Hypertrophic Cardiomyopathy (HCM)

HCM is the most common heart disease in cats--whether purbred or not. In HCM, the heart muscle (myocardium) comprising the left ventricle becomes thickened (hypertrophied). This is called left ventricular hypertrophy (LVH). While LVH can result from other diseases such as high blood pressure, HCM is a primary disease (meaning LVH develops without another cause).

HCM is associated with increased risk of cardiac arythmias and sudden death, congestive heart failure, and clot formation leading to thromboembolism (and typically hind-limb paralysis). There are not currently any treatments that can reverse the disease nor any that have been proven to slow its progression. On the other hand, some cats have milder forms that do not progress rapidly, and in such cats, various medications may be able to improve heart performance enough for the cats to live a fairly normal life for a number of years. However, the most effective treatment for any particular cat remains uncertain, and not all cats respond to any of the standard treatments. It remains controversial whether treating asymptomatic cats is worthwhile.

Because HCM in several breeds of cat is thought to be familial--i.e., inherited--one focus of HCM research in cats has been to identify genetic mutations responsible for HCM. In 2005, Dr. Meurs and collegues identified a mutation in the MYBPC3 gene that can result in HCM in Maine Coon cats. The MYCPC3 gene codes for a cardiac protein known as Myosin binding protein C, cardiac (MYBPC3), also called Cardiac Myosin binding protein-C (cMyBP-C). Mutations in this same gene are generally stated as the most common cause of (familial) HCM in humans. The particular mutation is referred to as A31P. In 2007, Dr. Meurs and collegues identified a different mutation in the same MYBPC3 gene that can cause HCM in Ragdoll cats. This mutation is referred to as R820W. It was subsequently also indentified in humans, also leading to HCM. These two mutations are quite specific to the two breeds. A study done on 3757 cats in Europe found the Maine Coon mutation in only one non-Maine Coon cat, a British Longhair, and of the 2744 Maine Coons in the study, none had the Ragdoll mutation. Research continues to try to identify mutations related to HCM in these breeds and others. A second mutation (A74T) in the MYCPC3 gene has been identified, which may also lead to HCM in Maine Coons (though studies involving this mutation are very limited).

Genetic testing is now readily available for both the MYBPC3-A31P Maine Coon and the MYBPC3-R820W Ragdoll mutations, from Dr. Meurs' lab and several other labs worldwide (see website links). Because cats have two copies of the MYBPC3 gene (one from each parent), there are three possible genotypes that can be found from the testing:

  1. Homozygous wild-type: both copies of the gene are normal/unmutated;
  2. Heterozygous mutated: one normal/unmutated copy and one mutated version of the gene;
  3. Homozygous mutated: both copies of the gene are the mutated version;

Genotype (1) is negative for the mutation, while genotypes (2) and (3) are both positive for the mutation.

HCM is considered autosomal dominant, meaning it can occur in heterozygous mutated cats. However, as is the case with other genetic diseases--including familial HCM in humans--being positive for the mutation does not necessarily lead to clinical HCM nor to early death, etc. This is often expressed as: genotype does not completely determine phenotype. In other words, being mutation-positive does not necessarily lead to a cat that would be diagnosed as "having HCM" based on echocardiographic evaluation and/or being symptomatic. This is referred to as incomplete penetrance. The fact that familial HCM in cats has incomplete penetrance (particularly with heterozygous animals) has led some people to label it a recessive trait. However, being a recessive trait would mean that hetero-mutated cats would have to be at zero risk due to the mutation, but the majority of the research to date contradicts this. Thus, the correct categorization of familial/genetic HCM in cats would seem to be that it is dominant, but with incomplete penetrance and variable pneotype (expression). This is precisely the way human FHCM is categorized in many research papers. Due to the limited amount and scope of the research that has been done to date, there remains considerable uncertainty about the likelihood of mutation-positive cats developing clinical (apparent) HCM, their likelihood of experiencing sudden death, and their expected lifespans. This is particularly true for heterozygous Maine Coons. The Ragdoll mutation seems to be more severe in its consequences, and homozygous mutated Maine Coons also seem to be more likely to develop HCM and to have more severe forms than those that are heterozygous mutated (more on this below). Incomplete penetrance and significant phenotype variation is not unknown for genetic diseases and has been shown to be the case for human HCM due to MYCPC3 and other mutations (more on this below).

Unfortunately, uncertainty about the relationship between Maine Coons being mutation positive and developing clinical HCM has led some breeders to question the value of testing for the mutation in Maine Coons. We were frankly rather shocked to find that the Cat Fanciers Association genetics testing program has removed the Maine Coon HCM test, stating: "We no longer carry out the genetic test for HCM-Maine Coon. The association between the genetic marker we were testing for and the HCM disease in Maine Coons has been found to be poor. At this point, it is recommended owners of Maine Coons get routine ultrasounds (Fries et al. 2008; Kittleson et al. 2010)."

We have reviewed the relevant literature on Maine Coon HCM as well as a number of papers covering human HCM research. Based on this review, we consider the CFA testing statement to represent a mischaracterization of what the majority of research on the Maine Coon mutation has shown, as well as demonstrating a lack of understanding of what should reasonably be expected from genetic disease testing. It is virtually certain that the Maine Coon MYCPC3 mutation results in the production of a defective heart muscle protein. That in some cats this does not lead to what would be classified as HCM does not in any way eliminate the fact that these mutations represent genetic defects, with only negative consequences for the breeds (there is zero evidence of positive traits co-occuring in only mutated cats). One of the misconceptions embodied in the above CFA statement is that if cats don't develop clinical HCM then being mutation positive is irrelevant. There are at least two reasons why this type of thinking is wrong headed. First, just because some mutation-positive cats do not develop clinical HCM, there is absolutely no evidence that their descendents that inherit the mutation will also not develop clinical HCM. Thus, continuing to propagate the mutation means continuing to produce cats that might develop HCM as a direct result of this known mutation (which results in defective heart muscle proteins). Second, there are good reasons to believe that even if mutation-positive cats do not develop clinical HCM, their hearts contain defective muscle proteins, and so are not 100% healthy. Human research suggests an increased risk of sudden death for carriers of MYCPC3 mutations even if they do not develop clinical HCM.

We continue to believe that responsible Ragdoll and Maine Coon breeders should be testing all breeding cats to identify mutation-positive cats, and avoiding breeding positive cats as much as possible, with a goal of eventually eliminating the mutations from the breeds. There is reliable evidence that the identified Maine Coon MYCPC3-A31P mutation is the most common cause of HCM in Maine Coons. Just because being negative does not guarantee a Maine Coon will not develop HCM (or some other heart condition) and being positive does not necessarily mean it will, it seems quite certain that these mutations represent genetic defects. Certainly from the perspective of a potential purchaser of a Maine Coon kitten, there are ample reasons to consider a mutation-positive kitten to be "defective." If one were considering buying a car and found that some had been built using tires manufactured using a substandard rubber compound that led to a fraction of the tires failing prematurely, most people would want to avoid buying those cars or at least get a discount. Ending up with a cat that develops HCM can be both heartbreaking and expensive. Why would potential owners as well as breeders not try to do everything reasonable to reduce the risk of this happening? The HCM mutation tests are easy and relatively inexpensive (around US$60). Not doing the testing because they do not definitively predict clinical HCM, makes no sense to us. An excellent response to CFA's line of thought was written by Dr. Lyons in the UC Davis Veterinary Genetics Laboratory: PDF. Dr. Meurs continues to offer Maine Coon testing services, as do other labs around the world.

Now it is true that breeders should also be having yearly echocardiograms done by vet cardiology specialists in order to identify those cats that while negative for the known mutations, develop HCM from other causes (or develop other heart conditions--since HCM is by no means the only heart disease in cats). People considering purchasing Maine Coons and Ragdolls should strongly consider purchasing only from breeders that do genetic testing and echocardiogram testing on their breeding cats. While we believe that breeders should aim to eventually eliminate the known mutations from the breeds, since the mutation is found in 30-40% of the cats of each breed, simply ceasing all breeding from positive cats is probably not advisable since this might cause a significant reduction in the gene pool (though it is not clear whether this is true, given the relatively high level of inbreeding that has taken place). If hetero cats are bred only to negative cats, about half the offspring will be negative, and these negative cats than then be used in future breedings to propagate the line's characteristics. This does, of course, also mean that about half the offspring will be positive (heterozygous). We recently ran across a Maine Coon breeder who has decided to quit genetic testing, and one of the reasons given was because it was difficult to sell mutation-positive kittens, so better just not to know. Wow! So to make it easier on themselves, they want to be able to sell potentially defective kittens for full price to unsuspecting people. Pretty much a textbook example of being unethical! Sure, one one could educate potential buyers about the mutation status of their kitten and what it might mean for them in the future, and one might have to sell positive kittens for less than full price to offset expenses that the purchasers could encounter--but apparently that is just too hard, so better to "play dumb."

Also, while the now known mutations in Maine Coons and Ragdolls appear to be the most common causes of HCM in these breeds, being negative for the mutations does not guarantee a Maine Coon or Ragdoll will not develop HCM, as it is believed that there are other mutations that can cause HCM. Furthermore, there are obviously heart conditions other than HCM that can occur in cats.

Maine Coon HCM Research

All published studies of HCM in Maine Coons suffer from potentially serious sampling (ascertainment) bias because they involve acquired populations of cats typically in the 2-6 year old age range. This will result in a consistent underestimation of both the overall incidence of HCM and its correlation with mutations that can in fact lead to HCM: (1) seriously ill cats (such as those that are homozygous mutated) may have already died by the minimum ages of study cats, so will not be included, and (2) cats that are evaluated as being clinically negative for HCM may develop it as they age (HCM in hetero cats may not become clinically apparent until 8-10 years of age). What needs to happen is a study that follows a population of negative and positive cats from birth to death.

to be continued later...

Ragdoll HCM Research

coming later...

Relevant Human HCM Research

HCM is also a relatively common heart disease in humans (1 per 500), where it has been studied more extensively than in cats. HCM caused by an inheritable genetic mutation is often referred to as familial HCM (FHCM or just FHC). In humans, more than 400 genetic mutations involving at least ten genes have been identified that are associated with increased risk of developing HCM. Up to 60% of humans diagnosed with HCM are found to have one of these already identified genetic mutations. Many believe that HCM (as a primary disease) always has a genetic basis (with more mutations to be identified). Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype (just as in cats).

to be continued later...

Treatments for HCM in Cats

coming later...