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A new diagnostic test for arrrhythmogenic right ventricular cardiomyopathy.

Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE. N Engl J Med 2009: 360:1075-84

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disorder characterized by fibro-fatty replacement of cardiac myocytes and special predilection by right ventricle1. Main complications are ventricular arrhythmias, heart failure and sudden cardiac death2.
Myocardial Disease


Natural history of ARVC usually include progressive phases, since concealed phase, characterized by absence or minor signs and symptoms, but during which sudden death could be the first manifestation3; till final stage of biventricular failure4. Diagnosis of ARVC is based on presence of major and minor criteria that include structural, histological, electrocardiographic, arrhythmic, and familial factors5. These recognized diagnostic criteria are specific but may lack sensitivity in those cases with mild phenotype and borderline abnormalities that overlap with normality. Thus, diagnosis of ARVC at its early stages remains a clinical challenge4. Moreover, endomyocardial biopsy is not always useful because of patchy cardiac muscle affection and preservation of subendocardial layers6. Genetic background of the disease includes mutations in desmosomal protein genes, which could be detected in almost 50% of cases. Desmosomal proteins (plakoglobin, plakophilin-2, desmoplakin, desmoglein-2 and desmocollin-2) are components of the cardiac desmosome that have important role in the pathogenesis of ARVC. Desmosomes have an important role in supporting structural stability through cell-cell adhesion, regulating transcription of genes involved in adipogenesis and apoptosis, and maintaining proper electrical conductivity through regulation of gap junctions and calcium homeostasis7.

Asimaki et al.8, in the March issue of The New England Journal of Medicine, presented a new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. They analyzed samples obtained on autopsy or endomyocardial biopsy of 11 subjects who were known to have ARVC and 30 blinded heart-biopsy samples from subjects who had been evaluated in the John Hopkins ARVC registry, 11 of whom fulfilled clinical criteria of ARVC. Then they stained each sample with antibodies against plakoglobin, desmoplakin, plakophilin-2, N-cadherin and connexin-43, and compared to a panel of controls using immunohistochemical analysis. Results showed reduced immunoreactive signal levels for plakoglobin at intercalated discs in ARVC patients compared to controls, even in those samples taken from uncommon target disease regions (left ventricle and septum). Signal levels of plakopillin-2 and desmoplakin varied in the ARVC samples whereas connexin-43 showed marked reduction. To determine whether reduced signal levels for plakoglobin and connexin-43 at intercalated discs were specific for ARVC, authors analyzed samples from the native hearts of subjects who had undergone cardiac transplantation for end-stage heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy and ischemic heart disease).

In every case, these transplanted hearts showed high plakoglobin signal levels at intercalated discs, indistinguishable for control samples, whereas they had clearly diminished expression of connexin-43. Taken together, these results suggested that diminished signal level for plakoglobin is a consistent feature of ARVC but not of other forms of severe heart disease. Furthermore, reduced signal levels for the major ventricular gap-junction protein, connexin-43, indicate that the remodeling of gap-junctions is a fundamental feature of ARVC as well as of others ischemic and non-ischemic heart diseases. This new test, using an immunohistochemical technique to measure plakoglobin signal level in conventional biopsy samples, appears to be a highly sensitive (91%) and specific (82%) diagnostic test for ARVC.

Main important finding of this paper is the development of a new, simple and cost reliable test to diagnose ARVC, even in early and concealed phases of the disease. It is also remarkable the finding of a common pathogenic mechanism for the development of ARVC secondary to the presence of mutations in different desmosomal genes. In these cases, immunohistochemical analysis could be useful as all these different mutations would cause a loss of the normal plakoglobin binding to desmosomes. One theory coming from recent functional studies suggests that this could cause a migration of plakoglobin to the nucleus, where it would induce signaling pathways related to cell death and adipogenesis9.

One of the most interesting applications of this novel technique is that it could become a gold standard method for the evaluation of the pathogenicity of desmosomal mutations. In some cases available clinical data is sufficient to decide if a specific genetic variant is causative or not, but this matter is usually difficult, especially with novel mutations or mutations with limited previous information. However, Asimaki et al.8 only tested the diagnostic accuracy of the test for a limited number of mutations (eight) in four different genes, and we cannot assume that these results are applicable to other mutations in the same or different genes (like desmocollin-2).
Another advantage of this technique is that it may enhance the diagnostic accuracy of conventional endomyocardial biopsy or autopsy samples. Endomyocardial biopsies samples, for reasons of safety, are usually taken from septum, a region uncommonly involved by ARVC6. Asimaki et al.8 demonstrated the presence of reduced plakoglobin signal levels even in regions appeared to be structurally normal.

Finally, the fact that reduction in the signal level of plakoglobin is present in structural and histologically normal regions, suggests that remodeling of desmosomes and gap junctions could start years before that histological changes appear. It is also possible that fibro-fatty replacement would not be necessary to induce conduction abnormalities that promote arrhythmias in ARVC. In this way, it would be important to consider the possibility of ARVC in cases of sudden death in structurally normal hearts.

Conclusion:

The paper by Asimaki et al.8 opens a completely new perspective for the diagnosis and understanding of ARVC. An accurate and early diagnosis of ARVC is the clue for the prevention of sudden death associated with this disease, which is presently a challenge for clinicians, both in cardiology and in sport medicine. However we have to be cautious with the generalization of paper conclusions. The authors demonstrated high degree of sensitivity and specificity for this method in a very limited number of patients and mutations. In order to confirm these results, newest studies in larger series will be necessary. If these results are confirmed, this work could probably be considered not only the paper of the month, but the paper of the year.

References


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  2. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med. 1988 Jan 21;318(3):129-33.
  3. Furlanello F, Bertoldi A, Dallago M, Furlanello C, Fernando F, Inama G, et al. Cardiac arrest and sudden death in competitive athletes with arrhythmogenic right ventricular dysplasia. Pacing Clin Electrophysiol 1998;21:331-5.
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  5. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, Camerini F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. 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. Br Heart J. 1994;71(3):215-8.
  6. Angelini A, Basso C, Nava A, Thiene G. Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy. Am Heart J. 1996; 132:203–206.
  7.  Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008 May;5(5):258-67.
  8. Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med. 2009 Mar 12;360(11):1075-84. 
  9. Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest. 2006 Jul;116(7):2012-21
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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