Ventricular Cardiomyopathy Dysplasia Clarified

Gaetano Thiene, Andrea Nava, Frank I. Marcus

The first monograph on arrhythmogenic right ventricular 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 diagnosis 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 Proceedings. In addition, some topics were added in a similar 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 disease has been impressive. This is the logical consequence 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 consequences into an "army" for the fight against the disease.

An International Registry was considered mandatory in order to collect study material and concentrate efforts on this rare disease [2].

It was then decided to apply for grants to the European Commission (EC) and to the National Institute of Health (NIH). Two teams were created, one in Europe coordinated by Gaetano Thiene [3] and one in North America coordinated by Frank Marcus [4]. Utilizing a similar database and having some Core Laboratories in common, the two projects were initiated. The structure was somewhat different: the European Registry enrolled patients who were both previously diagnosed as well as those with the recent onset of symptoms, whereas the North American Registry enrolled only newly diagnosed patients. Guidelines for diagnostic criteria and protocols were implemented. Genetic investigation was an integral part of both studies. Fortunately, the two projects were approved and funded for 5 years, thus allowing the start of a major interdisciplinary study of ARVC/D. The results exceeded our best expectations, resulting in numerous important publications in well-recognized cardiovascular journals. 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-familial, monogenic disease has been clarified. Despite genetic heterogeneity with rare variants, it has been demonstrated that both autosomal and recessive forms are due to defects of genes encoding desmosomal proteins of the intercalated disc: plakoglobin [5], desmoplakin, [6] plakophilin [7], desmoglein [8], and desmocollin [9]. This explains why the disease is now called a desmoso-mal cardiomyopathy [10,11]. To date, seven disease genes have been identified during the course of the EC and NIH research projects - an unbelievable achievement. Genetic screening is now feasible for the detection of gene carriers and early 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 potentially trigger a cascade of events following parietal stretch (apoptotic cell death, fibrofatty replacement, electrical instability). There is now evidence 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 expanding the previous concept that the disease is confined to the right ventricle [14-16]. The diagnostic 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. Magnetic resonance imaging is being expanded in scope not only to study the morphology and dysfunction of the ventricles, but also to identify tissue composition, particularly fibrosis utilizing gadolinium late enhancement.

4. With regard to advances in the invasive diagnostic techniques, electroanatomic mapping is being evaluated to detect areas of decreased electrical activity, which has been found to correspond to diffuse segmental fibrofatty atrophy [17]. This may be important not only for the diagnosis of the disease, but also for the identification of areas that may be the target for catheter ablation. Nevertheless, the precise diagnostic role of elec-troanatomic mapping needs further clarification. Also the role of ablation for treatment of ventricular arrhythmias needs to be reinvestigated utilizing the technique of electroanatomic mapping.

5. It is indisputable that the implantable cardioverter defibrillator (ICD) has been lifesaving in patients with ARVC/D who have malignant ventricular arrhythmias including hemodynamically unstable 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 "veniforas, Lazare" (John's Gospel chapter 11, line 43-44) (Fig. 1). Whether the ICD should be employed as primary as well as for secondary prevention 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 participation 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 viduals at risk, including those with ARVC/D. In Italy, sudden death of young athletes declined five fold after the implementation of preparticipation screening primarily due to identification of cardiomyopathies [20]. The recognition of ARVC/D as a disease entity, as well as the utilization of strict diagnostic criteria [21], accounts for this important achievement. 7. Recent developments from in vitro and in vivo analyses of mutated proteins in transgenic mice are providing mechanistic explanations, with targeted therapies on the horizon for affected patients [22-25].

These studies suggest that sudden cardiac death in patients with ARVC/D may be prevented by different approaches (Fig. 2):

Curative therapy

Sports disqualification, lifestyle



Cardiac ARREST

Implant of defibrillator

Arrhythmic MECHANISM

Drug therapy, ablation

Fig. 2 • Diagram illustrating the various levels of interventions for sudden death prevention in ARVC/D

Fig. 2 • Diagram illustrating the various levels of interventions 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 compared to the rescue from cardiac arrest by ICD; ecg tracing,courtesy of Dr.Moss

Fig.1 • The resuscitation of Lazarus, painted by Giotto in the Scrovegni Chapel in Padua (C. 1304), is compared to the rescue from cardiac arrest by ICD; ecg tracing,courtesy of Dr.Moss

Fig. 3 • The heart specimen with ARVC/D of the original patient 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

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 individual patient awaits further investigation.

All the above-mentioned therapeutic and preventive measures are palliative, not curative. The definitive cure of the disease is still elusive. Cardiac transplantation is employed to treat end-stage cardiac failure 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, inflammation, and fibrofatty replacement, the basic mechanisms of myocardial injury and repair, will require 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].


A Secretion Cubiculo, Archiatri Politificii




Fig.4 • The first description of ARVC/D was reported in this book of Giovanni Maria Lancisi, Professor of Anatomy in Rome, 1736

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 ultimately 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 underwent transplantation due to end-stage cardiac failure. Interestingly, the heart specimen showed severe right ventricular enlargement with a nearly normal 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 unrecognized and important cause of sudden death in the young [30]. However, the first description of the disease 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 palpitations, heart failure, dilatation and aneurysms of the right ventricle, and sudden death, all features consistent with the current diagnostic criteria of the disease. Thus, we know that the disease is not new, only newly investigated. Nevertheless, tremendous strides have been made in recognition and understanding of the disease which are summarized in this monograph.

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