Causes of HCM

written by: Mark D. Kittleson, DVM, PhD, Diplomate ACVIM (Cardiology)

HCM is diagnosed when left ventricular hypertrophy is identified that is not caused by another disease. Left ventricular hypertrophy similar to HCM may be caused by diseases such as systemic hypertension (high blood pressure; most commonly associated with kidney disease) or hyperthyroidism, but such cases are not properly termed HCM.

Several hundred mutations in over a dozen genes have been identified that cause HCM in humans. Almost all these mutations are inherited as an autosomal dominant trait with variable expression and incomplete penetrance. This means that a gene mutation from only one parent is needed to cause the disease to develop in the child (and that the child has a 50:50 chance of inheriting that abnormal gene), that its severity can vary, and that it's possible for some people to have an HCM gene mutation but not develop the disease at all. Almost all people with an HCM-causing mutation are heterozygous for that mutation, meaning they have only one copy of the defective gene in each cell (each cell has two copies, called alleles – one from the father and one from the mother).

There are a number of theories as to how an HCM gene mutation causes disease, but the exact mechanisms remain to be proven and they are likely different from one mutation to another. Mutations cause a defective heart muscle contractile protein to be produced. In a heterozygous individual there is a normal gene (allele) that creates normal protein and a mutant gene that creates abnormal protein. The defective protein may be incorporated into a contractile unit or may be degraded and so not present at all. A defect in a particular protein can cause dysfunction in the heart muscle through the creation of abnormal sarcomeres (the small units in the heart muscle that are responsible for contraction). The heart muscle compensates for the abnormal sarcomeres by creating more sarcomeres. This increase in the number of sarcomeres leads to the wall thickening.

In cats, two mutations in the same gene have been identified that cause HCM – one in Maine Coon cats and one in Ragdolls. Both mutations are present in the cardiac myosin binding protein C (MYBPC3) gene. Mutations in the MYBPC3 gene are the most common cause of HCM in humans, so it is not unexpected that mutations in this gene were the first to be identified in cats. As in humans, HCM in Maine Coon cats is inherited as an autosomal dominant trait. It is assumed that this is the case in Ragdolls also. Cats that are heterozygous for these mutations variably express the disease – some have no evidence of the disease when examined with cardiac ultrasound (echocardiography) while others have obvious evidence of the disease. Unlike in humans, cats are relatively commonly homozygous for the mutation (both copies in each cell are mutated) because of inbreeding. These cats generally get severe disease. In some cats, clinical disease develops when the cat is fairly young (one or two years of age); in other cats, clinical disease doesn’t develop until the cat is older (up to at least seven years of age).

Maine Coon and Ragdoll cats in breeding programs should be tested for their respective mutations so that they can be removed from the breeding pool. Testing is done at the Veterinary Cardiac Genetics Laboratory at Washington State University.

Maine Coon cats and Ragdolls are often targeted as breeds that are prone to HCM. They are, but there are numerous other breeds that are similarly afflicted, including but not limited to Persians, American and British Shorthairs, Turkish Vans, and Norwegian Forest cats.

It is often said that HCM is most commonly diagnosed in crossbred (non-purebred) cats and that is true, for a reason. Since mutations that cause HCM are apparently prevalent in different breeds and since these mutations are inherited as an autosomal dominant trait, these mutations easily get disseminated into the general feline population and frequently produce HCM. And since crossbred cats are so much more prevalent than purebred cats it stands to reason that veterinarians see more of these cats with HCM than they do purebred cats.

Although HCM is genetic and so inherited, it is not technically a congenital (i.e., clinically present at birth) disease. Neither humans nor cats have echocardiographic evidence of the disease at birth. Sometime after birth – which may be months or years – the disease starts to develop. In cats homozygous for the mutation, HCM may become evident during the first year of life. In others it may not become evident until two or three years of age. In a cat heterozygous for the mutation, HCM may not become apparent until a cat is middle-aged, and some may never develop clinical evidence of the disease. In humans, 1 in 500 people have HCM. While HCM can produce devastating consequences in humans, the annual mortality from the disease is only approximately 0.7%. Although in cats current evidence suggests that the prevalence in certain breeds is much higher than it is in humans and its mortality rate also much greater, it again is not unexpected that many cats have disease that never causes problems but which they pass on to their offspring as a potential silent killer.