1 Orphanet Journal of Rare Diseases 2007 Vol: 2(1):45. DOI: 10.1186/1750-1172-2-45

Arrhythmogenic right ventricular cardiomyopathy/dysplasia

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias. Its prevalence has been estimated to vary from 1:2,500 to 1:5,000. ARVC/D is a major cause of sudden death in the young and athletes. The pathology consists of a genetically determined dystrophy of the right ventricular myocardium with fibro-fatty replacement to such an extent that it leads to right ventricular aneurysms. The clinical picture may include: a subclinical phase without symptoms and with ventricular fibrillation being the first presentation; an electrical disorder with palpitations and syncope, due to tachyarrhythmias of right ventricular origin; right ventricular or biventricular pump failure, so severe as to require transplantation. The causative genes encode proteins of mechanical cell junctions (plakoglobin, plakophilin, desmoglein, desmocollin, desmoplakin) and account for intercalated disk remodeling. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance has been proven. Recessive variants associated with palmoplantar keratoderma and woolly hair have been also reported. Clinical diagnosis may be achieved by demonstrating functional and structural alterations of the right ventricle, depolarization and repolarization abnormalities, arrhythmias with the left bundle branch block morphology and fibro-fatty replacement through endomyocardial biopsy. Two dimensional echo, angiography and magnetic resonance are the imaging tools for visualizing structural-functional abnormalities. Electroanatomic mapping is able to detect areas of low voltage corresponding to myocardial atrophy with fibro-fatty replacement. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, dialted cardiomyopathy and sarcoidosis. Only palliative therapy is available and consists of antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator. Young age, family history of juvenile sudden death, QRS dispersion ≥ 40 ms, T-wave inversion, left ventricular involvement, ventricular tachycardia, syncope and previous cardiac arrest are the major risk factors for adverse prognosis. Preparticipation screening for sport eligibility has been proven to be effective in detecting asymptomatic patients and sport disqualification has been life-saving, substantially declining sudden death in young athletes.

Mentions
Figures
Figure 1: Graphic showing the various causes of juvenile sudden cardiac death in Northeast Italy. ARVC/D ranks second (13%) after atherosclerotic coronary artery disease. ARVC = arrhythmogenic right ventricular cardiomyopathy; ATS CAD = atherosclerotic coronary artery disease; DMC = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; NonATS CAD = non-atherosclerotic coronary artery disease; Postop CHD = postoperative congenital heart disease. Figure 2: A 17 year old asymptomatic male athlete who died suddenly during a soccer game. 12 lead ECG showing inverted T waves up to V4 (a) and isolated premature ventricular beats (b). In vitro MRI (c) and corresponding cross section of the heart (d) show RV dilatation with anterior and posterior aneurysms. Figure 3: Same case of . Note the biventricular involvement at long axis in vitro MRI (a), with transmural fibro-fatty replacement in the RV free wall (b) and focal subepicardial in the LV free wall (c). Figure 4: ECG recording of VT with left bundle branch block (LBBB) morphology. Figure 5: ECG recording: (a) post-excitation epsilon wave (arrows) in right precordial leads; (b) positive late potentials at signal-averaged electrocardiography (SAECG). Figure 6: Heart specimen coming from heart transplantation. Note the biventricular involvement both at gross examination (a, b) and histology (c, d). Figure 7: Typical histologic features of ARVC/D. Ongoing myocyte death (a) with early fibrosis and adipocytes infiltration (b). Figure 8: In vivo tissue characterization by endomyocardial biopsy: a) transvenous jugular approach of the bioptome; b) cross section of the heart showing that the septum is spared to underlie the need to perform the biopsy at the level of the RV free wall; c) fibro-fatty replacement of two bioptic samples. Figure 9: RV angiocardiography features of ARVC/D: RV dilatation with deep horizontal fissures in trabecular hypertrophy ("pile d'assiettes" profile) as well as subtricuspid aneurysm. Figure 10: Two dimensional echocardiography findings in ARVC/D: note the presence of a typical inferior subtricuspid bulging (TV= tricuspid valve, parasternal long axis view of the RV). Figure 11: MRI in a patient affected by ARVC/D (long axis view of the right ventricle): note the transmural diffuse bright signal in the RV free wall on spin echo T1 (a) due to massive myocardial atrophy with fatty replacement (b). Figure 12: Invasive electro-anatomic mapping by CARTO. a) 12 lead ECG with inverted T waves up to V4 and LBBB premature ventricular beat; b) four chamber 2D echo showing RV dilatation and apical aneurysm; c) low voltages RV areas (red) by Carto mapping; d, e) extensive fibro-fatty replacement of the RV myocardium at endomyocardial biopsy (modified from Corrado et al., 2005) [39]. Figure 13: Scheme of the molecular structure of the desmosome, site of defective proteins in ARVC/D. PG = plakoglobin, DSP = desmoplakin, PP = plakophilin, DSG = desmoglein, DSC = desmocollin Figure 14: Transmission electron microscopy of the intercellular junction between two adjacent myocytes in ARVC/D. Note the presence of abnormal desmosomes, either long (arrows) or short-repeated structures (insert) (modified from Basso et al., 2006) [31]. Figure 15: Efficacy rates of different antiarrhythmic drugs for treatment of ventricular tachycardia in ARVC/D (modified from Wichter et al., 2005) [76]. Figure 16: Long term follow-up after catheter ablation in ARVC/D (modified from Wichter et al., 2005) [77]. Figure 17: Long term follow-up after ICD implantation in ARVC/D patients for secondary prevention (modified from Corrado et al., 2003) [38]. Figure 18: Proposed algorithm for management of ARVC/D (modified from Wichter et al., 2005) [76]. Figure 19: Diagram illustrating the different levels for prevention of sudden death in ARVC/D. Figure 20: Relative risk of sport-related sudden death in ARVC/D (modified from Corrado et al., 2003) [79]. Figure 21: Trends of sudden cardiac death incidence in athletes vs non-athletes, Veneto Region of Italy, 1979–2002: note the sharp decrease (modified from Corrado et al., 2006) [80].
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References
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    • . . . In the last 25 years, it was possible to identify the disease 1, to realize its heredo-familiar character 2 and the risk of sudden death 3, to report the pathology 4, to put forward clinical diagnostic criteria 5, to find therapeutic measures 6 and, finally, to discover the genetic background 7. . . .
    • . . . However, we had to wait until the 80's to find the first clinical and pathologic series of patients with ARVC/D reported by Drs Marcus, Nava and Thiene 123. . . .
    • . . . Marcus et al. in 1982 reported the disease in adults, first emphasizing the origin of arrhythmias from the RV and the histopathological substrate consisting of fibro-fatty replacement of the RV free wall, accounting for epsilon wave and ventricular arrhythmias of RV origin with left bundle branch block (LBBB) morphology 1. . . .
    • . . . This implies a weakness of the free wall resulting in RV dilatation and aneurysms, typically located at the inferior, apical and infundibular walls (the so-called triangle of dysplasia) 1 . . .
  2. A Nava; G Thiene; B Canciani; R Scognamiglio; L Daliento; G Buja; B Martini; P Stritoni; G Fasoli Familial occurrence of right ventricular dysplasia: a study involving nine families J Am Coll Cardiol 12, 1222-1228 (1988) .
    • . . . In the last 25 years, it was possible to identify the disease 1, to realize its heredo-familiar character 2 and the risk of sudden death 3, to report the pathology 4, to put forward clinical diagnostic criteria 5, to find therapeutic measures 6 and, finally, to discover the genetic background 7. . . .
    • . . . In the Veneto Region, Italy, the prevalence of the disease has been estimated to vary from 1:2,000 to 1:5,000 2. . . .
    • . . . However, we had to wait until the 80's to find the first clinical and pathologic series of patients with ARVC/D reported by Drs Marcus, Nava and Thiene 123. . . .
    • . . . Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance was first proven by Nava et al. in 1987–1988 211. . . .
    • . . . The classical form is an autosomal dominant disease with variable penetrance 211 . . .
  3. G Thiene; A Nava; D Corrado; L Rossi; N Pennelli Right ventricular cardiomyopathy and sudden death in young people N Engl J Med 318, 129-133 (1988) .
    • . . . In the last 25 years, it was possible to identify the disease 1, to realize its heredo-familiar character 2 and the risk of sudden death 3, to report the pathology 4, to put forward clinical diagnostic criteria 5, to find therapeutic measures 6 and, finally, to discover the genetic background 7. . . .
    • . . . However, we had to wait until the 80's to find the first clinical and pathologic series of patients with ARVC/D reported by Drs Marcus, Nava and Thiene 123. . . .
    • . . . In 1988, Thiene et al. observed an impressive series of sudden deaths in the young (≤ 35 years), with pathology consisting of ARVC/D, mostly occurring during effort, and all characterized by inverted T-waves in the right precordial leads at electrocardiogram (ECG) and apparently benign ventricular arrhythmias of LBBB morphology 3 . . .
    • . . . ARVC/D has been reported as the second cause of sudden death in the young 3 (Figs. 1, 2, 3) and the main cause of sudden death in competitive athletes in the Veneto Region, Italy 43 . . .
    • . . . The disease consists of a replacement of the myocardium of the RV by fibro-fatty tissue 34 . . .
  4. C Basso; G Thiene; D Corrado; A Angelini; A Nava; M Valente Arrhythmogenic right ventricular cardiomyopathy: dysplasia, dystrophy or myocarditis ? Circulation 94, 983-991 (1996) .
    • . . . In the last 25 years, it was possible to identify the disease 1, to realize its heredo-familiar character 2 and the risk of sudden death 3, to report the pathology 4, to put forward clinical diagnostic criteria 5, to find therapeutic measures 6 and, finally, to discover the genetic background 7. . . .
    • . . . The pathological profile was described in detail by Basso et al. in 1996, emphasizing the frequent left ventricular (LV) involvement and an inflammatory component 4. . . .
    • . . . The disease consists of a replacement of the myocardium of the RV by fibro-fatty tissue 34 . . .
    • . . . Histology of the RV myocardium discloses severe atrophy of the myocardium, replaced by fibro-fatty tissue, which should be regarded as an healing phenomenon following myocyte deaths 4 . . .
  5. WJ McKenna; G Thiene; A Nava; F Fontaliran; C Blomstrom-Lundqvist; G Fontaine; F Camerini 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 71, 215-218 (1994) .
    • . . . In the last 25 years, it was possible to identify the disease 1, to realize its heredo-familiar character 2 and the risk of sudden death 3, to report the pathology 4, to put forward clinical diagnostic criteria 5, to find therapeutic measures 6 and, finally, to discover the genetic background 7. . . .
    • . . . Improvements in the diagnostic procedures led the proposal of diagnostic criteria, whether major or minor, based upon RV dysfunction or structural alterations at imaging, tissue characterization at biopsy, repolarization or depolarization abnormalities and arrhythmias at the ECG, and family history of sudden death 5. . . .
    • . . . Diagnostic criteria have been put forward 5 and divided into major and minor (Table 1) . . .
  6. T Wichter; M Borggrefe; W Haverkamp; X Chen; G Breithardt Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachicardia Circulation 86, 29-37 (1992) .
    • . . . In the last 25 years, it was possible to identify the disease 1, to realize its heredo-familiar character 2 and the risk of sudden death 3, to report the pathology 4, to put forward clinical diagnostic criteria 5, to find therapeutic measures 6 and, finally, to discover the genetic background 7. . . .
    • . . . Wichter et al. reported the various efficacy rates by demonstrating that sotalol is superior with a complete or partial efficacy in 68% of patients vs 26% for amiodarone 6 (Fig. 15). . . .
  7. A Rampazzo; GA Danieli Arrhythmogenic in right ventricular cardiomyopathy/dysplasia. Advances in genetics: Dominant forms Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia , 7-14 (2007) .
    • . . . In the last 25 years, it was possible to identify the disease 1, to realize its heredo-familiar character 2 and the risk of sudden death 3, to report the pathology 4, to put forward clinical diagnostic criteria 5, to find therapeutic measures 6 and, finally, to discover the genetic background 7. . . .
  8. MW Norman; WJ McKenna Arrhythmogenic right ventricular cardiomyopathy/dysplasia: perspectives on diseases Z Kardiol 88, 550-554 (1999) .
    • . . . The prevalence of approximately 1 in 5,000 people has been estimated 8 . . .
  9. GM Lancisi De Motu Cordis et Aneurysmatibus. Naples , (1736) .
    • . . . The disease was first described by Giovanni Maria Lancisi in 1736, who in his book De Motu Cordis et Aneurysmatibus reported a family with disease recurrence in four generations: the affected members presented with palpitations, heart failure, dilation and aneurysms of the RV and sudden death 9. . . .
  10. S Dalla Volta; G Battaglia; E Zerbini "Auricularization" of right ventricular pressure curve Am Heart J 61, 25-33 (1961) .
    • . . . Dalla Volta et al. in 1961 reported a patient with "auricularization" of the RV pressure curve, emphasizing the peculiar hemodynamic picture of this non-ischemic heart muscle disease with RV behaving like an atrium 10 . . .
  11. A Nava; G Thiene; B Canciani; R Scognamiglio; L Daliento; GF Buja; B Martini; P Stritoni; G Fasoli Familial occurrence of right ventricular dysplasia: a study involving nine families J Am Coll Cardiol 12, 1222-1228 (1988) .
    • . . . Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance was first proven by Nava et al. in 1987–1988 211. . . .
    • . . . The classical form is an autosomal dominant disease with variable penetrance 211 . . .
  12. BJ Maron Right ventricular cardiomyopathy: another cause of sudden death in the young N Engl J Med 318, 178-180 (1988) .
    • . . . They accounted for 20% of all sudden deaths in the young and for the first time it was acknowledged that ARVC/D is another important cause of sudden death in the young 12. . . .
  13. R Scognamiglio; G Fasoli; A Nava; G Miraglia; G Thiene; S Dalla-Volta Contribution of cross-sectional echocardiography to the diagnosis of right ventricular dysplasia at the asymptomatic stage Eur Heart J 10, 538-542 (1989) .
    • . . . The diagnostic imaging was then implemented to visualize the RV, either non-invasively through echocardiogram 13 or invasively through angiography 14. . . .
  14. L Daliento; G Rizzoli; G Thiene; A Nava; M Rinuncini; R Chioin; S Dalla Volta Diagnostic accuracy of right ventriculography in arrhythmogenic right ventricular cardiomyopathy Am J Cardiol 66, 741-745 (1990) .
    • . . . The diagnostic imaging was then implemented to visualize the RV, either non-invasively through echocardiogram 13 or invasively through angiography 14. . . .
    • . . . Angiographic evidence of akinetic/diskinetic bulgings localized in infundibular, apical and subtricuspid region has a high diagnostic specificity (>90%) 14. . . .
  15. P Turrini; A Angelini; G Thiene; G Buja; L Daliento; G Rizzoli; A Nava Late potentials and ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy Am J Cardiol 83, 1214-1219 (1999) .
    • . . . Signal averaged ECG proved to be a sensitive tool to detect delay in the electric impulse transmission in the RV myocardium 15 . . .
  16. A Rampazzo; A Nava; GA Danieli; G Buja; L Daliento; G Fasoli; R Scognamiglio; D Corrado; G Thiene The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24 Hum Mol Genet 3, 959-962 (1994) .
    • . . . The first gene locus (ARVD1) was found by Rampazzo et al. in 1994 at chromosome 14q23 16 . . .
    • . . . In the 90's, gene loci have been mapped to various chromosomes, the first (ARVD1) by Rampazzo et al. to chromosome 14q23 16 . . .
  17. P Richardson; McKenna; M Bristow; B Maisch; B Mautner; J O'Connel; E Olsen; G Thiene; J Goodwin; I Gyarfas; I Martin; P Nordet Report of the 1995 WHO/ISFC Task Force on the definition and classification of cardiomyopathies Circulation 93, 841-842 (1996) .
    • . . . In 1995, ARVC/D was included among cardiomyopathies in the revised World Health Organization (WHO) classification 17 and progressive cell death (apoptosis) in myocyte was proven 1819. . . .
  18. Z Mallat; A Tedgui; F Fontaliran; R Frank; M Durigon; G Fontaine Evidence of apoptosis in arrhythmogenic right ventricular dysplasia N Engl J Med 335, 1190-1196 (1996) .
    • . . . In 1995, ARVC/D was included among cardiomyopathies in the revised World Health Organization (WHO) classification 17 and progressive cell death (apoptosis) in myocyte was proven 1819. . . .
    • . . . An apoptotic mechanisms of myocyte death has been proven, either at post-mortem 18 or in vivo in endomyocardial biopsy specimens 19. . . .
  19. M Valente; F Calabrese; G Thiene; A Angelini; C Basso; A Nava; L Rossi In vivo evidence of apoptosis in arrhythmogenic right ventricular cardiomyopathy Am J Pathol 152, 479-484 (1998) .
    • . . . In 1995, ARVC/D was included among cardiomyopathies in the revised World Health Organization (WHO) classification 17 and progressive cell death (apoptosis) in myocyte was proven 1819. . . .
    • . . . An apoptotic mechanisms of myocyte death has been proven, either at post-mortem 18 or in vivo in endomyocardial biopsy specimens 19. . . .
  20. D Corrado; G Fontaine; FI Marcus; WJ McKenna; A Nava; G Thiene; T Wichter Arrhythmogenic right ventricular dysplasia/cardiomyopathy: Need for an international registry. 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 Circulation 101, E101-E106 (2000) .
    • . . . The need of an International Registry of the disease was raised 20 and two research programs were implemented in both sides of the Atlantic Ocean 2122. . . .
  21. F Marcus; JA Towbin; W Zareba; A Moss; H Calkins; M Brown; K Gear ARVD/C Investigators. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): a multidisciplinary study: design and protocol Circulation 107, 2975-2978 (2003) .
    • . . . The need of an International Registry of the disease was raised 20 and two research programs were implemented in both sides of the Atlantic Ocean 2122. . . .
  22. C Basso; T Wichter; GA Danieli; D Corrado; E Czarnowska; G Fontaine; WJ McKenna; A Nava; N Protonotarios; L Antoniades; K Wlodarska; F D'Alessi; G Thiene Arrhythmogenic right ventricular cardiomyopathy: clinical registry and database, evaluation of therapies, pathology registry, DNA banking Eur Heart J 25, 531-534 (2004) .
    • . . . The need of an International Registry of the disease was raised 20 and two research programs were implemented in both sides of the Atlantic Ocean 2122. . . .
  23. PR Fox; BJ Maron; C Basso; SK Liu; G Thiene Spontaneously occurring arrhythmogenic right ventricular cardiomyopathy in the domestic cat: A new animal model similar to the human disease Circulation 102, 1863-1870 (2000) .
    • . . . Meanwhile, spontaneous occurrence of ARVC/D have been observed in cats 23 and dogs 24. . . .
  24. C Basso; PR Fox; KM Meurs; JA Towbin; AW Spier; F Calabrese; BJ Maron; G Thiene Arrhythmogenic right ventricular cardiomyopathy causing sudden cardiac death in boxer dogs: a new animal model of human disease Circulation 109, 1180-1185 (2004) .
    • . . . Meanwhile, spontaneous occurrence of ARVC/D have been observed in cats 23 and dogs 24. . . .
  25. N Protonotarios; A Tsatsopoulou; P Patsourakos; D Alexopoulous; P Gezerlis; S Simitsis; G Scampardonis Cardiac abnormalities in familial palmoplantar keratosis Br Heart J 56, 321-326 (1986) .
    • . . . The first gene defect was discovered in the recessive variant of the disease (identified since 1985) from the Naxos island and consisting of a cardiocutaneous syndrome (ARVC/D, palmoplantar keratosis and woolly hair) 25 . . .
    • . . . The key for interpretation came from a recessive form of ARVC/D, the so-called Naxos disease, a cardiocutaneous syndrome featured by palmoplantar keratosis, woolly hair and heart muscle disease 2562 . . .
  26. G McKoy; N Protonotarios; A Crosby; A Tsatsopoulou; A Anastasakis; A Coonar; M Norman; C Baboonian; S Jeffery; WJ McKenna Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease) Lancet 355, 2119-2124 (2000) .
    • . . . A deletion was detected in the gene encoding plakoglobin, a cell junction protein 26. . . .
    • . . . A deletion in plakoglobin was first found in Naxos disease in 2000 26, followed by mutation of demoplakin in 2002 27, plakophilin-2 in 2004 28, desmoglein-2 in 2006 29 and desmocollin-2 also in 2006 30 (Table 3) . . .
  27. A Rampazzo; A Nava; S Malacrida; G Beffagna; B Bauce; V Rossi; R Zimbello; B Simionati; C Basso; G Thiene; JA Towbin; GA Danieli Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy Am J Hum Genet 71, 1200-1206 (2002) .
    • . . . Thereafter, other genes encoding cell junction proteins were found defective in the dominant, classical form of ARVC/D: desmoplakin 27, plakophilin-2 28, desmoglein-2 29, desmocollin-2 30 . . .
    • . . . A deletion in plakoglobin was first found in Naxos disease in 2000 26, followed by mutation of demoplakin in 2002 27, plakophilin-2 in 2004 28, desmoglein-2 in 2006 29 and desmocollin-2 also in 2006 30 (Table 3) . . .
  28. B Gerull; A Heuser; T Wichter; M Paul; CT Basson; DA McDermott; BB Lerman; SM Markowitz; PT Ellinor; CA MacRae; S Peters; KS Grossmann; B Michely; S Sasse-Klaassen; W Birchmeier; R Dietz; G Breithardt; E Schulze-Bahr; L Thierfelder Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy Nat Genet 36, 1162-1164 (2004) .
    • . . . Thereafter, other genes encoding cell junction proteins were found defective in the dominant, classical form of ARVC/D: desmoplakin 27, plakophilin-2 28, desmoglein-2 29, desmocollin-2 30 . . .
    • . . . A deletion in plakoglobin was first found in Naxos disease in 2000 26, followed by mutation of demoplakin in 2002 27, plakophilin-2 in 2004 28, desmoglein-2 in 2006 29 and desmocollin-2 also in 2006 30 (Table 3) . . .
  29. K Pilichou; A Nava; C Basso; G Beffagna; B Bauce; A Lorenzon; G Frigo; A Vettori; M Valente; J Towbin; G Thiene; GA Danieli; A Rampazzo Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy Circulation 113, 1171-1179 (2006) .
    • . . . Thereafter, other genes encoding cell junction proteins were found defective in the dominant, classical form of ARVC/D: desmoplakin 27, plakophilin-2 28, desmoglein-2 29, desmocollin-2 30 . . .
    • . . . A deletion in plakoglobin was first found in Naxos disease in 2000 26, followed by mutation of demoplakin in 2002 27, plakophilin-2 in 2004 28, desmoglein-2 in 2006 29 and desmocollin-2 also in 2006 30 (Table 3) . . .
  30. P Syrris; D Ward; A Evans; A Asimaki; E Gandjbakhch; S Sen-Chowdhry; WJ McKenna Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2 Am J Hum Genet 79, 978-984 (2006) .
    • . . . Thereafter, other genes encoding cell junction proteins were found defective in the dominant, classical form of ARVC/D: desmoplakin 27, plakophilin-2 28, desmoglein-2 29, desmocollin-2 30 . . .
    • . . . A deletion in plakoglobin was first found in Naxos disease in 2000 26, followed by mutation of demoplakin in 2002 27, plakophilin-2 in 2004 28, desmoglein-2 in 2006 29 and desmocollin-2 also in 2006 30 (Table 3) . . .
  31. C Basso; E Czarnowska; M Della Barbera; B Bauce; G Beffagna; EK Wlodarska; K Pilichou; A Ramondo; A Lorenzon; O Wozniek; D Corrado; L Daliento; GA Danieli; M Valente; A Nava; G Thiene; A Rampazzo Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies Eur Heart J 27, 1847-1854 (2006) .
    • . . . These mutations were found to account for intercalated disk remodeling at the ultrastructural level 31 . . .
    • . . . Ultrastructural investigation in endomyocardial biopsy of patients with ARVC/D and cell junction gene mutations revealed intercalated disk remodeling with a decrease in the number and length of desmosomes and intercellular gap widening 31 (Fig. 14). . . .
  32. N Tiso; DA Stephan; A Nava; A Bagattin; JM Devaney; F Stanchi; G Larderet; B Brahmbhatt; K Brown; B Bauce; M Muriago; C Basso; G Thiene; GA Danieli; A Rampazzo Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) Hum Mol Genet 10, 189-194 (2001) .
    • . . . Other variants of the disease were explained by mutation of the ryanodyne 2 receptor 32 and transforming growth factor β3 genes 33. . . .
    • . . . One is the gene encoding for the cardiac ryanodine receptor 2, which is located in the smooth sarcoplasmic reticulum and mediates calcium release for electroanatomical coupling (ARVD2 with polymorphic ventricular arrhythmias) 32 . . .
  33. G Beffagna; G Occhi; A Nava; L Vitiello; A Ditadi; C Basso; B Bauce; G Carraro; G Thiene; JA Towbin; GA Danieli; A Rampazzo Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1 Cardiovasc Res 65, 366-373 (2005) .
    • . . . Other variants of the disease were explained by mutation of the ryanodyne 2 receptor 32 and transforming growth factor β3 genes 33. . . .
    • . . . Another form of ARVC/D was found to be associated with regulatory mutations in the TGFβ gene 33 . . .
  34. B Bauce; A Rampazzo; C Basso; A Bagattin; L Daliento; N Tiso; P Turrini; G Thiene; GA Danieli; A Nava Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death J Am Coll Cardiol 40, 341-349 (2002) .
    • . . . The discovery of these gene mutations allowed preliminary genotype-phenotype correlations to be made 34353637. . . .
  35. B Bauce; C Basso; A Rampazzo; G Beffagna; L Daliento; G Frigo; S Malacrida; L Settimo; G Danieli; G Thiene; A Nava Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations Eur Heart J 26, 1666-1675 (2005) .
    • . . . The discovery of these gene mutations allowed preliminary genotype-phenotype correlations to be made 34353637. . . .
    • . . . Genotype-phenotype correlations revealed that the desmoplakin mutation is associated with a high occurrence of sudden death and frequent LV involvement 35, sometimes so pronounced as to deserve the term arrhythmogenic LV cardiomyopathy 67 . . .
  36. N Protonotarios; A Tsatsopoulou; A Anastasakis; E Sevdalis; G McKoy; K Stratos; K Gatzoulis; K Tentolouris; C Spiliopoulou; D Panagiotakos; W McKenna; P Toutouzas Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin J Am Coll Cardiol 38, 1477-1484 (2001) .
    • . . . The discovery of these gene mutations allowed preliminary genotype-phenotype correlations to be made 34353637. . . .
    • . . . Syncope is reported as a distinct high risk factor, particularly in the young 3675. . . .
  37. S Sen-Chowdhry; P Syrris; D Ward; A Asimaki; E Sevdalis; WJ McKenna Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression Circulation 115, 1710-1720 (2007) .
    • . . . The discovery of these gene mutations allowed preliminary genotype-phenotype correlations to be made 34353637. . . .
  38. D Corrado; L Leoni; MS Link; P Della Bella; F Gaita; A Curnis; JU Salerno; D Igidbashian; A Raviele; M Disertori; G Zanotto; R Verlato; G Vergara; P Delise; P Turrini; C Basso; F Naccarella; F Maddalena; NA Estes; G Buja; G Thiene Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia Circulation 108, 3084-3091 (2003) .
    • . . . The implantable cardioverter defibrillator (ICD) represented a major advance in therapy 38. . . .
    • . . . Corrado et al. 38 found a freedom from electric shock, delivered in case of ventricular flutter/fibrillation, in 76% of patients at 48 months after implantation, whereas the survival curve was excellent with 96% of patients alive at the same time period . . .
  39. D Corrado; C Basso; L Leoni; B Tokajuk; B Bauce; G Frigo; G Tarantini; M Napodano; P Turrini; A Ramondo; L Daliento; A Nava; G Buja; S Iliceto; G Thiene Three-dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/displasia Circulation 111, 3042-3050 (2005) .
    • . . . Finally, electroanatomic mapping proved to be a sensitive tool for identifying areas of fibro-fatty replacement with low amplitude electrical activity 39. . . .
    • . . . Among invasive procedures, three dimensional electroanatomic mapping shows low-voltage areas which correspond to fibro-fatty myocardial replacement 39 (Fig. 12) . . .
  40. E Garcia-Gras; R Lombardi; MJ Giocondo; JT Willerson; MD Schneider; DS Khoury; AJ Marian Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy J Clin Invest 116, 2012-2021 (2006) .
    • . . . Study of ARVC/D in transgenic mice 4041 models may help elucidate the pathogenesis of the disease and elaborate therapeutic strategies. . . .
    • . . . With gene mutations available, transgenic mice are now being developed to gain an insight into the etiopathogenetic mechanisms of the disease, with possible therapeutic implications 4041. . . .
    • . . . Nothing is available so far and transgenic animal models are ideal to investigate the pathogenesis of the diseases and to figure out curative therapies 4041. . . .
  41. Z Yang; NE Bowles; SE Scherer; MD Taylor; DL Kearney; S Ge; VV Nadvoretskiy; G DeFreitas; B Carabello; LI Brandon; LM Godsel; KJ Green; JE Saffitz; H Li; GA Danieli; H Calkins; F Marcus; JA Towbin Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy Circ Res 99, 646-655 (2006) .
    • . . . Study of ARVC/D in transgenic mice 4041 models may help elucidate the pathogenesis of the disease and elaborate therapeutic strategies. . . .
    • . . . With gene mutations available, transgenic mice are now being developed to gain an insight into the etiopathogenetic mechanisms of the disease, with possible therapeutic implications 4041. . . .
    • . . . Nothing is available so far and transgenic animal models are ideal to investigate the pathogenesis of the diseases and to figure out curative therapies 4041. . . .
  42. G Thiene; A Nava; A Angelini; L Daliento; R Scognamiglio; D Corrado Anatomoclinical aspects of arrhythmogenic right ventricular cardiomyopathy Advances in cardiomyopathies , 397-408 (1990) .
    • . . . The following clinical pictures of the disease have been observed 42: . . .
  43. D Corrado; G Thiene; A Nava; L Rossi Sudden death in young competitive athletes: clinicopathologic correlations in 22 cases Am J Med 89, 588-596 (1990) .
    • . . . ARVC/D has been reported as the second cause of sudden death in the young 3 (Figs. 1, 2, 3) and the main cause of sudden death in competitive athletes in the Veneto Region, Italy 43 . . .
  44. F Marcus Prevalence of T-wave inversion beyond V1 in young normal individuals and usefulness for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia Am J Cardiol 95, 1070-1071 (2005) .
    • . . . Basal ECG may disclose inverted T waves in the right precordial leads (a T wave inverted beyond V1 after 14 years of age is almost pathognomonic of ARVC/D) 44 (Fig. 2) . . .
  45. G Fontaine Arrhythmogenic right ventricular dysplasia Curr Opin Cardiol 10, 16-20 (1995) .
    • . . . QRS enlargement of more than 110 ms and epsilon wave are strongly indicative of intraventricular impulse conduction delay 45 . . .
  46. P Turrini; D Corrado; C Basso; A Nava; B Bauce; G Thiene Dispersion of ventricular depolarization-repolarization: a noninvasive marker for risk stratification in arrhythmogenic right ventricular cardiomyopathy Circulation 103, 3075-3080 (2001) .
    • . . . Signal average ECG (wide amplitude superficial ECG) may help to disclose fragmented low amplitude late potentials at the end of the QRS complex 46 (Fig. 5) . . .
  47. C Basso; G Thiene Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat? Cardiovasc Pathol 14, 37-41 (2005) .
    • . . . Presence of replacement-type fibrosis and myocyte degenerative changes are essential to provide a clear-cut diagnosis, besides remarkable fat replacement 47 (Fig. 7). . . .
  48. HS Uhl A previously undescribed congenital malformation of the heart: almost total absence of the myocardium of the right ventricle Bull Johns Hopkins Hosp 91, 197-209 (1952) .
    • . . . The myocardial atrophy is progressive with time and by no way is present at birth, as seen in Uhl's disease, a congenital heart defect in which the RV myocardium failed to develop during embryonic life 48 . . .
  49. L Daliento; P Turrini; A Nava; G Rizzoli; A Angelini; G Buja; R Scognamiglio; G Thiene Arrhythmogenic right ventricular cardiomyopathy in young versus adult patients: similarities and differences J Am Coll Cardiol 25, 655-664 (1995) .
    • . . . Instead, the myocardial loss is the consequence of cell death occurring after birth, usually during childhood 49 . . .
  50. D Corrado; C Basso; G Thiene; WJ McKenna; MJ Davies; F Fontaliran; A Nava; F Silvestri; C Blomstrom-Lundqvist; EK Wlodarska; G Fontaine; F Camerini Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study J Am Coll Cardiol 30, 1512-1520 (1997) .
    • . . . More than half of the hearts studied at post-mortem disclosed LV involvement, usually limited to the subepicardium of the postero-lateral free wall 50 . . .
    • . . . In refractory congestive heart failure, cardiac transplantation is the only therapeutic option 50. . . .
  51. G Thiene; G Thiene; A Angelini; C Basso; F Calabrese; M Valente Novel heart diseases requiring transplantation Adv Clin Path 2, 65-73 (1998) .
    • . . . In the most severe cases requiring transplantation, aneurysms may be seen also in the LV 51. . . .
  52. G Thiene; D Corrado; A Nava; L Rossi; A Poletti; GM Boffa; L Daliento; N Pennelli Right ventricular cardiomyopathy: is there evidence of an inflammatory aetiology? Eur Heart J 12, 22-25 (1991) .
    • . . . Death of single or multiple myocytes may be seen at histology, as proof of the acquired nature of myocardial atrophy, and may be associated with inflammatory infiltrates 52. . . .
  53. G Thiene; C Basso Arrhythmogenic right ventricular cardiomyopathy: An update Cardiovasc Pathol 10, 109-117 (2001) .
    • . . . Myocardial inflammation may be seen in up to 75% of hearts at autopsy, and probably it plays a role in triggering ventricular tachyarrhythmias 53 . . .
  54. NE Bowles; J Ni; F Marcus; JA Towbin The detection of cardiotropic viruses in the myocardium of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy J Am Coll Cardiol 39, 892-895 (2002) .
    • . . . Viruses have been detected in the myocardium of some ARVC/D patients and have been claimed to support an infective etiology of the disease 54 . . .
  55. F Calabrese; C Basso; E Carturan; M Valente; G Thiene Arrhythmogenic right ventricular cardiomyopathy/dysplasia: is there a role for viruses? Cardiovasc Pathol 15, 11-17 (2006) .
    • . . . Others say that the viruses are innocent bystanders or that spontaneous cell degeneration may serve as a milieu favoring viral settlement in the myocardium 55. . . .
  56. A Angelini; G Thiene; G Boffa; I Calliari; L Daliento; M Valente; R Chioin; A Nava; S Dalla Volta Endomyocardial biopsy in right ventricular cardiomyopathy Int J Cardiol 40, 273-282 (1993) .
    • . . . Transvenous endomyocardial biopsy may be of great help for an in vivo morphological demonstration of fibro-fatty myocardial replacement 56 (Fig. 8) . . .
  57. A Angelini; C Basso; A Nava; G Thiene Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy Am Heart J 132, 203-206 (1996) .
    • . . . A residual amount of myocardium <45%, due to fibrous or fibro-fatty replacement, has been proven to have a high diagnostic accuracy 57 . . .
  58. D Le Guludec; MS Slama; R Frank; M Faraggi; G Grimon; MH Bourguignon; G Motte Evaluation of radionuclide angiography in diagnosis of arrhythmogenic right ventricular cardiomyopathy J Am Coll Cardiol 26, 1476-1483 (1995) .
    • . . . Its diagnostic concordance with RV angiography is nearly 90% 58. . . .
  59. MS Hamid; M Norman; A Quraishi; S Firoozi; R Thaman; JR Gimeno; B Sachdev; E Rowland; PM Elliott; WJ McKenna Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria J Am Coll Cardiol 40, 1445-1450 (2002) .
    • . . . A modification of Task Force Criteria for the diagnosis of ARVC/D has been proposed in case of family members for early detection of the disease 59 . . .
  60. H Tandri; M Saranathan; ER Rodriguez; C Martinez; C Bomma; K Nasir; B Rosen; JA Lima; H Calkins; DA Bluemke Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging J Am Coll Cardiol 45, 98-103 (2005) .
    • . . . Among non-invasive investigations, MRI with gadolinium late enhancement has been demonstrated to be able to detect fibrosis in the RV and LV myocardium 60 . . .
  61. D Corrado; C Basso; L Leoni; B Tokajuk; P Turrini; B Bauce; F Migliore; A Pavei; G Tarantini; M Napodano; A Ramondo; A Nava; G Buja; S Iliceto; G Thiene Three-dimensional electroanatomic voltage mapping and histological evaluation of myocardial substrate in right ventricular outflow tract tachycardia , .
    • . . . Moreover, this procedure is useful to distinguish early-minor forms of ARVC/D from idiopathic RVOT tachycardia, a non-familial benign arrhythmic disorder without substrate and a preserved electrogram voltage 61. . . .
  62. N Protonotarios; A Tsatsopoulou Naxos disease and Carvajal syndrome: Cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy Cardiovasc Pathol 13, 185-194 (2004) .
    • . . . The key for interpretation came from a recessive form of ARVC/D, the so-called Naxos disease, a cardiocutaneous syndrome featured by palmoplantar keratosis, woolly hair and heart muscle disease 2562 . . .
    • . . . Thus, ARVC/D was found to be a cell junction disease also in the dominant form, with the plakophilin-2 as the most frequent disease gene 6263646566 . . .
  63. S Sen-Chowdhry; P Syrris; WJ McKenna Genetics of right ventricular cardiomyopathy J Cardiovasc Electrophysiol 16, 927-935 (2005) .
    • . . . At its C-terminal, desmoplakin anchors desmin intermediate filaments to the cardiomocyte surface 63. . . .
    • . . . Thus, ARVC/D was found to be a cell junction disease also in the dominant form, with the plakophilin-2 as the most frequent disease gene 6263646566 . . .
  64. D Dalal; C James; R Devanagondi; C Tichnell; A Tucker; K Prakasa; PJ Spevak; DA Bluemke; T Abraham; SD Russell; H Calkins; DP Judge Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy J Am Coll Cardiol 48, 1416-1424 (2006) .
    • . . . Thus, ARVC/D was found to be a cell junction disease also in the dominant form, with the plakophilin-2 as the most frequent disease gene 6263646566 . . .
    • . . . In contrast, the plakophilin mutation results in a more extensive disease manifestation with life-threatening ventricular arrhythmias 64 . . .
  65. JP Van Tintelen; MM Entius; ZA Bhuiyan; R Jongbloed; AC Wiesfeld; AA Wilde; J van der Smagt; LG Boven; MM Mannens; IM van Langen; RM Hofstra; LC Otterspoor; PA Doevendans; LM Rodriguez; IC van Gelder; RN Hauer Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy Circulation 113, 1650-1658 (2006) .
    • . . . Thus, ARVC/D was found to be a cell junction disease also in the dominant form, with the plakophilin-2 as the most frequent disease gene 6263646566 . . .
  66. P Syrris; D Ward; A Asimaki; S Sen-Chowdhry; HY Ebrahim; A Evans; N Hitomi; M Norman; A Pantazis; AL Shaw; PM Elliott; WJ McKenna Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy Circulation 113, 356-364 (2006) .
    • . . . Thus, ARVC/D was found to be a cell junction disease also in the dominant form, with the plakophilin-2 as the most frequent disease gene 6263646566 . . .
  67. M Norman; M Simpson; J Mogensen; A Shaw; S Hughes; P Syrris; S Sen-Chowdhry; E Rowland; A Crosby; WJ McKenna Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy Circulation 112, 636-642 (2005) .
    • . . . Genotype-phenotype correlations revealed that the desmoplakin mutation is associated with a high occurrence of sudden death and frequent LV involvement 35, sometimes so pronounced as to deserve the term arrhythmogenic LV cardiomyopathy 67 . . .
  68. L Antoniades; A Tsatsopoulou; A Anastasakis; P Syrris; A Asimaki; D Panagiotakos; C Zambartas; C Stefanadis; WJ McKenna; N Protonotarios Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis Eur Heart J 27, 2208-2216 (2006) .
    • . . . Plakoglobin and plakophilin mutations leads to similar cardiac phenotypes with RV preponderance 68. . . .
  69. JA Towbin; NE Bowles The failing heart Nature 415, 227-233 (2002) .
    • . . . Cell junction protein mutations may account for a final common pathway, namely disruption of intercellular junction, myocyte death and structural changes, which are the substrate of life-threatening ventricular arrhythmias 69. . . .
  70. EE Norgett; SJ Hatsell; L Carvajal-Huerta; JC Cabezas; J Common; PE Purkis; N Whittock; IM Leigh; HP Stevens; DP Kelsell Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma Hum Mol Genet 9, 2761-2766 (2000) .
    • . . . Carvajal disease 70, characterized by keratoderma, woolly hair and a biventricular form of ARVC/D 71, with distinct ultrastructural abnormalities of intercalated discs and decreased immunoreactive signals for desmoplakin, plakoglobin and Cx 43. . . .
  71. SR Kaplan; JJ Gard; L Carvajal-Huerta; JC Ruiz-Cabezas; G Thiene; JE Saffitz Structural and molecular pathology of the heart in Carvajal syndrome Cardiovasc Pathol 13, 26-32 (2004) .
    • . . . Carvajal disease 70, characterized by keratoderma, woolly hair and a biventricular form of ARVC/D 71, with distinct ultrastructural abnormalities of intercalated discs and decreased immunoreactive signals for desmoplakin, plakoglobin and Cx 43. . . .
  72. SR Kaplan; JJ Gard; N Protonotarios; A Tsatsopoulou; C Spiliopoulou; A Anastasakis; CP Squarcioni; WJ McKenna; G Thiene; C Basso; N Brousse; G Fontaine; JE Saffitz Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease) Heart Rhythm 1, 3-11 (2004) .
    • . . . Moreover, remodeling of intercalated disc may lead to widening of myocyte gap junction, which may also contribute to the arrhythmogenicity of the disease and enhance the risk of sudden death 72. . . .
  73. SG Priori; C Napolitano; N Tiso; M Memmi; G Vignati; R Bloise; V Sorrentino; GA Danieli Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia Circulation 103, 196-200 (2001) .
    • . . . Similar mutations have been shown to account for cathecolaminergic VT, a peculiar malignant arrhythmic disease in normal hearts 73 . . .
  74. B Bauce; A Nava; A Rampazzo; L Daliento; M Muriago; C Basso; G Thiene; GA Danieli Familial effort polymorphic ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy map to chromosome 1q42-43 Am J Cardiol 85, 573-579 (2000) .
    • . . . Mild pathologic substrates have been described in ARVD2 74, but clearly this disease is different from the classical form of ARVC/D and most probably we are dealing with the same nosographic entity as cathecolaminergic VT. . . .
  75. P Turrini; D Corrado; C Basso; A Nava; B Bauce; G Thiene Dispersion of ventricular depolarization-repolarization: a noninvasive marker for risk stratification in arrhythmogenic right ventricular cardiomyopathy Circulation 103, 3075-3080 (2001) .
    • . . . Young age, "malignant" family history, QRS dispersion ≥ 40 ms, T-wave inversion beyond V1, LV involvement, VT, syncope or previous cardiac arrest are considered the major determinants for adverse prognosis and impending sudden death 75. . . .
    • . . . Syncope is reported as a distinct high risk factor, particularly in the young 3675. . . .
  76. T Wichter; M Paul; L Eckardt; P Gerdes; P Kirchhof; D Bocker; G Breithardt Arrhythmogenic right ventricular cardiomyopathy. Antiarrhythmic drugs, catheter ablation, or ICD? Herz 30, 91-101 (2005) .
    • . . . Catheter ablation has been accomplished in VT refractory to drug treatment 76 . . .
  77. T Wichter; M Paul; C Wollman; T Acil; P Gerdes; O Ashraf; TD Tjan; R Soeparwata; M Block; M Borggrefe; HH Scheld; G Breithardt; D Bocker Implantable cardioverter/defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: single-center experience of long-term follow-up and complications in 60 patients Circulation 109, 1503-1508 (2004) .
    • . . . In case of sustained VT and/or syncope, ICD is also indicated in the presence of risk factors (extensive RV dysfunction, LV involvement, polymorphic VT, late potentials and epsilon wave, family history) 77 . . .
  78. D Corrado; G Thiene Arrhythmogenic right ventricular cardiomyopathy/dysplasia: clinical impact of molecular genetic studies Circulation 113, 1634-1637 (2006) .
    • . . . Gene therapy is still far from being established 78 and no treatment to limit disease progression has been conceived so far . . .
  79. D Corrado; C Basso; G Rizzoli; M Schiavon; G Thiene Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 42, 1959-1963 (2003) .
    • . . . Sport activity increases 5 fold the risk of sudden death in the young 79 (Fig. 20) . . .
  80. D Corrado; C Basso; A Pavei; P Michieli; M Schiavon; G Thiene Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program JAMA 296, 1593-1601 (2006) .
    • . . . Preparticipation screening and sport disqualification, with a choice of life style without strenuous efforts, has been shown to be quite effective in preventing sudden death in athletes 80 . . .
    • . . . In the Veneto Region, following implementation of obligatory preparticipation screening there was a sharp decline in sudden death in athletes from 1:28,000 per year in the pre-screening period to 1/250,000/year in the late screening period, mostly due to identification and disqualification of patients affected by ARVC/D 80 (Fig. 21). . . .
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