Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a multidisciplinary study: design and protocol.

Abstract

HomeCirculationVol. 107, No. 23Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBArrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)A Multidisciplinary Study: Design and Protocol Frank Marcus, MD, Jeffrey A. Towbin, MD, Wojciech Zareba, MD, PhD, Arthur Moss, MD, Hugh Calkins, MD, Mary Brown, MS, Kathleen Gear, RN and Frank MarcusFrank Marcus From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author , Jeffrey A. TowbinJeffrey A. Towbin From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author , Wojciech ZarebaWojciech Zareba From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author , Arthur MossArthur Moss From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author , Hugh CalkinsHugh Calkins From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author , Mary BrownMary Brown From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author , Kathleen GearKathleen Gear From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author and From the Sarver Heart Center, University of Arizona College of Medicine (F.M., K.G.), Tucson, Az; Baylor College of Medicine (J.A.T.), Houston, Tex; University of Rochester, School of Medicine (W.Z., A.M., M.B.), Rochester, NY; and Johns Hopkins University (H.C.), Baltimore, Md. Search for more papers by this author and for the ARVD/C Investigators Originally published17 Jun 2003https://doi.org/10.1161/01.CIR.0000071380.43086.29Circulation. 2003;107:2975–2978Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a relatively newly recognized disease. A clinical profile of patients with this condition was first published in 1982.1 In that report, it was observed that the majority of patients were male. Patients presented with ventricular tachycardia of left bundle-branch block morphology. An enlarged right ventricle due to fibrofatty infiltration of the right ventricular free wall and a familial association were noted. It was considered to be a rare disease of unknown cause. Since then, it has been diagnosed with increasing frequency and has been reported to account for 3% to 5% of unexplained sudden cardiac death under the age of 65 years.2,3 Evidence of the disease is found in 30% to 50% of family members who are studied by noninvasive tests, including ECG, echocardiography, and signal-averaged ECG.4,5 It has been suggested that MRI may also be used for diagnostic purposes, but this remains controversial.6,7 Six genetic loci have been reported to be associated with ARVD/C, and 3 genes have been identified: ryanodine receptor (RyR2),8 plakoglobin (JUP),9and desmoplakin (DSM).10 There is autosomal dominant transmission with all the genetic forms except Naxos disease8 and Carvahal syndrome,11 both of which have autosomal recessive transmission. These 2 autosomal recessive disorders are variants of ARVD/C that are associated with skin and hair abnormalities. The cardiac presentation in Carvahal syndrome is that of a left ventricular cardiomyopathy and arrhythmias.With the recognition that ARVD/C is frequently familial and can cause arrhythmic death, the clinical challenge is how to definitively identify individuals with ARVD/C who have mild or minimal structural abnormalities of the right ventricle. Definite identification of minimal structural abnormalities of the right ventricle can be difficult because of the irregular shape and asymmetrical contractile pattern of the highly trabeculated right ventricle.12 Some of these individuals may be family members who may or may not have premature ventricular beats. The ventricular ectopy can be asymptomatic. Others may present with nonsustained ventricular tachycardia or may have sustained ventricular tachycardia. A young individual resuscitated from sudden cardiac death who has no overt evidence of structural heart disease must also be suspected of having ARVD/C. The most frequent ventricular arrhythmias in young people arise from the right ventricular outflow tract. Evaluation for ARVD/C, usually by a series of diagnostic tests, should be considered in individuals with ventricular arrhythmias from the right ventricular outflow tract. Treatment for patients diagnosed with ARVD/C is empirical. There is incomplete knowledge of factors that might permit accurate risk stratification to determine which patient should be treated with an implantable cardioverter defibrillator.13Because of the relative rarity of this disease and the difficulty and importance of establishing the diagnosis, and to obtain further information regarding risk stratification and treatment of this disease, a multidisciplinary study of ARVD/C was initiated under the leadership of Dr Frank Marcus (University of Arizona, Tucson, Ariz) and has been funded by the National Heart, Lung, and Blood Institutes.ObjectivesThe specific aims of the Multidisciplinary Study of RVD/C are as follows: (1) to establish a North American ARVD/C Registry enrolling ARVD/C patients and their family members, based on standardized diagnostic test criteria, in a prospective longitudinal follow-up study; (2) to determine the genetic background of ARVD/C by identifying chromosomal loci and specific gene mutations associated with this disorder; (3) to determine the influence of the genotype on the clinical course of patients with ARVD/C and explore phenotype-genotype associations that will contribute to improve diagnosis, risk stratification, and therapy; and (4) to develop quantitative methods to assess right ventricular function to enhance the specificity and sensitivity of the diagnosis of ARVD/C.DesignThe Multidisciplinary Study of ARVD/C represents a collaborative effort of research groups from the University of Arizona, Baylor College of Medicine, and the University of Rochester, in cooperation with enrolling centers and several expert groups serving as core laboratories. Figure 1 shows the organizational structure of the study. The study uses a World Wide Web-based operation that was developed at the University of Rochester under the leadership of Wojciech Zareba, MD, and Mary Brown, MS. This system facilitates management of all aspects of the study, including patient screening, enrollment, data collection and encryption, phenotypic classification, quality control, and coordination of this complex multicenter study. Figure 2 shows the design of the study. Download figureDownload PowerPointFigure 1. Organizational structure of study.Download figureDownload PowerPointFigure 2. Flow design of screening, enrollment, data collection, and analysis. EP indicates electrophysiology; SAECG, signal-averaged ECG; and Angio, angiography.Patients suspected of having ARVD/C will be screened in enrolling medical centers, geographically distributed in the United States and Canada. They will undergo a series of noninvasive tests according to specifically developed standardized protocols that include an ECG, ambulatory ECG monitoring, signal-averaged ECG, and MRI. If the data are consistent with the diagnosis of ARVD/C using the task force criteria,14 the patient will be qualified for enrollment and will be required to have invasive testing, including right ventricular angiography, right ventricular biopsy, and electrophysiology testing (if not done before enrollment). Blood will be sent to the Genetic Center Laboratory under the direction of Dr Jeffrey Towbin (Houston, Tex), who will be collaborating closely with Dr Gian Antonio Danieli (Padua, Italy) to identify causative genes. Myocardial tissue samples from endomyocardial biopsy will be screened for viral RNA. Experts in the respective core laboratories will analyze and interpret the tests. On the basis of the results of these tests, the patient will be classified as being phenotypically affected, borderline, or unaffected. Patients will be treated by their own physicians and followed up by yearly contact.If enrolled probands are diagnosed as having ARVD/C on the basis of core laboratory evaluation, then first-degree relatives will be asked to undergo noninvasive screening and submit blood for genetic study. If cardiac abnormalities suggestive of ARVD/C are found in first-degree relatives by noninvasive testing, it will be recommended that the family members undergo complete diagnostic evaluation, including invasive testing.An important part of this study is the evaluation of the diagnostic task force criteria that were proposed in 199414 (Table). These guidelines represent an important landmark in establishing minimal criteria for this diagnosis. The Task Force recognized that there is no single test that is diagnostic of ARVD/C. A combination of major and minor criteria were proposed but have not been evaluated prospectively. There were no protocols prepared for imaging the right ventricle by echocardiography, angiography, or MRI. Interpretation of contraction abnormalities observed by these imaging modalities is largely subjective and requires considerable technical and interpretive expertise. In the present study, imaging of the right ventricle by the above modalities will be performed according to protocol and interpreted in core laboratories. As part of this study, techniques are being developed to quantify right ventricular structure and function. Although the percentage of abnormal test findings can be compared with one another, the diagnostic accuracy of these imaging tests will require gene identification of the proband and family members. Task Force Criteria for Diagnosis of Right Ventricular Dysplasia/CardiomyopathyThe diagnosis of ARVD/C would be fulfilled by the presence of 2 major, 1 major plus 2 minor, or 4 minor criteria from different groups. LV indicates left ventricular.I. Global and/or regional dysfunction and structural alterations* Major Severe dilatation and reduction of right ventricular ejection fraction with no (or only mild) LV impairment. Localized right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulging). Severe segmental dilatation of the right ventricle. Minor Mild global right ventricular dilatation and/or ejection fraction reduction with normal left ventricle. Mild segmental dilatation of the right ventricle. Regional right ventricular hypokinesia.II. Tissue characterization of wall Major Fibrofatty replacement of myocardium on endomyocardial biopsy.III. Repolarization abnormalities Minor Inverted T waves in right precordial leads (V2and V3) in people aged >12 years, in absence of right bundle-branch block.IV. Depolarization/conduction abnormalities Major Epsilon waves or localized prolongation (>110 ms) of the QRS complex in right precordial leads (V1–V3). Minor Late potentials (signal-averaged ECG).V. Arrhythmias Minor Left bundle-branch block type ventricular tachycardia (sustained and nonsustained) by ECG, Holter, or exercise testing. Frequent ventricular extrasystoles (>1000/24 hours) (Holter).VI. Family history Major Familial disease confirmed at necropsy or surgery. Minor Family history of premature sudden death (<35 years) due to suspected right ventricular dysplasia. Familial history (clinical diagnosis based on present criteria).Identification of genes for the typical clinical form of the disease is challenging. First, phenotypic identification is difficult. Second, a significant percentage of patients have sudden death, which limits the size of the pedigrees for study. Incomplete penetrance and variable expressivity are pronounced in this condition, which makes gene identification a challenge. Two of the genes that have been identified are associated with atypical variants of the disease.8,11 Recently, a third gene has been identified in a dominant form of ARVD that causes a mutation in desmoplakin, a cellular adhesion protein.10 This recent finding should facilitate further gene localization. The identification of the gene(s) will have tremendous diagnostic impact and hopefully will provide an explanation as to why ARVD/C is primarily seen in the right ventricle.15 With the completion of the Human Genome Project and a potential understanding of the “final common pathway,” we anticipate improvement in the ability to identify these disease-causing genes.16This integrative research project offers a substantial prospect of expanding the clinical knowledge regarding ARVD/C and of localizing the genetic mutations responsible for this disorder. Physicians are urged to refer patients suspected of ARVD/C to one of the principal investigators of this study (Figure 1). For further details, please refer to the following World Wide Web sites: www.arvd.org or www.arvd.com. An ARVD/C study is now under way in Europe under the direction of Gaetano Thiene (Padua, Italy) using the same data forms and a parallel computerized database to facilitate collaboration between the North American and European operations. Physicians in Europe with patients who are suspected of having ARVD/C are encouraged to contact the following enrolling physicians: Dr Guy Fontaine (Paris, France), Dr William J. McKenna (London, UK), Dr Andrea Nava (Padua, Italy), and Dr Thomas Wichter (Muenster, Germany).Guest editor for this article was Hein J.J. Wellens, MD, Cardiovascular Research Institute, the Netherlands.FootnotesCorrespondence to Frank I. Marcus, MD, 1501 N Campbell Ave, Tucson, AZ 85724-5037. E-mail [email protected] References 1 Marcus FI, Fontaine GH, Guiraudon G, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982; 65: 384–398.CrossrefMedlineGoogle Scholar2 Loire R, Tabib A. Mort subite cardiaque inattendue, bilan de 1000 autopsies. Arch Mal Coeur. 1996; 89: 13–18.MedlineGoogle Scholar3 Maron BD, Shirani J, Poliac LC, et al. Sudden death in young competitive athletes. JAMA. 1996; 276: 199–204.CrossrefMedlineGoogle Scholar4 Nava A, Thiene G, Canciani B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol. 1988; 12: 1222–1228.CrossrefMedlineGoogle Scholar5 Hermida JS, Minassian A, Jarry G, et al. Familial incidence of late ventricular potentials and electrocardiographic abnormalities in arrhythmogenic right ventricular dysplasia. Am J Cardiol. 1997; 79: 1375–1380.CrossrefMedlineGoogle Scholar6 Marcus FI. Update of arrhythmogenic right ventricular dysplasia. Card Electrophysiol Review. 2002; 6: 54–56.CrossrefMedlineGoogle Scholar7 Calkins H, Marcus F. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. In: Braunwald E, ed. Harrison’s Advances in Cardiology. New York, NY: McGraw Hill; 2002; 59: 378–383.Google Scholar8 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: 189–194.CrossrefMedlineGoogle Scholar9 McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000; 355: 2119–2124.CrossrefMedlineGoogle Scholar10 Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002; 71: 1200–1206.CrossrefMedlineGoogle Scholar11 Norgett EE, Hatsell SJ, Carvahal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet. 9: 2671–2766.Google Scholar12 Boxt LM. Radiology of the right ventricle. Radiol Clin North Am. 1999; 37: 379–400.CrossrefMedlineGoogle Scholar13 Corrado D, Fontaine G, Marcus FI, et al, on behalf of the Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Circulation. 2000; 101: e101–e106.LinkGoogle Scholar14 McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Br Heart J. 1994; 71: 215–218.CrossrefMedlineGoogle Scholar15 Towbin JA, Vatta M, Li H. Genetics of Brugada, long QT, and arrhythmogenic right ventricular dysplasia syndromes. J Electrocardiol. 2000; 33: 11–22.CrossrefMedlineGoogle Scholar16 Bowles ND, Bowles KR, Towbin JA. The “final common pathway” hypothesis and inherited cardiovascular disease: the role of cytoskeletal proteins in dilated cardiomyopathy. Herz. 2000; 25: 168–175.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Femia G, Sy R and Puranik R (2017) Systematic review: Impact of the new task force criteria in the diagnosis of arrhythmogenic right ventricular cardiomyopathy, International Journal of Cardiology, 10.1016/j.ijcard.2017.03.069, 241, (311-317), Online publication date: 1-Aug-2017. Sarma A, Sanborn D, Picard M and Marcus F (2017) Authors' Reply, Journal of the American Society of Echocardiography, 10.1016/j.echo.2017.07.012, 30:10, (1043-1045), Online publication date: 1-Oct-2017. CHOUDHARY N, TOMPKINS C, POLONSKY B, MCNITT S, CALKINS H, MARK ESTES N, KRAHN A, LINK M, MARCUS F, TOWBIN J and ZAREBA W (2016) Clinical Presentation and Outcomes by Sex in Arrhythmogenic Right Ventricular Cardiomyopathy: Findings from the North American ARVC Registry, Journal of Cardiovascular Electrophysiology, 10.1111/jce.12947, 27:5, (555-562), Online publication date: 1-May-2016. Kayvanpour E, Katus H and Meder B (2015) Determined to Fail—the Role of Genetic Mechanisms in Heart Failure, Current Heart Failure Reports, 10.1007/s11897-015-0264-6, 12:5, (333-338), Online publication date: 1-Oct-2015. Ruwald A, Marcus F, Estes N, Link M, McNitt S, Polonsky B, Calkins H, Towbin J, Moss A and Zareba W (2015) Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy, European Heart Journal, 10.1093/eurheartj/ehv110, 36:27, (1735-1743), Online publication date: 14-Jul-2015. Wichter T and Paul M (2014) Arrhythmogene rechtsventrikuläre KardiomyopathieArrhythmogenic right ventricular cardiomyopathy, Der Kardiologe, 10.1007/s12181-014-0556-1, 8:2, (179-196), Online publication date: 1-Apr-2014. Link M, Laidlaw D, Polonsky B, Zareba W, McNitt S, Gear K, Marcus F and Estes N (2014) Ventricular Arrhythmias in the North American Multidisciplinary Study of ARVC, Journal of the American College of Cardiology, 10.1016/j.jacc.2014.04.035, 64:2, (119-125), Online publication date: 1-Jul-2014. Sadjadieh G, Jabbari R, Risgaard B, Olesen M, Haunsø S, Tfelt-Hansen J and Winkel B (2014) Nationwide (Denmark) Study of Symptoms Preceding Sudden Death due to Arrhythmogenic Right Ventricular Cardiomyopathy, The American Journal of Cardiology, 10.1016/j.amjcard.2013.12.038, 113:7, (1250-1254), Online publication date: 1-Apr-2014. (2014) References Cardiac CT Made Easy, 10.1201/b16792-17, (323-356), Online publication date: 19-May-2014. Wichter T and Paul M (2014) Arrhythmogene rechtsventrikuläre KardiomyopathieArrhythmogenic right ventricular cardiomyopathy, Der Kardiologe, 10.1007/s12181-013-0495-2, 8:1, (85-98), Online publication date: 1-Feb-2014. Romero J, Mejia-Lopez E, Manrique C and Lucariello R (2013) Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC/D): A Systematic Literature Review, Clinical Medicine Insights: Cardiology, 10.4137/CMC.S10940, 7, (CMC.S10940), Online publication date: 1-Jan-2013. Harrington C and Kasper E (2013) Cardiomyopathies and Myocarditis Essential Cardiology, 10.1007/978-1-4614-6705-2_33, (577-587), . Ahmed J, Smith W, Ruygrok P and Occleshaw C (2012) Right ventricular morphology on catheter angiography: Variations and its implications for the diagnosis of arrhythmogenic right ventricular cardiomyopathy, Heart, Lung and Circulation, 10.1016/j.hlc.2012.06.002, 21:11, (700-705), Online publication date: 1-Nov-2012. Indik J, Dallas W, Gear K, Tandri H, Bluemke D, Moukabary T and Marcus F (2011) Right ventricular volume analysis by angiography in right ventricular cardiomyopathy, The International Journal of Cardiovascular Imaging, 10.1007/s10554-011-9915-1, 28:5, (995-1001), Online publication date: 1-Jun-2012. Thiene G (2012) Arrhythmogenic cardiomyopathy: from autopsy to genes and transgenic mice (SCVP Achievement Award Lecture, San Antonio, TX, February 27, 2011), Cardiovascular Pathology, 10.1016/j.carpath.2011.09.012, 21:4, (229-239), Online publication date: 1-Jul-2012. Elmaghawry M, Alhashemi M, Zorzi A and Yacoub M (2012) A global perspective of arrhythmogenic right ventricular cardiomyopathy, Global Cardiology Science and Practice, 10.5339/gcsp.2012.26, 2012:2, (26), Online publication date: 1-Dec-2012. Paul M, Wichter T, Fabritz L, Waltenberger J, Schulze-Bahr E and Kirchhof P (2012) Arrhythmogenic right ventricular cardiomyopathyArrythmogene rechtsventrikuläre Kardiomyopathie, Herzschrittmachertherapie + Elektrophysiologie, 10.1007/s00399-012-0233-7, 23:3, (186-195), Online publication date: 1-Sep-2012. Thiene G, Corrado D, Bauce B and Basso C (2011) Arrhythmogenic Cardiomyopathy: A Historical Overview, Cardiac Electrophysiology Clinics, 10.1016/j.ccep.2011.02.006, 3:2, (179-191), Online publication date: 1-Jun-2011. Wood M (2011) Ablation of Ventricular Tachycardia Associated with Nonischemic Cardiomyopathies Catheter Ablation of Cardiac Arrhythmias, 10.1016/B978-1-4377-1368-8.00029-5, (508-531), . Behera S, Pattnaik T and Luke A (2011) Practical Recommendations and Perspectives on Cardiac Screening for Healthy Pediatric Athletes, Current Sports Medicine Reports, 10.1249/JSR.0b013e3182141c1e, 10:2, (90-98), Online publication date: 1-Mar-2011. Kamath G, Zareba W, Delaney J, Koneru J, McKenna W, Gear K, Polonsky S, Sherrill D, Bluemke D, Marcus F and Steinberg J (2011) Value of the signal-averaged electrocardiogram in arrhythmogenic right ventricular cardiomyopathy/dysplasia, Heart Rhythm, 10.1016/j.hrthm.2010.10.007, 8:2, (256-262), Online publication date: 1-Feb-2011. Wichter T, Indik J and Paul M (2011) Ventricular Angiography in Arrhythmogenic Cardiomyopathy, Cardiac Electrophysiology Clinics, 10.1016/j.ccep.2011.02.008, 3:2, (255-267), Online publication date: 1-Jun-2011. Paul M, Stypmann J, Gerss J, Wirdeier S, Zumhagen S, Breithardt G, Schulze-Bahr E and Wichter T (2011) Safety of Endomyocardial Biopsy in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2011.06.015, 4:10, (1142-1148), Online publication date: 1-Oct-2011. Huttin O, Mandry D and Brembilla-Perrot B (2011) Arrhythmogenic right ventricular cardiomyopathy: Magnetic resonance imaging does not detect early stages of the disease, International Journal of Cardiology, 10.1016/j.ijcard.2010.10.003, 147:1, (167-169), Online publication date: 1-Feb-2011. Xu T, Yang Z, Vatta M, Rampazzo A, Beffagna G, Pillichou K, Scherer S, Saffitz J, Kravitz J, Zareba W, Danieli G, Lorenzon A, Nava A, Bauce B, Thiene G, Basso C, Calkins H, Gear K, Marcus F and Towbin J (2010) Compound and Digenic Heterozygosity Contributes to Arrhythmogenic Right Ventricular Cardiomyopathy, Journal of the American College of Cardiology, 10.1016/j.jacc.2009.11.020, 55:6, (587-597), Online publication date: 1-Feb-2010. Avella A, d'Amati G, Zachara E, Musumeci F and Tondo C (2010) Comparison between electroanatomic and pathologic findings in a patient with arrhythmogenic right ventricular cardiomyopathy/dysplasia treated with orthotopic cardiac transplant, Heart Rhythm, 10.1016/j.hrthm.2010.01.016, 7:6, (828-831), Online publication date: 1-Jun-2010. Ellinor P, MacRae C and Thierfelder L (2010) Arrhythmogenic Right Ventricular Cardiomyopathy, Heart Failure Clinics, 10.1016/j.hfc.2009.12.003, 6:2, (161-177), Online publication date: 1-Apr-2010. Ng A and Swanevelder J (2010) Cardiomyopathies Core Topics in Transesophageal Echocardiography, 10.1017/CBO9780511730238.017, (247-267) Asimaki A, Tandri H, Huang H, Halushka M, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna W, Calkins H and Saffitz J (2009) A New Diagnostic Test for Arrhythmogenic Right Ventricular Cardiomyopathy, New England Journal of Medicine, 10.1056/NEJMoa0808138, 360:11, (1075-1084), Online publication date: 12-Mar-2009. Basso C, Corrado D, Marcus F, Nava A and Thiene G (2009) Arrhythmogenic right ventricular cardiomyopathy, The Lancet, 10.1016/S0140-6736(09)60256-7, 373:9671, (1289-1300), Online publication date: 1-Apr-2009. Herren T, Gerber P and Duru F (2009) Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a not so rare “disease of the desmosome” with multiple clinical presentations, Clinical Research in Cardiology, 10.1007/s00392-009-0751-4, 98:3, (141-158), Online publication date: 1-Mar-2009. Abbara S and Miller S (2009) Pericardial and Myocardial Disease Cardiac Imaging, 10.1016/B978-0-323-05527-7.50016-0, (265-296), . Marcus F, Zareba W, Calkins H, Towbin J, Basso C, Bluemke D, Estes N, Picard M, Sanborn D, Thiene G, Wichter T, Cannom D, Wilber D, Scheinman M, Duff H, Daubert J, Talajic M, Krahn A, Sweeney M, Garan H, Sakaguchi S, Lerman B, Kerr C, Kron J, Steinberg J, Sherrill D, Gear K, Brown M, Severski P, Polonsky S and McNitt S (2009) Arrhythmogenic right ventricular cardiomyopathy/dysplasia clinical presentation and diagnostic evaluation: Results from the North American Multidisciplinary Study, Heart Rhythm, 10.1016/j.hrthm.2009.03.013, 6:7, (984-992), Online publication date: 1-Jul-2009. Sorrell V, Kumar S and Kalra N (2009) Cardiac imaging in right ventricular cardiomyopathy/dysplasia—how does cardiac imaging assist in understanding the morphologic, functional, and electrical changes of the heart in this disease?, Journal of Electrocardiology, 10.1016/j.jelectrocard.2008.12.019, 42:2, (137.e1-137.e10), Online publication date: 1-Mar-2009. VASAIWALA S, FINN C, DELPRIORE J, LEYA F, GAGERMEIER J, AKAR J, SANTUCCI P, DAJANI K, BOVA D, PICKEN M, BASSO C, MARCUS F and WILBER D (2009) Prospective Study of Cardiac Sarcoid Mimicking Arrhythmogenic Right Ventricular Dysplasia, Journal of Cardiovascular Electrophysiology, 10.1111/j.1540-8167.2008.01351.x, 20:5, (473-476), Online publication date: 1-May-2009. Yerra L, Caskey D, Modi K and Reddy P (2008) Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Clinical Profile of Four Patients and Review, Southern Medical Journal, 10.1097/01.smj.0000308364.02545.f2, 101:3, (309-316), Online publication date: 1-Mar-2008. Steel K and Kwong R (2008) Application of cardiac magnetic resonance imaging in cardiomyopathy, Current Heart Failure Reports, 10.1007/s11897-008-0021-1, 5:3, (128-135), Online publication date: 1-Sep-2008. Chan L, Chan P, Zheng Y, Wong A, Liu Y and Benzie I (2008) DICOM-Based Multidisciplinary Platform for Clinical Decision Support: Needs and Direction Advances of Computational Intelligence in Industrial Systems, 10.1007/978-3-540-78297-1_9, (191-212), . Calkins H and Marcus F Ventricular Arrhythmias in Right Ventricular Dysplasia/Cardiomyopathy Electrical Diseases of the Heart, 10.1007/978-1-84628-854-8_45, (643-653) H. Fischer A, van der Loo B, M. Shär G, Zbinden R, Duru F, Brunckhorst C, Rousson V, Delacrétaz y E, Stuber T, Oechslin E, Follath F and Jenni R (2008)