2005 ARVD Family Conference Summary April 30, 2005
by
Joe Kovarik

Speakers from Johns Hopkins:

Hugh Calkins MD, FACC
Director, ARVD Program
Professor of Medicine and Pediatrics
Director of Electrophysiology Cynthia James, ScM, PhD
Geneticist
Genetic Counselor Crystal Tichnell, MGC
Program Coordinator
Genetic Counselor David A. Bluemke, MD, PhD
Associate Professor, Radiology
Clinical Director, MRI Daniel Judge, MD
Assistant Professor of Medicine
Cardiomyopathy and Heart Failure Practice
Genetics

Stuart Russell, MD
Associate Professor of Medicine
Clinical Director, Cardiomyopathy and Heart Failure Practice
 

Guest Speakers:

Guy Fontaine, MD, PhD, HDR
Director of Research, Bicetre, Paris, France
Fellow of the FACC, FESC, FAHA
International Fellow of the American Heart Association
Coordinator French ARVD registry
Partner of European ARVC/D registry

Dr. Jeffrey A. Towbin, MD
Professor, Departments of Pediatrics (Cardiology), Cardiovascular Sciences, and Molecular and Human Genetics
Chief, Pediatric Cardiology, Texas Children's Hospital
Texas Children's Hospital Foundation Chair in Pediatric Cardiac Research, Texas Children's Hospital
Director, Phoebe Willingham Muzzy Pediatric Molecular Cardiology Laboratory
Medical Director, John Welsh Cardiovascular Diagnostic Laboratory
Medical Director, Pediatric Heart Failure and Transplantation Service, Texas Children's Hospital, Baylor College of Medicine, St. Luke's Episcopal Hospital, Texas Heart Institute
Co-Director, Cardiovascular Genetics Clinic, Texas Children's Hospital
Director of Research, Department of Pediatrics (Cardiology)
 

I drove down from Philadelphia where my daughter lives. Since I wasn't sure how long it would take, I left quite early and was the first to arrive at 7:00AM. The bad timing of this early arrival earned me a door prize of a nice JH coffee mug for being the first one there.

I'm going to try to summarize from my notes. Please understand that I was writing rapidly so may have made some mistakes in spelling and meaning. Take whatever I write as being from imperfect notes meant to convey the gist of the lectures.
 

Hugh Calkins opened with an introduction of the JH program and an overview of ARVD:
Some statistics he noted about ARVD:

• Its occurrence is 1 in 5000 people
• It accounts for 20% of the sudden cardiac deaths (SCD) of those under 35
• It rarely progresses to right heart failure

Cindy James and Crystal Tichnell then spoke briefly on the JH program and their roles, and then gave a review of the days agenda.

Dr. Calkins next went into more detail of the JH program:
The original purpose was to look at the US experience of ARVD and to see if it differed from ARVD in other countries. They examined 100 cases of ARVD of which 69 were diagnosed with ARVD while living. At the last follow up, 66 patients were alive of which 44 had an ICD in place, 5 had signs of heart failure, 2 had a heart transplant, and 18 were on drug therapy. Thirty-four patients died at presentation or during follow-up.

• A family history was observed in 32 patients
• 2 of the 69 had received a heart transplant
• Half of the patients were athletic
• Palpitations and syncope were the most common symptoms
• 21 presented with sudden cardiac death
• 15 were asymptomatic at presentation

He then showed a time line of each patient. The time line depicted ages on initial symptoms, diagnosis of ARVD, events such as syncope, ICD implantation, ICD firings, and, as appropriate, death or transplant. The combined graph of all patients very well depicted the varying age of onset, an undiagnosed phase, and periods of non-events.
 

Dr. Fontaine then spoke about his early years investigating ARVD:

He mentioned that "Right Ventricular Cardiomyopathy" is a descriptive term which includes subgroups that may have totally different characteristics depending on environmental and/or genetic factors. He outlined each of the subgroups giving a brief description of each of them:

1. Pure form of patent ARVD...
2. Uhl's anomaly...
3. ARVD mimicking Uhl's anomaly...
4. Pure form of Biventricular Dysplasia...
5. Dysplasia complicated by Myocarditis...
6. Right Ventricular Outflow Tract Tachycardia and so-called "Benign Extrasystoles"...
7. Venetian Cardiomyopathy...
8. Desmoplakin Right Ventricular Cardiomyopathy...
9. Ryanodine Right Ventricular Cardiomyopathy...
10. Plakoglobin Right Ventricular Cardiomyopathy (Naxos Disease)...
11. Desmoplakin Right Ventricular Cardiomyopathy...
12. Plakophilin Right Ventricular Cardiomyopathy...
13. Fat Dissociation Syndrome...
14. Brugada syndrome...
15. Miscellaneous: Biventricular Spongy Dysplasia, Carvajal Huerta disease, association with cardiac Sarcoidosis, syndrome X…

He reminded...

"However it should be kept in mind that in all aspects of RV cardiomyopathies, presence of arrhythmias is only observed in case of particular electrophysiologic properties in some parts of myocardium, therefore the non-arrhythmogenic forms of the disease may be as frequent or more frequent than the arrhythmogenic forms.

The histologic pattern of typical ARVD in patients devoid of arrhythmias is observed in 3.7% of the general population."

My impression was that all of the above had genetic background – but that they could possibly be triggered by environmental circumstances (e.g. virus, exercise, stress.)

He then addressed some questions he had from our Support Group as submitted by Tink.

He has concluded that ARVD patients are more susceptible to virus than those without ARVD.

He mentioned that the first symptoms in children are racing heart, irregular beats, chest pain, and heart pain - which may wake the children in the night.) He gave possible explanations for this pain, "arrhythmias or coronary spasm (small vessel disease.)"

He recommended that ARVD patients avoid competitive sports.

He commented that adults should not participate in endurance sports since it stretches the myocardium.

His explanation of disease progression was when more and more myocardium is replaced by fat and fibrous tissue.
 

Dr. Bluemke then reviewed MRI's:

JH has done pioneering work to use the MRI as the gold standard for diagnosis of ARVD. He showed MRI images of normal and diseased hearts, and it was very clear to identify the disease. JH has developed a technique to do MRI on persons with pacemakers and in limited cases ICD's.
 

Dr. Towbin next discussed the genetics of ARVD:

He gave a brief primer on genetics and basically pointed out that when genetic code on the chromosomes is abnormal, it will cause a disease. What and where the abnormality is will influence the type and severity of ARVD.

He reviewed cell structure and talked about the desmosome which is the cell-cell junction that connects the plasma membrane, it is the glue of the cells. It can breakdown because of a faulty genetic message, which leads to the onset of the disease. Dr. Towbin described several genes causing ARVD and the majority of these encode desmosome proteins.

He postulated that in some patients a virus in the myocardium can be the cause of the disease as it triggers the disease by causing inflammation in the heart that may disrupt the desmosome. His studies have shown that less than 1% of the normal population have the virus but it is present in a significant number of ARVD patients. He believes this may cause 10-20% of ARVD. (I didn't write down, nor do I remember, any more detail about this virus discussion.)

He speculates that within 5 years blood tests will be available that can eliminate or establish the diagnosis of ARVD. Currently they do not know enough about the interplay of all the genes.

He also postulates that the addition of extreme exercise in someone with a genetic abnormality of the desmosome stretches the myocardium and cell "glue" desmosome. Over time the desmosome may breakdown making it more susceptible to ARVD disease, hence we often see a late onset of the disease.
 

Dr. Judge then reviewed the JH genetics program and emphasized the difference between research genetic studies and clinic genetic results:

JH is a research clinic and cannot convey specific results to the patients however, if a result becomes available, they will notify the participant and help arrange for clinical confirmation of a research. Any costs of clinical tests would be borne by the patient.

He noted that more ARVD patients appear to have a gene change or mutation in the plakophilin gene (PKP2) than any other gene identified to date (30-40%) and can be tested for it. Genetic testing is not available for everyone.
 

Dr. Russell next spoke of heart failure management:

He noted that hard exercise may trigger SCD and should be avoided, also that SD may be prevented through lifestyle change and exercise management. He then reviewed exercises that could and could not be done.

He reviewed the VO2 measurement as a good means of evaluating heart failure.

He then briefly reviewed heart transplants, noting that in the JH study heart transplant was relatively rare (2 of the 100). Some relative statistics are:

• 10 year survival rate is 50%
• About 70% of the heart transplants do not work primarily because of insurance and medical cost issues
• About 90% of heart transplant patients have no limit on their activity.

We all then broke from a very nice lunch, with some patients and families going to the hospital area for testing.

Some individuals then joined Dr Fontaine in a smaller and more intimate environment:

His charming personality and genuine concern for patients really had an opportunity to come out during this session. Some highlights of this period are:

• A forensic study was done in France. This study reported that 3.5% of the Sudden Deaths had the presumable cause of ARVD and occurred during sports. In the JH population they have learned that 50% of their population were active in competitive sports before their diagnosis. In Dr. Fontaine's population they have learned that 75% were active in competitive sports before their diagnosis.
• Most experience arrythmias during routine activities.
• In Europe they are making AED readily available to the patient in his home.
• Dr. Fontaine paid tribute to Tink (one of our online Support Group moderators, living in California) and commented that he spent a few days with her at her home. He suggested that an event such as the JH ARVD Family Conference be held on the West Coast to reach more people.
• He spoke some of possible stem cell therapy. In essence he said there may be some possibilities but there is a lot of research to be done.
• He thinks environmental and other factors play a major role in ARVD.
• I asked if a virus could cause ARVD even without a genetic abnormality. He noted that research done in Japan had isolated some viruses that impacted only the right side of the heart, so he speculated that it was possible that a virus alone may cause ARVD.
• There is no direct correlation between number of AICD shocks and progression of the disease.
• He noted recent advances in the use of lasers to remove leads. This would be particularly beneficial to young people who may have to have leads removed.

And that is about it. I finally left around 5:00PM.

In Summary: The meeting was of great benefit. I hope my notes will help to convey that which was communicated at the meeting. Keep in mind they are probably incomplete and, in many cases, reflected opinions of the doctors rather than proven/published research. My only criticism would be that there was not enough time for questions and answers from the audience. Dr. Calkins worked hard to keep it all on track and on schedule.

Joe Kovarik
 

EDITORIAL NOTE:

Joe Kovarik was 44 years old when he was originally diagnosed with ARVD. His first probable indication of having this SD disease was in 1967 when he was 21 years old. At that time, a physical examination showed that he had an inverted T-wave. It was concluded that this was, "just an anomaly, nothing to be concerned about."

In the mid 1980s, Joe took up "recreational running." Recreation led to his "frankly becoming a little obsessed" in reaching "the level of running the Pike's Peak Marathon." This mountain race climbs 7500 feet and 13 miles to the summit of Pike's Peak.

In 1985, training became more difficult for Joe. He began to feel faint during some of his runs. These episodes occurred several months apart and were considered to be "quite mild." They were thus attributed to "too much heat, not the right diet, not enough sleep etc."

Running less, Joe continued to do a lot of summer mountain climbing and winter skiing. In late 1989, he had three episodes of fainting in a relatively short period of time. One occurred while he was hiking, another while he was running and the last while he was skiing. It was at that point in time that Joe realized something was wrong and went to see a doctor.

In 1990, Joe was diagnosed with ARVD. In July of 2001, he received a heart transplant due to right heart failure.

Currently, Joe serves as a member of the external advisory board of the Colorado University Cardiovascular Institute. Their mission is to eliminate heart disease through the corroboration of University researchers, biologists, geneticists, and cardiologists.