Introduction
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inheritable
heart muscle disease that predominantly affects the right ventricle (RV) and predisposes
to ventricular arrhythmias and sudden cardiac death (SCD).
1–17
In the last three decades, there have been a significant number of studies defining
the pathogenesis, genetic aspects, and clinical manifestations of the disease (See
‘Etiology, pathogenesis, diagnosis and natural history’ as Supplementary material
online). In 1994 and 2010, an International Task Force (ITF) document proposed guidelines
for the standardized diagnosis of ARVC/D based on electrocardiographic (ECG), arrhythmic,
morphological, histopathological, and clinico-genetic factors.
18,19
The growing knowledge regarding arrhythmic outcome, risk factors, and life-saving
therapeutic interventions, make it particularly timely to critically address and place
into perspective the issues relevant to the clinical management of ARVC/D patients.
The present ITF consensus statement is a comprehensive overview of currently used
risk stratification algorithms and approaches to therapy, either pharmacological or
non-pharmacological, which often poses a clinical challenge to cardiovascular specialists
and other practitioners, particularly those infrequently engaged in the management
of ARVC/D. This document should be regarded as a guide to clinical practice where
rigorous evidence is still lacking, because of the relatively low disease prevalence
and the absence of controlled studies. Recommendations are based on available data
derived from non-randomized and observational studies and consensus within the conference
panellists. When development of prognostic-therapeutic algorithms was controversial,
management decisions were recommended to be individualized.
Recommendation and level of evidence of specific management options were classified
according to predefined scales, as outlined in Tables 1
and
2
(http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx).
Because randomized studies are not available, most consensus recommendations on treatment
of ARVC/D are based on data derived from follow-up registries and/or experts opinions
(i.e. level of evidence B or C).
Table 1
Classes of recommendations
Classes of recommendations
Definition
Suggested wording to use
Class I
Evidence and/or general agreement that a given treatment or procedure is beneficial,
useful, effective.
Is recommended/is indicated
Class II
Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy
of the given treatment of procedure.
Class IIa
Weight of evidence/opinion is in favour of usefulness/efficacy.
Should be considered
Class IIb
Usefulness/efficacy is less well established by evidence/opinion
May be considered
Class III
Evidence or general agreement that the given treatment or procedure is not useful/effective,
and in some cases may be harmful
Is not recommended
Table 2
Levels of evidence
Level of evidence A
Data derived from multiple randomized clinical trials or meta-analysis
Level of evidence B
Data derived from a single randomized clinical trial or large non-randomized studies
Level of evidence C
Consensus of opinion of the experts and/or small studies, retrospective studies, registries.
All members of the writing group of this consensus document provided disclosure statements
of all relationships that might present conflicts of interest.
Risk stratification
The natural history of ARVC/D is predominantly related to ventricular electrical instability
which may lead to arrhythmic SCD, mostly in young people and athletes.
2,8,10
In advanced disease, progression of RV muscle disease and left-ventricular involvement
may result in right or biventricular heart failure.
3,4
The available outcome studies are based on small patients cohorts followed for a relatively
short follow-up period (Table 3
).
22–36
The estimated overall mortality rate varies among different studies, ranging from
0.08% per year during a mean follow-up of 8.5 years in the series by Nava et al.
20
to 3.6% per year during a mean follow-up of 4.6 years in the series by Lemola et al.
21
Table 3
Clinical variables associated with an increased risk of major arrhythmic events in
arrhythmogenic right-ventricular cardiomyopathy/dysplasia*
Risk factor
Definition
Patients, n
Study endpoint
HR/OR
95% CI
P-value
References
Cardiac arrest
Aborted SCD due to VF
132
ICD interventions on rapid VT/VF
79
6.8–90.6
<0.001
Corrado et al. Circulation 2003
22
Unstable sustained VT
Sustained (>30 s) VT causing syncope or haemodynamic collapse
ICD interventions on rapid VT/VF
14
1.7–21.1
0.015
Sustained VT or VF
VT lasting >30 s or VF
108
Any appropriate ICD intervention
N/A
N/A
0.003
Link et al. JACC 2014
23
VT lasting >30 s or VF
50
Cardiac death (SCD in 67% and heart failure in 33%)
22.97
2.33–2.66
0.007
Watkins et al. Heart Rhythm 2009
24
Syncope
Syncopal episodes unrelated to extracardiac causes and occurring in the absence of
documented ventricular arrhythmias and/or circumstances clearly leading to reflex-mediated
changes in vascular tone or heart rate
132
ICD interventions on rapid VT/VF
7.5
0.84–1.81
0.07a
Corrado et al. Circulation 2003
22
Idem
106
Any appropriate ICD intervention
2.94
1.83–4.67
0.013
Corrado et al. Circulation 2010
25
ICD interventions on rapid VT/VF
3.16
1.39–5.63
0.005
N/A
50
Cardiac death (SCD in 67% and heart failure in 33%)
10.73
1.88–61.8
0.008
Watkins et al. Heart Rhythm 2009
24
Non-sustained VT
≥3 consecutive ventricular beats with a rate >100 beats/min, lasting <30 s, documented
during exercise testing or 24-h Holter
84
Any appropriate ICD intervention
10.5
2.4–46.2
0.003
Bhonsale et al. JACC 2011
26
Idem
106
Any appropriate ICD intervention
1.62
0.96–4.62
0.068a
Corrado et al. Circulation 2010
25
LV dysfunction
Angiographic LV EF <55%
132
ICD interventions on rapid VT/VF
0.94
0.89–0.95
0.037
Corrado et al. Circulation 2003
22
Angiographic LV EF <40%
130
Cardiac death (SCD in 33% and heart failure in 67%)
10.9
2.8–41.7
<0.001
Hulot et al. Circulation 2004
27
Angiographic LV EF <55%
60
Any appropriate ICD intervention
1.94
0.93–4.05
0.078a
Wichter et al. Circulation 2004
28
Echocardiographic LV EF <50%
61
Cardiac death and heart transplantation (SCD in 53%, heart failure death in 13%, heart
transplantation in 34%)
N/A
N/A
<0.05
Lemola et al. Heart 2005
21
Angiographic LV EF <55%
313
Sudden cardiac death
14.8
2.37–53.5
<0.001
Peters, J Cardiovasc Med 2007
39
RV dysfunction
Angiographic RV EF <45%
60
Any appropriate ICD intervention
2.09
1.03–4.23
0.041
Wichter et al. Circulation 2004
28
FAC % per unit decrease
70
Composite (death in 0%, heart transplantation in 7%, ventricular fibrillation in 10%,
sustained ventricular tachycardia in 36%, arrhythmic syncope in 4%).
1.08
1.04–1.12
<0.001
Saguner, Circ Cardiovasc Imaging 2014
29
RV dilation
RV end-diastolic area, cm2, per unit increase
70
As above
1.05
1.01–1.08
0.004
Saguner, Circ Cardiovasc Imaging 2014
29
Right-atrial dilation
Right atrium, short axis, mm, per unit increase
70
As above
1.03
1.00–1.06
0.037
Saguner, Circ Cardiovasc Imaging 2014
29
Biventricular dysfunction
Echocardiographic RV and LV dysfunction (EF <50%)
96
Cardiac death and heart transplantation (SCD in 30%, heart failure death in 30%, death
of unknown cause in 5%, heart transplantation in 35%)
6.3
2.17–17.5
<0.001
Pinamonti, Eur Heart J 2011
30
Heart failure
Clinical signs of RV heart failure
130
Cardiac death (SCD in 33% and heart failure in 67%)
13.7
2.58–71.4
0.002
Hulot et al. Circulation 2004
27
Clinical signs or symptoms of congestive heart failure
61
Cardiac death and heart transplantation (SCD in 53%, heart failure death in 13%, heart
transplantation in 34%)
N/A
N/A
<0.05
Lemola et al. Heart 2005
21
Young age
Per 5 years increment
132
ICD interventions on rapid VT/VF
0.77
0.57–0.96
0.007
Corrado et al. Circulation 2003
22
Per 1 year increment
108
ICD interventions on rapid VT/VF
N/A
N/A
0.03
Link et al. JACC 2014
23
Male gender
215
Composite (cardiac arrest in 9%, ICD intervention in 22%, sustained VT in 69%)
1.8
1.2–2.8
0.004
Bhonsale et al.
Circ AE 2013
31
134
Composite (SCD in 5%, cardiac arrest 27%, sustained VT 64%, ICD shock 5%)
2.76
1.19–6.41
0.02
Rigato et al. Circ Gen 2013
32
Complex genotype
Compound or digenic heterozygosisity
134
Composite (SCD in 5%, cardiac arrest 27%, sustained VT 64%, ICD shock 5%)
3.71
1.54–8.92
0.003
Rigato et al. Circ Gen 2013
32
Proband status
First family member affected by the genetic defect who seeks medical attention because
of the occurrence of clinical manifestations
215
Composite (cardiac arrest in 9%, ICD intervention in 22%, sustained VT in 69%)
7.7
2.8–22.5
<0.001
Bhonsale et al. Circ AE 2013
31
Inducible VT/VF
VT or VF that lasted >30 s or required termination because of haemodynamic compromise
84
Any appropriate ICD intervention
4.5
1.4–15.0
0.013
Bhonsale et al. JACC 2011
26
N/A
60
Any appropriate ICD intervention
2.16
0.94–5.0
0.069a
Wichter et al.
Circulation 2004
28
N/A
ICD intervention on fast VT/VF
N/A
N/A
N/A
VT that lasted >30 s or required termination because of haemodynamic compromise. Induction
of VF not considered
62
Composite (cardiac death in 13%, heart transplantation in 10%, unstable VT/VF in 70%,
syncope in 7%).
2.5
1.0–6.2
0.04
Saguner, Am J Cardiol 2013
33
Extent of electroanatomic scar on RV endocardial voltage mapping
low-voltage (<0.5 mV) areas on bipolar electroanatomic voltage mapping. Per 5% increment.
69
Composite arrhythmic (SCD in 5%, ICD intervention in 37%, sustained VT in 58%)
1.6
1.2–1.9
<0.001
Migliore et al. Circ AE 2013
34
Fragmented electrograms on RV endocardial voltage mapping
Multiple (>3) discrete deflections, amplitude <1.5 mV, and duration >100 ms
95
Any appropriate ICD intervention
21.2
1.8–251.8
0.015
Santangeli et al. Heart Rhythm 2012
35
T-wave inversion in inferior leads
Negative T-waves in leads II, III, aVF
108
Any appropriate ICD intervention
N/A
N/A
0.02
Link et al. JACC 2014
23
Inverted T waves in 2 of 3 inferior leads
111
Composite (6% cardiac death; 8% heart transplantation; 16% VF; 67% sustained VT; 3%
arrhythmic syncope)
2.4
1.2–5.2
0.02
Saguner, AJC 2014
36
Extent of T-wave inversion
Inverted T waves in ≥3 precordial leads
215
Composite arrhythmic (cardiac arrest in 9%, ICD intervention in 22%, sustained VT
in 69%)
4.2
1.2–14.5
0.03
Bhonsale et al. Circ AE 2013
31
QRS fragmentation
Additional deflections/notches at the beginning of the QRS, on top of the R wave,
or in the nadir of the S wave in either 1 right precordial lead or in >1 lead including
all remaining leads
111
Composite (6% cardiac death; 8% heart transplantation; 16% VF; 67% sustained VT; 3%
arrhythmic syncope)
2.7
1.1–6.3
0.03
Saguner, AJC 2014
36
Precordial QRS amplitude ratio
Sum of QRS voltages in V1–V3/sum of QRS voltages in V1–V6 < 0.48
111
Composite (6% cardiac death; 8% heart transplantation; 16% VF; 67% sustained VT; 3%
arrhythmic syncope)
2.9
1.4–6.2
0.005
Saguner AJC 2014
36
The list includes predictor variables that have been associated with an increased
risk of major arrhythmic events (i.e. SCD, appropriate ICD interventions, or ICD therapy
on fast VT/VF) in at least one published multivariable analysis in prospective studies.
FAC, fractional area change; EF, ejection fraction; LV, left ventricle; RV, right
ventricle; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular
tachycardia.
aBorderline statistical significance.
The adverse prognosis of ARVC/D patients has been initially overestimated by reports
from tertiary referral centres largely composed of patients referred because of their
high-risk status or severe clinical manifestations requiring specialized therapeutic
interventions, such as catheter ablation or implantable defibrillator (ICD).
21,27,37,38
Studies from community-based patient cohorts and clinical screening of familial ARVC/D
reported a much lower overall annual mortality rates (<1%).
24,30–32,36,39
These latter data provide a more balanced view of the natural history of ARVC/D, in
which the disease may occur with no or relatively mild disability and without the
necessity for major therapeutic interventions.
10,12–17
The mechanism of SCD in ARVC/D is cardiac arrest due to sustained ventricular tachycardia
(VT) or ventricular fibrillation (VF), which may occur as the first manifestation
of the disease in young people without previous symptoms.
2,7,40
Data from autopsy series and observational clinical studies on ARVC/D have provided
a number of clinical predictors of adverse events and death. Table 3
reports the clinical variables identified as independent predictors of poor outcome
including malignant arrhythmic events (i.e. SCD, cardiac arrest due to VF, appropriate
ICD interventions, or ICD therapy on fast VT/VF), non-SCD, or heart transplantation,
which were found in at least one published multivariable analysis. Patients who have
experienced sustained VT or VF are at highest risk of experiencing life-threatening
arrhythmic events.
22–24
Unexplained syncope has been associated with an increased arrhythmic risk in some
but not in all studies.
22,25,26
Of note, unexplained syncope is defined as a loss of consciousness that: (i) occurs
in the absence of documented ventricular arrhythmias and/or circumstances clearly
leading to reflex-mediated changes in vascular tone or heart rate such as a micturition,
defaecation, cough, or other similar conditions; and (ii) remains unexplained after
a detailed clinical evaluation aimed to exclude other cardiac or extracardiac causes.
25
Other independent risk factors for adverse events include non-sustained VT on 24-h
Holter monitoring’;
25,26
dilation/dysfunction of RV, left ventricle (LV), or both;
21,22,27–30,39
male gender;
31,32
compound and digenic heterozygosity of desmosomal-gene mutations;
32
young age at the time of diagnosis;
22,23
proband status;
31
inducibility at programmed ventricular stimulation;
26,28,33
amount of electroanatomic scar
34
and electroanatomic scar-related fractionated electrograms;
35
extent of T-wave inversion across precordial and inferior leads;
23,31,36
low QRS amplitude
36
and QRS fragmentation.
36
Electrophysiological study
Electrophysiological study (EPS) is a valuable diagnostic test for differential diagnosis
between ARVC/D and idiopathic right ventricular outflow tract tachycardia and may
provide useful information regarding the VT inducibility for optimization of detection/discrimination
algorithms and effective antitachycardia pacing protocols in patients undergoing ICD
implantation.
11,28
However, conflicting data exist concerning the role of inducibility of sustained VT
or VF for prediction of long-term arrhythmic outcome in ARVC/D patients.
22,23,25,26,33
Discrepancies between the study results may be explained by differences in arrhythmic
endpoints (i.e. life-saving vs. any appropriate ICD discharge).
The largest multicentre studies on ARVC/D patients who received an ICD demonstrated
that EPS is of limited value in identifying patients at risk of arrhythmic cardiac
arrest because of its low predictive accuracy.
22,25
In these studies, the reported incidence of ‘life-saving’ ICD discharges for treatment
of fast VT or VF did not differ significantly in patients who were and were not inducible
at EPS, regardless of the specific indication for ICD implantation. The study by Corrado
et al.
25
on the outcome of 106 ARVC/D patients receiving an ICD for primary prevention reported
that the positive and negative predictive value of inducibility for VT or VF was 35
and 70%, respectively. In this study, the type of ventricular tachyarrhythmia inducible
at the time of EPS (i.e. VT or VF) did not predict a statistically different arrhythmic
outcome over the follow-up. The North American Multidisciplinary study on 98 ARVC
patients receiving an ICD confirmed that inducible VT or VF at pre-implant EPS did
not predict appropriate interventions on fast VT or VF during a mean follow-up of
3.3 years.
23
On the contrary, in the cohort of ARVC/D patients reported in the Johns Hopkins studies,
inducibility was the most significant independent predictor of appropriate ICD firing.
However, in the study by Bhonsale et al.,
26
the positive and negative predictive values of inducibility were 65 and 75%, respectively,
and a sizeable proportion of patients experienced ICD interventions during follow-up
despite a lack of inducibility of VT/VF. Moreover, the predictive value of inducibility
for ‘life-saving’ ICD discharges was not demonstrated by either univariate or multivariate
analysis. In asymptomatic patients, Bhonsale et al.
26
reported that the combination of ≥2 factors such as inducibility at EPS, proband status,
non-sustained VT, and PVCs ≥1000/24 h, predicts an incremental risk of appropriate
ICD interventions; however, a statistically significant association with life-saving
shocks for treatment of rapid VT or VF has not been demonstrated. In the study by
Saguner et al.
33
inducible VT was an independent predictor of composite endpoint including cardiac
death, heart transplantation, unstable VT/VF, and syncope.
According to available studies on ARVC/D patients, the protocol of programmed ventricular
stimulation should include a minimum of two drive-cycle lengths and three ventricular
extrastimuli while pacing from two RV sites (apex and RV outflow tract); inducibility
is defined as the induction of either VF or sustained VT, i.e. lasting >30 s or requiring
termination because of haemodynamic compromise.
21,22,25,41
Recent studies showed that demonstration and quantification of bipolar RV electroanatomic
scar area
34
as well as identification of scar-related fractionated electrograms and late potentials
35
on endocardial voltage mapping during EPS may provide significant added value for
arrhythmic risk assessment in ARVC/D. Because endocardial voltage mapping is an invasive,
expensive, and highly operator-dependent technique with a significant risk of inaccurate
interpretation of low-voltage recordings in areas of normal myocardium due to suboptimal
catheter contact, it is not recommended as a routine diagnostic tool.
Recommendations
- EPS should be considered in the diagnosis and/or evaluation of patients with suspected
ARVC/D (class IIa).
- Programmed ventricular stimulation may be considered for arrhythmic risk stratification
of asymptomatic ARVC/D patients (class IIb).
- Endocardial voltage mapping may be considered in the diagnostic and prognostic evaluation
of ARVC/D patients (class IIb).
Follow-up
Patients with ARVC/D should undergo lifelong clinical follow-up to periodically evaluate
new onset or worsening of symptoms, progression of morphological and/or functional
ventricular abnormalities, and ventricular arrhythmias in order to reassess the risk
of SCD and optimize the treatment. Cardiac evaluation of affected patients including
resting 12-lead ECG, echocardiography, 24-h Holter monitoring, and exercise testing
(for detection of effort-induced ventricular arrhythmias) should be performed on a
regular basis (every 1–2 years) depending on the age, symptoms, and disease severity.
Due to the age-related penetrance of ARVC/D, healthy gene carriers and family members
should also be offered repeat clinical assessment (every 2–3 years), mostly during
adolescence and young adulthood.
Therapy
The most important objectives of clinical management of ARVC/D patients include: (i)
reduction of mortality, either by arrhythmic SCD or death from heart failure; (ii)
prevention of disease progression leading to RV, LV, or biventricular dysfunction
and heart failure; (iii) improvement of symptoms and quality of life by reducing/abolishing
palpitations, VT recurrences, or ICD discharges (either appropriate or inappropriate);
and (iv) limiting heart failure symptoms and increasing functional capacity. Therapeutic
options consist of lifestyle changes, pharmacological treatment, catheter ablation,
ICD, and heart transplantation.
Lifestyle changes
A link has been established between SCD and intense exertion in young individuals
with ARVC/D. Competitive sports activity has been shown to increase the risk of SCD
by five-fold in adolescent and young adults with ARVC/D.
42
Early (i.e. pre-symptomatic) identification of affected athletes by pre-participation
screening and their disqualification from competitive sports activity may be ‘life-saving’.
8,43
In addition, physical exercise has been implicated as a factor promoting development
and progression of the ARVC/D phenotype. Kirchhof et al.
44
demonstrated that in heterozygous plakoglobin-deficient mice, endurance training accelerated
the development of RV dilatation, dysfunction, and ventricular ectopy, suggesting
that chronically increased ventricular load might contribute to worsening of the ARVC/D
phenotype. It has been postulated that impairment of myocyte cell-to-cell adhesion
may lead to tissue and organ vulnerability, which may promote myocyte death especially
during mechanical stress, which occurs during competitive sports activity.
45,46
Studies in humans confirmed that endurance sports and frequent exercise increase age-related
penetrance, risk of VT/VF, and occurrence of heart failure in ARVC/D desmosomal-gene
carriers.
47,48
Recommendations
- It is recommended that patients with a definite diagnosis of ARVD/C not participate
in competitive and/or endurance sports (Class I).
- Patients with a definite diagnosis of ARVD/C should be restricted from participation
in athletic activities, with the possible exception of recreational low-intensity
sports (Class IIa).
- Restriction from competitive sports activity may be considered in ARVC/D family
members with a negative phenotype, either healthy gene carriers (class IIa) or with
unknown genotype (class IIb).
Pharmacological therapy
Pharmacological options in ARVC/D treatment consist of antiarrhythmic agents, beta-blockers,
and heart failure drug therapy.
Antiarrhythmic drugs
The aim of antiarrhythmic drug (AAD) therapy in patients with ARVC/D is to improve
the quality of life by preventing symptomatic ventricular arrhythmias. There are no
prospective and randomized trials on AAD therapy in ARVC/D and systematic comparison
of treatment strategies.
Moreover, the assessment of efficacy of specific AAD therapy is difficult because
ARVC/D patients tend to have multiple arrhythmic events over time and drugs are often
changed.
41,49
Available data are limited to case–control studies, retrospective analyses, and clinical
registries. Hence, indication for AAD therapy and choice of drug are based on an empirical
approach resulting from extrapolation from other diseases, personal experience, consensus,
and individual decisions.
The available evidence suggests that amiodarone (loading dose of 400–600 mg daily
for 3 weeks and then maintenance dose of 200–400 mg daily), alone or in combination
with beta-blockers, is the most effective drug for preventing symptomatic ventricular
arrhythmias with a relatively low proarrhythmic risk even in patients with ventricular
dysfunction, although its ability to prevent SCD is unproved.
49
Corrado et al.
22
reported that the majority of life-saving ICD interventions in high-risk patients
occurred despite concomitant AADs, a finding supporting the concept that AAD therapy
may not confer adequate protection against SCD.
Recommendations
- AADs are recommended as an adjunct therapy to ICD in ARVC/D patients with frequent
appropriate device discharges (class I).
- The use of AADs should be considered to improve symptoms in patients with frequent
premature ventricular beats and/or non-sustained VT (class IIa).
- AADs may be considered as an adjunct therapy to catheter ablation without a back-up
ICD in selected ARVC/D patients with recurrent, haemodynamically stable VT (class
IIb).
- AAD treatment of asymptomatic ARVC/D patients without documented ventricular arrhythmias
and healthy gene carriers is not recommended (class III).
Beta-blockers
Ventricular arrhythmias and cardiac arrest in ARVC/D are frequently triggered by adrenergic
stimulation and occur during or immediately after physical exercise.
8,40,42,47,48
Autonomic dysfunction with increased sympathetic stimulation of ventricular myocardium
and subsequent reduction of beta-adrenoceptor density was demonstrated by Wichter
et al.
50,51
with the use of radionuclide imaging and quantitative positron emission tomography.
The indication for the use of beta-blocker drugs in ARVC/D relies on their proven
efficacy to prevent effort-induced ventricular arrhythmias, their proven efficacy
in heart failure management, and their potential but unproven ability to hinder myocardial
disease progression by lowering RV wall stress.
Because studies are not available to compare the efficacy of individual beta-blockers
and to define the most effective dosage, we recommend using non-vasodilating beta-blockers
titrated to maximum tolerated dose for age and weight.
Recommendations
- Beta-blocker therapy is recommended in ARVC/D patients with recurrent VT, appropriate
ICD therapies, or inappropriate ICD interventions resulting from sinus tachycardia,
supraventricular tachycardia, or atrial fibrillation/flutter with high-ventricular
rate (class I).
- Beta-blocker therapy should be considered in all patients with ARVD/C irrespective
of arrhythmias (class IIa).
- The prophylactic use of beta-blockers in healthy gene carriers is not recommended
(class III).
Preload-reducing drug therapy
Fabritz et al.
52,53
provided experimental evidence that ventricular preload-reducing therapy prevents
or tempers the development of ARVC/D in genetically susceptible murine hearts. Therapy
with furosemide and nitrates completely prevented training-induced development of
RV enlargement and normalized VT inducibility, thereby rendering treated plakoglobin-deficient
mice phenotypically indistinguishable from their trained wild-type littermates.
Preload-reducing drug therapy is not yet part of clinical practice because the results
of the animal studies demonstrating its beneficial effects require validation in other
ARVC/D models and patients.
Heart failure and antithrombotic drug therapy
The prevalence of RV or biventricular dysfunction leading to progressive heart failure
and death in ARVC/D is variable in the published series, mostly depending on the selection
criteria of patients, whether referred for arrhythmias or heart failure.
20–27,30–33,36,39,44,48,54,55
Left-ventricular involvement was originally considered an end-stage complication of
ARVC/D, occurring late during the disease course and leading ultimately to biventricular
pump failure.
3,4
More recently, genotype–phenotype correlations have shown early and greater LV involvement
in genetically predisposed ARVC/D patients.
54–58
In ARVC/D, thromboembolic complications may result from intracardiac thrombus formation
into ventricular aneurysms, sacculations, or ventricular dilatation due to either
global or regional ventricular dysfunction. A retrospective study by Wlodarska et
al.
59
on 126 ARVC/D patients with severe RV dilatation reported a 0.5% annual incidence
rate of thromboembolic complications during a mean follow-up period of 99 ± 64 months.
Recommendations
- For ARVC/D patients who developed right- and/or left-sided heart failure standard
pharmacological treatment with angiotensin-converting-enzyme inhibitors, angiotensin
II receptor blockers, beta-blockers, and diuretics is recommended (class I).
- Long-term oral anticoagulation is generally indicated for secondary prevention in
patients with documented intracavitary thrombosis or venous/systemic thromboembolism
(class I).
- For ARVC/D patients with asymptomatic RV and/or LV dysfunction treatment with angiotensin-converting-enzyme
inhibitors or angiotensin II receptor blockers may be considered (class IIb).
- Prophylactic anticoagulation for primary prevention of thromboembolism on the basis
of ventricular dilatation/dysfunction, either global or regional, is not recommended
(class III).
Catheter ablation
Catheter ablation is a therapeutic option for ARVC/D patients who have VT. Fibrofatty
replacement of RV myocardium creates scar regions that are regarded as arrhythmogenic
substrate for VT. Ventricular tachycardia is the result of a scar-related macro-reentry
circuit, similar to that observed in the post-myocardial infarction setting, which
is suitable for mapping and interruption by catheter ablation. Catheter ablation may
be guided by either conventional electrophysiological or substrate-based mapping during
sinus rhythm.
60–72
Fontaine et al.
60,62
first studied the effects of direct current fulguration and demonstrated the feasibility
of VT ablation in ARVC/D. Subsequently, several studies have reported on acute and
long-term results of endocardial catheter ablation of VT using radiofrequency current.
63–73
Overall, acute success was achieved in 60–80% of patients, whereas the recurrence
rates during long-term follow-up of 3–5 years were as high as 50–70% (see Supplementary
material online
, Table S1
). The high frequency of VT recurrences and the discrepancy between the successful
acute results and the unfavourable long-term outcome have been explained by the progressive
nature of the ARVC/D substrate (i.e. fibrofatty scar), which predisposes to the occurrence
of multiple reentry circuits and new arrhythmogenic foci over time.
10,68
Recently, studies have suggested that epicardial location of some VT reentry circuits,
which reflects the propensity of ARVC/D lesion to originate and progress from the
epicardium, may partly explain the failure of conventional endocardial mapping/catheter
ablation. Garcia et al.
70
first reported the feasibility and efficacy of epicardial catheter ablation in ARVC/D
patients who underwent an epicardial approach after previously failed endocardial
VT mapping/ablation procedures. In these patients, the extent of electroanatomical
scar area at voltage mapping was larger on the epicardial side of the RV wall than
on the endocardium. Complete success was achieved in 85% of cases (partial success
in 92%) and 77% of patients were free of VT during 18 months of follow-up. Phillips
et al.
72
compared the efficacy of traditional electrophysiological VT mapping/catheter ablation
with other strategies including substrate-based and epicardial catheter approaches.
The recurrences of VT were significantly reduced irrespective of the mapping/ablation
strategy. The cumulative freedom from VT following procedures using 3D-electroanatomical
mapping and/or epicardial approach was significantly greater than conventional ablation,
although the recurrence rates remain considerable. Freedom from VT after epicardial
ablation of 64 and 45% at 1 and 5 years was found, which was significantly improved
compared with studies using the endocardial approach. According to Berruezo et al.,
71
complete scar de-channelling with elimination of either endo or epicardial scar conducting
channels (i.e. intra-scar, inter-scar, or between scar and valvular annuli) in addition
to ablation of clinical VT is a promising approach to improve long-term success rate
of catheter ablation.
According to available data, catheter ablation of VT in ARVC/D patients should be
considered a potentially effective strategy for eliminating frequent VT episodes and
ICD shocks rather than a curative therapeutic approach, until long-term efficacy has
been consistently documented. Catheter ablation has not been proved to prevent SCD
and should not be looked upon as an alternative to ICD therapy in ARVC/D patients
with VT, with the exception of selected cases with a drug refractory, haemodynamically
stable, single morphology VT.
22
Additional AAD therapy and repeated ablation procedures as well as back-up ICD implantation
are required to provide clinical control of VT and SCD prevention.
Recommendations
- Catheter ablation of VT is recommended in ARVC/D patients with incessant VT or frequent
appropriate ICD interventions on VT despite maximal pharmacological therapy, including
amiodarone (class I).
- An epicardial approach to VT ablation is recommended in patients who fail one or
more attempts of endocardial VT ablation (class I).
- Catheter ablation of VT should be considered in ARVC/D patients with incessant VT
or frequent appropriate ICD interventions on VT who have failed pharmacological therapy
other than amiodarone (class IIa).
- A combined endocardial/epicardial VT ablation approach as an initial ablation strategy
should be considered, provided that the operator and electrophysiologic laboratory
are experienced performing epicardial VT ablation in patients with ARVC/D (class IIa).
- Catheter ablation of VT may be considered in ARVC/D patients with incessant VT or
frequent appropriate ICD interventions on VT who have not failed pharmacological therapy
and who do not wish to be treated with pharmacological therapy (class IIb).
- Catheter ablation may be indicated as first choice therapy without a back-up ICD
for selected patients with drug-refractory, haemodynamically stable, single-morphology
VT (class IIb).
- Catheter ablation is not recommended as an alternative to ICD for prevention of
SCD in ARVC/D (class III).
Implantable defibrillator therapy
Implantable defibrillator therapy is the most logical therapeutic strategy for patients
with ARVC/D, because the natural history is primarily characterized by the risk of
SCD and, only secondarily, by contractile dysfunction leading to progressive heart
failure. Prospective randomized trials are currently not available for ethical reasons
and because of practical limitations predominantly linked to relatively low disease
prevalence and low event rate. The available data, coming from observational studies/registries
of large populations of ARVC/D patients, have established efficacy and safety of ICD
therapy.
22,25,26,28,74–81
The main results of available studies on ICD therapy in ARVC/D are summarized in Supplementary
material online, Table S2
. These studies consistently document that ICD successfully interrupts lethal ventricular
tachyarrhythmias and improves long-term outcome of selected high-risk ARVC/D patients.
Overall, between 48 and 78% of patients received appropriate ICD interventions during
a mean follow-up period of 2–7 years after implantation. Many of these patients experienced
multiple ICD discharges during this period and VT storm was not infrequently reported.
In most studies, the survival benefit of the ICD was evaluated by comparing the actual
patient survival rate with the projected freedom of ICD interventions for fast VT
(>240 b.p.m.) or VF (i.e. ‘life- saving’ ICD interventions), which were used as a
surrogate for aborted SCD, based on the assumption that these tachyarrhythmias would
have been fatal without termination by the device.
22,25,28,77
The endpoint was reached by device interrogation and review of stored electrocardiograms
regarding ICD interventions in response to fast VT/VF during follow-up. In the largest
multicentre study, the fast VT/VF-free survival rate was 72% at 36 months compared
with the actual patient survival of 98%, with an estimated survival benefit of 26%.
22
The largest single-centre experience found an estimated improvement of overall survival
of 23, 32 and 35% after 1, 3 and 7 years of follow-up, respectively.
28
These results were confirmed by other series reporting rates of life-saving ICD interventions
in 30–50% of patients during follow-up. Despite the relatively short follow-up of
the available studies, the time between implantation and the first appropriate discharge
was ≥1 year in a large proportion of patients with a maximal interval of 5.5 years.
25,26,74–81
This finding suggests that ICD implantation is a lifelong preventive measure with
life-saving interventions occurring even after particularly long phases of dormant
ventricular electrical instability.
It is important to recognize that survival benefit of ICD treatment is obtained at
the expense of significant complications during follow-up, with estimated rates of
lead/device related complications and inappropriate ICD therapies of 3.7%/year and
4.4%/year, respectively (see Supplementary material online
,
Table S2
). Detailed information on ICD-related complications in the published ICD studies
is provided by the recent meta-analysis by Schinkel.
82
In the long-term study (80 ± 43 months) by Wichter et al.,
28
37 of 60 (62%) ARVC/D patients had a total of 53 serious adverse events (31 lead-related),
10 occurring during the perioperative phase and 43 during follow-up. This high rate
of lead-related adverse events may be explained by the peculiar ARVC/D pathobiology
which leads to progressive loss of myocardium with fibrofatty replacement, also affecting
the site of RV lead implantation. In this regard, Corrado et al. reported that ∼4%
of ARVC/D patients required an additional septal lead owing to loss of ventricular
sensing/pacing functions at the apical RV free wall during a follow-up of 3.3 years.
22
Therefore, particular attention should be paid to progressive loss of R-wave sensing
amplitude during follow-up, which may compromise adequate device function and may
indicate disease progression.
Inappropriate ICD interventions occur in 10–25% of patients with ARVC/D, mostly at
young age,
77
and are usually caused by sinus tachycardia or atrial tachyarrhythmia (see Supplementary
material online,
Table S2
). Inappropriate interventions are painful and may have a profound clinical and psychological
impact on patients.
83
The incidence of inappropriate ICD discharges can be lowered by appropriate ICD programming
84
and administration of beta-blockers or sotalol. Although the use of dual-chamber detection
algorithms offers the potential to reduce the number of inappropriate interventions
by improving discrimination of ventricular from supraventricular arrhythmias, an additional
lead in atrium predisposes to a higher incidence of early and late post-operative
complications.
Indications for ICD implantation
The published studies on ARVC/D patients that provided information about the independent
predictors for major arrhythmic events (i.e. SCD, cardiac arrest due to VF, sustained
VT, and appropriate ICD interventions) during follow-up (Table 3
), have been used to construct three categories of risk for SCD (high, intermediate,
and low) that were determined by consensus (Figure 1
). The recommendations for ICD implantation for each risk category were based not
only on the statistical risk, but also on the general health, socioeconomic factors,
the psychological impact and the adverse effects of the device.
Figure 1
Flow chart of risk stratification and indications to ICD implantation in ARVC/D. Based
on the available data on annual mortality rates associated to specific risk factors,
the estimated risk of major arrhythmic events in the high-risk category is >10%/year,
in the intermediate ranges from 1 to 10%/year, and in the low-risk category is <1%/year.
Indications to ICD implantation were determined by consensus taking into account not
only the statistical risk, but also the general health, socioeconomic factors, the
psychological impact and the adverse effects of the device. SCD, sudden cardiac death;
VF, ventricular fibrillation; VT, ventricular tachycardia; RV, right ventricle; LV,
left ventricle. *See the text for distinction between major and minor risk factors.
The high-risk category includes patients who experienced cardiac arrest due to VF
or sustained VT. This group of patients has an estimated rate of life-threatening
arrhythmic events >10%/year and most benefits for ICD therapy.
22–24
A prophylactic ICD implantation is also recommended in patients with severe RV dysfunction
(RV fractional area change ≤17% or RV EF ≤35%) or LV dysfunction (LV EF ≤35%) who
are considered at high risk by consensus, even in the absence of life-threatening
ventricular arrhythmias.
21,22,27,28,30,39
Because the specific arrhythmic risk of ventricular dysfunction is still undermined
for patients with ARVC/D, the inclusion of this clinical variable into the high-risk
category was based on extrapolation from other cardiomyopathies and personal experience.
The low-risk category comprises probands and relatives without risk factors as well
as healthy gene carriers who show a low rate of malignant arrhythmic events (estimated
annual event rate <1%/year
25,31
) over a long-term follow-up and do not require any treatment, including ICD therapy.
Between the two categories there are ARVC/D patients with ≥1 risk factors who are
deemed to have an intermediate risk (estimated annual event rate between 1 and 10%
25,26
). Among the consensus experts there was general agreement that syncope, non sustained
ventricular tachycardia (NSVT), or moderate ventricular dysfunction, either RV (RV
fractional area change between 24 and 17% or RV EF between 40 and 36%), or left-ventricular
(LV EF between 45 and 36%), are ‘major’ risk factor that justify (weight of opinion
in favour of ICD) a prophylactic ICD. On the other hand, there was general consensus
that the other factors reported in Table 3
(‘minor’ risk factors) are associated with a risk of major arrhythmic events not sufficiently
high (or controversial) to warrant systematic ICD implantation for primary prevention
(weight of opinion against ICD). The decision to implant an ICD in patients of this
category should be made on individual basis, by assessing the overall clinical profile,
the age, the strength of the risk factor identified, the level of SCD risk that is
acceptable to the patient, and the potential risk of inappropriate interventions and
complications.
It is noteworthy that indications for ICD implantation may vary in different countries
as a consequence of several non-clinical factors such as cultural background, socio-economic
conditions, health system, availability of advanced technology, cost–benefit considerations,
and liability. Compared with the conservative approach of many European countries,
the current threshold for decision to implant an ICD in the USA is lower.
13
It is particularly important to outline the potential risk of inappropriate ICD implants
due to a false diagnosis of ARVC/D based on misinterpretation of imaging studies including
cardiac magnetic resonance.
85
Recommendations
- Implantation of an ICD is recommended in ARVC/D patients who have experienced ≥1
episodes of haemodynamically unstable, sustained VT or VF (class I).
- Implantation of an ICD is recommended in ARVC/D patients with severe systolic dysfunction
of the RV, LV, or both, irrespective of arrhythmias (class I).
- Implantation of an ICD should be considered in ARVC/D patients who have experienced
≥1 episodes of haemodynamically stable, sustained VT (class IIa).
- Implantation of an ICD should be considered in patients who have ‘major’ risk factors
such as unexplained syncope, moderate ventricular dysfunction, or NSVT (class IIa).
- Implantation of an ICD may be considered in patients with ‘minor’ risk factors after
a careful discussion of the long-term risks and benefits of ICD implantation (class
IIb).
- Prophylactic ICD implantation is not recommended in asymptomatic ARVC/D patients
with no risk factors or healthy gene carriers (class III).
Device selection
A single-chamber ICD system is recommended in order to minimize the incidence of long-term
lead-related complications, mostly in young patients.
Experience with ICD therapy consistently highlights the beneficial effect of antitachycardia
pacing which is highly effective in terminating VT episodes in ARVC/D patients. The
precise clinical role of leadless subcutaneous ICD in patients with ARVC/D remains
to be defined. A decision whether to implant a leadless device needs to be patient
specific, balancing lead-related complications with the likelihood of recurrent VT
that may be effectively pace-terminated.
Additional cardiac resynchronization therapy appears reasonable for those ARVC/D patients
with a LV EF ≤35% and a wide QRS with a left bundle branch block pattern, even though
clinical benefit is extrapolated from resynchronization therapy in other disease states.
86
Right-ventricular resynchronization therapy has been proposed as a therapy for patients
with congenital heart disease and chronic RV heart failure;
87
however, no data are available concerning the clinical and haemodynamic effects of
RV pacing in ARVC/D patients with RV dysfunction and a wide QRS with right bundle
branch block pattern.
Heart transplantation
Arrhythmogenic right-ventricular cardiomyopathy/dysplasia patients with untreatable
heart failure or uncontrollable ventricular tachyarrhythmias may require heart transplantation.
Tedford et al.
88
reported the Johns Hopkins Registry experience with 18 ARVC/D patients (61% males;
mean age 40 ± 14 year) undergoing heart transplantation. The most common indication
for cardiac transplantation was heart failure, with less than one-third of patients
receiving transplants for intractable ventricular arrhythmias. Patients who received
heart transplants were significantly younger (mean age at the time of first symptoms
24 ± 13 years) and had a more prolonged clinical course (time from first symptoms
to transplant ∼15 years) compared with other ARVC/D registry participants. One-year
after transplant, the survival was 94 and 88% of patients were alive at an average
post-transplant follow-up of 6.2 ± 4.8 years.
Heart transplantation is recommended as a final therapeutic option in ARVC/D patients
with either severe, unresponsive congestive heart failure or recurrent episodes of
VT/VF which are refractory to catheter (and surgical) ablation in experienced centres
and/or ICD therapy.
Other surgical therapies
There is currently no clinical role of surgical therapies such as RV cardiomyoplasty,
89
RV disarticulation,
90
beating heart cryoablation,
91
and left cardiac sympathetic denervation
92
in the treatment of patients with ARVC/D.
Conclusions
The therapeutic management of patients with ARVC/D has evolved over the years and
continues to be an important challenge. To further improve risk stratification and
treatment of patients, more information is needed on the natural history, long-term
prognosis, and risk assessment. Special attention should be focused on the identification
of patients who would benefit from ICD implantation in comparison to pharmacological
and other non-pharmacological approaches. Data from prospective studies/registries
with larger number of patients and longer follow-up as well as data obtained from
multicentre randomized controlled trials are required to provide evidence-based recommendations
for the best care of ARVC/D patients.
Current therapeutic and preventive measures are palliative, not curative. The definitive
cure of ARVC/D will be based on the discovery of the molecular mechanisms that are
involved in the aetiology and pathogenesis of the disease.
Supplementary material
Supplementary material is available at European Heart Journal online.
Funding
This work was supported in part by the TRANSAC Research Grant of the University of
Padua, Italy.
Conflict of interest: H.C. reports grants from Medtronic and St. Jude Medical, during
the conduct of the study; F.D. and C.B. report grants from the Georg and Bertha Schwyzer-Winker
Foundation; M.N.A.M.E. reports personal fees from Boston Scientific Corporation, St.
Jude Medical, and from Medtronic. The other authors report no conflicts of interest.