International Journal of Cardiology 172 (2014) e375–e376

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Letter to the Editor

Arrhythmogenic right ventricular cardiomyopathy — An update S. Peters St. Elisabeth Hospital Salzgitter gGmbH, Cardiology, Liebenhaller Str. 20, 38259 Salzgitter, Germany

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Article history: Received 19 December 2013 Accepted 30 December 2013 Available online 10 January 2014 Keywords: Arrhythmogenic right ventricular cardiomyopathy T wave inversions Epsilon waves Electroanatomic scar Brugada syndrome

The cardiac entity called arrhythmogenic right ventricular cardiomyopathy was first presented in Germany in the Deutsche Ärzteblatt in 1998 [1]. New aspects are worthwhile to be presented again: ARVC/D is meanwhile a well-known form of cardiomyopathy. In 2006 it was published as genetic form of disease by Barry Maron in the journal Circulation [2]. Only hypertrophic cardiomyopathy is more often found (0.0008% of patients with ARVC/D in contrast to 0.002%). All other forms of cardiomyopathies are rare. Dilated cardiomyopathy, for example, has a frequency of 0.0004% up to 0.0002%. In 2010 diagnostic criteria of ARVC/D are modified [3]. Aspects of imaging techniques (echocardiography, angiography and MRI) have been concretized. Electrocardiographic criteria have changed. Major criteria of ARVC/D are right precordial T wave inversions and so-called epsilon waves. The criterion of QRS prolongation in right precordial leads of more than 110 ms is no longer accepted, as only in a few countries a ECG writing technique with 50 mm/s is used. Also localized right precordial QRS prolongation [4] was left, as in most countries the ECG writing technique does not provide a more detailed analysis. In about 12% of patients normal or unspecific ECG was found [5]. In these cases other criteria such as localized right precordial QRS prolongation [4] or QRS fragmentation [6] should be used. With the help of these ECG criteria ARVC/D can be supposed in the majority of patients. What is not published up to now are ECG changes in lead aVR, which help to identify patients with suspected ARVC/D in more than 95% of cases. The typical ECG signs in lead aVR are deep Q waves, a small R wave of less than 3 mm and negative T waves as a hint for electroanatomic scar and myocardial atrophy (unpublished data by S. Peters). Positive genetic criteria with desmosomal gene mutations are meanwhile a major criterion of ARVC/D, although it is known by recent 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved.

publications that so-called non-desmosomal gene mutations gain more and more interest. A change of diagnostic criteria is in progress [7]. Numerous non-desmosomal gene mutations have been described: phospholamban [7], lamin A/C [8], titin [9], desmin [10], TMEM 43 [11], RYR 2 [12] and TGF-ß3 [13]. RYR 2 and TGF-β3 gene mutations result in typical forms of ARVC/D, the other ones differ with regard to left ventricular involvement and conduction abnormalities. By the identification of non-desmosomal gene mutations a differentiation of ARVC/D or dilated cardiomyopathy is nearly impossible. These are familial mutations encoding phospholamban, lamin A/C, and titin. It is well known that in cardiosurgical centers, a possibility of heart transplantation dilated cardiomyopathy is often diagnosed and after heart explantation arrhythmogenic right ventricular cardiomyopathy with excessive left ventricular involvement is the true diagnosis. Further aspects of non-desmosomal gene mutations are conduction abnormalities with the need of pacemaker or ICD implantation [14]. Furthermore, cardiac sarcoidosis with similarities to ARVC/D [15] leads to impressive conduction disease. The diagnosis of cardiac sarcoidosis can be only made by myocardial biopsy. For a long period of time it was discussed whether ARVC/D and Brugada syndrome have the same origin. In a recent publication cases with typical ARVC/D and co-existing Brugada syndrome were found in 8% [16]. In typical ARVC/D a Brugada ECG was provocable in 16% of cases [16]. These data are in very good correlation to the analysis of another working group [17]. A true congenital Brugada syndrome is characterized by a QT interval which is in all precordial leads nearly the same. Provocable Brugada ECG on the basis of ARVC/ D is characterized by an increase of right precordial QT interval [18]. Early repolarization and pharmacologically provocable Brugada ECG is a hint for further investigations to diagnose subtle structural abnormalities, for example ARVC/D [19,20]. In these cases the arrhythmic risk is increased. Risk stratification in ARVC/D is of important interest. Non-aborted sudden cardiac death, unstable ventricular tachycardia and syncope are still indications for ICD implantation [21,22]. Recent literature implies that the extent of T wave inversions can be used to decide whether a patient is an ideal candidate for ICD implantation [23]. In the case of normal T waves or T wave inversion in right precordial leads, the electroanatomic scar tissue is small and the arrhythmic risk is low. If T wave inversion exceeds the lateral or inferior leads, the electroanatomic scar tissue in endocardial voltage mapping is large and the arrhythmic risk is high. Treadmill test belongs to investigational testing in arrhythmogenic right ventricular cardiomyopathy, as the profile of arrhythmia is best analyzed by increasing treadmill work capacity [24].


S. Peters / International Journal of Cardiology 172 (2014) e375–e376

Meanwhile it is clear that physical activity in asymptomatic patients with ARVC/D increases age dependent penetration and the arrhythmic risk [25]. These aspects were known up to now only in animal models [26]. References [1] Peters S, Götting B, Peters H, Thierfelder L. Pathologie und Diagnostik der arrhythmogenen rechtsventrikulären Dysplasie-Kardiomyopathie. Dtsch Ärztebl 1998;95:1726–31. [2] Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology; Heart Failure and Transplantation Committee; Quality of Care and outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807–16. [3] Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806–14. [4] Peters S, Trümmel M. Diagnosis of arrhythmogenic right ventricular dysplasia–cardiomyopathy: value of standard ECG revisited. Ann Noninvasive Electrocardiol 2003;8:238–45. [5] Te Riele AS, James CA, Bhonsale A, et al. Malignant arrhythmogenic right ventricular dysplasia/cardiomyopathy with a normal 12-lead electrocardiogram: a rare but under recognized clinical entity. Heart Rhythm 2013;10:1484–91. [6] Peters S, Trümmel M, Koehler B. QRS fragmentation in standard ECG as a diagnostic marker of arrhythmogenic right ventricular dysplasia–cardiomyopathy. Heart Rhythm 2008;5:1417–21. [7] Groeneweg JA, van den Zwaag PA, Olde Nordkamp LR, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 Task Force Criteria with inclusion of non-desmosomal phospholamban mutation carriers. Am J Cardiol 2013;112:1197–206. [8] Quarta G, Syrris P, Ashworth M, et al. Mutations in the lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 2012;33:1128–36. [9] Taylor M, Graw S, Sinagra G, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy–overlap syndromes. Circulation 2011;124:876–85. [10] Von Tintelen JP, Van Gelder IC, Asimaki A, et al. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm 2009;6:1574–83. [11] Hodgkinson KA, Connors SP, Merner N, et al. The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a S358L mutation in TMEM43. Clin Genet 2013;83:321–31.

[12] Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001;10:189–94. [13] Beffagna G, Occhi G, Nava A, et al. Regulatory mutations in transforming growth factor-beta 3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res 2005;65:366–73. [14] Peters S. Conduction abnormalities in arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 2013;168:4920–1. [15] Vasawala SC, Finn C, Delpriore J, et al. Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia. J Cardiovasc Eletrophysiol 2009;20:473–6. [16] Duthoit G, Fressart V, Hidden-Lucet F, et al. Brugada ECG pattern: a physiopathological prospective study based on clinical, electrophysiological, angiographic and genetic findings. Front Physiol 2012;3:47. [17] Peters S, Trümmel M, Denecke S, Koehler B. Results of ajmaline testing in patients with arrhythmogenic right ventricular dysplasia–cardiomyopathy. Int J Cardiol 2004;95:207–10. [18] Peters S. Advances in the diagnostic management of arrhythmogenic right ventricular dysplasia–cardiomyopathy. Int J Cardiol 2006;113:4–11. [19] Bastiaenen R, Raju H, Sharma S, et al. Characterization of early repolarization during ajmaline provocation and exercise tolerance testing. Heart Rhythm 2013;10:247–54. [20] Peters S. Early repolarization pattern in patients with provocable Brugada phenocopy: a marker of additional arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 2013;168:4928–9. [21] Corrado D, Calkins H, Link MS, et al. Prophylactic implantable defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation or sustained ventricular tachycardia. Circulation 2010;122:1144–52. [22] Corrado D, Leoni L, Link MS, et al. Implantable cardioverter–defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2003;108:3084–91. [23] Zorzi A, Migliore F, Elmaghawry M, et al. Electrocardiographic predictors of electroanatomic scar size in arrhythmogenic right ventricular cardiomyopathy: implications for arrhythmic risk stratification. J Cardiovasc Electrophysiol 2013;24:1321–7. [24] Perrin MJ, Angaran P, Laksman Z, et al. Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2013;62:1772–9. [25] James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy associated desmosomal mutation carriers. J Am Coll Cardiol 2013;62:1290–7. [26] Kirchhof P, Fabritz L, Zwiener M, et al. Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobindeficient mice. Circulation 2006;114:1799–806.

Arrhythmogenic right ventricular cardiomyopathy--an update.

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