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.