Arrhythmogenic Right Ventricular Dysplasia
An overview. From concept to registry and fund raising.

Guy Fontaine

Introduction

Right Ventricular Dysplasia (RVD) is a heart muscle disease that is characterized by structural and functional abnormalities due to replacement of myocardial tissue by fat and fibrosis. This disease affects mostly the right ventricle (RV) and to a lesser extend the left ventricle (LV). Clinical manifestations of the disease include various arrhythmias generally of right ventricular origin including isolated extrasystoles, non sustained or sustained ventricular tachycardia and ventricular fibrillation leading to sudden death. When these arrhythmias are present, the disease is called "Arrhythmogenic Right Ventricular Dysplasia" (ARVD). Congestive heart failure is also observed in the most severe forms of the disease.

Since the first description of ARVD in 1977, there have been significant advances concerning the understanding of the etiopathogenesis, its morbid anatomy and the clinical diagnosis of this condition. However, there is still a great lack of information regarding the natural history of the disease, its risk stratification, efficacy of therapy in suppressing life-threatening ventricular arrhythmias and prevention of sudden death, as well as the results of modern treatment of heart failure.

This brief introduction will focus on the considerable advances made in the study of ARVD but will also stress the most important unsolved problems. The better way to achieve these goals needs the accumulation of relevant information in a centralized International Registry and the use of Internet to exchange quickly relevant informations with patients and investigators.

Genetics

In 30-90% of cases, ARVD is familial. The most common pattern of inheritance is autosomal dominant with a penetrance in family members is ranging from 20-35% in most places reaching 50% in the Veneto region in Italy. However, an autosomal recessive pattern has also been reported in a form localized in the Greek Island of Naxos where dysplasia is associated with palmoplantar keratosis. In this condition, signs of the disease are more severe and penetrance in family members is 90%. Genetic abnormalities have been located on chromosome 1, 2, 3, 7 and 14 suggesting a multi-genic form of the disease. A genetic test for the preclinical diagnosis of ARVD is not currently available.

Morbid anatomy and histology

The most striking morphological feature of the disease is the diffuse or segmental loss of the myocardium of the right ventricular free wall which is replaced by fatty tissue. Only the subendocardial layers are preserved. Those layers are frequently occupied by dissecting fibrosis. Persisting strands of cardiomyocytes bordered by or embedded in a variable extent of fibrosis are observed in the epicardial and mediomural layers inside fat. In contrast, the trabeculae carne of the apex and the right aspect of the ventricular septum are hypertrophied. This explains some of the images provided by contrast angiography. Variable signs suggesting myocarditis are observed in nearly 2/3rd of the cases.

The disease is largely overlooked by routine autopsy because the limit between dysplasia and normal tissue is unclear. It is now recognized that presence of fat interspersed with cardiomyocytes is observed in a sizeable number of normals. This purely adipose form is characterized by partial or almost total replacement of right ventricular wall by fatty tissue, and predominant involvement of the right ventricular apex and infundibulum. In that case, there is no area of fibrosis and inflammatory infiltrates are absent. RVD appears as a specific feature of the human species. In this case, the risk of sudden unexpected death is minimal. However, fat dissociating myocardial fibers isolate strands of cardiomyocytes which could lead to a major slowdown of the speed of conduction within myocardium. This may constitute in some rare circumstances an arrhythmogenic substrate and may explain mysterious cases of sudden death.

The fibro-fatty form was the original type of description, characterized by fibrosis bordering or embedding cardiomyocytes, thinning of the right ventricular wall with aneurysmal dilatation and inflammatory infiltrates. In this situation there is involvement of the postero-inferior wall and, segmentally, of the septum and even some plans of the left ventricular wall.

Etiopathogenesis

ARVD already present in the fetus and maybe in the embryo is therefore an inherited congenital anomaly leading to a loss of the right ventricular myocardium. It has been added to the group of cardiomyopathies in a recent classification of the World Health Organization under the name of "Arrhythmogenic Right Ventricular Cardiomyopathy". The benefit of this new term is to encompass the multiple clinical forms of the disease. The loss of RV myocardium has been related to three basic mechanisms :

• Apoptosis or programmed cell death is producing only minor fibrosis.
• Inflammatory phenomenon is generally observed later in life. It may be the trigger of cardiac arrhythmias. When an inflammatory phenomenon is present, a spectrum of clinical presentations may be observed going from hyperacute myocarditis leading to fulminant heart failure to complete healing without clinical signs. This later situation may be associated with deposition of additional fibrosis. In the severe forms of the disease, inflammatory changes are generally involving both the right and the left ventricles, producing an increased amount of replacement fibrosis. This could be an on-going process suggesting an autoimmune phenomenon leading to congestive heart failure mimicking idiopathic dilated cardiomyopathy.
• Major replacement of myocardium by fat is presently unclear, however it seems independent of myocarditis.

Epidemiology

The incidence and prevalence of ARVD is unknown. Patients with a clinical diagnosis of ARVD performed on the basis of appropriate symptoms, right precordial ECG changes, right ventricular arrhythmias with both structural and functional RV abnormalities represent only one extreme of the disease spectrum. A number of clinically silent cases are not recognized because they are asymptomatic until the first presentation which could be sudden death. On the other extreme of the spectrum, patients with congestive heart failure with or without cardiac arrhythmias in whom the diagnosis of dysplasia was not recognized at the beginning of the evolution could be another subset of cases sometimes wrongly diagnosed as idiopathic dilated Cardiomyopathy.

The differences in frequency observed in different places in the world could be either due to clustering of the disease in some geographic areas or due to the fact that this entity is being presently underdiagnosed because of unclear diagnostic criteria or both.

Clinical diagnosis

Standardized diagnostic criteria have been proposed by the Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of World Heart Federation (WHF). Diagnosis of ARVD is based on the presence of major and minor criteria encompassing structural, electrocardiographic, arrhythmic and genetic factors. However, these criteria based on the opinion of clinicians aware of this condition have to be reconsidered on more objective grounds classified according to the origin of the patients.

The recognition of mild or frust forms of the disease remains a clinical challenge. It is difficult to diagnose ARVD in patients with minimal RV abnormalities at echocardiographic and even contrast angiographic examination. MRI is a promising technique in evidencing RV anatomy and function as well as in characterizing the composition of the RV wall, especially with regard to the presence of fatty tissue. However, its diagnostic sensitivity and specificity still need to be defined since the quality of images detected are, at the present time, interobserver-dependent.

Disease progression and left ventricular involvement.

Whatever the etiopathogenetic mechanisms involved, there is definite clinico-pathologic evidence that ARVD is a progressive heart muscle disease. Long-term follow-up data from clinical studies indicate that ARVD may lead with time to a more diffuse RV changes and left ventricular involvement which may culminate in heart failure. The Task Force of the Scientific Council on Cardiomyopathies of the WHF endorsed a multicenter clinico-pathologic investigation aimed to redefine the anatomoclinical profile of ARVD with special reference to disease progression and left ventricular involvement. Examination of 42 affected whole hearts mostly originating from the Veneto region where the disease seems more severe (as in Naxos) was correlated with pathologic findings with patient clinical history. The study demonstrated that at least in this subgroup made of autopsies and heart transplant which represents an extreme in the disease spectrum, ARVD can no longer be regarded as an isolated disease of the right ventricle. LV involvement, histological and/or macroscopic, was found in 76% of hearts with ARVD. It was age dependent, was more common in patients with longstanding clinical history and progressed during serial echocardiographic examination in some patients. Moreover, LV lesions were associated with clinical arrhythmic events, more severe cardiomegaly, inflammatory infiltrates, and heart failure.

Natural history

The natural history of ARVD is a function of both the electrical instability of diseased ventricular myocardium and ventricular dysfunction and heart failure.

• Cardiac arrhythmias are an epiphenomenon which can be observed at any time during the disease course. It could be expressed by isolated or multiple aspects of extrasystoles, non sustained or sustained ventricular tachycardias leading to ventricular fibrillation or unexpected cardiac arrest and sudden death mostly observed in young people and athletes.
• Progressive myocardial loss of contractile forces that results in ventricular dysfunction and heart failure is the second important factor.

The following clinico-pathologic phases can be considered :

1. "Concealed" phase characterized by subtle RV structural changes,
2. The same structure as before associated with minor or moderate right ventricular arrhythmias.
3. "Overt electrical disorder" in which severe right ventricular arrhythmias and impending cardiac arrest associated with overt RV functional and structural abnormalities and non significant left heart involvement.
4. "Right ventricular failure" due to the progression and extension of the RV muscle disease that provokes global RV dysfunction with a relatively preserved left ventricular function (LVEF > 40%).
5. Final stage of "biventricular pump failure" due to significant LV involvement generally as a result of a superimposed phenomenon of ongoing myocarditis. At this stage, ARVD mimics biventricular dilated cardiomyopathy leading to congestive heart failure and related complications.

However, this speed of progression and the severity of symptoms seems to be highly variable from case to case depending on the role played by genetic as well as environmental factors.

Therapy

At present, too little is known about the clinical course of ARVD even in patients with overt disease and significant ventricular arrhythmias and even less in asymptomatic affected family members. Since the clinical findings that predict life-threatening cardiac arrhythmia are incompletely known, there are no precise rules to select those patients who should be treated. Moreover, the modality to assess the efficacy of both pharmacological and non pharmacologic therapy in patients with ARVD is not defined. Therefore, there are no well-established guidelines in the management of patients and the strategy is largely based on the local experience gained by the different centers. Patients with non-life-threatening ventricular arrhythmias are usually treated empirically with antiarrhythmic drugs including sotalol, beta-blockers, flecainide, propafenone, and amiodarone alone or in combination therapy. In patients with sustained ventricular tachycardia or ventricular fibrillation, antiarrhythmic drug therapy guided by programmed ventricular stimulation with serial drug testing seems effective to treat successfully ventricular arrhythmias but is unable to prevent sudden death. Non-pharmacological therapy, mostly catheter ablation, is reserved to those patients with life-threatening ventricular arrhythmias in whom drug therapy either proves ineffective, is associated with serious side effects, or is not applicable due to the inability to reproducibly induce the clinical ventricular arrhythmias during repeat electrophysiologic studies. Implantable defibrillator which represents the only effective safe-guard against sudden death needs to be evaluated on a large series of patients.

In case of heart failure, appropriate analysis of cardiac function is necessary and new noninvasive techniques are investigated. This seems important to understand the complicated as well as the non complicated forms of the disease.

The International Registry

This Registry has been established by the Task Force of the Scientific Council on Cardiomyopathies of WHF and by the Working Group on Myocardial and Pericardial Disease of the European Society of Cardiology and it will officially start on January 1st, 1999.

The primary objective of the ARVD International Registry will be to follow up a large patient population for at least 10 years with the following aims.

• Clinical diagnosis : To prospectively validate the criteria for the clinical diagnosis of ARVD and to further evaluate clinical diagnosis accuracy, long term outcome, and therapy efficacy in well classified populations (geographic factors of prevalence).
• Natural History : To assess the natural course of the disease - particularly the occurrence of sudden death and heart failure - in different ARVD clinical subgroups of patients as well as asymptomatic family members.
• Risk stratification : To determine which and how initial or subsequent findings predict poor ARVD long term outcome.
• Antiarrhythmic therapy : To improve clinical management by evaluating long term efficacy of "empiric" and "electrophysiologically guided" antiarrhythmic drug therapy, and non pharmacologic treatment including catheter ablation and automatic implantable defibrillator.
• Treatment of congestive heart failure :
  • To detect the mechanisms of inflammatory signs involving both the right and the left ventricles.
  • To evaluate the benefit of modern treatments of heart failure with regards to alphablocking .

The aim of this announcement is to invite Cardiologists to cooperate by entering their patients in the ARVD International Registry. Enrollment forms with detailed entry criteria and semiannual follow-up forms will be provided for each patient. Of note, the clinical management of enrolled patients will be not be influenced by the Registry participation. Participating physicians will provide data regarding particular clinico-therapeutic questions. The ARVD International Registry can be contacted at the addresses listed below.

It is hoped that the International Registry will also enhance cooperation among scientific colleagues.

Internet

The role of Internet is :

• To inform patients of the most recent data concerning the treatments of the disease and their results.
• To provide them a list of clinicians who are experienced in this disease.
• To collect research funds to promote research projects on ARVD and related cardiomyopathies.
• To help patients who need expensive treatment (defibrillator).
• To work as a forum to exchange relevant scientific observations between researchers. This is not supposed to replace presentation of abstracts in scientific meetings or the publication of articles in scientific journals or books.

It is our hope that this structure will promote the study of this under-recognized fascinating disease which is still in its phase of discovery but which may play an important general risk factor of death in the general population presently unknown.

This presentation represents the thoughts of the author at the time of writing and may continue to change as long as the discovery of the disease continues...