What is dilated cardiomyopathy?
Cardiomyopathy is a general term which refers to a class of heart
disease with several specific subtypes. What these have in common is
a dysfunction of the heart muscle (myocardium) which interferes with
its ability to pump oxygenated blood out of the heart to supply the
muscles and other structures of the body. Ultimately, cardiomyopathy
results in heart failure, disturbances in heart rhythm (arrhythmia)
or sudden death in canines.
Dilated cardiomyopathy or DCM, as discussed in the context of the
Great Dane, is a precisely defined subtype of cardiomyopathy. DCM
results from disruption of one or more of the processes necessary to
build and maintain normal heart tissue. The heart muscle loses its
elasticity and becomes stretched out and thin, a process referred to
as dilatation. As the chambers of the heart lose elasticity, their
ability to contract becomes impaired and the heart’s efficiency in
pumping the blood declines. The heart enlarges, not only due to
dilatation, but also as an attempt to compensate so that blood
pressure and fluid balance in the body can be maintained. Disruption
of the electrical pathways of the heart also occurs, producing
arrhythmias and in some cases, sudden death. DCM is rapidly
progressive and usually fatal within a few weeks or months of
diagnosis.
DCM as it occurs in Great Danes is very different from the
“arrhythmogenic” type of cardiomyopathy seen in Boxers, Bulldogs and
other breeds where the primary defect is in the electrical
conduction system of the heart. Most of what you read in the
literature about “cardio” in those breeds does not apply to the
Great Dane.
In Great Danes DCM shows a distinct preference for males: about
90-95% of cases are male. Most are middle-aged, but onset in young
adult males is not uncommon, especially in families with a history
of DCM (Meurs et al., 2001). Careful analysis of pedigrees usually
reveals affected relatives or unexplained deaths, particularly among
male relatives of the dam.
In many instances there are no warning signs of DCM. The dog
collapses and dies suddenly, probably as a result of cardiac
arrhythmia/fibrillation which de-synchronizes the contractions of
the heart chambers, thereby arresting circulation of the blood. This
happens because DCM damages the muscle cells along the electrical
(nerve) pathway, interrupting the circuit and causing the heart to
“short” much like what happens when an electrical cord is damaged.
If a dog is examined while alive, as a result of symptoms or routine
screening, typical findings of early DCM include abnormal rhythm or
heart sounds on auscultation (listening to the heart with the
stethoscope). Signs of cardiac congestion and/or edema (fluid
accumulation/swelling) may be present in the chest, abdomen or
extremities. Laboratory abnormalities and anorexia are typically
seen in advanced cases of DCM (Bonagura, 2002). When these signs and
symptoms are present, the vet might make a tentative diagnosis of
DCM, but this needs to be confirmed by cardiac ultrasound
(echocardiography). Although other abnormalities may be present, a
left ventricular ejection fraction (sometimes referred to as
fractional shortening) of less than 25%, along with an end-systolic
volume index >30 ml/m2 body surface area, are considered diagnostic
for DCM (Meurs et al., 2001).
My dogs don’t have DCM. Why should I be concerned?
According to GDCA’s 2002 National Health Survey (Zanetos et al.,
2004), cardiomyopathy has emerged as the major preventable health
problem facing Great Danes today. It ranked as the #1 cause of death
among male Great Danes, having overtaken cancer and bloat, ranked #2
and #3, respectively. The statistical relationship between
cardiomyopathy and male sex was highly significant (p<0.0001), in
fact the strongest correlation observed for any health condition
when incidence was analyzed by gender, color family, etc. Survey
respondents ranked cardiomyopathy/heart problems as #3 among the top
10 health problems in their own household and as the #2 problem
facing the breed as a whole. This is clear and compelling evidence
of a serious problem and one which will become more prevalent in the
future if breeders do not act quickly to identify and eliminate
affected males and their daughters from the breeding pool.
How is DCM inherited?
Published case-series (Meurs et al., 2001) as well as pedigree
analysis of over 40 additional Great Danes with DCM submitted to the
authors (MAZ and JPY) provide compelling evidence, not only that DCM
is inherited, but that it is inherited as an x-linked recessive
trait.
What exactly is an X-linked recessive trait? Saunders (2002)
provides the following explanation: Back in high school biology, you
probably learned that females have two X chromosomes and males have
one X chromosome and one Y chromosome. At the time of conception,
the female provides one of her two X chromosomes, and the male
provides either an X or a Y chromosome. If the father gives an X,
the offspring will be female. If he gives a Y, the offspring will be
male. For most traits, there are many possible versions (alleles) of
each gene. Often, one version will be silent when paired with any
other version. A gene version of this type is called "recessive"
because it will be expressed only if it is not paired with a more
powerful, or "dominant," version. For non-sex (autosomal)
chromosomes, that means the recessive gene must exist on both
chromosomes of the pair in order to manifest itself. In the case of
the sex chromosomes, however, the single X-linked (X-chromosome
linked) recessive gene will manifest itself in males because it is
"unopposed" by anything on the Y chromosome. This means if a male
offspring inherits an X-linked recessive gene from his mother, he
will manifest that gene's influence.
The practical significance of this is that male offspring of a sire
with DCM cannot inherit his DCM gene (since the sire, by definition,
always contributes his Y to his sons). On the other hand, his
daughters all inherit his defective gene since the sire must
contribute his X to produce a daughter (XX). Since this is a
recessive trait, his daughters will manifest DCM only if they
receive TWO copies of the defective gene. If, as is usually the
case, the daughter inherits only one copy of the defective X, she is
called a carrier. Carrier bitches appear normal and show no signs of
DCM if tested, yet they transmit the defective DCM gene to their
offspring.
Male offspring of carrier bitches have a 50:50 chance of inheriting
the gene for DCM since they will inherit either her normal X or the
X she got from her sire which carries the DCM defect. Because this
is a recessive/unopposed gene in males, it takes only one copy of
the DCM gene to produce a son with DCM. For a bitch to have DCM, she
must inherit two defective genes for DCM. This is very unlikely, but
it can occur in tightly linebred pedigrees or where two families,
each with DCM, combine.
X linked recessive pattern of inheritance explains several things
which have long been observed about DCM in Great Danes: (1) it
nearly always affects males; (2) it appears to skip a generation (or
sometimes two) in pedigrees; (3) daughters of DCM males (carriers)
produce sons with DCM, regardless of what sire is chosen.
Saunders (2002) provides an excellent explanation of x-linked
inheritance along with diagrams of all the potential combinations of
affected, carrier and clear (normal) parents and the corresponding
probabilities of DCM in the resulting offspring. These can be found
at:
http://www.ginnie.com/DaDane300.shtml
Why don’t some DCM “cases” fit the expected pattern?
1. Statistical probabilities may not be accurately reflected in
any single litter. But like flipping a coin, if averaged over
large numbers of litters, the incidence seen in the real world will
approximate the theoretical odds. In the case of sex-linked traits,
if all of the pups in a litter sired by a DCM male happen to be
males, no offspring will inherit DCM from him and the trait will die
out in that generation of the pedigree. Small litters often do not
provide sufficient numbers of pups for affected pups to emerge and
reveal the pattern in a pedigree. Sometimes siblings of the dogs
which appear in your pedigree are the family members affected by DCM.
These dogs must be counted, too.
2. Competing causes of death. Because DCM typically affects
middle-age males, some who carry the gene die of other causes before
becoming old enough to manifest DCM. Several well known males died
of other causes but were “outed” as having the DCM gene after
multiple daughters produced DCM sons.
3. Insufficient pedigree information. Some DCMs reported to
the authors come from obscure pedigrees where no information on the
health of relatives is available. Sometimes breeders are unwilling
to discuss or confirm cause of death of dogs in vital positions in
the pedigree. In other cases there was no definite diagnosis
established prior to death and/or no autopsy, so DCM remains a
possible, but unconfirmed, cause of death. Consequently many
pedigrees have missing or questionable links
.
4. Some pedigrees show fathers and sons with DCM. While on
the surface it appears there is direct inheritance, usually upon
investigation, previously unknown carrier bitches are identified and
the cases then fit the expected pattern. This is most apt to occur
in linebred pedigrees where the same individuals or sibs of the same
individuals appear on both sides.
5. Misfits occur as a result of “muck”, that is, lumping dogs
whose DCM diagnosis was only presumptive or rumored with cases whose
diagnosis was confirmed by echo or autopsy and admitted by the
owners. Including dogs with other types of heart disease or sudden
death in case series of DCMs tends to obscure the pattern of
inheritance since the latter produce exceptions which don’t conform
to the expected pattern. This can result in false labeling of
carriers and must be avoided.
6. Not all heart disease or sudden death in Great Danes is due to
DCM. At least one major family of Danes has exhibited an
inherited form of arrhythmogenic cardiomyopathy (ACM), much like
“Boxer cardio” over multiple generations. These dogs usually drop
dead without prior diagnosis. Many are quite young, typically under
two years of age. At autopsy, they do not have marked dilatation of
the heart, the hallmark of DCM. Like Boxer cardio, ACM seems to be
inherited as an autosomal dominant trait which would be perfectly
compatible with father or mother to pup transmission. Unlike DCM,
ACM shows little or no predisposition towards males (Meurs et al.,
1999). Subaortic stenosis (SAS) also occurs in Great Danes,
especially those with a family history of sudden deaths. SAS is
caused by a congenital heart defect which normally emerges prior to
breeding age. SAS is one of several heart conditions which would be
detected by screening tests such as cardiac OFA, especially if an
echo is performed. In all cases of sudden death, an autopsy is
essential to reveal the true cause of death and to prevent such
cases from being misclassified as DCMs.
If DCM is a male disease, why are elderly Great Dane bitches
diagnosed with “cardiomyopathy”? Is this the same clinical entity as
DCM?
Many vets use the term, “cardio” or cardiomyopathy as a generic term
to refer to any disease of the heart muscle. This includes
congestive heart failure similar to that seen in elderly humans
where the heart cannot pump effectively due to decreased elasticity
of the muscle and/or incompetent valves which permit only partial
expulsion of the blood from the chambers of the heart with each
beat. Basically these are old hearts that are wearing out. This
condition can be distinguished from DCM in that it does not involve
massive dilatation of the heart or the specific pathologic changes
characteristic of DCM. The authors have seen a few cases of echo or
autopsy-confirmed DCM in young or middle aged bitches. These were
invariably from families with many affected relatives. In one such
case, a previously undiagnosed sire was taken for evaluation based
on the diagnosis of DCM in his daughter and this dog was found to
have DCM.
What about alternative explanations? Isn’t DCM a “new” problem?
Vaccines, toxins, infections, taurine or carnitine deficiency and
many other non-genetic theories have been proposed as the cause of
DCM. Most of these have been researched and debunked in
peer-reviewed scientific journals. Importantly, none of these
alternatives explain the male predominant, generation-skipping and
carrier bitch pattern of incidence observed in DCM.
Although proponents of alternative (non-genetic) explanations of DCM
state that DCM was unknown until the late 70's in the attempt to
connect it with parvovirus, old time Great Dane breeders confirm
that DCM has been a problem in certain bloodlines as early as they
can remember. My sources document cases back at least to the 1950s.
Part of why we perceive DCM as a recent phenomenon has to do with
better detection. Echocardiography was not available or widely used
by vets until the early 80's. Prior to this, DCM cases were usually
diagnosed at autopsy, which (as now) is performed in only a minority
of sudden deaths.
The other reason for perceiving DCM as an emerging problem is a
genuine increase in incidence. Until recently we did not fully
understand how this disease is inherited, so while breeders may have
removed their DCM males from further breeding, they did not realize
the proliferation of DCM is mainly due to his carrier daughters.
Therefore, they continued to breed them. Others have failed to
accept the evidence that DCM is inherited. Breeders who convince
themselves DCM is due to viruses, environmental pollution, dietary
deficiencies, vaccines, or other non-genetic cause feel justified in
continuing to breed DCM males or their daughters. In doing so, they
sustain and perpetuate the DCM problem. Those who experience sudden
deaths of their dogs and simply guess at the cause also contribute
to the problem. Often they attribute sudden death to stroke,
aneurysm, allergic reaction or unwitnessed trauma. These may or may
not be the correct cause. But failure to rule out DCM via autopsy
can and does allow offspring of some DCMs to remain in the breeding
pool.
While it is true that cases of DCM arising in Danes with
long-standing undiagnosed hypothyroidism have been documented, these
are by far the exception. Unlike typical DCMs, these cases often
improve dramatically after thyroid replacement therapy is
instituted. Viral and bacterial infections can produce inflammation
of the lining of the heart (endocarditis), but this can be
distinguished from DCM by its abrupt onset, different pathologic
changes and/or laboratory tests which enable identification of the
specific bacteria or viruses involved (Tidholm and Jonsson, 2005).
What can I do if I’ve already had a litter/litters that had
individuals with DCM?
First, be absolutely sure the dog(s) in question has/had DCM.
Evidence in the form of chest x-ray, auscultation or symptoms really
needs to be confirmed via echocardiography. All sudden deaths and
any death without a previously diagnosed illness should be
autopsied. Even if a non-cardiac cause is identified as the
immediate cause of death, the heart should be subjected to a
thorough examination by an experienced pathologist to rule out DCM
as an underlying or secondary cause. Deaths owners attribute to
pneumonia, accidental injury, insect bite, allergic reaction, etc.,
are sometimes reclassified as DCM or other heart disease at autopsy.
Conversely, sudden deaths presumed to be DCM may turn out to be
aneurysm, stroke, DIC, poisoning, metabolic crisis or other
non-cardiac cause when thoroughly investigated.
Once the cause of death is established,
keep careful records of
this dog and as many of his relatives as possible. Frequently,
clues to DCM lie in the siblings of your dogs’ parents and
grandparents, so it’s essential to look at the extended family.
Maintain copies of postmortem reports.
While it is possible that DCM may be caused or moderated by more
than one gene and that certain health and environmental factors may
influence its age of onset, it seems clear that the x-linked
recessive pattern of inheritance applies to the vast majority of
confirmed cases. The following advice, therefore, is based on
minimizing your risk, under that assumption.
Managing your risk:
1. The DCM dog itself: Once any dog, male or female, is confirmed
as a DCM, eliminate it from further breeding. Label this dog on
your pedigrees and consider disposal of any frozen semen.
2.
Daughters of DCM males should be labeled as carriers on
your pedigrees. Due to their high probability of producing both DCM
sons and carrier daughters (50% chance, assuming their mate is
clear) these individuals should ideally be eliminated from your
breeding program.
3. Littermates and full siblings of the DCM dog are at high risk.
Litter brothers have a 50% chance of having the gene for DCM and
litter sisters, a 50% chance of being a carrier, again assuming
there is no DCM gene to inherit from the other side of the pedigree.
Annual echocardiography exams, coupled with “watchful waiting” (see
#5 below) are recommended, if possible.
4. Sons of DCM males theoretically should not be at risk since they
do not inherit the defective gene from their sires. However, the
authors have found that such dogs sometimes have currently
unrecognized carrier dams, especially in the case of linebred
pedigrees. For this reason, sons of DCM males should be used very
cautiously.
5. Sons of carrier bitches have a 50% chance of having the gene for
DCM. Conversely, there is a 50% chance they do not. If these are
exceptional individuals and vital to your breeding program,
“watchful waiting” is one possible strategy for managing your risk.
This involves postponing breeding until the dog is past the age when
DCM is likely to develop (6-7 years old). If he is healthy and
echocardiography reveals no sign of heart disease at that age, one
could consider breeding using frozen semen collected in his prime.
For this you would select a bitch who is almost certainly not a
carrier and whose owners understand and are willing to undertake
some risk. An even safer option is to wait until the dog dies of old
age and perform an autopsy, including detailed pathologic studies of
the heart. It is worth noting that histological changes indicative
of early stage DCM can be identified even before clinical and
echocardiographic signs of heart disease are present (Tidholm and
Jonsson, 2005). Assuming there is no evidence of DCM, this dog could
be bred cautiously, using frozen semen and a presumably clear bitch
with an informed and willing owner, as described above.
What can be done to prevent DCM in future generations?
Although it would seem obvious, breeding to dogs you have not seen
in person and/or whose relatives are not well known increases the
chance of unwittingly introducing DCM into your breeding program.
The authors have seen instances of novice (and not so novice)
breeders using frozen semen from historic sires or modern sires who
died young which had disastrous results. If you are contemplating
such breedings, it is essential to know for certain the cause of
death of the stud dog and to interview breeders who knew this dog
and the get he produced while alive. Be suspicious of any young male
death which was not previously diagnosed or autopsied. Whenever
possible, select sires from families with long-lived males.
Even though DCM is increasing and spreading throughout the
population of Great Danes, there are still breeders and bloodlines
which have a lower risk of DCM. Ironically, just as linebreeding
within families that already have DCM tends to increase the risk
(since it puts affected individuals on both sides of the pedigree),
linebreeding within families where DCM is not present reduces risk
since the number of outside dogs introduced into the breeding
program is minimized.
The current popular practice of breeding black bitches to fawn males
is likely to produce an increase in DCM among blacks since the
problem appears to be more prevalent among fawns and brindles than
among pure color bred blacks.
Of what value are cardiac screening tests?
Unfortunately, periodic cardiac screening, even using
echocardiography, cannot be relied upon as a global preventive
strategy. This is because DCM strikes quickly and develops
rapidly. There is no long “silent” period during which the disease
is present and can be detected by echocardiography prior to the
onset of clinical symptoms of DCM. Seemingly healthy dogs who show
positive or suspicious findings during routine screening usually
develop overt clinical symptoms within a few weeks (Sleeper et al.,
2003). Also, since DCM typically develops in middle age, dogs
intended for breeding have usually sired or produced litters before
symptoms emerge. It should also be mentioned that cardiac screening
is useless for detecting carrier bitches because there is no
abnormality to detect. For these reasons careful analysis of
pedigrees and removal of affected and high risk individuals from the
breeding pool is really the most effective strategy for preventing
the spread of DCM.
Having said that, cardiac screening is still the best tool we have
for detecting affected individuals. Males used for breeding
should be screened annually, even well past breeding age. It is a
myth that if a dog reaches 6-7 and does not have DCM, he will not
get it. The authors have seen several confirmed DCMs emerge at age 7
or later. Detection of DCM at the earliest possible stage provides a
clinical benefit. Available medical therapies can slow the
progression of DCM, ease symptoms and generally improve quality of
life. Therapy instituted before major dilatation and damage has
occurred is apt to be more successful.
The real salvation will be a genetic test which can identify dogs
that have the DCM gene prior to breeding. Such testing could also be
performed on frozen semen, so it may be prudent to store semen on
valuable dogs whose DCM status is currently unknown. Research is
currently underway to develop such a test. See:
http://www.gdca.org/health/cardiostudy.htm
Conclusion:
We owe it to ourselves and to our breed to recognize DCM as a major
health problem and to devote our efforts to identifying affected
dogs and carriers and eliminating them from our breeding programs.
The keys to this are: (1) frank and honest exchange of information
regarding dogs in our pedigrees; (2) diligence in determining and
documenting cause of death for all sudden deaths or any death where
there was no previously diagnosed illness; and (3) cessation of
further use of affected males and carrier bitches upon diagnosis of
DCM or production of an affected puppy.
These are not easy decisions. Breeders have invested heavily in
rearing, training and showing the dogs we intend to use in our
breeding programs. And when DCM or sudden death occurs, our first
instinct is to deny, make excuses or conceal this information
because we take it personally or fear what others will say about the
dogs we’ve devoted our time, money and emotions to developing. That
is human nature. But the future of our breed lies in the decisions
breeders make today, in how those with DCM problems elect to deal
with their misfortune, and importantly, how fellow breeders treat
those who make the difficult decision to eliminate dogs from
breeding and disclose the reason so that others do not suffer the
same fate.
References Cited:
Zanetos MA, Slater M, DeAnda N, Harbison J.
GCDA National Health Survey: Highlights and Special Topics: Parts
1-5.
Dane World Magazine Issues 1-5, 2004. Also see the full text of the
survey report at:
http://www.gdca.org/health/healthsurvey.htm
Meurs KM, Miller MW, Wright NA.
Clinical Features of Dilated Cardiomyopathy in Great Danes and
Results of a Pedigree Analysis: 17 cases (1990-2000).
J Am Vet Med Assoc. 2001 Mar 1; 218(5)729-32.
Bonagura J.
Canine Cardiomyopathy.
World Small Animal Veterinary Association World Congress-Vancouver,
2001.
http://www.vin.com/VINDBPub/SearchPB/Proceedings/PR05000/PR00034.htm
Meurs KM, Spier AW, Miller MW, Lehmkuhl L, Towbin
JA.
Familial Ventricular Arrhythmias in Boxers.
J Vet Intern Med 1999 Sep-Oct;13(5):437-9.
Saunders, G.
DCM in the Great Dane.
DaDane of DaWeek 07/08/02 issue http://www.ginnie.com/DaDane300.shtml
Also see:
http://www.ginnie.com/DaDane299.shtml
Tidholm A, Jonnson L.
Histologic Characterization of Canine Dilated Cardiomyopathy.
Vet Pathol. 2005 Jan; 42(1):1-8.
Sleeper MM, Henthorn PS, Vijayasarathy C, Dambach DM, Bowers T,
Tijskens P, Armstrong CF, Lankford EB.
Dilated Cardiomyopathy in Juvenile Portuguese Water Dogs.
J Small Anim Pract. 2003 Apr;44(4):196-7.
Additional information:
http://www.gdca.org/healthandwelfare.htm
http://www.gdca.org/health/cardio.htm
http://www.vetgo.com/cardio/concepts/concsect.php?sectionkey=1§ion=Acquired%20Heart%20Disease
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