Introduction: Past, Present and Future of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Frank I. Marcus, M.D.
Professor of Medicine
Section of Cardiology
University of Arizona
1501 N. Campbell Ave.
P.O. Box 24-5037
Tucson, AZ 85724
Tele: 520-626-6358
Fax: 520-626-4333

"You see only what you look for; you recognize only what you know"

Merril C. Sosman (1)

In 1977, Fontaine and colleagues provided an anatomical and clinical description of several cases of ARVD discovered during surgical treatment of ventricular tachycardia (2). Dr. Fontaine introduced me to this condition when I visited him in Paris in 1979. At that time he had personally seen 15 cases with ARVD since 1973. Since the patients were referred from a large geographic area, I realized that this was a condition that physicians were not recognizing because it was unknown to them. I decided to spend my sabbatical year studying this entity. Together with others at the Jean Rostand Hospital, Ivry, France, we published a composite clinical description of ARVD in 1982 (3). In the 15 years since the publication of this paper, there has been considerable progress in our understanding of this disease in the following areas:

A) Familial Incidence and Identification of the Chromosomal Locus of the Disease. Although several early reports stated that ARVD could be present in more than one member of the family, an unusually large prevalence of patients were seen in the out-patient clinic in the cardiology division at the University of Padua Medical School, Padua, Italy, by Professor Nava and associates. In addition, they noted a high incidence of familial cases. They then embarked on a systematic investigation of nine families consisting of 72 members (4). These studies demonstrated that the condition is consistent with a genetic pattern of autosomal dominance with variable and age related penetrance and a polymorphic phenotype: Family members could present with sudden death, overt clinical ventricular arrhythmias, or the concealed form of ventricular abnormalities with no or minimal arrhythmias (5). The large number of family members then permitted genetic studies that resulted in identification of at least 3 disease loci on chromosomes 14q 23-q24, on the long arm of chromosome 14 and also 1q 42-q43 (6,7,8). These investigations should eventually provide precise identification of the gene(s) responsible for ARVD with the ultimate aim of identifying the molecular defect that causes this disease.

B) ARVD as a Cause of Sudden Cardiac Death in Young People Particularly During Exertion. It was a startling revelation that 20% of patients under the age of 35 years who died suddenly and unexpectedly in Northern Italy had histologic findings consistent with ARVD (9). This high incidence has not been duplicated in other studies; nevertheless it did highlight that this condition has undoubtedly been overlooked as a cause of sudden cardiac death in young as well as in older individuals.

C) Standardization of Clinical and Laboratory Criteria for the Diagnosis of ARVD. In the past, the literature pertaining to ARVD has suffered from lack of uniformity of diagnostic criteria. This has not posed a problem in patients who have the typical clinical and angiographic features of this disease. However, it has been difficult to be certain of the diagnosis in patients with the milder forms of ARVD. Recently, standardized diagnostic criteria have been proposed based on the presence of major and minor criteria encompassing structural, histological, electrocardiographic, arrhythmic, and genetic factors (Table 1) (10). Based on this classification the diagnosis of right ventricular dysplasia would be fulfilled by the presence of two major criteria or one major plus two minor criteria or four minor criteria from different groups.

The diagnosis of ARVD is hampered by the fact that it is an unusual disease and many of the diagnostic imaging tests such as echocardiography, angiography and MRI are operator dependent and the operator must understand this condition and perform the test focusing on the right ventricle to look for segmental abnormalities and/or dilatation of this chamber. Criteria and normal values have been established for 2D echocardiography (10) but are not well known. When a physician refers a patient with possible ARVD to have an echocardiogram performed, it is important to be certain that the echocardiographer is aware of this condition and knows what to look for. The appropriate measurements should be made as suggested by Foale et al (11).

The right and left ventricular ejection fractions by nuclear radiography, using the first pass method and the MUGA respectively are well established.

D) Pathogenesis of ARVD Due to Apoptosis. The possibility that ARVD may be due to apoptosis or programmed cell death gone awry is an exciting one. Evidence for this is detailed in the chapter by Dr. James.

E) Clarification of the Pathology of ARVD. Painstaking efforts have been made by several groups of pathologists to clarify the gross and histological pathology of this condition and this is summarized in the chapter by Drs. Thiene and Virmani.

Fontaliran et al (12) have emphasized the characteristic histological features of RVD. They have consistently observed that the surviving myocardial cells should be imbedded or surrounded by a thin rim of fibrous tissue. This is important for differential diagnosis since fatty infiltration of the right ventricular free wall can be a normal variant of right ventricular histology.

Despite the progress noted above there is much information that is lacking about ARVD.

1. Diagnosis. Although it is relatively easy to diagnose this condition in a patient who presents with ventricular tachycardia of left bundle branch morphology with the characteristic ECG changes and echocardiographic features, it can be challenging to be certain that a patient who has ventricular ectopy of left bundle branch block morphology with inferior axis has the entity called right ventricular outflow tract (RVOT) tachycardia and not right ventricular dysplasia. Abnormalities in the right ventricular outflow tract may be present in patients with RVOT tachycardia (13). This latter entity needs to be more clearly defined, particularly with regard to the type and degree of abnormalities of the right ventricle by MRI in order to differentiate it from ARVD.

Magnetic resonance imaging (MRI) is increasingly becoming an important and primary diagnostic tool to confirm the presence of fat in the right ventricular free wall. The cine MRI promises to be particularly useful for the non-invasive demonstration of right ventricular wall motion abnormalities. The technique of performing the MRI is operator dependent and there has not been agreement among radiologists with regard to the optimal technique to perform this test in patients with suspected ARVD. This could result in divergent results due to different sensitivity and specificity for detecting abnormalities of the right ventricle. A consensus of experts who perform this test is needed to solve this problem.

Even though right ventricular angiography is considered the gold standard to confirm the diagnosis, there is no acceptable technique available to physicians at their institution to assess whether indeed the right ventricular volume is normal or whether the wall motion in a particular area of this chamber is normal or slightly or moderately hypokinetic. Thus it is difficult to diagnose a patient who has suspected ARVD but may have minimal angiographic abnormalities. The availability of a computer based analytic system would greatly facilitate diagnostic accuracy in these borderline cases.

The above diagnostic problems are becoming particularly relevant since it is known that the disease is familial. What are the most sensitive yet reliable diagnostic tests to suggest for family members of a patient with ARVD? The MRI may be the single best non-invasive test to determine tissue characteristics and right ventricular wall motion abnormalities and volume. However, the optimal protocol to achieve these goals needs to be determined.

2. Therapy. There is no unanimity of opinion as to which type of antiarrhythmic drugs are most effective, although there is a growing consensus that Class III drugs, including amiodarone and sotalol may be preferable (14). Although physicians may have strongly held opinions as to the best technique to assess drug efficacy (i.e. electrophysiologic testing (EPS), there is no reliable data to indicate that one method or another is more predictive of drug efficacy then empiric treatment. In the ESVEM trial that compared EPS with Holter monitoring in conjunction with exercise testing to assess drug efficacy in a large group of patients primarily with coronary artery disease, there was no difference in outcome (15). Do these results apply to patients with ARVD? Is empiric antiarrhythmic treatment with a Class III drug as effective as EP guided therapy? Which patients with ARVD and sustained ventricular arrhythmia are likely to have cardiac arrest? Since the anticipated arrhythmic death rate is estimated to be only 1% per year, how can patients be selected who are at high risk of arrhythmic death? In patients who do not have ARVD and whose disease primarily affects the left side, left ventricular ejection fraction is a major determinant of drug efficacy. A larger percent of patients will be effectively treated by antiarrhythmic drugs if they have a higher left ventricular ejection fraction. In patients who have a left ventricular ejection fraction of <30% it is not clear if drug efficacy can be predicted by any assessment method. Are these same guidelines applicable to patients with right ventricular dysplasia with regard to right ventricular function? The identification of patients with ARVD who are at high risk with sudden cardiac death has been elusive. Certain risk predictors including a history of syncope or presyncope have repeatedly been observed (16). Other risk predictors include a markedly enlarged right ventricle with spontaneous sustained ventricular tachycardia. However, sudden cardiac death may be the first manifestation of this disease. At what point in time and in whom should implantable cardioverter defibrillators be inserted once the disease has been diagnosed? Should this device be used prophylactically in family members with patients with ARVD who have died suddenly?

It is hoped that the genetic studies will eventually result in the identification a gene that will lead to the elucidation of the molecular abnormality responsible for ARVD. Until then we should strive to standardize diagnostic tests to enhance the accurate diagnosis of this condition. We need to accumulate information in a centralized registry to assist in answering important clinical questions regarding diagnosis and treatment of this condition. Toward this end, an international registry has been established by the author in conjunction with Dr. Fontaine. It is hoped that physicians will cooperate by entering their patients into this registry.

References 1. Sosman MC: In the disorders of cardiac rhythm, edited by Schamroth L. Oxford and Edinburgh, Blackwell, 1971, p 335.

2. Fontaine G, Guiraudon G, Frank R, Vedel J, Grosgogeat Y, Cabrol C, Facquet J. Stimulation studies and epicardial mapping in VT: Study of mechanisms and selection for surgery. In: HE Kulbertus (ed.): Reentrant arrhythmias. Lancaster, PA, MTP Publishers, 1977, pp. 334-350.

3. Marcus FI, Fontaine G, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y. Right venticular dysplasia: A report of 24 cases. Circulation 1982;65:384-399.

4. Nava A, Thiene G, Canciani B, Scognamiglio R, Daliento L, Buja GF, Martini B, Stritoni P, Fasoli G. Familial occurrence of right ventricular dysplasia: A study involving nine families. JACC 1988;12:1222-1228.

5. Nava A, Scognamiglio R, Thiene G, Canciani B, Daliento L, Buja GF, Stritoni P, Fasoli G, Dalla Volta S. A polymorphic form of familial arrhythmogenic right ventricular dysplasia. Am J. Cardiol 1987;59:1405-1409.

6. Rampazzo A, Nava A, Danieli GA, Buja GF, Daliento L, Fasoli G, Scognamiglio R, Corrado D, Thiene G. The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24. Hum Mol Genet 1994;3:959-962.

7. Rampazzo A, Nava A, Erne P, Eberhard M, Vian E, Slomp P Tiso N, Thiene G, Danieli GA. A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43. Hum Mol Genet 1995;4:2151-2154.

8. Severini GM, Krajinovic M, Pinamonti B, Sinagra G, Fioretti P, Brunazzi MC, Falaschi A, Camerini F, Giacca M, Mestroni L, and the Heart Muscle Disease Study Group. A new locus for arrhythmogenic right ventricular dysplasia on the long arm of chromosome 14. Genomics 1996;31:193-200.

9. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988;318:129-133.

10. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, Camerini F, on behalf of 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 the International Society and Federation of Cardiology, supported by the Schoepfer Association. Diagnosis of arrhythmogenic right venticular dysplasia/cardiomyopathy. Br Heart J 1994;71:215-218.

11. Foale RA, Nihoyannopoulos P, McKenna W, Klienebenne A, Nadazdin A, Rowland E, Smith G. Echocardiographic measurement of the normal adult right ventricle. Br Heart J 1986;56:33-44.

12. Fontaliran F, Fontaine G, Fillette F, Aouate P, Chomette G, Grosgogeat Y. Frontieres nosologiques de la dysplasie arythmogene. Variations quantitatives du tissu adipeux ventriculaire droit normal. Arch Mal Coeur 1991;84:33-38.

13. Marcus FI. Is arrhythmogenic right ventricular dysplasia, Uhl's anomaly and right ventricular outflow tract tachycardia a spectrum of the same disease? Cardiology in Review 1997;5:1-5.

14. Wichter T, Borggrefe M, Haverkamp W, Chen X, Breithardt G. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricualr tachycardia. Circulation 1992;86:29-37.

15. Mason JW, For the Electrophysiologic Study verses Electrocardiographic Monitoring Investigators. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias. N Engl J Med 1993; 329:445-451.

16. Marcus FI, Fontaine GH, Gallagher, FR, Reiter, JJ. Long term follow up in patients with Arrhythmogenic Right Ventricular Disease. European Heart Journal 1989; 10 (Supplement D):68-73.