(October 4, 2001, Gazette)

Arrythmogenic right ventricular cardiomyopathy
Newfoundland families share fatal disease

Corey Winter with his wife Christine and son Travis.Submitted photo
Corey Winter was cutting wood in February 2000 when his heart stopped. He was brought back to life by an internal cardiac defibrillator. This photo, taken shortly before the birth of his second son, shows Corey with his wife Christine and son Travis.

In February 2000, a 28-year-old man in the Clarenville area was working alone in the woods with a chainsaw. He suddenly felt strange, put the chainsaw down, and didn’t know anything else until he awoke on the ground.

Luckily for Corey Winter, he was already a research patient at Medical Genetics in the Faculty of Medicine. Because of his family history of sudden cardiac death, he had been through a number of clinical investigations and was determined to be a candidate for a rare genetic condition known as ARVC (arrythmogenic right ventricular cardiomyopathy). Cardiologist Dr. Sean Connors installed an ICD, or internal cardiac defibrillator, a preventive measure that saved his life basically by acting as an internal “electric paddle” to restart his heart.

“Newfoundland probably has the highest incidence of this condition in the world,” said Dr. Connors, who heads up a research project investigating the genetics and treatment of ARVC.

Elizabeth DicksPhoto by HSIMS
Elizabeth Dicks, research nurse coordinator, spends half her working time on the ARVC Study. Ms. Dicks is seen above at her desk with her laptop and ECG machine. She demonstrates the light weight of the ECG in the inset photo.

Elizabeth Dicks, a research nurse-coordinator who works part-time on the ARVC study, said analysis of Mr. Winter’s defibrillator after this incident showed that he did, in essence, die briefly. “When he came to us we were able to put the defibrillator’s record on a computer and interrogate it. We could see the events that happened 24 hours previously and see that his heart stopped for a number of seconds before it kicked in and he was able to walk out of the woods. Can you imagine the devastation it would have caused his wife and young family if he hadn’t had that device installed?”

For Dr. Connors, assistant professor of medicine (cardiology), ARVC patients are only too familiar. “The problem is that the people affected often have no symptoms, so the first time we know that they have this disease is when they die. However, we are now able to show through our research study that members of these families have a similar clinical picture, a specific electrocardiogram (ECG) pattern. If we determine an individual is at high risk then we can install an internal cardiac defibrillator, which we check every six months.”

Dr. Sean ConnorsPhoto by HSIMS
Dr. Sean Connors, principal investigator on a research study for ARVC in Newfoundland, shows the ICD (internal cardiac defibrillator).

Dr. Connors jokingly refers to the ICD as the “Dick Cheney” device in reference to the U.S. vice-president, who has one. “More people are now familiar with this device and are less apprehensive at having it installed. In fact, I put two in yesterday,” he said last Wednesday during a Gazette interview.

The small ICD is installed just under the collarbone. Because of the relatively large number of ARVC patients in the province, Newfoundland is among those Canadian provinces that offer this service. The cost of an ICD versus a pacemaker is higher — about $23,000 versus $5,000, but for a young man it can mean many years of good-quality life.

“There aren’t many jobs you can’t keep doing once this device is installed,” explained Dr. Connors. “The only real restriction would be something like arc welding where there is a strong electrical discharge that might interfere with the device. But otherwise there is no interference from everyday items like microwaves and cell phones. It’s like having a 911 in your chest.”

Map showing location of ARVC families Map showing location of ARVC families

Although there are few successes in the new world of ARVC research and treatment (the research project at Memorial is less than two years old), there are many more frustrations and disappointments. Ms. Dicks explained that one of the problems is that there is no single test to determine if a person is at risk for ARVC. “We are presently doing a series of investigations which include an ECG, a signal-averaged ECG, a Holter monitor, an echocardiogram and a MRI (magnetic resonance image). We then look at all of these to see if we can find differences from the norm or similarities that really shouldn’t be there.”

Although Memorial’s ARVC study is relatively new, one person has been working on research and counseling for this disease for the last six years. Kathy Hodgkinson started as a genetic counselor and quickly became interested in the research aspect of the sudden cardiac death families.

“When I began to work with Medical Genetics in 1995, some of the families here had been referred for ‘cardiomyopathy,’ a catch-all phase that didn’t offer a diagnosis,” she explained. “We knew there were a group of families where there were a lot of cardiac deaths with different parts of the family having different diagnoses. But you usually don’t have three different cardiomyopathies (chronic disease of the heart muscle) in the same family. I began to sort the families and so far have been able to define a population of about 5,000 people in nine families. The smallest extended family pedigree is about 200 people. We know all of them must be related because they all share the same DNA haplotype on the short arm of Chromosome 3 — they share a linked set of markers.

“In effect this means that we are able to determine in some family members those who are at a genetically higher risk of having the gene,” said Ms. Hodgkinson. “This is possible because we have DNA samples from many individuals over several generations, and can ‘follow’ the high-risk Chromosome 3 from affected individual to affected individual. The ARVC gene is somewhere in the linked set of markers. In effect, we know which ‘street’ the gene is on, but we still need the house number.”

Pieces of the puzzle

While the health-care services for ARVC patients come through MCP, research investigations must look to other sources of funding. To date, Memorial’s ARVC study has received $40,000 from the Newfoundland and Labrador Centre for Applied Health and further funding is anticipated through the Regional Partnership Program of the Canadian Institutes of Health Research.

Researchers involved in this study all agree they are slowly putting together pieces of the puzzle that will eventually result in identifying the gene for ARVC. Ms. Hodgkinson said there is a unique opportunity in Newfoundland to study a population which shares a similar haplotype. “We want to understand what’s going on at the level of the gene. When that gene is identified by our colleagues in Berlin, we’ll be able to drop half the patients from clinical follow-up because we’ll know they aren’t at risk,” said Ms. Hodkinson.

Ms. Dicks added that it is encouraging to know that the gene is on the short arm of Chromosome 3. “That’s a whole lot more information than we had three years ago.”

The worst part of researching this disease is seeing close-up the anguish it causes in families. Ms. Dicks recounted that there are some families in the study who have lost two sons to sudden cardiac death, in addition to other male relatives. “Even though we know how malignant and how serious this disease is, affecting males as young as 17, we have patients where there are almost no signs and symptoms. That’s why we’re beginning to investigate children in these families from about age 10. We hope to start an ARVC clinic at the Janeway, working in collaboration with Dr. Suryakant Shah.

“We can now tell people in these families whether they have the high-risk haplotype or low-risk,” said Ms. Dicks. “Some, however, do not have their genetic risk changed. This is because genetic recombination can occur in the formation of egg and sperm, disrupting the linked markers. We are hoping that more research with clinical tests will determine a clearer way to make the diagnosis. We can’t just sit back and wait until the gene is found.”

From Ms. Hodgkinson’s point of view, the really important part of this study is to keep the families fully informed about research findings. “I believe people have a right to know any results and we have always taken it as our policy that any genetic information we get is available to the families — as long as they understand the limitations of the research and potential reasons why the information we give them may not be completely correct.

“Family members participate for many reasons. In some families it is very difficult to come to terms with the knowledge that they have a disease and that it is inherited,” said Ms. Hodgkinson. “But our position is that if we do identify people early, we now have a treatment that can really help them. This is different from the experience of previous generations, and provides hope where none previously existed.”

What we know

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disorder that can have widely different symptoms even in the Newfoundland families who share a common haplotype (a set of genetic markers located on a single chromosome). It is considered the second-most common cause of sudden cardiac death in young people, assuming that it is always correctly diagnosed.

Some features of ARVC include electrocardiographic (ECG) polarization changes, abnormalities of the structure and function of the muscular tissue of the heart, and symptoms such as arrhythmias of right (sometime left) ventricular origin, or sudden cardiac death. From a pathological point of view, the disease is characterized by the right (sometimes left) heart muscle tissue being replaced by fibre and fat.

Probably 90 per cent of ARVC cases are genetic, with an autosomal (non sex-determining) dominant mode of inheritance. This means that for any person carrying the gene, there is a 50/50 chance of any child of theirs also carrying it. For unknown reasons, the disease affects men more severely than women, and at a younger age. In the Newfoundland population, recent statistical analysis has shown that before treatment, 80 per cent of men with the gene were dead by age 50.

About 5,000 individuals in the province have been mapped on family trees spanning nine generations. Although the gene has not yet been cloned, the disease is on the short arm of Chromosome 3 at position 25.

The research team

ARVC in Newfoundland is being researched by a team that includes principal investigator Dr. Sean Connors, Cardiology, Faculty of Medicine; molecular genetics collaborator Ludwig Thierfelder, Max-Delbreuck Centre, Berlin, Germany; and external clinical collaborators Drs. Mark Norman and William McKenna, St. George’s Hospital, London, England. At Medical Genetics in the Faculty of Medicine, Kathy Hodgkinson is the researcher, genetic counselor and a PhD student. Elizabeth Dicks is the part-time research nurse. Pathologists involved in the project include Dr. Barry Gallagher of Gander and Dr. Vincent Falk, formerly of Grand Falls-Windsor. In St. John’s the pathologists involved are Drs. Lynn Morris-Larkin and Simon Avis. Dr. Patrick Parfrey is the senior researcher responsible for the clinical epidemiology section of the research.

Further information about ARVC may be obtained from Ms. Dicks at 777-8040 or by e-mail at edicks@mun.ca