Circulation. 2004;109:1445-1447
doi: 10.1161/01.CIR.0000121322.91189.2E
(Circulation. 2004;109:1445-1447.)
© 2004 American Heart Association, Inc.
Implantable Cardioverter Defibrillator in Arrhythmogenic Right Ventricular Cardiomyopathies
Guy Fontaine, MD, PhD;
Catherine Prost-Squarcioni, MD, PhD
From the Institut de Cardiologie, Hôpital de la Salpêtrière, Paris, France.
Correspondence to Institut de Cardiologie, Hôpital de la Salpêtrière, 47 Boulevard de lHôpital, 75013 Paris, France. E-mail guy.fontaine{at}bct.ap-hop-paris.fr
Key Words: Focused Perspectives cardiomyopathy arrhythmia defibrillation cardioversion
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Introduction
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In the present issue of
Circulation, Wichter et al
1 report the
largest single-center experience demonstrating the benefit of
implantable cardiac defibrillators (ICDs) in the treatment of
patients with arrhythmogenic right ventricular cardiomyopathy
(ARVC). The patients seem well defined, and they meet the task
force criteria. In addition, 50 of 60 patients have had the
diagnosis confirmed by endocardial biopsy. Advances in molecular
biology and genetics, however, suggest that the term
ARVC encompasses
a large spectrum of diseases with similar clinical presentations
and histological features. This was discussed in part in a previous
editorial in
Circulation.
2 Recent information suggests that
there is an overlap in the different forms of diseases included
under the general term
ARVC.
See p 1503
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Terminology
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The term
right ventricular cardiomyopathy, which was introduced
by the World Heart Federation and World Health Organization
in 1996 in the new classification of cardiomyopathies, was selected
to encompass arrhythmogenic right ventricular dysplasia (ARVD)
and several other clinical entities, some of them known by a
different name. In the classical article by Marcus et al,
3 the
term
right ventricular dysplasia was taken from a book chapter
on reentrant arrhythmias published in 1977.
4 This work reported
the results of antiarrhythmic surgery in young male patients
with good left ventricular function who had ventricular tachycardia
(VT) originating in the right ventricle. The term
dysplasia was chosen because the right ventricle of 3 operated patients
was covered by fat. The remaining myocardium was present only
in the subendocardium. This striking feature, which suggested
the replacement of myocardium by fat, was strengthened by microscopic
examination that showed strands of cardiomyocytes bordered by
or sometimes embedded in fibrosis or adipose tissue. It was
suspected that myocardial replacement by fat and fibrous tissue
started early in life, possibly in the embryo. This concept
was reinforced by a report of the heart of a 24-week-old fetus
with arrhythmias in utero.
2 The role of apoptosis was also demonstrated
as one of the factors contributing to myocardial remodeling
in ARVD.
5
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Molecular Biology
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In recent years, an extended classification of subgroups of
these right ventricular cardiomyopathies has been proposed on
the basis of genetic studies.
6 This information may impact the
selection of patients for ICD therapy on the basis of genotype-phenotype
relationship. Among them, Naxos disease was particularly informative
because this inherited condition with a recessive form of transmission
is associated with clinically obvious ectodermic dysplasia (keratoderma,
woolly hair) and has the typical histological pattern of ARVD.
This association prompted the identification of a nonsense mutation
of a gene coding for a protein (plakoglobin) that could explain
both ectodermal manifestations and cardiac dysplasia.
7 In another
form of the disease identified in Ecuador, presenting clinically
as idiopathic dilated cardiomyopathy without fatty infiltration,
a mutation of a gene coding for a protein in the same category
of cellcell adhesion (desmoplakin) was discovered,
8 and
a mutation on the gene encoding for desmoplakin was identified
in the Veneto region of Italy in a familial dominant form of
ARVD.
9 A third genetic abnormality was identified in Italy in
patients with a familial dominant form of exercise-induced ventricular
arrhythmia.
10 In these patients, however, the mutation involved
the sarcoplasmic reticulum calcium release channel (ryanodine
receptor).
The right ventricular ST-segment elevation (Brugada syndrome) frequently associated with signs of delayed conduction in the right bundle branch is due to a cardiomyopathy in some cases.11 This syndrome carries the risk of nocturnal sudden death, particularly in young adults. Arrhythmic death is not prevented by antiarrhythmic drugs, with the possible exception of quinidine.12 The sodium channel (SCN5A) was originally involved in 50% of the patients studied. However, the relation between the Brugada syndrome and ARVD is not always clear. Examination of the pathological material in patients with the Brugada syndrome who died suddenly showed that one third had structural heart disease, consisting of fat and fibrosis strongly suggestive of ARVD and/or signs of inflammation. A systematic study of a group of 60 ARVD patients in our center showed that 26% had ST-segment elevation
1 mm in leads V1 through V3.13 Therefore, there is a significant overlap between ARVD and Brugada syndrome that needs further investigation.
Another form of ventricular arrhythmia frequently observed in the young is right ventricular outflow tract (RVOT) VT. A few patients who have benign ventricular extrasystoles arising from the RVOT may develop rapid VT degenerating into ventricular fibrillation. These patients are candidates for the implantable defibrillator. However, ablation of the arrhythmic focus involving the Purkinje system was able to prevent recurrence of life-threatening arrhythmias.14 In addition, the autopsy material in one case of RVOT demonstrated the presence of fat and fibrosis in surviving fibers, plus signs of inflammation in the infundibular area, which suggested a localized form of ARVD.6
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Antiarrhythmic Drugs
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In the article by Wichter et al,
1 antiarrhythmic drugs were
used in 32% after ICD implantation and in 48% at the end of
the study. However, only 2 patients were given a drug combination.
One could speculate that the rate of appropriate ICD discharges,
including those for antitachycardia therapy, might be lower
than reported in this series if a combination of antiarrhythmic
drugs were used. In our experience, the most effective combination
is the combination of amiodarone plus ß-blocking drugs,
as used in the Canadian Amiodarone MI Arrhythmia Trial (CAMIAT)
and European Myocardial Infarct Amiodarone Trial (EMIAT).
15 In patients with good left ventricular function, the combination
of flecainide with sotalol may be used. One could speculate
whether the number of appropriate ICD discharges would have
been substantially reduced in a cohort of patients treated with
these drug combinations. The answer to this question will require
a prospective standardized trial of antiarrhythmic drug combination
in patients with ARVD implanted with ICDs.
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Equipment Effectiveness
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The study demonstrates that the ICD therapy is an effective
treatment even though it was not a study randomizing patients
to ICD treatment or antiarrhythmic drug treatment. Only 2 patients
died of an arrhythmia over 80 months. The study also illustrates
that ICD therapy is not without its complications in the treatment
of the disease. A relatively high incidence of complications
would be expected during long-term follow-up of relatively young
patients. In addition, a complication that was rather common
and almost unique to the treatment of this disease by ICD is
the higher pacing thresholds and lower amplitude of endocardial
potentials because of diffuse involvement by fat and fibrosis
of the right ventricle at the site of ICD lead placement. The
implanter needs to be aware of this problem and prepared to
use alternative sites, including active fixation of the electrode
in the septum, which is generally not involved in this disease
process. In addition, this situation may worsen with time because
of disease progression and dilatation of the right ventricle.
6 Because these patients are in the younger age group, it is anticipated
that they will need several generator replacements and are likely
have one or more lead changes, as well as lead fracture and
premature battery exhaustion. The use of modern leads with the
same diameter (isodiametric lead) will greatly facilitate lead
withdrawal.
In the report by Wichter et al,1 there is no mention of high defibrillation thresholds. However, we are aware of high defibrillation thresholds in patients with ARVD as well as in the Brugada syndrome. The reason for this situation is unknown. Of note, there is very little right ventricular free wall perforation reported in ARVD. This potential complication would have been expected because of the thinness of right ventricular free wall in ARVD.
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Indications for ICD in ARVD
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A major clinical question that was not completely addressed
in this study was whether it would be possible to identify with
a high degree of certainty those patients with ARVD who would
benefit from ICD implantation on the basis of anticipated knowledge
of those who would have an arrhythmic cardiac death. With good
left ventricular function, many patients with ARVD can tolerate
a rapid ventricular rate, even exceeding 240 bpm, without syncope
or near syncope. An alternative analytic approach would be to
restrict the high-risk group to those individuals who have VT
and who have had syncope or near syncope.
The most frequent and difficult problem in deciding who requires an ICD relates to family members. Wichter et al1 found that electrophysiological study positive for the induction of fast unstable VT/ventricular fibrillation is an independent predictor of life-threatening events during follow-up. Therefore, it is tempting to deduce that VT induction in a family member can be valuable for identifying individuals at risk.
It is hoped that it will be possible to identify patients with ARVD at risk of sudden cardiac death by noninvasive techniques, such as advanced methods of electrocardiography16 and echocardiography, and invasive approaches, such as electrophysiological study and contrast angiography.17
It is also hoped that these questions about risk stratification and indication for ICD therapy in high-risk subgroups of right ventricular cardiomyopathies will be answered with the help of registries. More data prospectively collected from many centers are needed to answer the important questions, on the basis of clinical presentation, genetics, and baseline characteristics, as to who would require ICD therapy. It is hoped that this information will be forthcoming from the two major ARVD registries, the European and the North American Registries. Physicians are encouraged to enter their patients suspected of ARVD into these registries so that we will be able to make a judgment of who requires ICD therapy on the basis of prospectively collected data from a large number of patients.1821
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Acknowledgments
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This work has been supported by grants from the European Commission
QLG1-CT-2000-01091, French registry No. 99 b 0691; Le Téléton
(AFM) No. 5774; and La Fondation Gustave et Simone Prévot,
Genève, Suisse.
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Footnotes
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The opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
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References
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