Update on Arrhythmogenic Right Ventricular Cardiomyopathy / Dysplasia: Interview with Frank I. Marcus, MD

Results from the North American Multidisciplinary Study, published in the HeartRhythm Journal, the official journal of the Heart Rhythm Society, provide new information about the diagnostic evaluation of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).1 In this interview, we learn more about ARVC/D from Principal Investigator Dr. Frank Marcus at the University of Arizona. What was the purpose of the Multidisciplinary Study of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia? The major purpose was to study the clinical characteristics and diagnostic evaluation of a large group of patients with newly identified arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). I would like to emphasize the term ‘newly diagnosed’, because the literature is besieged with information from patients with severe disease and their clinical findings may be quite different from patients who are newly diagnosed with ARVC/D and who may not have major enlargement or abnormalities of the right ventricle. We were also interested in obtaining information about how accurate and efficient the various tests are for the diagnosis of the disease as well as studying the genetics of ARVC/D. How many patients were enrolled, and what were the start and completion dates? There were a total of 108 newly diagnosed patients with suspected ARVC/D. They were enrolled in the study from 2001 to 2008. Tell us about the proband population makeup. In addition, how many had previously been competitive athletes? The age at enrollment was 39 ± 14 years. Thirty-four percent of these patients participated in competitive or professional sports prior to diagnosis, and of these, 68 percent were male. There also was an additional 36 percent of patients who were active in recreational sports. Thus, a very high percentage of patients were very active in competitive or recreational sports. Tell us about arrhythmogenic right ventricular cardiomyopathy/ dysplasia. Who does it affect? How many patients are affected in the United States? In the literature, the ratio of men to women is quite variable, with as high a male/female ratio of 3:1. In our study 58 percent of the patients were male, so it was an almost equal male/female ratio. We do not yet know how many patients are affected by ARVC/D in the US, but in some parts of the world, the disease can account for up to 20 percent of sudden cardiac deaths (SCDs) in individuals below the age of 35. What advancements have been made in ARVC/D over the last few years? Tell us about the genetic findings. About 50 percent of individuals with this disease have genetic abnormalities. In patients who have a family history of the disease, that percentage increases to about 70 percent. The most common genetic abnormality is in a gene called plakophilin-2 (PKP-2). The genetic abnormality primarily involves proteins at the gap junction that are responsible for holding the cells together and maintaining cell integrity, both mechanical as well as electrical. It is important, however, to realize that there is not a strict relationship between the presence of a genetic abnormality and the expression of the disease. In our study, for example, in families that have the gene, one individual can be affected and have cardiac problems, whereas another will have the same gene and have no abnormality. A minority of patients will have 2 genes that are affected, and when this occurs, the expression of the disease may be more severe. One of the important lessons we have learned from our study is that it can be difficult to be certain about the diagnosis. We have found that the interpretation of the tests, particularly the imaging tests by MRI or echocardiogram, from the referring center may be quite different from the interpretation of the tests by the experts at the core laboratories. This is important, because a number of patients are referred for the diagnosis of ARVC/D based primarily on some abnormality of the MRI. Careful analysis of the imaging study may not confirm the possible abnormality. Thus, the disease can be overdiagnosed, and that is a major problem because the individual could be implanted unnecessarily with a defibrillator. It could also initiate evaluation of family members suspected with the disease, which is completely unnecessary and can provoke a great deal of anxiety. In 1994, it was recognized that ARVC/D was difficult to diagnose. A task force was established and recommended a number of major and minor criteria that are required in order to assist in the diagnosis. It is important for clinicians not to rely upon any one test to make the diagnosis, but to utilize the task force criteria. Recently these criteria have been revised to be made more quantitative; these were established by a task force and this report has been submitted to Circulation for consideration. Which tests showed a better diagnostic performance when performed individually and when evaluated in combination? We are not absolutely certain about that, since not all of the tests were done in all of the individuals, but the best performance was achieved when the echocardiogram, RV angiogram, electrocardiogram, signal-averaged ECG, and Holter were used. These were the tests that were found to be most useful either singly or in combination in order to make the diagnosis. However, it is important that all of the tests be considered; for example, RV biopsy was not included among the most valuable tests. On the other hand, we found that in addition to the 108 patients with ARVC/D, there were 4 patients who met all the criteria for RV cardiomyopathy/dysplasia, but were found to have sarcoidosis that was established either by cardiac biopsy or lymph node biopsy. Therefore, the biopsy has utility under certain circumstances. What were some of the unique aspects of this study? The major aspects were that it was a large group of patients studied systematically, generally with the same diagnostic tests that were reevaluated by experts in core laboratories so that the initial interpretation could be compared with an interpretation by experts. Frequently it was found that the MRI was overinterpreted by the hospitals or physicians who referred the patients for enrollment. I think this is related to the fact that the MRI is often very difficult to interpret. What further testing will be done? We are applying for another grant from the National Institutes of Health to do follow-up studies on the individuals who were enrolled from selected centers. We are also planning to enroll more patients to enhance our knowledge of the genetics as well as the molecular basis of the disease. That is being planned in conjunction with Dr. Jeffrey Towbin at the University of Cincinnati, Dr. Jeffrey Saffitz of Harvard University, myself, and Dr. Luisa Mestroni from the University of Colorado. This is in addition to the data coordinating center under the direction of Dr. Wojciech Zareba and the core laboratories. What treatments are available for ARVC/D? Treatments are primarily directed to either the prevention of sudden death or for the prevention or treatment of ventricular arrhythmias. Over 70 percent of the patients in our study were treated with an implanted defibrillator. Other treatments include ablation of the ventricular arrhythmias by radiofrequency energy, and there is progress being made in the technique of ablation, specifically epicardial ablation. An important question that needs to be answered is whether drugs that decrease the force of the contraction of the heart, such as beta blocking drugs or other agents, can decrease the progression of the disease. At the present time we recommend that individuals who either have the genetic abnormality or have the disease restrict their physical activities so that the heart is not stressed. Is there anything you’d like to add? I think we have made some good progress, and we look forward to improving the criteria for the diagnosis of ARVC/D by modifying the task force criteria. I think the next big steps are studies at the molecular/therapeutic level to try to prevent progression of the disease and to be able to accurately risk stratify the patients with ARVC/D.