Cardiomyopathy. Mechanisms An Update. Professor of Medicine (Cardiology) University of Ottawa

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1 Arrhythmogenic Right Ventricular Cardiomyopathy y TheDisease, The Genes and The Proposed Disease Mechanisms An Update Martin Green Professor of Medicine (Cardiology) University of Ottawa Saudi Heart Association, Feb 22,2011

2 Mr CH 36 year old high school teacher Syncopal episode while playing broomball with students No prior medical lhistory or previous syncope BP: 110/60 HR 60/min

3 Mr CH ECG

4 Mr CH Stress Echo

5 Mr CH MUGA

6 Mr CH Holter

7 Mr CH SAECG

8 Signal Averaged ECG Late Potentials Late potential +ve Late potential -ve (1) Total filtered QRS duration 122 ms for men, 115 ms for women (2) Duration of low amplitude signal (<40 V) in the terminal portion of the filtered QRS 41ms (3) Root-mean-square voltage of terminal 40 ms of filtered QRS 20 V Late potential +ve if 2/3 features +ve (Timmermans et al, PACE 1994;17: ) Turrini et al, Am J Cardiol 1999;83:1214

9 Mr CH Induced VT

10 Mr CH Induced VT

11 Arrhythmogenic Right Ventricular cardiomyopathy (ARVC) is a heart muscle disorder characterized by fibrofatty replacement of cardiomyoctyes. Pilichou K. et al; Circulation 2006;113;

12 What Is ARVC? Heritable, progressive cardiomyopathy characterized by: 1,2 - Loss of heart muscle cells - Replacementof the myocardium with fatty and fibrous tissue - Electrical instability, ventricular arrhythmias and sudden cardiac death Typically y inherited as an autosomal dominant trait. - Variable penetrance ranges from 15% to 100% 3,4 Exact prevalence is unknown. - Estimates range from 1 in 5,000 to 1 in 1,250 1,5 References: 1. Muthappan P, Calkins H. Arrhythmogenic right ventricular dysplasia. Prog Cardiovasc Dis. 2008;51: Sen Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50: Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112: Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82: Peters S. Advances in the diagnostic management of arrhythmogenic right ventricular dysplasia cardiomyopathy. Int J Cardiol. 2006;113:4 11.

13 Diagnostic Tests for ARVC ECG SAECG (signal averaged ECG) Echocardiogram Cardiac MRI Nuclear medicine imaging g( (RV size and EF) RV angiogram RV biopsy py Programmed ventricular stimulation Genetic analysis

14 Criteria for ARVC Global/regional dysfunction & structural alterations Major: Severe RV dilatation and dysfunction ( EF) with no/mild LV impairment Localised RV aneurysms (akinetic or dyskinetic areas with diastolic bulging) Severe segmental RV dilatation Jain A et al; Journal of Cardiovascular Magnetic Resonance, 10:32; 2008 *courtesy of Dr. Martin Green

15 ARVC Tissue characterisation of walls Major: Fibrofatty replacement of myocardium on endomyocardial biopsy Turrini P et al; Images in Paediatric Cardiology;6:18 37; 2001

16 Clinical Impact of ARVC 40% of ARVC probands experience sudden cardiac death as their first clinical manifestation. 1,2,3 Up to 20% of all sudden cardiac deaths are attributable to ARVC. 1 With early diagnosis and appropriate p treatment most ARVC patients have an excellent prognosis. 4 Treatment often includes implanting a cardioverter defibrillator. ill 5 References: 1. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112: Hamid MS, Norman M, Quraishi A, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol. 2002;40: Nava A, Bauce B, Basso C, et al. Clinical profile and long term follow up of 37 families with iharrhythmogenic h right ventricular cardiomyopathy. J Am Coll llcardiol. 2000;36: Sen Chowdhry S, Syrris P, MK McKenna WJ. Role of genetic analysis in the management of patients with ih arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50: Muthappan P, Calkins H. Arrhythmogenic right ventricular dysplasia. Prog Cardiovasc Dis. 2008;51:

17 Clinical Presentation of ARVC Symptoms include: palpitations, syncope, breathlessness, chest pain and sudden cardiac death. 1,2,3 May present at any age (age range 2 to 82) 1,2 - Typically presents between the second and fifth decades of life 12 1,2 Dilated RV and/or fatty infiltration of either ventricle 1,2 Three distinct patterns of ARVC disease expression: 4 Classic pattern predominantly affects the right ventricle Bi ventricular Left dominant patterns now recognized

18 Pathophysiology of ARVC RV Free Wall Histology Fibrofattyreplacement replacement ismostcommonlyseen seen in the so called triangle of dysplasia : 1 Formed by the anterior infundibulum, right ventricular apex and inferior aspect of the right ventricle

19 Genetic and Structural Basis of ARVC ARVC is largely regarded as a disease of the desmosome. 1 Desmosomes form mechanical couplings that attach adjacent myocytes at the intercalated disc Desmosome DSG2, desmoglein 2; DSC2, desmocollin 2; PKP2, plakophilin 2; PKG, plakoglobin; DSP, desmoplakin. Reference: 1. Sen Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50:

20 ARVC Diagnosis ECG abnormalities 1 RV abnormalities 1 Echocardiogram Angiography Magnetic resonance imaging (MRI) Myocardial biopsy abnormalities 1 Family history 1 Genetic testing 1 Reference: 1. 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 Feb 19.

21 Diagnostic Uncertainty in ARVC Each 1994Task Force diagnostic criterion either lacks sensitivity or is not specific for ARVC. 1 Reference: 1. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112:

22 ARVC Diagnostic Criteria Updated in 2010 Original diagnostic criteria developed in 1994* and never prospectively validated. 1,2 * By the Task Force of the Working Group of Myocardial and Pericardial Disease of the European Society of Cardiology and the Scientific Council of Cardiomyopathies. Task Force criteria updated in Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, while maintaining specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. i References: 1. McKenna WJ, Thiene G, Nava A, et al. 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: Sen Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50: 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 Feb 19.

23 ARVC Diagnostic Criteria Are Complex A definite diagnosis is fulfilled by the presence of: 1 2 major criteria or 1 major and 2 minor criteria or 4 minor criteria A borderline diagnosis: 1 1 major criteria and 2 minor or 3 minor criteria A possible diagnosis: 1 1 major criteria or 2 minor criteria Reference: 1. 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 Feb 19.

24 Criteria for the Diagnosis of ARVC PLAX parasternal long axis view; RVOT RV outflow tract; BSA body surface area; and PSAX parasternal short axis view Reference: 1. 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 Feb 19.

25 Criteria for the Diagnosis of ARVC Reference: 1. 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 Feb 19.

26 ECG Abnormalities in ARVC Up to 81% of ARVC patients have inverted T waves in V2 V3. V3 1 - May be seen in 3 5% of normal population after 12 years of age Up to 60% of ARVC patients have QRS prolongation in V1 V3. 1 Reference: 1. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112:

27 Mr CH ECG Epsilon wave

28 Epsilon Waves & Localised QRS Width

29 ARVC Diagnostic Criteria Structural and Functional Abnormalities PLAX parasternal long axis view; RVOT RV outflow tract; BSA body surface area; and PSAX parasternal short axis view Reference: 1. Marcus FI, McKenna WJ, Sherrill D,, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopia/dysplasia: Proposed Modification of the Task Force Criteria. Eur Heart J Feb

30 RV Structural and Motion Abnormalities Imaging can help determine: Presence and magnitude of RV dilation and wall motion abnormalities - 20% of ARVC patients have severe dilation/reduced function 1 Sacculations - 10% of ARVC patients have a localized right ventricular aneurysm 1 Additionally, MRI can help detect: Fatty infiltration of the myocardium - Detection of fatty infiltration by MRI may result in misdiagnosis 2 References: 1. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112: Bomma C, Rutberg J, Tandri H, et al. Misdiagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Electrophysiol. 2004;15:

31 Over-reliance on MRI Contributes to ARVC Misdiagnoses A study published by researchers at Johns Hopkins University revealed that up to 73% of ARVC diagnoses are made in error. 1 58% of patients previously diagnosed with ARVC were found to have idiopathic ventricular tachycardia (IVT). 1 The high rate of misdiagnosis is attributed to: 1 - Incomplete testing - Over reliance on the presence of intramyocardial fat andwall thinning onmri - The lack of awareness of 1994 Task Force criteria Reference: 1. Bomma C, Rutberg J, Tandri H, et al. Misdiagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Electrophysiol. 2004;15:

32 ARVC Diagnostic Criteria Histological Abnormalities Reference: 1. Marcus FI, McKenna WJ, Sherrill D,, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopia/dysplasia: Proposed Modification of the Task Force Criteria. Eur Heart J Feb 19. [epub ahead of print]. 32

33 Histological Abnormalities Adapted from: Thiene G, et al. Arrhythmogenic right ventricular cardiomyopathy/ dysplasia. Orphanet J Rare Dis. 2007;2:45. a. Endomyocardial Biopsy b. ARVC Heart Cross Section c. ARVC Bioptic Sample Biopsy of the RV free wall may show myocyte loss, fatty infiltration and fibrosis in ~40% of ARVC patients. 1 - Septum often not involved in the pathological process Negative biopsy evidence may be misleading since the ARVC is a segmental disease. 2 References: 1. Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112: Muthappan P, Calkins H. Arrhythmogenic right ventricular dysplasia. Prog Cardiovasc Dis. 2008;51:

34 Challenges of Early and Accurate ARVC Diagnosis There Is No SINGLE Clinical Criterion Sufficient for Making ARVC Diagnosis ARVC is associated with a highly variable clinical course and a broad spectrum of symptoms and ECG abnormalities. 1,2,3 The Differential Diagnosis of ARVC Can Be Difficult Idiopathic VT presents similarly to early-stage ARVC. 4 References: 1. Sen Chowdry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J AmColl Cardiol. 2007;50: Sen Chowdry S, Syrris P, McKenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol. 2005;16: Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112: Muthappan P, Calkins H. Arrhythmogenic right ventricular dysplasia. Prog Cardiovasc Dis. 2008;51: Differentiating IVT from ARVC is important because ARVC is often treated with an implantable cardioverter defibrillator, while IVT is not familial and generally benign. 34

35 ARVC Genes 40 50% of ARVC is attributed to mutations in desmosomal genes. 1 TMEM43 isa recently discovered ARVCgene associated with complete disease penetrance. 2 References: 1. Sen Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic h right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50: Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:

36 Genetics of farvc Autosomal dominant inheritance pattern is typical 1 Autosomal recessive patterns also occur Penetrance and expressivity is variable Variable penetrance ranges from 15% to 100% 2,3 Disease expression may be age and stress related 1 No strong clinical differences yet recognized between ARVC subtypes 1 Genotype phenotype correlations may one day become apparent References: 1. Sen Chowdhry S, Syrris P, Ward D, AsimakiA, 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: Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112: Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:

37 Role of Genetic Testing in ARVC References: 1. 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: Sen Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2007;50:

38 Genetic Evaluation of Cardiomyopathy y A Heart Failure Society of America (HFSA) Practice Guideline (2009) Letter grades are based on clinical validity and utility. The letter grade A corresponds to the highest score while C is the lowest. 1 The HFSA guideline supported genetic testing of an ARVC proband with its highest grade. 1 Reference: 1. Hershberger RE, Lindenfeld J, et al. Genetic evaluation of cardiomyopathy a heart failure society of America practice guideline. Journal of Cardiac Failure.2009;15:

39 HFSA Family Testing Recommendations Incorporate Genetic Testing Identifying an asymptomatic ARVC family member using clinical diagnostic tools is a significant challenge. 1 If a disease-causing mutation is identified in the proband but is NOT found in family members, the risk of developing ARVC is significantly reduced. 1 For asymptomatic at mutation-negative e family members, ongoing g clinical screening is NOT recommended. 1 Reference: 1. Hershberger RE, Lindenfeld J, et al. Genetic evaluation of cardiomyopathy a heart failure society of America practice guideline. Journal of Cardiac Failure.2009;15:

40 ACC/AHA/ESC Guidelines (2006) Recommend Genetic Testing to Identify ALL Mutation ti Genetic analysis is useful in families with RV cardiomyopathy, because whenever a Carriers in an ARVC Family pathogenic genetic mutation is identified, it becomes possible to establish a presymptomatic diagnosis of the disease among family members and to provide them with genetic counseling to monitor the development of the disease and to assess the risk of transmitting the disease to offspring. Based on current knowledge genetic testing does not contribute to risk stratification of ARVC. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death Reference: Zipes DP, Camm AJ, Borggrefe M, et al.acc/aha/esc 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. J Am Coll Cardiol. 2006;48:

41 Criteria for ARVC Repolarisation abnormalities Minor: T wave inversions in right precordial leads (V 2 and V 3 ) (>12 yrs & no RBBB) *courtesy of Dr. Martin Green

42 Criteria for ARVC Depolarisation conduction abnormalities Major: Epsilon waves or localised prolongation (>110 ( ms)) of QRS complex in right precordial leads (V1 V3)

43 48 year old former Olympic athlete post cardiac arrest Repolarisation abnormalities Minor: T wave inversions in right precordial leads (V2 and V3)

44 ECG analysis in ARVC Lead V2

45 Electrical Criteria for ARVC Depolarisation conduction abnormalities Minor: Late potential (signal averaged ECG) Late potential +ve Late potential ve (1) Total filtered QRS duration 122 ms for men, 115 ms for women (2) Duration of low amplitude signal (<40 V) in the terminal portion of the filtered QRS 41ms (3) Root mean square voltage of terminal 40 ms of filtered QRS 20 V Late potential +ve if 2/3 features +ve (Timmermans et al, PACE 1994;17: )

46 Arrhythmia Criteria for ARVC Arrhythmias Minor: Left Bundle Branch Block (LBBB) type VT (sustained or not) on ECG/Holter/exercise testing Frequent VE s (> 1000/24 hrs on Holter)

47 Criteria for ARVC Family history Major: Familial disease confirmed at necropsy or surgery Syrris P. et al; European Heart Journal; 28, ; 2007

48 ARVC Summary Potentiallylethal lethal cardiomyopathy Multiple genes mostly related to desmosome Difficult diagnosis i involving i electrical, l structural and inherited components Diagnostic criteria insensitive Majority of clinical cases have no obvious responsible mutation Thank You

49 Criteria for ARVC Family history Minor: Familial history or premature sudden death (<35 yrs) due to suspected ARVC Familial history (clinical diagnosis based on present criteria) ARVC if 2 major OR 1 major + 2 minor OR 4 minor criteria *courtesy of Dr. Martin Green

50 Some Types of ARVC (in which isolated RV dysplasia is observed) Pure Form ARVD Naxos Disease Venetian Cardiomyopathy Uhl s anomaly Noncoronary RV Precordial ST Segment Elevation RV Outflow Tract Tachycardia Benign Extrasystoles Mitral Valve Vl Prolapse Nonarrhythmogenic Forms of ARVD Fontaine G et al; Circulation 1998;97;

51 Pure Form ARVD Fontaine G et al; Circulation 1998;97;

52 Naxos Disease (

53 Venetian Cardiomyopathy

54 Uhl s anomaly 782X &tlng=en&lng=en&nrm=iso

55 Noncoronary RV Precordial ST Segment Elevation Risk of sudden death in rest or sleep Fontaine G et al; Circulation 1998;97;

56 RV Outflow Tract Tachycardia (RVOT) Structural heart disease Due to somatic cell mutation Lerman B et al. Journal for Clinical Investment ;101;12; June 1998,

57 Benign Extrasystoles Infundibular origins Large amounts of fibrous tissues surrounding theoutflow tractfromtheright the right ventricle cause constirction Similar il symptoms to RVOT Fontaine G et al; Circulation 1998;97;

58 Mitral Valve Prolapse valve stenosis/treatments/index?id=92b82649 EDEC 42F7 9CC1FADE0553AF47&section=section_02

59 Nonarrhythmogenic Forms of ARVD Arrhythmogenic substrate is not necessarily noticeable Fontaine G et al; Circulation 1998;97;

60 The Genes Desmoplakin (DSP) Links intermediate filaments to desmosomal plaques Mutations associated with cardiomyopathies, keratodermas and paraneoplastic pemphigus (an autoimmune disease)

61 The Genes Plakophilin 2 (PKP2) Memberofarmadilloprotein group Links cadherins to intermediate filaments in cytoskeleton

62 The Genes Desmoglein 2 (DSG2) Calcium binding transmembrane glycoproteins Mutations associated with familial ARVC

63 The Genes Desmocollin 2 (DSC2) Adhesive proteins of cell cell junction required for cell adhesion and desmosomal formation

64 The Genes Plakoglobin (Jup junction plakoglobin ) (JUP) common to submembranous plaques of desmosomes and intermediate junctions Mutations associated with Naxos Disease

65 T MEM 43 Recently described in a large Newfoundland kindred High mortality rate 50% of untreated males die prior to 45Y Journal of the American College of Cardiology, Volume 45, Issue 3, Pages

66 References 1. Antoniades L,Tsatsopoulou A, Anastasakis A et al. Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin 2 and plakoglobin 12. Lerman B, Dong B, et al. Right Ventricular Outflow Tract Tachycardia Due To a (Naxos disease) in families from Greece and Cyprus: genotype phenotype p Somatic Cell Mutation in G Protein Subunit. Journal of Clinical Investments 101:12 relations, diagnostic features and prognosis European Heart Journal 27(2006): (1998): Biomed central. Pub Med Biomed central. Pub Med. 13. McKoy G, Protonotarios N et al. Identification of a deletion in plakoglobin in 2. Asimaki A, Syrris P, Wichter T, A Novel Dominant Mutation in Plakoglobin Causes arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma Arrhythmogenic Right Ventricular Cardiomyopathy American Journal of Human and woolly hair (Naxos disease) The Lancet 355 ( 2000): Biomed Genetics. 81 (2007): Biomed central. Pub Med central. Pub Med. 3. Beffagna G, De Bortoli M, Nava A et al. Missense mutations in Desmocollin 2 N 14. Pilichou, Kalliopi, Andrea Nava, Cristina Basso et al. "Mutations in Desmoglein 2 terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy." intracellular localization of desmocollin 2 in vitro BMC Medical Genetics 8 (2007): Circulation 113 (2006): Biomed central. Pub Med Biomed central. PubMed 15. Sen Chowdhry S, Syrris P, Ward D, et al. Clinical and Genetic Characterization of 4. Coonar A, Protonotarios N et al. Gene for Arrhythmogenic Right Ventricular Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Cardiomyopathy With Diffuse Nonepidermolytic Palmoplantar Keratoderma and Provides Novel Insights Into Patterns of Disease Expression Circulation 115 Woolly Hair (Naxos Disease) Maps to 17q21 Circulation 97 (1998): (2007): Biomed central. Pub Med. Biomed central. Pub Med. 16. Syrris P, Ward D, Askimaki A et al. Clinical Expression of Plakophilin 2 Mutations in 5. Fontaine G, Fontaliran F and Frank R Arrhythmogenic Right Ventricular Familial Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation 113 Cardiomyopathies : Clinical Forms and Main Differential Diagnoses Circulation 97 (2006): Biomed central. Pub Med. (1998): Biomed central. Pub Med 17. Syrris P, Ward D, Asimaki A et al. Desmoglein 2 mutations in arrhythmogenic right 6. Garcia Gras Gras E, Lombardi R, Giocondo MJ. et al. Suppression of canonical Wnt/b ventricular cardiomyopathy: a genotype phenotype phenotype characterization of familial catenin signaling by nuclear plakoglobin recapitulates phenotype of disease European Heart Journal 28 (2007): Biomed central. Pub Med arrhythmogenic right ventricular cardiomyopathy The Journal of Clinical 18. Syrris P, Ward D, Evans A, et al. Arrhythmogenic Right Ventricular Investigation 116:7 (2006): Biomed central. Pub Med. Dysplasia/Cardiomyopathy Associated with Mutations in the Desmosomal Gene 7. Heuser A, Plovie E R, et al. Mutant Desmocollin 2 Causes Arrhythmogenic Right Desmocollin 2 The American Journal of Human Genetics 79 (2006): Ventricular Cardiomyopathy The American Journal of Human Genetics 79 ( 2006): Biomed central. Pub Med Biomed central. Pub Med. 19. Turrini P, Basso C, Daliento L, Nava A, Thiene G. Is arrhythmogenic right 8. Heuser A, Plovie E R, Ellinor P T et al. Mutant Desmocollin 2 Causes ventricular cardiomyopathy a paediatric problem too? Images of Paediatric Arrhythmogenic Right Ventricular Cardiomyopathy American Journal of Human Cardiology 6(2000): Biomed central. Pub Med. Genetics 79 (2006): Biomed central. Pub Med 20. van Tintelen, J. P, Entius M, Z Bhuiyan et al. Plakophilin 2 Mutations Are the Major 9. Jain, Aditya et al. "Role of cardiovascular magnetic resonance imaging in." Journal Determinant of Familial Arrhythmogenic Right Ventricular of Cardiovascular Magnetic Resonance 10 (2008): Biomed central. Pub Med. Dysplasia/Cardiomyopathy. Circulation 105 (2006): Biomed central. 10. Joshi Mukherjee R, Coombs W et al. Characterization of the molecular phenotype Pub Med. of two arrhythmogenic right ventricular cardiomyopathy (ARVC) related 21. Valente M, Calabrese F, In Vivo Evidence of Apoptosis in Arrhythmogenic Right plakophilin 2 (PKP2) mutations Heart Rhythm 5(2008): Biomed Ventricular Cardiomyopathy American Journal of Pathology 152 (1998): central. Pub Med Biomed central. Pub Med. 11. Kiès P, Bootsma M, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: di Screening, diagnosis, i and treatment t t Heart trhythm 3 (2006): Biomed central. Pub Med.