CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Srijita Sen-Chowdhry, MBBS, MD*,
Petros Syrris, PhD,
Sanjay K. Prasad, MD,
Siân E. Hughes, MBBS, PhD,
Robert Merrifield, PhD,
Deirdre Ward, MBBS,
Dudley J. Pennell, MD and
William J. McKenna, MD, DSc
* University College London, Inherited Cardiovascular Disease Group, The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, United Kingdom (Email: Srijita{at}aol.com).
We thank Dr. Di Bella and colleagues for their comments on our paper (1). With a number of qualifications, we concur. Shared morphology is an important but not the sole reason for misattribution of left-dominant arrhythmogenic cardiomyopathy (LDAC). In our study, 4 patients had prior diagnoses of idiopathic ventricular tachycardia/benign ventricular ectopy because investigation had been terminated on acquisition of a normal echocardiogram and coronary angiogram, with consequent failure to identify the myocardial substrate (1).
Among their examples of "other cardiomyopathies" that show morphological overlap with LDAC, Dr. Di Bella and colleagues cite biventricular arrhythmogenic cardiomyopathy. Because both are under-recognized subtypes of the same disease, similarities are expected. The proposed 3-way classification of arrhythmogenic cardiomyopathy (2) is simplistic; the reality is probably a continuum, at opposite ends of which lie the classic right- and left-dominant forms. Whether differentiating between left-dominant and biventricular subtypes is of clinical importance will depend on its bearing, if any, on management and outcomes. Evidence of significant differences in prognosis from follow-up studies will warrant clearer guidelines for subtype designation.
Of unequivocal clinical relevance is the distinction between dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy, regardless of subtype (1). Contrary to the assertion of Dr. Di Bella and colleagues, we have not advocated seeking "prominent right ventricular abnormalities added with left ventricular involvement." In this context, having excluded ischemic heart disease and other confounders, we noted that localized morphological changes favor a diagnosis of arrhythmogenic cardiomyopathy, and are frequently right-sided, even in LDAC (1). No structural feature, however, is specific to arrhythmogenic cardiomyopathy. Right ventricular aneurysms are observed in cardiac sarcoidosis and, as Dr. Di Bella and colleagues indicate, lipomatous metaplasia and subepicardial late enhancement occur in a variety of disorders. For these reasons, clinical diagnosis of arrhythmogenic cardiomyopathy is based on a combination of different criteria, never on morphological abnormalities alone (3), and clinical context is key. Dr. Di Bella and colleagues omit that LDAC is distinguished from DCM primarily on clinical grounds, by recognizing arrhythmogenicity exceeding the degree of morphological abnormality and systolic impairment (1). Thus, DCM presents with clinical heart failure, whereas arrhythmia is foremost in the symptomatology of LDAC. Morphological differences serve as a minor aid.
Fontaine and Fornès (4) have suggested that LDAC results from superimposition of chronic myocarditis on classic arrhythmogenic cardiomyopathy. Mice expressing C-terminal mutations in desmoplakin show early and prominent left ventricular dysfunction, suggesting that the genetic defect per se is a major determinant of phenotype (5). To reconcile the genetic basis of LDAC with a putative viral etiology, Dr. Di Bella and colleagues invoke enhanced susceptibility of the diseased myocardium to infection, as previously observed in dystrophin-deficient mice (6). Available data neither support nor exclude this mechanism in arrhythmogenic cardiomyopathy. In existing studies of the classic subtype, the prevalence of viral genome in myocardial biopsies ranges from 0% to 75% (maximum sample, n = 20) (7–9). Conversely, enteroviral deoxyribonucleic acid may also be present in tissue from patients with ischemic and valvular heart disease, suggesting a bystander role (10), while inflammation without detectable viral genome is documented in both familial DCM (11) and arrhythmogenic cardiomyopathy (7). Taken together, the contribution of viruses to genetically determined cases seems at most subsidiary and at present largely speculative.
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References
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1. Sen-Chowdhry S, Syrris P, Prasad SK, et al. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity J Am Coll Cardiol 2008;52:2175-2187.[Abstract/Free Full Text]2. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression Circulation 2007;115:1710-1720.[Abstract/Free Full Text] 3. McKenna WJ, Thiene G, Nava A, et al. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy Br Heart J 1994;71:215-218.[Free Full Text] 4. Fontaine GH, Fornès P. Letter regarding article by Norman et al, "Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy" Circulation 2006;113:e68-e69.[CrossRef][Web of Science][Medline] 5. Yang Z, Bowles NE, Scherer SE, et al. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy Circ Res 2006;99:646-655.[Abstract/Free Full Text] 6. Diong D, Knowlton KU. Dystrophin deficiency markedly increases enteroviral cardiomyopathy: genetic predisposition to viral heart disease Circulation 2001;104(Suppl II):II82. 7. Calabrese F, Angelini A, Thiene G, Basso C, Nava A, Valente M. No detection of enteroviral genome in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy J Clin Pathol 2000;53:382-387.[Abstract/Free Full Text] 8. Calabrese F, Basso C, Carturan E, Valente M, Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: is there a role for viruses? Cardiovasc Pathol 2006;15:11-17.[CrossRef][Web of Science][Medline] 9. Bowles NE, Ni J, Marcus F, Towbin JA. The detection of cardiotropic viruses in the myocardium of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy J Am Coll Cardiol 2002;39:892-895.[Abstract/Free Full Text] 10. Keeling PJ, Jeffery S, Caforio AL, et al. Similar prevalence of enteroviral genome within the myocardium from patients with idiopathic dilated cardiomyopathy and controls by the polymerase chain reaction Br Heart J 1992;68:554-559.[Abstract/Free Full Text] 11. Mahon NG, Zal B, Arno G, et al. Absence of viral nucleic acids in early and late dilated cardiomyopathy Heart 2001;86:687-692.[Abstract/Free Full Text]
Related Article
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Left Dominant Arrhythmogenic Cardiomyopathy: A New Clinical Entity Without a Typical Substrate of Myocardial Damage
- Gianluca Di Bella, Scipione Carerj, and Sebastiano Coglitore
J. Am. Coll. Cardiol. 2009 53: 1570-1571.
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