The following was Dr. Cattanach’s response to a discussion on the Showboxer Forum (www.showboxer-f.com) of whether Holter testing for BCM was doing more harm than good.
Ed.

Cardiomyopathy
by Dr. Bruce Cattanach

Skimming the correspondence on this subject one can only sympathise with the frustration being felt by US breeders. The situation sounds horrendous. It is horrendous. But if one steps out of the murk and into a better known situation it does not seem quite so complex.

I stick with cardiomyopathy (CM) as a name. I do not have the veterinary fascination with finding exactly the right descriptive name that best fits the condition as it is known at any point in time. So, CM, or heart muscle disease - caused by a number of external factors but also by a number of different gene mutations.

CM is probably the most extensively studied human genetic disease in present times. About nine different genes have been implicated, and by this I mean that mutations in any ONE of these can cause CM. This is why there are different CMs - as we know from studies in Boxers and Dobermans and other breeds, and with the added expectation that there will be different CMs even within breeds. We may, for example, have two differing CMs in UK Boxers.

Coming back to humans again, just about all the CMs show a single gene dominant inheritance but with variability within each (age of onset, severity, progression differences, type of CM). The responsible genes are concerned with energy metabolism. This is the prime defect. Arrhythmias, electrical effects, fibro-fatty deposits, etc., are down the line towards what one calls the phenotype. The types of mutations are known and in the main these produce abnormal proteins that compete with the normal proteins in carrier individuals. The abnormal gene messes up the normal gene action. The competition is the basis of the dominant inheritance. But here one has another 'wobble.' The interaction may vary from one individual to another, such that in humans, at least, a CM may be present at birth or may develop at any later time up to advanced old age. So, is this not exactly what we see in Boxers - a variable age of onset, some dogs affected early and others living out their whole lives normally but still producing progeny that are affected at younger ages?

If one accepts the dominant gene inheritance, then any dog/bitch that is carrying the gene, the heterozygote, should transmit it to half its offspring. From what is said above, it cannot be expected that this will be realized, and from what I have been able to see in the UK, it certainly is not the case. What we have here is a range of ages of onset, from 6 months or less occasionally, more at one year, more at three years and then a long 'tail' with cases developing up to late ages. We also know of dogs that carry the gene, as proved from their transmission to their offspring, that seem destined never to develop the disease themselves.

In our main UK family, about half the cases recorded are under 4 at age of onset and generally they don't live long thereafter. (Yours, so far as I can gather, are generally much older and this makes for added difficulty.) I had hoped to be able to collect data here that would tell us the incidence at this age [the age of 4] but this has proved impossible. Therefore, based on similarly inherited mutations in lab mice, I have 'guessed' that maybe only 10% of dogs carrying the gene might develop the disease by this age. This, in practical terms, means that if a transmitting dog sired 100 pups, about half of them (50) will inherit the gene but only 10% of these (5) may get CM. Five in 100! Pretty easy to miss. And that estimate might well be quite wrong. Here lies one major problem in trying to understand, let alone deal with, this disease. And your situation [in North America] may be worse, at least in terms of the time/age you have to wait.

Then we have the Holter monitor. Here we have a test system that seemingly can pick out dogs that are liable to develop the disease. Basically, it is the best test available. But what do the results mean? Frankly, I do not know. I gather that the VPC frequencies, runs, chains or whatever can vary from day to day. I gather that there is no clear prediction that high frequencies will mean earlier onsets of the full-blown disease. Maybe figures based on a month’s testing would be a more reliable indication, but this gets to be madness. Then, at the other end of the scale, what is normal, for a Boxer; and if a dog gets a normal score, does that mean he is clear? Certainly not. It only means that there is no indication of CM at the time of test. Next week, next month, next year may give a different answer.

Then there is another question that I must confess I had never thought of. Following from what Virginia Zurflieh has recently added, can Holter results be used as a quantitative measure of degree of effect. If they could, then one should be able to select for the projected healthiest dogs on the basis of VPC frequency or whatever. I could be quite wrong here, but I would never think of using Holter results in this way. This to me, at this stage of knowledge, would be over-interpretation. I would instead suggest that a 'high' VPC frequency, whatever that might be, is an indicator that a dog is likely to carry the gene and eventually, maybe, develop the disease and then, more certainly, transmit the gene to the next generation. But don't forget the other causes of CM – thyroid problems, viral infections, etc. They will cause abnormal heart function. And then in the oldest dogs, there may be all kinds of wear and tear damage to the myocardium that may finally express themselves as CM. Is this not hell?

So what is the bottom line for determining if an apparently healthy older dog carries the gene or not. The answer is as someone astutely recognized the other day lies with a scan of the progeny. Because this hypothetical dog has survived, this does not mean that all his progeny that have inherited the gene from him will also survive so long. There will always be a range, and some of his progeny are likely to develop the disease at earlier ages. So if you can show that a dog is transmitting CM, then he carries the gene and half of all his progeny will do likewise. This is where the Holter can prove useful. Regular Holter use can give you a few years (?) warning that CM is on its way, or even already present if one defines high VPC frequencies as existing rather than future CM. But then there are big problems with that idea, too: One has to be sure that this dog is actually the source of CM cases and not the bitch line/s; and that one does not place too much emphasis on single cases which may be one-offs (thyroid based etc). It is sheer hell!

So where does one go from here. I suggest that many of you have the right starting idea. A big database recording Holter results, onset of clinical signs, pedigrees, numbers of relatives, number affected, overall incidence of every indictor, distribution in the breed, in fact of everything one can think of. Only then may it be possible to see a way out.

Here, in the UK, the situation is potentially much easier. We know fairly clearly where CM lies in the breed and where it may be absent; the problem is relatively contained and not too widespread (as yet); the form of the disease shows an early onset such that one does not have to wait half a lifetime to see where one is; and we have a small tightly knit group of cardiologists located in a geographically small area. We therefore have a chance of dealing with the problem, and the primary objectives should be to find and rescue clear members of the affected line/s. If CM goes underground, as seems likely at the moment, then it will be a wipe out for those line/s, as people will avoid them like the plague, but the disease will still probably stay with us to sprout up again some day.

In the States where the problem is said to be widespread, recognition of the disease is harder and options to deal with it more limited, one does wonder if thrashing about in the dark with uncertain tests could indeed do more harm than good. If US CM is more a disease of old age than here, and if selecting older healthier dogs for breeding would shift the general onset to yet later ages, maybe this is something that could be accepted. Otherwise, testing and discarding too high a proportion of dogs might seem too high a price to pay for whatever might be achieved. I really don't know. The facts are not clear.

In the longer run, identification of the gene will provide the options. All one needs is the protein/s involved and one could run tests for these. I would be striving for this option, in the meantime making sure that one had all the needed material for such research and above all ensuring that not all CM is lumped together as one. Almost certainly there will be more than one type of CM in the States as is suggested here, quite apart from the spontaneous one-off cases. Progress in this research is clearly being made, and canine CM will be able to piggy-back on the huge strides that are being made with human CM. It is just what to do in the interim that is the problem.

I hope my spontaneous off the cuff input clarifies rather than confuses. It certainly is not nice simple little text book genetics.

Dr Bruce M Cattanach
Downs Edge, Reading Road
Harwell, Oxford OX11 0JJ
Tel/Fax (0)1235 835410
email bcattanach@steynmere.freeserve.co.uk
http://www.steynmere.com