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DILATED CARDIOMYOPATHY:
A GREAT DANE BREEDER’S GUIDE TO UNDERSTANDING AND PREVENTION
       by Mary Anne Zanetos, J. P. Yousha and Ginnie Saunders

© 2005 Mary Anne Zanetos
 with comments and for permission to reprint.

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&section=Acquired%20Heart%20Disease


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