Clinical presentation and therapy
The first clinical presentation was presyncopal S-VT in five patients,
resuscitated SCD in one, and heart failure in two patients. Cardiac
and genetic work-up led to the identification of seven asymptomatic
patients, as well as three non-affected asymptomatic carriers. Eight
carriers met the criteria for DCM, four for LVNC and seven carriers
also fulfilled the diagnostic criteria for the definitive diagnosis of
ARVC (Table 1).
Beta-blockers were started in all patients. Nine patients with
systolic impairment were on angiotensin-converting enzyme inhibitors
or ARB-II blockers. Spironolactone was started in four patients.
Five patients received an ICD for secondary prevention of sudden
death (A.III.1; A.III.5; B I.1; B II.1; and C.III.5) and four for its primary
prevention (A III.4; AIII.6; A.IV.6, and A.IV.7). Primary prevention
was considered in the presence of any of the following events:
moderate systolic impairment; frequent ventricular ectopic beats; and/or
couplets on Holter monitoring despite beta-blocker administration.
Two siblings (A.IV.6 and A.IV.7) had the ICD implanted for recurrent
chest pains and troponin rise anlongside with worsening of the
ejection fraction. During follow-up, two patients, B III.1 and C.III.5, had an
appropriate ICD shock due to S-VT.
Twelve-lead electrocardiogram and
Electrocardiograms from 16 mutation carriers were available for
analysis. Nine (56%) showed T wave inversion in the precordial and/or
frontal leads. Intraventricular conduction abnormalities were
present in 4 patients (LBBB in two patients, bi-fascicular block in
one, and non-specific conduction abnormalities in another case).
A SA-ECG was performed in 14 patients (two had died before the
study and two were excluded due to the existence of baseline wide
QRS). Six showed late potentials (43%) (Figure 3).
V .. 0 0 4 0 0 0 0 5 5 0 8 0 3 2 0 0 6 0
L .. 4 4 6 4 5 3 6 4 5 3 5 4 4 4 6 6 6 6
Twenty-four hour electrocardiogram-Holter monitoring, an exercise test and ICD recordings
NS-VT was evidenced in four patients using 24 h Holter monitoring.
Two additional patients had a NS-VT episode on ICD recordings, one
of which had an episode of NS-VT while undergoing an exercise
treadmill test. One patient suffered SVT one month after ICD
implantation requiring four shocks to restore sinus rhythm. Frequent
ventricular ectopics occurred during the treadmill test in two
cases. Another young carrier without ECG or MRI abnormalities
presented frequent ventricular ectopics and couplets.
An EPS was performed on 3 patients, 2 of which (B.I.1 and B.II.1) were
prior to ICD implantation. During the procedure the proband (B.I.1)
developed S-VT different from the one previously recorded during
hospitalization. Her daughter (B.II.1) developed S-VT during the
EPS similar to the one originally recorded. Successful ablation was
achieved. However, she did suffer a relapse 4 years later and
further VT ablation was required. Endocardial voltage mapping
using the CARTO navigator system in this later case showed no
low voltage areas.
cases, LV apical trabeculae fulfilling the diagnostic criteria for LVNC
were present. Neither RV enlargement nor dysfunction was detected
in any case.
Cardiac magnetic resonance
Cardiac magnetic resonance was performed in 10 patients.
Pathological findings were found in eight of them. Biventricular disease
was observed in three patients and isolated LV involvement was
present in six. Sub-epicardial myocardial fibrosis at the LV was the
hallmark and it was detected in six patients. Fibrosis was distributed
in the lateral wall in three cases, the inferoposterior wall in two, and it
was globally distributed two more patients. Five patients were
diagnosed with LVNC (Figure 4).
An EMB was analysed from C.III.5 during ICD implantation after
cardiac arrest. Histology showed normal cardiomyocytes and no
trace of either fibrofatty replacement, disarray, granuloma,
inflammatory infiltrates or apoptosis (Figure 5). Staining for N-cadherin,
desmoplakin, plakoglobin, connexin 43, and desmin was normal and no
differences when compared the case with a control were observed
An echocardiographic study showed global or inferoposterior
hypokinesia in 11 of 18 (61%) carriers. Two patients had severe systolic
dysfunction and five had moderate systolic impairment. In three
To date, 42 DSP mutations leading to premature termination of
translation have been reported. There is clinical information available on
120 carriers from 44 families. Of these, 86 (72%) are affected, with
18 (15%) SCD cases reported in carriers of one of these mutations. In
the 14 families where clinical cascade screening was possible, disease
penetrance was .50% in ten families (71%) and . 90% in seven
(50%) (Figure 7).
Herein, we present the largest series of carriers of the same DSP
truncating mutation reported to date. The microsatellite study suggests
DSP c.1339C.T to have a founder effect. Several ARVC and/or ALVC
families bearing truncating DSP mutations have been published, some of
them, suffering SCD as a first clinical manifestation.13 –15 These studies
have reported highly penetrant disease phenotypes, with predominant
LV involvement, a high incidence of malignant arrhythmias, and a poor
prognosis. In keeping with these studies, the novel mutation herein
presented is also associated with high disease penetrance (83%), LV
dysfunction, extensive fibrosis, mild/no LV enlargement, left/anterior
precordial lead repolarization abnormalities, and high prevalence of
ventricular arrhythmias. It is notable that myocardial fibrosis was
present even in young carriers (14 and 19 year olds). Such extensive
fibrosis at an early age is an uncommon finding in cardiomyopathies
and particularly rare in heterozygous carriers of autosomal dominant
mutations underlying ACM.
Characterizing a phenotype using an
Six percent of the patients showed ECG abnormalities, even in the
absence of overt structural disease. New diagnostic criteria for the
diagnosis of ARVC include T wave inversion in V4 – V6 as a marker
of LV involvement. In the light of our results and those previously
reported in other series13 we would like to point out that T-wave
inversion in inferior leads may be sensitive markers of ALVC even in the
absence of ventricular remodelling. Signal-averaged ECG findings
failed to correlate with ECG or imaging abnormalities.
Characterizing a phenotype with cardiac
Heterogeneous myocardial fibrosis pattern evidenced by means
of gadolinium on CMR has been associated with progression to
heart failure in patients with hypertrophic cardiomyopathy, and,
additionally, ventricular arrhythmias have been reported to be more
frequent in patients with LGE in ischemic and idiopathic DCM.16
The vast majority of the DSP c.1339C.T carriers showed extensive
fibrosis in the LV, particularly at the sub-epicardium, similar to that
seen in localized myocarditis. During a ‘hot phase’, ACM may
mimic myocarditis in its clinical presentation or CMR appearance.2,17
In our series, CMR was performed on clinically stable patients.
Despite morphological findings being compatible with the diagnosis
of LVNC in 5 patients, the presence of a truncating mutation in
DSP, arrhythmic burden being out of proportion with the degree of
systolic dysfunction and the family history led us to the diagnosis
Implications for prevention of malignant
arrhythmias and sudden death
Identifying individuals at high risk of SCD is of undisputed importance.
Whether ALVC is associated with a poorer prognosis than ARVC or
DCM remains a matter of debate. In terms of risk stratification in
ARVC, several factors have been proposed over the past few years,
the presence of which would prompt ICD implantation. These
include resuscitated cardiac arrest, syncope, recurrent or syncopal
S-VT, and severe RV or LV involvement.18,19 Other markers such
as family history of sudden death, induction of VT upon EPS, extensive
bipolar low voltage area in RV,20 fragmented potentials within the
scar,21 T wave inversion in three or more leads22 and dispersion of
depolarization and repolarization have been also reported.23,24 On
the other hand, primary ICD implantation in DCM is based almost
exclusively on the severity of impairment of LV ejection fraction
and functional status.25 The decision on ICD implantation in ALVC
poses a real challenge. To date, there is no general consensus in
support of the use of genetic studies for ICD implantation. There is,
however, no doubt that some genetic conditions such as
laminopathies are associated with a high incidence of arrhythmic events and
SCD, which may precede severe myocardial remodelling and
In recent years, the classic concept or ARVC has been broadened
to the general concept of ACM. We have found a high prevalence of a
LVNC-like phenotype in our families, leading us to recommend
screening for DSP mutations in LVNC patients affected by a high
burden of personal and familial arrhythmia. In this particular scenario,
LVNC may be another phenotype to be considered in the broad
spectrum of ACM.
Desmoplakin c.1339C>T: an unexpected
Through its N-terminus, desmoplakin associates with armadillo
proteins at the cell membrane. Through its C-terminus, it anchors
intermediate filaments tethering them to junctional sites. Herein, we
describe a novel truncating mutation in the N-terminal domain,
anticipated to disrupt the synthesis of desmoplakin.
Confocal microscopy revealed no difference in the expression of
desmoplakin, plakoglobin, connexine-43 and desmin compared
with the control (Figure 6). It is notable that the hallmark in ARVC
immunohistochemistry; plakoglobin shifting from junctions26 was not
present. This finding is in keeping with a series of phospholamban
mutation carriers where the plakoglobin distribution significantly
differed in the DCM phenotype compared with the ARVC phenotype.7
This difference in plakoglobin remodelling leads us to rise the
question whether the signalling pathways differs in ALVC and ARVC.
Further studies will be required to shed light on the pathophysiology
of this particular phenotype.
We have reported on a novel mutation in desmoplakin (c.1339C.T)
associated with a phenotype of ALVC and LVNC. Truncating
mutations in desmoplakin seem to consistently cause extensive LV fibrosis
with near normal RV performance. Ventricular arrhythmias and SCD
occur in the absence of overt LV dysfunction or dilatation, and as a
consequence, ICD implantation must be considered promptly.
Genetic information seems to be of paramount prognostic value in
The authors thank Dr Angeliki Asimaki and Dr Jeffrey E. Saffitz
(Boston, USA, BIDMC and Harvard Medical School) for their
essential help in the understanding of the pathophysiology of ACM; Dr FJ
Nicolas from the University of Murcia, for his lessons on confocal
microscopy; They also thank Mrs Mar´ıa Lo´ pez for her help with the
clinical examinations. Last but not least, they thank the families that
agreed to participate in this study.
Conflict of interest: Dr Lorenzo Monserrat is shareholder of
Health in Code S.L.
None of the authors have any conflict of interest to declare.
Juan Ramo´ n Gimeno received support from the RIC from the Carlos III
Health Institute (C03/01,RD06/0014/0017). Lorenzo Monserrat received
a Carlos III Health Institute grant (PI11/0260).
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