BOXERUpdate - ARVC2 GENE VARIANT IDENTIFIED Another Piece to Aid Understanding of the Boxer Heart Disease
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BOXER Update
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A NESTLÉ PURINA PUBLICATION DEDICATED TO BOXER ENTHUSIASTS VOLUME 20 | SPRING 2022
ARVC2 GENE VARIANT IDENTIFIED
Another Piece to Aid Understanding
of the Boxer Heart Disease
SPRING 2022
DISCOVERY OF SECOND ARRHYTHMOGENIC
RIGHT VENTRICULAR CARDIOMYOPATHY
GENE VARIANT IN BOXERS
PROVIDES ANOTHER TESTING TOOL
Arrhythmogenic right ventricular
PHOTO: ALEXANDRIA GAV
cardiomyopathy (ARVC) is a Boxer
heart disease with a lot of loopholes.
Although a dog may inherit a copy
of the ARVC1 or ARVC2 deletion
mutations, some Boxers never
develop clinical signs. Others have
mild, medically manageable cases.
Then, there are those Boxers that
have neither mutation, yet they
develop the potentially fatal disease.
ARVC occurs in adult dogs on
average at 6 years of age, often
after they have been bred. The
inherited disease affects the
heart’s electrical system and too
often results in sudden death or
congestive heart failure.
The latest discovery in 2021 of
a second gene variant (ARVC2),
believed to be an autosomal domi-
nant mutation, in a regulatory gene
involved in important cardiac proteins
comes with a disclaimer: Incomplete
Penetrance. Translated, this means
that not all Boxers testing positive
for ARVC2 will develop the disease.
A sense of déjà vu prevails. In
2008 when the first gene variant
(ARVC1) was identified in a gene
producing striatin, a key binding
protein that holds cells together,
it also was described as having
incomplete penetrance. Some dogs
that inherit a copy of the auto-
somal dominant ARVC1 deletion
mutation die suddenly following
a run of ventricular premature
“Wyatt” was diagnosed with ARVC at 3 years of age, earlier than the average age of complexes (VPCs), yet others
6 years. Despite having the heart disease, he went on to earn titles in obedience, rally and
coursing ability. When he passed away in August 2021 at nearly 9 years of age, his owner succumb over time from conges-
said she was blessed to have had an extra five and half years with him after the diagnosis. tive heart disease. As described
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BOXER Update
earlier, some dogs do not show
clinical signs or are mildly affected. CHIC HEART TESTS FOR BOXERS
“Incomplete penetrance is a poorly
understood concept that is very Among the recommended tests for Boxers to be eligible
common in human genetics as well. for certification by the Canine Health Information Center
The human form of ARVC is also (CHIC) are two tests to help identify dogs at risk for
complicated by incomplete pen- arrhythmogenic right ventricular cardiomyopathy (ARVC):
etrance,” says Kathryn M. Meurs, • An advanced cardiac examination by a board-certified veterinary
DVM, PhD, DACVIM (Cardiology), cardiologist that includes a Holter monitor test
the Randall B. Terry Distinguished • ARVC DNA test
Professor of Comparative Medicine The Orthopedic Foundation for Animals, working with the American
and Associate Dean of Research at Boxer Club, recommends these screening tests, along with a DNA
North Carolina State University. “In test for degenerative myelopathy and testing for hip dysplasia and
Boxers, we can identify which ones autoimmune thyroiditis, for all breeding stock. Dogs meeting these
have the ARVC1 and ARVC2 gene basic health screening requirements will be issued CHIC numbers.
mutations, but we cannot predict Note that for CHIC certification, a dog’s testing results do not need
the penetrance. This suggests that to be normal but must be made public so that responsible breeders
multiple genetic and nongenetic can make informed breeding decisions. In addition to these health
factors may contribute to whether requirements, a dog must be permanently identified via a microchip
a dog develops this disease.” or tattoo to qualify for a CHIC number.
In humans, the rare, familial heart
disease has been linked to 141 muta-
tions in eight genes. As with dogs, if there was another cause of ARVC.
fatty, fibrous tissue replaces normal She is the pioneer of this disease.
heart tissue and interrupts the Our collaboration led to her finding
heart’s normal electrical function- the first ARVC mutation after seven
ing. Occurring in young, apparently years of research. At the time, we
healthy individuals, ARVC may were elated, though we were seeing
GENETIC TESTING FOR
cause ventricular tachycardia and some dogs that were negative for
ARVC IN BOXERS
sudden cardiac death. ARVC1 that had clinical signs and
“The functionality of the genes we were dying.”
Genetic testing for the ARVC1
have identified in Boxers is very “Breeders should use mutation
and ARVC2 gene variants is
similar to what is currently known testing along with health testing,”
available via the Veterinary
about the disease in humans,” Dr. Dr. Meurs advises. “These tests are
Cardiac Genetics Laboratory at
Meurs says. “We have known for tools to guide breeding decisions
North Caroline State University.
several years not all Boxers that rather than to be used as an absolute
The cost for a combined test for
develop ARVC have the striatin gene recommendation for all dogs. Dogs
ARVC1 and ARVC2 is $70, and
mutation. It is similar to humans that carry these mutations also
each test separately is $48.
where there are multiple different carry important good genes that we
genes that can cause ARVC.” do not want to lose from the breed.
The quandary of another possible “A Boxer with positive attributes
genetic cause is what prompted the that is heterozygous for one or both
American Boxer Charitable Foun- mutations and does not show signs
dation (ABCF) to fund the latest of disease could be bred to a
study that produced the ARVC2 mutation-negative mate. A dog from
gene variant, a single-nucleotide this breeding that tests negative for
polymorphism affecting the tran- ARVC1 and ARVC2 and does not
scription factor of a regulatory gene. have clinical signs could be used
The AKC Canine Health Foundation to produce the next generation.”
administered the grant. Veterinarian Robert C. Hallock of
Longtime ABCF president Cheshire, Connecticut, who breeds
Dr. William Truesdale says, “We Boxers with his wife, Grace, under
encouraged Dr. Meurs to work to see the Pearlisle prefix, says, “ARVC
3
SPRING 2022
UNDERSTANDING HEART MALFUNCTIONING IN BOXERS WITH ARVC
aortic arch pulmonary arteries In a normal heart, the left atrium contracts to push blood into
the lower right ventricle, and then the ventricle contracts to
pulmonary
veins push the blood out to the body. Boxers with ARVC may develop
ventricular premature complexes (VPCs), in which the ventricle
left contracts earlier than it should and thus cannot produce a
atrium normal, effective contraction. If multiple, successive VPCs
right
atrium coronary occur, this results in stopping blood flow to the brain and
vein
other organs, potentially causing sudden cardiac death.
coronary Over time, the heart of Boxers with ARVC dilates to compen-
artery sate for the weakened heart muscle. As the thinned heart walls
continue to weaken, the diseased heart muscle fails to gener-
left ate enough force to pump the blood. As pressure rises in the
ventricle
right left atrium, it leads to fluid accumulation in the lungs, known
ventricle as pulmonary edema. Congestive heart failure follows.
is frustrating because you usually We did not yet have the test for
can’t diagnose it when dogs are ARVC2,” Dr. Hallock says. “She was
young. You may have a good dog clinically affected and died in 2017
that goes through its show career at 8 1/2 years of age.”
and you want to add this dog to Sometimes a breeder has to start
your breeding program only to learn over when ARVC runs through a
it is clinically affected by ARVC.” bloodline. “This disease was devas-
This was the case with the Hallocks’ tating to my breeding program,” says
Top 20 Boxer bitch “Meghan” (GCHB Trish Olinghouse of Lando Boxers
Pearlisle’s Trial By Fire CGC). “Meghan in Neosho, Missouri. “I basically had
was negative for the ARVC1 mutation. to start over when my male ‘Wyatt’
PHOTO: ALEXANDRIA GAV
Trish Olinghouse is shown with Wyatt, left, and “Nike,” whom she bought to start over
her bloodline after Wyatt, from her fourth generation, was diagnosed with ARVC.
4
BOXER Update
(BISS CH Lando’s I’m Your Huckel-
PHOTO COURTESY OF WASHINGTON STATE UNIVESITY COLLEGE OF VETERINARY MEDICINE
berry RN CGC CA BN) was diag- HOLTER MONITOR TESTING FOR BOXER ARVC
nosed with ARVC.”
A self-described stickler about A Holter monitor that records a dog’s
Holter monitor testing, Olinghouse heart rhythm continuously over 24 hours
also screens her Boxers for the has become the gold standard test
genetic mutations. “Since Wyatt’s to identify dogs potentially at risk for
parents tested negative for ARVC1, developing the heart disease arrhyth-
the only test available at the time, mogenic right ventricular cardiomy-
I thought the odds of him developing opathy (ARVC). A lifesaver, the Holter
ARVC were slim,” she says. “I was monitor allows treatment to begin
getting ready to Special Wyatt before a dog shows clinical signs.
when he had an abnormal Holter “Kate Meurs (Dr. Kathryn Meurs of North Carolina State University)
monitor test at 3 years of age. has virtually singlehandedly created a ‘Holter monitor culture’ in North
“He was healthy and fit, asymp- America that has greatly reduced the incidence of early death in
tomatic. After the abnormal Holter Boxers to ARVC,” says William Truesdale, DVM, president of the
monitor test, a veterinary cardiologist American Boxer Charitable Foundation.
diagnosed ventricular tachycardia, The size of a credit card worn in a vest with two leads to a dog’s chest,
a fast, abnormal heart rate that can be the Holter monitor effectively picks up ventricular premature complexes
life-threatening. Wyatt was sicker (VPCs), which cause arrythmia, the erratic heartbeats that can result
than we thought. I brought him home in cardiac arrest and sudden death. In contrast, an electrocardiogram
on antiarrhythmic medications, captures heart electrical activity for a brief period while a dog is at rest,
mexiletine and sotalol, which he thus it may miss the intermittent VPCs common in Boxers with ARVC.
took for the rest of his life.” An abnormal Holter monitor test predicts dogs that may later
The sweet-tempered Wyatt loved experience cardiac arrest or develop congestive heart failure. Impor-
people and going to dog shows and tantly, it enables diagnosis so that veterinary cardiologists can begin
training. “Wyatt didn’t know he was treatment with beta blockers and antiarrhythmic medications to help
sick,” Olinghouse says. “It was import- prevent severe arrhythmia or congestive heart failure. It is recommended
ant to me to allow Wyatt to remain that Boxers receive annual Holter monitor tests starting at age 3.
active and happy. After the diagnosis,
he went on to earn the Coursing
Ability, Rally Novice and Beginner older. “By the time clinical signs
Novice titles.” appear, the disease is typically
After researching bloodlines the well-progressed,” Dr. Meurs explains.
year after Wyatt was diagnosed with Boxers may experience a run of
ARVC, Olinghouse bought “Nike,” ventricular premature complexes,
a bitch with European and North or early contractions of the lower
American relatives, who has tested right ventricle of the heart. Fatty,
negative on both ARVC tests. OHBIS/ fibrous tissue that develops in the
BISS GCH Rocket N Lando VaVa Voom heart muscles causes these disturbed
BN RN CAA CGC TKN RATI would electrical impulses rather than a
carry Lando Boxers into the future — normal, steady, regular rhythm.
hopefully one free of dogs affected A dog having multiple, succes-
by the crushing heart disease. sive VPCs, or heartbeats without a
corresponding pulse, is not able to
UNDERSTANDING THE produce normal, effective contrac-
DYNAMICS OF ARVC tions, which results in decreased
Although arrhythmogenic right blood flow to the brain and other
ventricular cardiomyopathy occurs vital organs. A prolonged run of
in Boxers on average at 6 years of VPCs — the ventricular tachycar-
age, some dogs — like Wyatt — dia that Wyatt experienced — can
show clinical signs when they are lead to cardiac arrest and sudden
younger and some when they are death in otherwise healthy dogs.
5
SPRING 2022
TIMELINE OF ARVC DISCOVERIES IN BOXERS
EARLY
1970s
Boxers, even young, healthy adult dogs, begin EARLY
dying suddenly. Some had fainting episodes
during the months preceding their sudden death,
1980s
Now called Boxer cardiomyopathy, the condition
though others had no signs prior to dying. Some is believed to be hereditary. Boxers often have
of the breed’s most influential producers are already been bred when clinical signs develop.
among those that “just dropped dead.”
1997 1995
The American Boxer Charitable Foundation (ABCF)
While at The Ohio State University, Dr. Kathryn M.
conducts a breed health survey that indicates heart
Meurs determines that Boxer cardiomyopathy
disease is the top health concern of Boxer breeders.
is inherited as an autosomal dominant trait based
on DNA analysis from families of Boxers. The
research, supported by ABCH and the AKC
Canine Health Foundation, was published in 1999
in the Journal of Veterinary Internal Medicine. 2004
Dr. Meurs moves to Washington State University
1997-99 and continues this research. She renames the fatal
heart disease, arrhythmogenic right ventricular
Holter monitor testing of six large families of
cardiomyopathy (ARVC), to more precisely describe
Boxers at The Ohio State University finds that
the condition. She receives a three-year research
the disorder is primarily a familial heart
grant from the AKC Canine Health Foundation to
muscle disease associated with
study risk factors associated with ARVC, with a
substantial cardiovascular morbidity
goal of developing screening methods to identify
and risk of sudden death. Boxers are
asymptomatic affected dogs before they are bred.
deemed a new animal model for the
human disease. The research was
ARVC in Boxers is characterized by fatty or fibro-
published in 2004 in the journal
fatty replacement of the right and sometimes left
Circulation. ventricular myocardium and by ventricular tachycar-
dia. Although inherited as an autosomal dominant
trait, incomplete penetrance could be involved due
to the variance in presentation. The findings
2008 were published in Veterinary Clinics of North
America: Small-Animal Practice.
Dr. Meurs is the lead investigator
of research that identifies the
ARVC1 deletion mutation in the
striatin gene responsible for the
heart’s electrical functioning and
2021
holding cells together. The findings At the AKC Canine Health Founda-
that three of 33 dogs studied lacked tion National Parent Club Canine
the striatin mutation suggests there Health Conference, Dr. Meurs
is at least one other cause of the shares that a second gene variant,
disease in Boxers. This study was ARVC2, has been found in a
published in Human Genetics in regulatory gene involved in
2010 and the Journal of Veterinary important cardiac proteins.
Internal Medicine in 2013. The research was funded by
ABCF and administered by
PHOTO: GAY GLAZBROOK
the AKC Canine Health
Foundation.
Editor’s Note: The Boxer Update has covered arrhythmogenic right ventricular cardiomyopathy more than any other topic.
Counting the 2022 issue, we have published six stories starting with our first issue in 2002 that have reported on the disease and
research progress.
6
BOXER Update
Meanwhile, Boxers can develop 20 years ago, Dr. Meurs is not certain
congestive heart failure when fluid of the exact percentage today but
accumulates in the lungs, a condi- notes that the number of homo-
tion known as pulmonary edema. zygous positive dogs has reduced
Affected Boxers develop a cough, by about 60 percent. “We only see
shortness of breath and lethargy. about 3 to 4 percent of all dogs to
The ARVC1 and ARVC2 gene be positive homozygous,” she says.
variants help to explain why the Breeder Trish Olinghouse laments
heart malfunctions in clinically on the ongoing challenges. Her
affected dogs. ARVC1 is attributed to Boxer bitch, Nike, whom she bought
the deletion mutation in the striatin to start over her Lando Boxer
gene that produces a key binding bloodline, produced an outstanding
protein of the cardiac desmosome male, “Ford” (CH Lando N Rocket’s
responsible for the heart’s electrical Pickup Man @ Krisdan CA BCAT).
functioning and holding cells However, Ford turned out to be
together. Dr. Meurs’ initial ARVC1 a carrier for ARVC2, though he is
LOOKING TO REPRINT?
study found that 53 percent of clear for ARVC1. “We can’t take all
Boxer Update articles may be
Boxers were negative, 41 percent carriers out of the breeding pro-
reprinted provided the article is
were positive heterozygous, and gram,” she says. “I plan to selective-
used in its entirety and in a
6 percent were homozygous. ly breed him to bitches that are
positive manner. To request
In discovering ARVC2, Dr. Meurs clear and will continue to Holter
permission to reprint this article,
and her team at North Carolina State monitor test him every year.”
please contact the editor at:
University used whole-genome Dr. Meurs advocates that practice.
Barbara.Fawver@purina.nestle.
sequencing on DNA from Boxers with “Each dog and each family line
com. Reprints should include
confirmed ARVC that were negative should be considered individually,”
the following attribution:
for ARVC1. Their findings showed she says. “The removal of a signifi-
Used with permission from the
that 75 percent of the ARVC2 het- cant number of dogs from the breed-
Boxer Update, Nestlé Purina
erozygous-positive Boxers showed ing population could be very bad
PetCare.
clinical signs and 25 percent did not. for the Boxer breed. The field of
“About one-quarter of dogs have canine genetics is very new, and
both mutations. We are working to the field of cardias genetics is very
determine if dogs with both mutations complex. We are still learning how
have more severe disease,” Dr. Meurs to use these tools.”
says. “Our initial data suggests that Dr. Truesdale, Dr. Hallock and
they do have more severe disease, Olinghouse agree that the DNA
as it appears that they have a higher tests are important pieces of the
number of arrhythmias and abnormal puzzle. They also are open to the
heart muscle functions. There are possibility that other gene variants
still a few affected dogs that have and even nongenetic factors may
neither mutation.” contribute to this disease in Boxers.
“It’s heartbreaking that this
ANOTHER TOOL FOR disease plagues the Boxer breed,”
TESTING BOXERS Olinghouse says. “As a community,
Reflecting on the progress that has we cannot better the breed if we
been made over the past 20 years, don’t get our health right.” n
Dr. Meurs says, “The dedication
and commitment of the American Purina thanks Dr. Joyce Campbell,
Boxer Charitable Foundation to chair of the American Boxer Club
improve the health of the Boxer Health and Research Committee
breed is beyond what I have seen and a trustee of the American
in any other breed organization.” Boxer Charitable Foundation,
for helping us to identify this
Whereas 50 percent of Boxers
topic for the Boxer Update.
were clinically affected by ARVC
7
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