ventricular cardiomyopathy Newfoundland families share fatal disease
By Sharon Gray 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 didnt 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.
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. Winters defibrillator after
this incident showed that he did, in essence, die briefly. When
he came to us we were able to put the defibrillators 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 hadnt 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.
by HSIMS Dr. Sean Connors, principal investigator on
a research study for ARVC in Newfoundland, shows the ICD (internal cardiac
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 arent many jobs you cant 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. Its like having a 911 in your chest.
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 shouldnt be there.
Although Memorials 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 didnt 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 dont 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
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, Memorials 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
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 whats going on at the level of the gene. When that
gene is identified by our colleagues in Berlin, well be able to
drop half the patients from clinical follow-up because well know
they arent 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. Thats 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. Thats why were
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 cant just sit back and wait
until the gene is found.
From Ms. Hodgkinsons 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
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
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. Georges 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. Johns
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 firstname.lastname@example.org