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Current thinking on HCM (2017)

Discussion in 'Cat Health and Nutrition' started by Ceiling Kitty, Jan 11, 2018.


  1. Ceiling Kitty

    Ceiling Kitty Not available for comment

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    For anyone who is interested, I've attempted to summarise current scientific thinking on feline HCM based on the conferences I attended throughout 2017.

    If anything doesn't make sense, you need something explaining or wish to discuss it more, just drop a line on the thread below. :) It is quite heavy going!




    BACKGROUND AND GENETICS


    HCM in cats is defined as:
    - a left ventricular diastolic wall thickness of around ≥6mm (though different cut offs exist depending on what study you read, personal thoughts of the specialist involved etc);
    - myocyte disarray on histology.

    Cats are increasingly being used as models for the study of human HCM.


    Humans

    >1400 genetic mutations have been identified in humans with HCM. Around 70% of these are found in the MYH7 and MYBPC3 genes. Most human mutations are 'private', which means they are unique to a single family.

    The situation in humans is very complicated, with genetic testing also identifying thousands of single missense mutations that may or may not be relevant - these are known as 'variants of unknown significance'. In human medicine, patients receive genetic counselling prior to gene testing because of the complexity of interpreting their results.

    Morever, in humans the genes associated with HCM have incomplete penetrance, meaning that the HCM genotype results in a wide range of phenotypes amongst affected individuals.


    Cats

    As of early 2018, specific genes have only been identified for the Maine Coon and Ragdoll breeds. Work to identify genes in Norwegian Forest Cats is ongoing as we speak.

    Annotation of the feline genome in general is improving, especially with the work of Leslie Lyons in the States on her 99 Lives Project.
    http://felinegenetics.missouri.edu/

    The mutations identified in both Maine Coons and Ragdolls are, like a large proportion of humans, in the MYBPC3 (myosin binding protein C3) gene.

    The mutation in Maine Coons is A31P. 22-42% of Maine Coons are positive for this gene mutation - but some Maine Coons with HCM DON'T have it.

    The mutation in Ragdolls is R820W.

    Work in Ragdolls (Borgeat, J Vet Cardiol 2014) has shown that homozygous cats are more severely affected, with a higher risk of sudden death and earlier onset of disease.
    https://www.ncbi.nlm.nih.gov/pubmed/24906243

    Like in humans, we can see mixed phenotypes within feline families. It is currently not clear whether these are the result of multiple mutations, or different expressions of a single mutation. It has also been shown that phenotype can change over time and with age in cats.


    In addition, we know that Maine Coons homozygous for the A31P mutation have unusually reactive platelets and display vascular changes, which may increase their risk of developing thrombotic disease.


    Aetiology

    In humans, most HCM cases are due to the sarcomeric protein gene mutations discussed above, but systemic diseases, neuromuscular disease and glycogen storage diseases have also been highlighted as causes. Approximately 30% of human cases are of unknown cause.

    In humans, any heart showing the HCM phenotype is HCM until proven otherwise. This is not necessarily the case in cats, amongst whom HCM 'phenocopies' are common.

    Hyperthyroidism, hypertension, acromegaly and neoplastic infiltration (usually lymphoma) all cause a 'hypertrophic phenotype' in cats without known sarcomeric mutations and possibly no histological features. These cases may be reversible. Another example is the recently characterised transient myocardial thickening, which is discussed in more detail later.

    We still don't know for certain how the mutation in contractile proteins causes hypertrophy. Haploinsufficiency is not suspected, but current thinking supports the 'poison polypeptide' hypothesis, which proposes that mutant sarcomeric proteins incorporate into cardiac myofibrils and act as dominant negative proteins.

    Increased sensitivity of the cardiac muscle to calcium has been identified in homozygous Ragdolls.


    There are multiple current 'unknowns' in feline HCM, which can have implications for screening protocols. For example, we don't know for certain whether the onset of left ventricular (LV) hypertrophy is age-related, or whether it can be influenced by environmental factors such as obesity or neutering. The same is true in human medicine, with little understood.


    Prevalence of HCM

    0.2% people (1 in 500)
    15% cats
    16% DSH, 26% pedigrees



    DIAGNOSIS


    Definitive diagnosis of feline HCM requires histology, which is not possible ante-mortem. Even so, there is poor consensus regarding the pathology to create a histological 'gold standard' classification.

    The principle aim of diagnosis is to identify high-risk asymptomatic cats, who may need anti-thrombotic treatment due to a risk of developing aortic thromboembolism (ATE).


    Dynamic auscultation

    Feline heart murmurs are highly influenced by adrenaline. In the thesis linked below, which looked at heart murmurs in 103 outwardly healthy cats, 16% of the cats had a heart murmur at rest. This increased to 27% after a dynamic manoeuvre (lifting the cats quickly into the air at least twice).
    https://vtechworks.lib.vt.edu/bitstream/handle/10919/43704/CPAIGE_THESIS.pdf?sequence=2&isAllowed=y

    It is also known that inadvertent compression of the chest wall with a stethoscope can induce a DRVOTO (dynamic right ventricular outflow tract obstruction), which can cause a murmur.

    It seems that chest auscultation techniques are more complex than simply placing the stethoscope in different places on the chest in identifying feline heart murmurs.


    Echocardiography

    Echocardiography is the most common method of diagnosis. LAE (left atrial enlargement) is a major predictor of symptomatic disease in high risk cats.

    Unfortunately there are significant issues (which have been highlighted in studies) with poor inter-observer agreement - even amongst cardiac specialists - and even poor intra-observer agreement. It has not even been agreed across the profession that a LVDWT of 6mm is a suitable diagnostic criterion for HCM.

    Better criteria are needed for the diagnosis and classification of feline HCM.
    http://onlinelibrary.wiley.com/doi/10.1046/j.1439-0442.2003.00546.x/full
    http://www.sciencedirect.com/science/article/pii/S1760273410000603


    Electrocardiography

    ECG testing is very important in humans, and is sometimes used to screen young athletes for HCM. It is a sensitive test, meaning that a normal ECG is a good indication of a healthy heart, but poorly specific (lots of false positives can result). Echocardiography is used as a follow-up for abnormal ECG traces in humans.

    Currently, ECG seems less helpful in the cat. Some changes have been identified in cats with HCM, but at present we have no firm criteria for diagnosis.


    Other imaging techniques

    Cardiac MRI is important in humans, since it is more detailed than echo, can calculate LV mass and can identify myocardial fibrosis. However, is not useful in cats, as general anaesthesia is required in this species.

    CT scanning may be possible without general anaesthesia, using the new 'mousetrap' devices, and is less stressful than echo.

    Micro-CT is a new imaging modality in its infancy - not currently available in veterinary medicine, but a possible hope for the future. It is a CT scanning technique that is so detailed that it can examine the cardiac myofibres and myocytes on a microscopic level.

    Strain rate imaging - an echo technique looking at deformation of the heart muscle - is also promising but very new in veterinary medicine at the moment.


    Family history

    Veterinary cardiologist Virginia Luis-Fuentes, who has done a lot of work in feline HCM, believes that we need to spend more time incorporating family history (where known) in screening for feline HCM, and she has collaborated with the PawPeds database to try and improve this.


    Cardiac biomarkers

    The use of NT-proBNP is controversial amongst veterinary cardiologists.

    It was incorporated in JR Payne's recent 'CatScan' study, and found that it can identify high-risk cats but not low-risk cases, and cannot differentiate cats with HCM from those without HCM.
    http://onlinelibrary.wiley.com/doi/10.1111/jvim.12215/full

    A stepwise increase in mortality with increasing NT-proBNP has been shown in both humans and cats.



    TREATMENT


    There are very few new treatments for HCM in humans.

    There is currently NO published evidence that ANY medication can delay the onset of signs in cats with subclinical HCM. In human medicine, there is evidence that ACE inhibitors can prevent the remodelling of myocardium, and may modify disease progression. No such benefit has been shown in Maine Coons.

    Pimobendan is increasingly being used in feline congestive heart failure cases (unlicensed), and anecdotally seems to improve survival time and clinical response.

    A promising new molecule, MYK-461 (no chemical name yet) is currently undergoing tests. MYK-461 is an inhibitor of sarcomere force output, which reduces the contractility of myocardial sarcomeres. It may reduce cardiac work without compromising systolic function.

    In the following study, MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve (SAM - see below) and relieved LVOT pressure gradients.
    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168407


    ATE

    Following the FATCAT study a couple of years ago, clopidogrel (Plavix) is the current drug of choice for the prevention of ATE in cats with HCM, preferred to aspirin.
    http://www.vet.cornell.edu/news/FatCatStudy.cfm

    Other medications being worked on at the moment include direct thrombin anatgonists and factor Xa antagonists (a study comparing the latter with clopidogrel is ongoing).

    It has been shown that clopidogrel attentuates ADP-mediated P-selectin expression (involved in platelet aggregation and thrombus formation) in the homozygous Maine Coons with increased platelet reactivity, this reducing ADP-induced platelet aggregation.
    http://www.vetmed.ucdavis.edu/resea...Zeta_Research_Award_Nominatin_Ronald_Li-2.pdf



    SURVIVAL AND PROGNOSIS


    The median survival time reported in cats with HCM is approximately 13 years. This means that 50% of cats diagnosed with HCM were still alive at 13 years of age (and many will have lived longer). 50% died before they reached the age of 13 years.

    Mortality due to HCM can occur at any age.

    While a significant cause of feline mortality, it has been shown to be a less common cause of death than urinary tract disease, trauma and cancer.
    https://www.ncbi.nlm.nih.gov/pubmed/19780926

    Survival is worse in humans diagnosed under the age of 50 years. Over the age of 50, survival in HCM patients is no different to the general population. Whether or not a similar phenomenon exists in cats is currently not known.



    CARDIAC CHEST PAIN, MYOCARDIAL INFARCTION AND SAM/DLVOTO


    SAM - systolic anterior motion of the mitral valve.
    DLVOTO - dynamic left ventricular outflow tract obstruction (generally caused by SAM).

    SAM generally results from elongation of the mitral valve leaflet, abnormalities of the chordae tendine and enlargement of the papillary muscles. It can result from HCM, or may be a consequence of congenital mitral dysplasia. In humans, genetic mutations can cause these abnormalities as well as HCM.

    DLVOTO is present in around 1/3 of humans and cats with HCM. It is considered a significant issue in humans, resulting in chest pain, breathlessness and some cases of sudden death. In cats, the outcome is generally much better than in humans, though it may be painful, and MAY be associated with an increased risk of myocardial infarction (heart attack).

    Myocardial infarction, an extreme end point of ischaemia (tissue death due to interruption of the blood supply), is not uncommon in cats.

    A degree of ischaemia may be present in HCM cats before we see infarction. The cardiac biomarker cTnI may be a marker of ischaemia. Myocardial infarction can manifest as sudden death, arrhythmia or syncope (fainting). In surviving cats, the affected myocardium is replaced with fibrous tissue and can appear thin even in cats with a previous history of HCM. The coronary vasculature is unusual in these cats, due to angiogenesis.

    AliveCor is a mobile ECG monitor in human medicine, which may have future applications in feline medicine.



    TRANSIENT MYOCARDIAL THICKENING


    This is a relatively recent discovery in cats, backed up with very limited data at the moment (only one case series exists as of 2018).
    http://onlinelibrary.wiley.com/doi/10.1111/jvim.14897/full

    It is seen in young cats following an antecedent event (stress). There is sudden onset thickening of the myocardium - thought to be oedema of the muscle - with acute, low-output congestive heart failure. On bloodwork, cardiac troponin levels are high and reflective of severe acute muscle damage.

    The myocardial thickening in these cases does not mean the cat has HCM, and may not indicate immediate euthanasia. They usually respond quickly (if they survive at all), but it can take several weeks for the myocardial thickening to resolve. It is usually not recurrent.

    There is no way to distinguish transient myocardial thickening from true HCM on echo. Some cats will not survive the acute episode, even with intensive care.
     
  2. Sacremist

    Sacremist Resident Piss Artist

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    There is a research study currently underway on heart disease in Birmans. I have given permission for my cats medical records to be obtained from the University of Liverpool and will let them scan my cats if a day and location can be arranged not too far from where I live. I arranged to have bloods taken and sent to the researchers from one of my cats today. The other is not due another blood test just yet, but I will have his bloods sent to the study when it is time for his tests. Here's a link to the Birman Cat Club website with updates on research done and being done. http://www.birmancatclub.co.uk/heartfund.html
     
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  3. Ceiling Kitty

    Ceiling Kitty Not available for comment

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    That's good to know @Sacremist, thanks!

    If anyone is aware of any other genetic research for HCM in other breeds, please be sure to add it here!
     
    stockwellcat. likes this.
  4. stockwellcat.

    stockwellcat. PetForums VIP

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    Thank you for the above @Ceiling Kitty.

    Can I ask something?
    In December 2016 there was a publication in the Vet Times about a drug on trial in the US called MYK-461, was there any advancement on this drug at UC Davis? The drug from what I have read was showing real promise but there has been no updates. I tried emailing UC Davis and got no response.

    Thanks your input would be greatly appreciated.

    https://www.ucdavis.edu/news/new-drug-heart-disease-shows-promise-cats-and-humans/

    http://science.sciencemag.org/content/351/6273/617

    https://www.vettimes.co.uk/news/feline-heart-disease-treatment-shows-promise/

    http://mrcvs.co.uk/en/news/15340/New-heart-disease-drug-offers-hope-for-cats-and-humans

    http://www.2ndchance.info/MYK-461.htm

    Here's the research article:
    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168407
     
    #4 stockwellcat., Jan 11, 2018
    Last edited: Jan 11, 2018
  5. stockwellcat.

    stockwellcat. PetForums VIP

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    I see that studies have been carried out for Ragdolls and Maine coons but moggies also get HCM like my cat is a dsh and has HCM. Why hasn't studies been carried out in moggies?
     
  6. Ceiling Kitty

    Ceiling Kitty Not available for comment

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    @stockwellcat.

    What I've written about MYK-461 above is all I know about it at the moment. It takes years for things to develop from initial tests into a useable product, and of course unfortunately not all substances make it that far.

    Regarding the studies, the vast majority of them ARE in moggies. :)
     
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  7. Tigermoon

    Tigermoon PetForums VIP

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    I have also helped in the research currently ongoing in birmans. We are hoping for a test in the nearish future.
    There is also research for HCM in persians taking place now.
     
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  8. stockwellcat.

    stockwellcat. PetForums VIP

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    Thank you for answering my questions. I didn't realise moggies are included in the studies I just thought it was pedigree cats like those stated above. That's good news they are included.
     
  9. stockwellcat.

    stockwellcat. PetForums VIP

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    I hope you don't mind me just giving a little update on MYK-461 @Ceiling Kitty?

    I have had a reply from one of the researchers at UC Davis in the last 10 minutes via email.

    This is the latest situation with MYK-461.
     
    #9 stockwellcat., Jan 11, 2018
    Last edited: Jan 11, 2018
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  10. chillminx

    chillminx PetForums VIP

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    Great post @Ceiling Kitty :) . Very useful information for future reference.

    I believe the question of making a thread into a 'sticky' may be rather a delicate matter, but on the basis that 'she/he who doesn't ask, never gets' could I please ask @lymorelynn if there is any possibility of this thread being made a sticky? :)
     
  11. lymorelynn

    lymorelynn UN Peacekeeper in training
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    I'll have a look and see if there's room (after I made a mess of trying to tidy them up last year :oops::Bag)
    I did think when I saw it this morning it was something worth keeping
     
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  12. Sacremist

    Sacremist Resident Piss Artist

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    Just wanted to say that research being carried out in Birmans is being funded by the Birman Cat Club who raise money through Birman breeders and pet owners in the Birman loving community. I’m sure all research will ultimately help all cats.
     
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  13. TallulahCat

    TallulahCat PetForums VIP

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    Thanks for this @Ceiling Kitty

    My cat has HCM so this is interesting to read. He’s part Ragdoll, obviously from a BYB (I got him as a rescue).
     
  14. Bigsize9foot

    Bigsize9foot PetForums Junior

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    My 7 month old male moggy (rescued) has just been diagnosed with HCM. The vet leads me to believe it is rare in a cat so young.

    We are awaiting the cardiologist scan to give us prognosis but they will just say “guarded” at the moment. I’m hoping for some survival figures like the ones above.
     
  15. Tigermoon

    Tigermoon PetForums VIP

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    The club would like you to believe this, but it is not true.



    I was sent this article today. It is about cardiomyopathy in humans but gives some rather interesting detail into what goes on within the heart of a sufferer.
    https://theconversation.com/dilated...se-that-killed-george-michael-explained-74227
     
  16. QOTN

    QOTN PetForums VIP

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    I thought DCM and HCM are different. In DCM the heart is enlarged but in HCM the heart wall is thickened. Is this not true?
     
  17. Rufus15

    Rufus15 PetForums VIP

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    @Ceiling Kitty would you mind clarifying for me please, is the current school of thought that heart scans in Maine Coons are still beneficial to detect the onset of HCM or is gene testing and breeding from n/n parents the best option?
     
  18. Tigermoon

    Tigermoon PetForums VIP

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    Ideally you are should to do both as the gene test will only find the most gene responsible but there are probably others. Scans won't tell you if your cat is likely to get cardiomyopathy but it will tell you if there are any changes to the heart.
     
  19. Rufus15

    Rufus15 PetForums VIP

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    This is partly my question - is there much point in the scan as you can breed from a cat that has a normal heart at 1 but an abnormal heart at 6, after they've had a number of litters. Ceiling Kitty said:

    which as I understand it means that an echocardiogram is not an accurate form of diagnosis and, based on my experience in learning from long-term Maine Coon breeders, is not helpful when a cat displays late symptoms after producing litters.

    So I wonder whether it's somewhat fruitless to scan.
     
  20. Tigermoon

    Tigermoon PetForums VIP

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    A breeder who doesn't scan could be breeding from a cat with clear changes to the heart though couldn't they??? And cats have dropped dead at 9 months, 18 months, 2 years, 4 years ..... I therefore scan. At least I know that at the time I am breeding the cat wasn't showing anything that would be a cause for concern. Of course I have no gene test for my breeds. If I did I would test every breeding cat just as I do for PKD even though I know their parents are tested clear.
     
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