The first monograph on arrhythmogenic right ven- tricular cardiomyopathy/dysplasia (ARVC/D) was published 10 years ago [1]. Since then, there have been major advancements in the basic knowledge of the disease as well as a better understanding of the di- agnosis and treatment. A workshop was held in Venice, Italy on October 3, 2005, where research on various aspects of this disease, both biological and clinical was presented.
This book has assembled contributions in the form of a monograph rather than as the publication of Pro- ceedings. In addition, some topics were added in a sim- ilar format to that of the first monograph [1], which followed a meeting on ARVC/D held in Paris in 1996.
In the last 10 years our understanding of this dis- ease has been impressive. This is the logical conse- quence of a research strategy with clear goals.
At the turn of the millennium, following a series of meetings of experts from both sides of the Atlantic, it became evident that we had to merge the expertise of scientists and clinicians attracted by the mystery of ARVC/D and its devastating physical and social conse- quences into an “army” for the fight against the disease.
An International Registry was considered manda- tory in order to collect study material and concen- trate efforts on this rare disease [2].
It was then decided to apply for grants to the Eu- ropean Commission (EC) and to the National Institute of Health (NIH). Two teams were created, one in Eu- rope coordinated by Gaetano Thiene [3] and one in North America coordinated by Frank Marcus [4]. Uti- lizing a similar database and having some Core Labo- ratories in common, the two projects were initiated.
The structure was somewhat different: the European Registry enrolled patients who were both previously di- agnosed as well as those with the recent onset of symp- toms, whereas the North American Registry enrolled only newly diagnosed patients. Guidelines for diag- nostic criteria and protocols were implemented. Ge- netic investigation was an integral part of both studies.
Fortunately, the two projects were approved and fund- ed for 5 years, thus allowing the start of a major inter- disciplinary study of ARVC/D. The results exceeded our
best expectations, resulting in numerous important publications in well-recognized cardiovascular jour- nals. In this monograph the advances in our knowledge will be summarized in didactic presentations.
A brief overview of the major advances is as follows:
1. The genetic background of this hereditary-famil- ial, monogenic disease has been clarified. Despite genetic heterogeneity with rare variants, it has been demonstrated that both autosomal and re- cessive forms are due to defects of genes encod- ing desmosomal proteins of the intercalated disc:
plakoglobin [5], desmoplakin, [6] plakophilin [7], desmoglein [8], and desmocollin [9]. This ex- plains why the disease is now called a desmoso- mal cardiomyopathy [10, 11]. To date, seven dis- ease genes have been identified during the course of the EC and NIH research projects – an unbe- lievable achievement. Genetic screening is now feasible for the detection of gene carriers and ear- ly clinical diagnosis [12].
2. The pathological substrate of the disease has been clarified at the ultrastructural level with evidence of remodeling of intercalated disc (widening of intercellular space with abnormal desmosomes) [13]. These structural abnormalities can poten- tially trigger a cascade of events following parietal stretch (apoptotic cell death, fibrofatty replace- ment, electrical instability). There is now evi- dence that the left ventricle is also involved. In some variants of the disease it has been shown that the left ventricle is primarily affected, thus ex- panding the previous concept that the disease is confined to the right ventricle [14-16]. The diag- nostic role of endomyocardial biopsy has been improved by updating morphometric parameters.
3. Both the advantages and limitations of imaging modalities have been clarified and are beginning to be subjected to quantitative analysis. Magnet- ic resonance imaging is being expanded in scope not only to study the morphology and dysfunc- tion of the ventricles, but also to identify tissue composition, particularly fibrosis utilizing gadol- inium late enhancement.
Introduction: ARRHYTHMOGENIC RIGHT
VENTRICULAR CARDIOMYOPATHY/
DYSPLASIA CLARIFIED
Gaetano Thiene, Andrea Nava, Frank I. Marcus
5. It is indisputable that the implantable cardiovert- er defibrillator (ICD) has been lifesaving in pa- tients with ARVC/D who have malignant ventric- ular arrhythmias including hemodynamically un- stable ventricular tachycardia [18, 19]. The efficacy of the ICD in this setting is astonishing and recalls the miracle of the resuscitation of Lazarus, friend of Jesus Christ, from the tomb, painted by Giotto in the Scrovegni Chapel in Padua, where Jesus said
“veni foras, Lazare” (John’s Gospel chapter 11, line 43-44) (Fig. 1). Whether the ICD should be em- ployed as primary as well as for secondary pre- vention is still controversial.
6. Primary prevention of sudden death in the young and in athletes from ARVC/D may be possible by lifestyle changes, particularly avoiding participa- tion in vigorous and certainly in competitive sports. Preparticipation screening for those who engage in competitive sports has been shown to be highly effective for identification of the indi-
These studies suggest that sudden cardiac death in patients with ARVC/D may be prevented by different approaches (Fig. 2):
Cardiac ARREST
SUBSTRATE TRIGGER
Arrhythmic MECHANISM Curative
therapy
Sports disqualification,
lifestyle
Implant of defibrillator
Drug therapy, ablation
Fig. 2 • Diagram illustrating the various levels of interven- tions for sudden death prevention in ARVC/D
Fig. 1 • The resuscitation of Lazarus, painted by Giotto in the Scrovegni Chapel in Padua (C. 1304), is com- pared to the rescue from cardiac arrest by ICD; ecg tracing,courtesy of Dr.Moss
1. Avoiding the trigger, such as strenuous exercise in patients who are identified as having the disease by clinical or genetic screening;
2. Preventing life-threatening arrhythmias using drug therapy or ablation;
3. ICD implantation, an extremely effective therapy to treat life-threatening ventricular arrhythmias that can result in cardiac arrest.
The selection of appropriate therapy for the indi- vidual patient awaits further investigation.
All the above-mentioned therapeutic and preven- tive measures are palliative, not curative. The defini- tive cure of the disease is still elusive. Cardiac trans- plantation is employed to treat end-stage cardiac fail- ure or for refractory electrical instability, but this therapy is not without problems, particularly the need to prevent acute rejection as well as allograft vas- culopathy. Prevention of myocyte apoptotic death, in- flammation, and fibrofatty replacement, the basic mechanisms of myocardial injury and repair, will re- quire understanding the pathogenetic mechanisms of ARVC/D. At present, replacement of the defective genes (gene therapy) is theoretically possible only by disease identification at the early embryonic stage, with preimplantation genetic diagnosis, an issue that raises major ethical questions [26].
Thus, although the genetic basis of ARVC/D has been largely clarified, there is much work to be done to better understand the cell biology of the disease, to know how to slow disease progression, and ulti- mately to prevent disease transmission.
Finally, some historical notes. It was in 1961 that Professor Sergio Dalla Volta from the University of Padua reported cases with “auricularization of the right ventricular pressure” with an amazing fibrofat- ty, nonischemic pathology of the right ventricle [27].
One of those patients survived until 1995, and un- derwent transplantation due to end-stage cardiac failure. Interestingly, the heart specimen showed se- vere right ventricular enlargement with a nearly nor- mal left ventricle (Fig. 3).
Attention was focused on the disease following the clinical description of ARVC/D by Marcus et al. in 1982 [28]. In 1988 Nava et al. elucidated the pattern of transmission in family members [29], and Thiene et al. discovered the disease as a previously unrecog- nized and important cause of sudden death in the young [30]. However, the first description of the dis- ease can be traced to the book De Motu Cordis et Aneurismatibus by Giovanni Maria Lancisi, published in 1736. (Dr. Arnold Katz, personal communication) (Fig. 4). In the 5th chapter of this book, paragraph 47, Lancisi reported a family with disease recurrence in four generations. Signs and symptoms were palpita- tions, heart failure, dilatation and aneurysms of the right ventricle, and sudden death, all features consis- tent with the current diagnostic criteria of the disease.
Thus, we know that the disease is not new, only new- ly investigated. Nevertheless, tremendous strides have been made in recognition and understanding of the disease which are summarized in this monograph.
Fig. 4 • The first description of ARVC/D was reported in this book of Giovanni Maria Lancisi, Professor of Anatomy in Rome, 1736
Fig. 3 • The heart specimen with ARVC/D of the original pa- tient reported by Professor Dalla Volta in 1961. The patient underwent cardiac transplantation 35 years later because of right ventricular failure: note the massive dilatation of the right ventricle and the small, normal left ventricle
3. Basso C, Wichter T, Danieli GA et al (2004) Arrhyth- mogenic right ventricular cardiomyopathy: Clinical registry and database, evaluation of therapies, pathol- ogy registry, DNA banking. Eur Heart J 25:531-534 4. Marcus F, Towbin JA, Zareba W et al (2003) ARVD/C
Investigators. Arrhythmogenic right ventricular dys- plasia/cardiomyopathy (ARVD/C): A multidiscipli- nary study: Design and protocol. Circulation 107:2975- 2978
5. McKoy G, Protonotarios N, Crosby A et al (2000) Identification of a deletion in plakoglobin in arrhyth- mogenic right ventricular cardiomyopathy with pal- moplantar keratoderma and woolly hair (Naxos dis- ease). Lancet 355:2119-2124
6. Rampazzo A, Nava A, Malacrida S et al (2002) Muta- tion in human desmoplakin domain binding to plako- globin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 71:1200-1206
7. Gerull B, Heuser A, Wichter T et al (2004) Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.
Nat Genet 36:1162-1164
8. Pilichou K, Nava A, Basso C et al (2006) Mutations in desmoglein-2 gene are associated with arrhythmo- genic right ventricular cardiomyopathy. Circulation 113:1171-1179
9. Syrris P, Ward D, Evans A et al (2006) Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin- 2. Am J Hum Genet 79:978-984
10. Thiene G, Basso C, Corrado D (2004) Cardiomy- opathies: Is it time for a molecular classification? Eur Heart J 25:1772-1775
11. Maron BJ, Towbin JA, Thiene G et al (2006) Contem- porary definitions and classification of the cardiomy- opathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quali- ty of Care and Outcomes Research and Functional Ge- nomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 113:1807-1816
16. Sen-Chowdry S, Prasad SK, Syrris P et al (2006) Car- diovascular magnetic resonance in arrhythmogenic right ventricular cardiomyopathy revisited: Compari- son with task force criteria and genotype. J Am Coll Cardiol 48:2132-2140
17. Corrado D, Basso C, Leoni L et al (2005) Three- dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricu- lar cardiomyopathy/dysplasia. Circulation 111:3042-3050 18. Corrado D, Leoni L, Link MS et al (2003) Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 108:3084-3091
19. Wichter T, Paul M, Wollmann C et al (2004) Im- plantable cardioverter/defibrillator therapy in ar- rhythmogenic right ventricular cardiomyopathy. Sin- gle-center experience of long-term follow-up and com- plications in 60 patients. Circulation 109:1503-1508 20. Corrado D, Basso C, Pavei A et al (2006) Trends in sud-
den cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA 296:1593-1601
21. McKenna WJ, Thiene G, Nava A et al (1994) Diagno- sis of arrhythmogenic right ventricular dysplasia/car- diomyopathy. Task Force of the Working Group My- ocardial and Pericardial Disease of the European Soci- ety of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 71:215-218 22. Garcia-Gras E, Lombardi R, Giocondo MJ et al (2006)
Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of ar- rhythmogenic right ventricular cardiomyopathy. J Clin Invest 116:1825-1828
23. Yang Z, Bowles NE, Scherer SE et al (2006) Desmoso- mal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/car- diomyopathy. Circ Res 99:646-655
24. Kirchhof P, Fabritz L, Zwiener M et al (2006) Age and training dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin deficient mice. Circulation 114:1799- 1806
25. Marcus F, Towbin JA (2006) The mystery of arrhyth- mogenic right ventricular dysplasia/cardiomyopathy.
From observation to mechanistic explanation. Circu- lation 114:1794-1795
26. Sermon K, Van Steirteghem A, Liebaers I (2004) Preim- plantation genetic diagnosis. Lancet 363:1633-1641 27. Dalla Volta S, Battaglia G, Zerbini E (1961) “Auricu-
larization” of right ventricular pressure curve. Am Heart J 61:25-33
28. Marcus FI, Fontaine GH, Guiraudon G et al (1982) Right ventricular dysplasia: A report of 24 adult cases.
Circulation 65:384-398
29. Nava A, Thiene G, Canciani B et al (1988) Familial oc- currence of right ventricular dysplasia: A study involv- ing nine families. J Am Coll Cardiol 12:1222-1228 30. Thiene G, Nava A, Corrado D et al (1988) Right ven-
tricular cardiomyopathy and sudden death in young people. N Engl J Med 318:129-133
