Two mutations in cardiac myosin binding protein C (MYBPC3), a gene within the cardiac sarcomere, have been identified in Maine Coons (A31P mutation) and Ragdolls (R820W mutation).7,8 Other variants of these mutations very likely exist given that Maine Coons and Ragdolls without these mutations also develop HCM.⁹ By comparison, over 1400 gene variants have been reported in human patients with HCM. Some researchers suggest that cats with both copies of the mutation (homozygotes) are at high risk for developing severe HCM, whereas others have detected homozygous cats with no evidence of HCM. There is a high prevalence in Maine Coons (34% in one study).¹⁰ However, the penetrance (detection of the HCM phenotype) is low in Maine Coons with a heterozygous genotype, and cats with the homozygous genotype can remain healthy.⁹ This association between appearance of disease and genotype is also apparent in Ragdoll cats.¹¹ Sphynx, Norwegian Forest Cats, American Shorthairs, Scottish Folds, Persians, Siamese, Abyssinians, Himalayans, and Birmans are all breeds considered to be predisposed to cardiomyopathies.¹² However, studies demonstrating a hereditary relationship are limited.

Taurine deficiency was identified as a major cause of DCM in cats in the mid-1980s.13 Subsequent supplementation of commercial diets with taurine has led to the almost complete disappearance of taurine-deficient myocardial failure in cats. However, homemade diets or feeding low taurine canine diets (such as lamb and rice diet) can still occasionally lead to taurine deficiency, resulting in DCM.

Electrocardiography is ineffective as a screening tool for occult cardiac disease in cats. The basis for using ECG as a screening tool relies on its ability to detect either chamber enlargement or shifts in the mean electrical axis (MEA). However, ECG is extremely insensitive and relatively imprecise in detecting chamber enlargement (or myocardial concentric hypertrophy), and although it can identify deviations in the MEA, these occur relatively infrequently in the general population and can occur in cats with and without underlying structural disease. Only one study has examined the ability of ECG to identify left atrial enlargement in cats.26 This study showed poor sensitivity (12% to 60%) and good specificity (72% to 100%), suggesting that very few cats with p-wave abnormalities have normal left atria. No equivalent studies exist that specifically examine the sensitivity and specificity of ECG in detecting ventricular enlargement in cats; however, studies in humans and other species suggest sensitivities of approximately 50% and specificities of 80% (similar to those found by Schober and colleagues for left atrial enlargement).²⁶ Two studies have examined ECG abnormalities in cats with heart disease. Ferasin and colleagues identified 106 cats with varying degrees of HCM; of these 41 (39%) had no identifiable ECG abnormalities.²⁷ Riesen and colleagues examined 395 cats with various symptomatic heart diseases, including 169 cats with HCM; of these 35 (21%) had no identifiable ECG abnormalities.²⁸ This study identified morphologic changes (i.e., chamber enlargement patterns) in only 15 of 169 (10%) cats with HCM, whereas Ferasin and colleagues found morphologic changes in 30 of 61 (50%) cats with HCM. If these data are combined, morphologic changes indicative of chamber enlargement occur in fewer than 20% of cats with HCM. However, this may be an overestimation, because individual animals in these studies might have had more than one morphologic change; we have assumed that each observation is independent, which gives the “best-case scenario.” Thus, the sensitivity of ECG in detecting morphologic changes consistent with chamber enlargement or HCM, based on these two studies, is 20%. If one assumes that 15% of the general feline population has heart disease, the positive predictive value of morphologic changes on the ECG is approximately 15%, and the negative predictive value is approximately 85%. Thus, a clinician is six times as likely to find a false-positive result as a true-positive result when screening cats by ECG, resulting in substantial expense to clients in pursuit of nonexistent disease. With lower prevalence, the probability of a false-positive finding only increases. A negative result would strongly suggest that the cat is “unaffected” because most cats examined are going to be normal. However, most cats with HCM that are examined will also have normal ECG results, so these cats will not be identified.

Presence of pathologic arrhythmias (ventricular premature contraction [VPC], atrial premature contraction [APC], atrial fibrillation [AF]) occurred in 17 of 169 (10%) of HCM cats in one study,²⁸ and 8 of 106 (8%) in another study²⁷—again, whether these were independent observations or whether multiple arrhythmias were present in the same cat was not apparent. However, this again results in a sensitivity of 10%, preventing the clinician from effectively ruling out the presence of HCM in the absence of arrhythmias.

Given the prevalence of occult cardiac disease (specifically HCM) in cats, the availability of a reliable and inexpensive screening test is desirable. Echocardiography is the diagnostic test of choice; however, it can present a diagnostic limitation due to availability and/or expense. The biomarker NTproBNP has been demonstrated to be significantly higher in cats with heart disease compared to normal cats; however, it has limited utility in differentiating cats with mild HCM from more severe forms of disease and is therefore likely not sensitive enough to detect mild forms of HCM for screening purposes.35 Two small studies have evaluated cTnI in and have found significantly higher cTnI levels in cats with heart disease compared to normal cats.³⁶ Therefore, echocardiography remains the diagnostic choice for screening mild cardiac disease, and stratifying disease severity. However, NTproBNP may have some use in screening for patients that may require further workup.

An alternative use for biomarkers has been directed at discriminating causes of dyspnea or respiratory distress. The utility of cTnI is limited, given that although cTnI has been demonstrated to be significantly higher in patients with cardiac versus noncardiac respiratory distress, there is much overlap between the groups, leaving many patients in a “gray zone.”36 However, measurement of NTproBNP appears to be more promising and is more accurate at distinguishing between cardiac and noncardiac causes. Cutoff values for various studies assessing cats with CHF range from 214–277 pmol/L with a sensitivity of around 85% and specificity of 84%–88%. However, due to changes in the assays over the past few years, different studies and cutoff values cannot be directly compared. In general, a cutoff value of >270 pmol/L can reliably differentiate CHF from respiratory disease.^37,38 Another potential use of NTproBNP is its measurement in pleural fluid to differential cardiac versus noncardiac pleural effusion. Humm and coworkers demonstrated that NTproBNP concentrations are significantly higher in pleural fluid than plasma.³⁹ This may represent a useful and reliable alternative to additional restraint in dyspneic patients for venipuncture or thoracic radiography until the patient is appropriately stabilized for further diagnostics.

Any screening test should only be applied to an “at-risk” population, rather than being performed indiscriminately. Furthermore, a screening test should be either specific or sensitive (depending on whether the veterinarian wishes to rule in a disease or to rule out a disease), or both (which is rare). It should be affordable. An early diagnosis should allow intervention that either alters disease outcome or reduces risk of adverse events. It could be argued that every adult cat is at risk for having subclinical heart disease. However, there are currently no therapies known to alter disease progression in cats with heart disease (except for the almost extinct taurine-deficient myocardial failure). Thus, identifying HCM early in the course of the disease does not allow the clinician to alter the outcome for that patient. Furthermore, in humans, systemic disease has been demonstrated to affect circulating biomarker levels. Although the literature is conflicting, one study demonstrated that NTproBNP concentrations are increased in cats with severe azotemia.40 Because of these concerns, random testing is not recommended, insofar as the probability of false-positive results (with consequent costly further investigations) far exceeds the probability of true-positive results. Cardiac biomarkers should therefore be considered a clinically useful tool to be used in conjunction with, rather than a replacement of, traditional diagnostic tools (history, physical examination, radiography, echocardiography) at the clinician’s disposal.

Cats with HCM can present with a variety of clinical signs and physical examination findings. Murmurs are present in approximately 50% of cats with HCM. Conversely, cats with murmurs do not necessarily have HCM or even cardiac disease. Therefore, presence or absence of a murmur is not useful in identifying cats with HCM. Murmurs in cats with HCM are often associated with systolic anterior mitral valve motion, which produces both a dynamic left ventricular outflow obstruction and mitral regurgitation (Fig. 23.4). Some cats with HCM can develop dynamic right ventricular outflow tract obstruction.

Arrhythmias are commonly observed in cats with subclinical HCM and most apparently healthy cats with ventricular arrhythmias have evidence of structural heart disease echocardiographically.16,18 Therefore, the presence of an arrhythmia, even in apparently healthy cats, warrants further evaluation with echocardiography to assess for structural disease.

Most commonly, cats with clinical HCM present with left-sided CHF. Cats often display subtle signs of CHF until they reach a critical tipping point, at which time they decompensate rapidly. Subtle clinical signs can include mild tachypnea, altered grooming behavior or activity, and decreased appetite. Coughing is a rare clinical finding in cats with CHF; most cats with cough have noncardiac disorders, such as asthma. Congestive heart failure in cats with HCM manifests as pulmonary edema, pleural effusion, or both. Pericardial effusion can also be detected, but this is generally mild and of no clinical hemodynamic consequence. The distribution and radiographic pattern of pulmonary edema in cats with CHF is highly variable.³⁴ Therefore clinicians should not rely on identification of “typical” radiographic findings when making the diagnosis of CHF. Pleural effusion often accompanies pulmonary edema (Fig. 23.5), but substantial effusion will obscure the radiographic pattern of pulmonary edema. Pleural effusion can be a modified transudate or chylous.

Diagnosis of HCM requires echocardiography. A left ventricular wall thickness (either globally or regionally), measured at the standard submitral location, that exceeds 6 mm constitutes a tentative diagnosis of HCM (Fig. 23.6). Cats with wall thickness exceeding 7 mm are considered to have moderate left ventricular hypertrophy. Hypertrophy can be focal or diffuse. More controversy exists regarding basilar septal bulges or thickening. This is a common finding in older cats and can cause dynamic left ventricular outflow tract obstruction. However, whether this constitutes HCM or simply is a consequence of aging is unclear.

Biomarkers do not currently appear to be of use in diagnosis of subclinical HCM. Their use in the diagnosis of CHF is more promising. An NTproBNP cutoff value of >270 pmol/L has been reported to accurately differentiate respiratory disease from CHF in dyspneic patients.46 However, given the potential for false positive results, biomarker testing should always be reserved for patients with an index of suspicion for cardiac disease, and be utilized in conjunction with rather than a replacement for thoracic radiography and echocardiography.

Genetic testing is available for specific cardiac mutations associated with HCM. These tests are reserved for specific breeds (e.g., Maine Coon, Ragdoll) in which the mutations have been identified rather than as a general screening tool. The investigators who identified these mutations have suggested increased penetrance and an early onset of disease in cats homozygous for the mutation. However, studies in Europe have identified cats homozygous for the mutation both with and without echocardiographic evidence of HCM.^9,47 These investigators have further contested the hypothesis that the proposed mutation in Maine Coons is associated with HCM in that breed. However, the European investigators used different methodology to identify and determine genotype in their cats and examined predominantly younger cats, in which the disease might not yet be apparent. Thus, whether the mutation is causal and differences in phenotype merely reflect expressivity of the trait or whether the mutation is a noncausal polymorphism is still subject to debate. Additional evidence for causality has been proposed by the investigators who originally identified the mutation, in which the authors demonstrated altered methylation of CpG sites within the MyBPC gene.⁴⁸

Additionally, Maine Coons without the MyBPC mutation have been identified with HCM, both in the colony where the mutation was initially identified and in the general Maine Coon population.^9,47 Therefore a normal genotype in this breed does not exclude the diagnosis of HCM.

Treatment of HCM is controversial. Currently, no therapeutic studies exist demonstrating clinically important outcomes in cats with subclinical HCM.49 No drugs have demonstrated a delay in progression or reversal of hypertrophy in cats with subclinical HCM. One study examining angiotensin converting enzyme (ACE) inhibitor therapy in subclinical disease failed to show regression of hypertrophy over 1 year; however, the study did not examine whether long-term therapy with ACE inhibitors prevented or delayed the onset of CHF or arterial thromboembolism (ATE).⁵⁰ One unpublished study showed that beta blockers reduced the dynamic outflow obstruction in cats with subclinical disease better than calcium channel blockers.⁵¹ However, another study demonstrated no increase in morbidity or mortality in cats with systolic anterior motion of the mitral valve,⁴⁵ and another demonstrated no significant difference in cardiac mortality between cats with HCM treated or untreated with atenolol.⁵² Arguments that reducing obstruction alters “demeanor” or “behavior” are difficult to accept because these cats are, by definition, without clinical signs. Furthermore, beta blockers have psychotropic effects, so attributing any change in behavior to reduction in left ventricular outflow tract obstruction without a controlled study is improper.

Treatment of CHF in cats is similarly devoid of published evidence. Diuretics are the mainstay of therapy, both in acute and chronic settings. One unpublished study that compared addition of beta blockers, calcium channel blockers, ACE inhibitors, or placebo to furosemide on survival of cats with chronic CHF failed to demonstrate a benefit of any therapy.⁵³ In that study, ACE inhibitors tended to improve outcomes, and beta blockers worsened outcomes, compared with placebo. A prior study of calcium channel blockers and beta blockers in cats with CHF and HCM suggested a survival benefit of diltiazem; however, no placebo group was included in that study to determine whether the difference was due to a benefit of diltiazem or harm from beta blockade.⁵⁴ A retrospective study of cats with CHF secondary to HCM demonstrated a significant survival benefit with adjunctive pimobendan therapy, and another retrospective study reported pimobendan to be well-tolerated with few side effects.^55,56 However, the current available data is retrospective, and should be interpreted with caution without further prospective studies. The pharmacokinetic properties of pimobendan are different in cats than in dogs, with a longer half-life and higher peak serum concentration in cats, and consequently the optimal feline dosage is not known (although anecdotally the same mg/kg dosage for dogs is administered to cats).⁵⁷ Clinicians should carefully consider their treatment strategies for cats with CHF, remembering that polypharmacy in cats is often substantially more difficult than in dogs and that adding drugs may not improve clinical outcomes and may worsen quality of life for both client and patient.

Acute treatment of CHF in cats is best accomplished by adhering to several simple rules:

Clinicians who adhere to these guidelines are likely to resolve an acute CHF crisis in most of their feline patients.

Clinical signs of ATE depend on the vascular bed occluded and the degree of occlusion. Most commonly, clients observe acute paresis or paralysis, which is accompanied by acute and severe pain in the absence of obvious trauma. The acute pain response is a hallmark of ATE. Pain can persist for several hours and subsides as neuronal ischemia develops. Typically, the pain subsides after 24 to 48 hours of complete ischemia. Reperfusion or incomplete occlusion can produce ongoing or recurrent pain. Ultimately, anesthesia of the affected limb (or limbs) ensues. Physical examination can reveal a loss of pulse in the affected limb. Depending on the severity and duration of occlusion, affected limbs can feel hypothermic, with loss of motor and sensory function (Fig. 23.11). Nail beds and foot pads can appear cyanotic. Clipping a toenail on the affected limb to the quick will result in no bleeding or oozing of dark deoxygenated blood. Over several hours swelling and rigidity of affected limb musculature (e.g., gastrocnemius, biceps) can be palpated if the occlusion is severe and persistent. Clinical chemistry analysis will usually reveal elevated serum creatine kinase and aspartate aminotransferase owing to the ischemic myonecrosis.

Much of ATE treatment is anecdotal and without substantial clinical trials to demonstrate benefit or harm. A prospective study (FAT CAT) compared treatment with aspirin versus clopidogrel and demonstrated a significant reduction in the likelihood and median time to recurrent thromboembolic event, and consequently clopidogrel has supplanted the use of aspirin in most feline ATE patients.68 The FAT CAT study is the only available prospective, double blind, randomized treatment study published at this time.

Treatment of acute ATE can be divided into several aims: thrombolysis, promotion of collateral circulation, prevention of additional thrombosis, control of pain, and treatment of any underlying heart disease.

Thrombolytic therapy has been attempted with various chemical and mechanical approaches, including streptokinase,⁶⁹ urokinase,⁷⁰ tissue plasminogen activator,⁷¹ and intravascular thrombectomy.⁷² All these approaches resulted in either substantial peri-interventional mortality (e.g., reperfusion injury) or failure to resolve the thrombus. Thus, this author finds it difficult to recommend aggressive thrombolytic therapy in acute ATE.

Fluid therapy is theoretically of benefit (to promote collateral circulation). However, because most of these cats have severe heart disease underlying the ATE, fluid therapy should be used judiciously for fear of producing CHF. Other approaches for improving collateral circulation, such as the use of vasodilators (e.g., acepromazine), have not proved effective. No reports exist regarding the use of more potent arteriodilators such as amlodipine, nitroprusside, and hydralazine, so their use cannot be recommended at this time. Clopidogrel therapy before experimental induction of ATE has been shown to maintain collateral circulation by an as yet unknown mechanism,⁷³ and has been demonstrated to significantly decrease the likelihood of recurrence compared with aspirin.⁶⁸

Prevention of additional thrombosis during the acute phase of the disease has been promoted by various authors. Most commonly, low-molecular-weight heparin (LMWH; enoxaparin) is administered (1 mg/kg every 12 hours, subcutaneously).⁷⁴ However, no clinical studies have demonstrated any benefit to such heparin therapy. Oral antithrombotic therapies have not been shown to be useful in the acute setting of feline ATE.⁶³ Experimentally, pretreatment with antithrombotics can reduce ATE; however, this does not reflect the clinical scenario of ATE, in which thrombosis exists at the time of presentation.⁷⁵

Pain management is paramount in acute ATE. Cats should have routine pain control with fentanyl in patches (applied over the more cranial body to ensure absorption) or by constant rate infusion or another acute analgesic therapy such as buprenorphine. Pain control can be reduced after 48 to 72 hours, provided that the patient is comfortable.

Treatment of the underlying heart disease is performed as necessary. Unless there is overt CHF, treatment of the heart disease should be delayed until the patient recovers from the acute ATE episode.

Published case series of ATE suggested that up to 65% of patients can be discharged from the hospital alive (what percentage recovered, and to what degree, was not detailed).^61,63 Presence of CHF does not appreciably alter these statistics. Hypothermia, loss of anal sphincter tone, and loss of tail tone are considered poor prognostic indicators (because they demonstrate more profound thromboembolism). Additional studies of prognostic indicators (e.g., return of function) are needed to allow the clinician to better advise clients before they incur substantial costs.

Once circulation begins to return, clinicians should monitor the color of the foot pads or temperature of the limbs. Furthermore, reperfusion can be painful and associated with hyperkalemia. Serum potassium should be evaluated if there is concern for reperfusion injury, or in high risk patients (severe affected patients) for which reperfusion injury is high. In these patients, ECG is typically closely monitored for evidence of peaked T waves (suggestive of serum K+ greater than 5.5 mEq/L), widened QRS duration (suggestive of serum K+ greater than 6.5 mEq/l), and decreased P waves amplitude (suggestive serum K+ greater than 7 mEq/L) which are changes commonly associated with increased serum potassium. However, ECG can be an insensitive screen for hyperkalemia as ECG changes can also be influenced by changes in sodium and calcium levels, as well as acidosis. Therefore, if there is concern, a serum potassium level should be obtained.

Chronic therapy of ATE during the recuperative period can include physical therapy. Gentle limb massage and manipulation might help improve circulation or return of function (although there are no studies demonstrating any benefit); in any case, they have little potential for harm, provided the patient tolerates it. Clinicians should advise clients to watch for gangrenous necrosis, the presence of which necessitates either limb amputation or euthanasia. Permanent loss of function in a single limb can be addressed with amputation; however, the underlying heart disease and strong predisposition to recurrent thromboembolism should temper the clinician’s eagerness to perform such radical therapy. Clients can be taught to monitor foot pads for changes of color or temperature that might indicate a return of circulation.

Limited case series have examined the recurrence of ATE in cats that survive the initial episode.61,63 Some of these suggest that most cats will suffer a second event within 6 months of the first, even if they fully recover from the first. There are some patients that have had multiple episodes from which they recovered; however, this is uncommon, at least in part because most owners are unwilling to endure multiple bouts of ATE. Most patients are euthanized if they suffer a second bout of ATE.

Therapy to prevent or delay the occurrence of subsequent episodes of ATE includes the use of aspirin, LMWH,⁷⁶ and clopidogrel. Of these, only clopidogrel has been evaluated critically in a randomized trial, which demonstrated a significantly reduced likelihood of recurrent ATE compared to aspirin. One concern with this study is that the comparative group was prescribed aspirin rather than placebo. However, given the lack of evidence of the efficacy of aspirin (low-dose or high-dose), one might argue that aspirin is, in effect, a placebo. No clinical studies of the efficacy of LMWH are available. This, coupled with the expense of LMWH therapy and the need for daily injections, makes it difficult to recommend such therapy in cats without additional evidence of efficacy. Some clinicians have considered combining aspirin with clopidogrel, or LMWH with clopidogrel to reduce ATE recurrence or occurrence, but no evidence supports this approach. The author has also noted rare cases of spontaneous bleeding (typically epistaxis), with the latter approach, and therefore recommends diligent client education as well as monitoring packed cell volume and total solids in the initial phases of treatment.

Prevention of initial episodes of ATE involves the use of the same drugs as for prevention of recurrence: aspirin, clopidogrel, and LMWH, either alone or in combination. Other classes of anticoagulants, including factor Xa inhibitors such as apixaban,⁷⁷ are also currently under investigation and have been used anecdotally.