doi: 10.1161/CIRCULATIONAHA.105.581868
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(Circulation. 2006;113:e68-e69.)
© 2006 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Norman et al, "Novel Mutation in Desmoplakin Causes Arrhythmogenic Left Ventricular Cardiomyopathy"
Institute of Pathological Anatomy, University of Padua Medical School, Padua, Italy
Division of Cardiology, University of Padua Medical School, Padua, Italy
Norman et al1 reported a family with autosomal dominant arrhythmogenic cardiomyopathy resulting from a novel mutation in desmoplakin. From their clinicopathological findings, the authors conclude that we are dealing with arrhythmogenic left ventricular cardiomyopathy (ALVC).
After our molecular discovery of desmoplakin as a disease-causing gene in dominant arrhythmogenic right ventricular cardiomyopathy (ARVC),2 we recently reported the first genotype-phenotype analysis in 4 families.3 Sen-Chowdhry et al4 wrote an editorial on this article, emphasizing that 50% of desmoplakin carriers had clinical evidence of LV involvement, data in keeping with previously reported pathology findings.5 In their family, the presence of positive late potentials in 64% of mutation carriers and the MRI evidence of RV abnormalities in all are strongly in favor of an RV disease. Data on QRS duration and epsilon wave on 12-lead ECG are not reported. Moreover, while describing patchy LV late gadolinium enhancement, they fail to mention the RV. The patient who underwent an RV endomyocardial biopsy had evidence of fibrosis. Thus, the reported features seem more in keeping with ARVC with prominent LV involvement than with an arrhythmogenic cardiomyopathy confined to the LV.
Noteworthy, the postmortem description of the heart in the boy who died suddenly is scanty. Neither macroscopic nor histopathological findings of the RV and septal myocardium are mentioned. In our experience, 2 young patients carrying desmoplakin mutations died suddenly.3 In both instances, the LV was involved in the subepicardial inferolateral free wall, showing ongoing myocyte death and early granulation tissue repair in the former and advanced fibrofatty myocardial replacement in the latter. However, the RV also was involved.
Thus, the patients described by Norman and colleagues appear to be part of the spectrum of cardiomyopathies that include ARVC, Carvajal syndrome, and Naxos syndrome. We would like to propose that this group of cardiomyopathies be called "desmosome cardiomyopathies."6
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1. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, Sen-Chowdhry S, Rowland E, Crosby A, McKenna WJ. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation. 2005; 12: 636–642.
2. Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002; 71: 1200–1206.[CrossRef][Medline] [Order article via Infotrieve]
3. Bauce B, Basso C, Rampazzo A, Beffagna G, Daliento L, Frigo G, Malacrida S, Settimo L, Danieli GA, Thiene G, Nava A. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J. 2005; 26: 1666–1675.
4. Sen-Chowdhry S, Syrris P, McKenna W. Desmoplakin disease in arrhythmogenic right ventricular cardiomyopathy: early genotype-phenotype studies. Eur Heart J. 2005; 26: 1582–1584.
5. Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M. Arrhythmogenic right ventricular cardiomyopathy: dysplasia, dystrophy or myocarditis? Circulation. 1996; 94: 983–991.
6. Thiene G, Corrado D, Basso C. Cardiomyopathies: is it time for a molecular classification? Eur Heart J. 2004; 25: 1772–1775.
Institut de Cardiologie, Unité de Rythmologie, Hôpital de la Salpêtrière, Paris, France
Laboratoire d’Anatomie et de Cytologie Pathologiques, Hôpital Européen Georges Pompidou, Paris, France
To the Editor:
We read with great interest the article by Norman et al1 on a new gene mutation in arrhythmogenic right ventricular cardiomyopathy (ARVC). They claimed that this "novel mutation in desmoplakin causes left ventricular cardiomyopathy." In the present work, detailed left ventricular (LV) histology has been restricted to only 1 case. Histological features strongly suggest chronic myocarditis. In addition, magnetic resonance imaging shows replacement fibrosis mostly in the LV subepicardial layers, suggesting pericardo-myocarditis. Fibrosis also has been reported in biopsies from patients with ARVD and superimposed myocarditis.2
Figure 3, a typical ECG, shows inverted T waves in the left precordial leads; however, the T waves in the right precordial leads also are abnormal. Arrhythmias are originating mostly from the LV, but right origin is not rare: 2 right bundle-branch block ventricular tachycardias versus 1 left bundle-branch block ventricular tachycardia, and 8 of 11 left premature ventricular contractions versus 2 of 11 right premature ventricular contractions. LV sites of ventricular arrhythmias and left T-wave inversion have been observed in typical forms of ARVC. In the present work, of the only 4 magnetic resonance images performed, all showed an abnormal RV structure. For these reasons, we think that this "novel mutation in desmoplakin " does not "causes left ventricular cardiomyopathy" but is the result of a dominant form of transmission of ARVC3 accompanied by superimposed chronic myocarditis. LV replacement fibrosis is likely to explain ECG findings and induction of LV arrhythmias.4
Whether myocarditis also is genetically determined and related to ARVC is a subject of interest (Christine Seidman, personal communication, Cardiostim, 2004). This discussion may have important therapeutic implications.5
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Disclosures
None.
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TopReferencesAcknowledgments References Acknowledgments References |
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1. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, Sen-Chowdhry S, Rowland E, Crosby A, McKenna WJ. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation. 2005; 112: 636–642.
2. Fontaine G, Brestescher C, Fontaliran F, Himbert C, Tonet J, Frank R. Modalités évolutives de la dysplasie ventriculaire droite arythmogène: a propos de 4 observations. Arch Mal Coeur. 1995; 88: 973–980.[Medline] [Order article via Infotrieve]
3. Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002; 71: 1200–1206.[CrossRef][Medline] [Order article via Infotrieve]
4. Fontaine G, Hebert JL, Prost-Squarcioni C, Fornes P, Frank R, Thomas D. Nouveautés dans la dysplasie ventriculaire droite arythmogène. Arch Mal Coeur Vaiss. 2004; 97: 1155–1159.[Medline] [Order article via Infotrieve]
5. Kuehl U, Noutsias M, Seeberg B, Schultheiss HP. Antiviral interferon therapy in DCM patients with viral persistence. Circulation. 2004; 110 (supp III): III–724.Abstract.
Response
Cardiology in the Young Program, Heart Hospital, University College London, London, UK
Department of Cardiological Sciences, St George’s Hospital Medical School, London, UK
Department of Medical Genetics, St George’s Hospital Medical School
Department of Histopathology, Royal Free and University College Medical School, University College London and UCL Hospitals NHS Trust, London, UK
We thank Dr Basso and colleagues for their interest in our study1 and the opportunity to clarify several issues. The 2034insA mutation in desmoplakin resulted in a phenotype with early and prominent left-sided involvement that we termed arrhythmogenic left ventricular cardiomyopathy (ALVC). The terminology was not intended to signify a new disease bearing no relation to arrhythmogenic right ventricular cardiomyopathy (ARVC); rather, we strongly concur that the 2 entities are part of the same genetic, clinical, and pathological spectrum.2
None of the 2034insA family had localized prolongation of the QRS complex or epsilon waves in V1 through V3. Cardiovascular magnetic resonance studies in 4 individuals revealed wall motion abnormalities and/or aneurysms in the RV, sometimes associated with intramyocardial fat; late enhancement findings were not reported owing to the difficulty in distinguishing fibrosis from fat in the thin-walled RV. At no point did we contend that the disease was confined to the LV; the right-sided structural abnormalities were recognized as typical of ARVC.1
Nevertheless, we justify using the term ALVC to underscore the following features: (1) prominent arrhythmia of LV origin; (2) isolated T-wave inversion in the lateral leads (V4 through V6); and (3) LV involvement preceding development of significant RV dysfunction, a notable departure from the proposed natural history of ARVC.2
A similar phenotype was identifiable in the family with the c.423 to 1G>A mutation reported by Bauce et al.3 Highlighted in our accompanying editorial was the presence of isolated lateral T-wave inversion and LV impairment in the setting of relatively preserved RV function.4 In contrast, among other families in the Padua desmoplakin cohort, LV dysfunction was observed solely in the context of marked RV dilation and impairment.4,5
Drs Fontaine and Fornès, whom we also thank for their comments, attribute the conspicuous LV manifestations in the 2034insA family to chronic myocarditis with replacement fibrosis. Predominant left-sided involvement has been documented in conjunction with at least 3 desmoplakin mutations (2034insA, c.423 to 1G.A,4 and 7901delG [Carvajal syndrome]),3,5 suggesting a genetic basis. The mutations are postulated to have dual functional impact: impaired cell adhesion at the N terminus and truncation of the desmin-binding C terminus, with reduced cytoskeletal support. The desmosomal model predicts myocyte loss under conditions of mechanical stress, accompanied by inflammation and fibrofatty repair.2 Myocarditis therefore plays a key role in pathogenesis of but arises as a corollary of the desmosomal mutation rather than a sporadic phenomenon fortuitously superimposed on the underlying disease process.
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Acknowledgments |
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TopReferencesAcknowledgments References Acknowledgments References |
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Disclosures
None.
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References |
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TopReferencesAcknowledgments References Acknowledgments References |
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1. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, Sen-Chowdhry S, Rowland E, Crosby A, McKenna WJ. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation. 2005; 112: 636–642.
2. Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol. 2005; 16: 927–935.[CrossRef][Medline] [Order article via Infotrieve]
3. Bauce B, Basso C, Rampazzo A, Beffagna G, Daliento L, Frigo G, Malacrida S, Settimo L, Danieli GA, Thiene G, Nava A. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J. 2005; 26: 1666–1675.
4. Sen-Chowdhry S, Syrris P, McKenna W. Desmoplakin disease in arrhythmogenic right ventricular cardiomyopathy: early genotype-phenotype studies. Eur Heart J. 2005; 26: 1582–1584.
5. Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet. 2000; 9: 2761–2766.
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