ARVD Study Update: Interview With Frank Marcus, MD

Dr. Marcus from the University of Arizona Sarver Heart Center in Tucson, Arizona, and a founding member of its cardiology program, is Principal Investigator of the Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD) study. ARVD primarily affects the heart muscle in the right ventricle, causing potentially fatal ventricular arrhythmias. It accounts for a significant percentage of sudden death in athletes and young people, and is responsible for about 5% of unexplained cardiac deaths for those under the age of 65. The study is funded by a 5-year grant from The National Institutes of Health (NIH). There are 22 enrolling centers in the US and Canada.

How did you get involved in the field of EP? It was in 1979 or 1980 when I decided to change my focus of research. Before that time, I was involved with cardiac pharmacology that was primarily focusing on antiarrhythmic drugs and pharmakokinetics of antiarrhythmic drugs, as well as drug interactions. At that time, I decided to take a sabbatical and try to change the focus of my research, so I decided to do that in electrophysiology.

When did you first begin to study ARVD? What made you get involved in this trial? Had you treated ARVD patients before? I visited a number of labs to determine which would be the best for me to study EP. I decided to do that with Dr. Fontaine in Paris, France. At that time, I was introduced by Dr. Fontaine to patients with right ventricular dysplasia. I had not known of this disease before there had never been a clinical profile of these patients in the literature. He had a number of these patients and I was certain after seeing them that we were missing them. Therefore, I decided to make that the focus of my sabbatical, and in 1982 I published in Circulation the profile of right ventricular dysplasia in patients. Thus, that was the origin of my interest in EP as well as in right ventricular dysplasia. Subsequently I decided to become more proficient in ablation, particularly in supraventricular arrhythmias, and in 1994 I took a six-month sabbatical with Dr. Michel Hassiguerre in Bordeaux, France. I then returned to the University of Arizona, where I started to do ablation for supraventricular arrhythmias such as WPW, AVNRT, etc.

Are you still performing procedures or are you primarily working in the ARVD study? I am no longer in the lab. I am fortunate that I have two excellent, well-trained colleagues Drs. Peter Ott and Julia Indik who are doing the procedures. I now spend most of my time on the ARVD study.

Who does ARVD affect? Does it occur commonly in athletes? It has a predisposition to affect males more than females the ratio has been a variable in literature, but is approximately about 2 to 1. It also is more prevalent clinically in competitive athletes, but we certainly find this disease present in the elderly and in non-athletes as well.

What do you know about the genetic makeup of ARVD? How is it diagnosed? ARVD appears to be endemic in the Venetian area in Italy, and there is a prevalence of familial disease. It is difficult to study the familial impact in the United States because the families are so scattered, whereas in places like Italy, they are much more concentrated in the same area and it is easier to study them. However, in general about 30-50% of the patients with arvd have been reported to have a familial disease, if one systematically studies family members with echocardiograms, signal-averaged ECG and ECG.

Describe stepwise screening, in which first-degree relatives are screened. It is generally advised that this be done because of the familial nature of the disease, and because one would like to identify affected members early to try to prevent the relatively small incident of sudden cardiac death that may occur in family members.

What is the goal of the study? There are a number of objectives. One is to establish a North American Registry of patients and their family members based on standardized diagnostic test criteria, and to study them in a prospective longitudinal follow-up, so we can get more information about the disease, because any one center sees only a few of these patients per year. Also, one of the goals is to try to identify the chromosomal loci and specific gene mutations associated with this disorder. Finally, we would like to determine the influence of the genotype on the clinical course of patients with ARVD and explore the genotype/phenotype associations. We hope this will contribute to improved diagnosis, risk stratification, and therapy.

What treatments do you see becoming available for ARVD? ICDs? What other advances do you think will occur in EP in coming decades? We hope to identify which patients are at risk and which patients are at much lower risk, so we can utilize the present therapies that we have now in a more logical fashion. At the present time, we do not have information as to how best to risk stratify patients with right ventricular dysplasia. If we have information as to who is at high risk, then those patients would certainly deserve to be treated with automatic implantable defibrillators. Those patients who were low risk would not have this therapy. Even though this is an effective therapy, these individuals are still young and would be subjected to life-long treatment with icds, including all the complications associated with its long-term use. With regard to therapy, we would like to determine which antiarrhythmic therapy or combinations of therapy would be most effective so we can select patients more carefully for this type of treatment. When we are able to identify the genes, this will give us an idea of the biochemical basis for the disease and give us a focus of how to counteract the defect. This will hopefully produce a therapy that will be available in the future.

Is there anything else you would like to add? This trial will be successful only with the cooperation and collaberation of electrophysiologists throughout North America. I would urge electrophysiologists who have patients suspected of having this disease to refer their patients to the enrolling centers for registration and evaluation in this study. One of the advantages to their patients is that they are studied with a systematic protocol; it can be difficult to be certain about the diagnosis of arvd, and it is important to make this diagnosis. Physicians and electrophysiologists can obtain information about enrolling centers at our two websites: www.arvd.org and www.arvd.com.

Where are the enrolling centers? Is this trial limited to those only in the United States? There is also a European Registry that we are collaborating with and have shared our database and our website with this Registry, but ours is a separate study. We continually update the information on ARVD and share this with physicians at national meetings.

The facts:

Occurs more commonly in men than women. It is most commonly diagnosed in adults aged 20-30. Currently, ARVD is difficult to diagnosis since there is no single test which can definitively make the diagnosis. Tests include echocardiograms, ECGs, exercise stress tests, Holter monitors, chest X-rays, MRIs, and EP studies). It is believed that not everyone who inherits the gene will develop symptoms of ARVD. An affected person has a 50% chance of passing on the gene to his or her children.

The study is recruiting newly diagnosed patients who do not yet have an ICD/defibrillator or have had an ICD implanted within the last 6 months. Each of these patients will be evaluated with standardized non-invasive and invasive tests to confirm the diagnosis at one of the participating enrolling centers. Family members of an affected individual will also be asked to undergo non-invasive testing. Several of the tests will be sent to carefully chosen core laboratories for their expert opinion. Genetic studies will be carried out in an effort to find the genes responsible for ARVD and to see how the genes affect the onset, course, and severity of the disease in an individual or in a family. The primary goal is to identify 100 patients with definite ARVD and their family members.