ACVIM consensus statement guidelines for the classification, diagnosis, and management of cardiomyopathies in cats.

Cardiomyopathies are a heterogeneous group of myocardial disorders of mostly unknown etiology, and they occur commonly in cats. In some cats, they are well-tolerated and are associated with normal life expectancy, but in other cats they can result in congestive heart failure, arterial thromboembolism or sudden death. Cardiomyopathy classification in cats can be challenging, and in this consensus statement we outline a classification system based on cardiac structure and function (phenotype). We also introduce a staging system for cardiomyopathy that includes subdivision of cats with subclinical cardiomyopathy into those at low risk of life-threatening complications and those at higher risk. Based on the available literature, we offer recommendations for the approach to diagnosis and staging of cardiomyopathies, as well as for management at each stage.

The ESC classification is based on the traditional phenotypic categories of hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), dilated cardiomyopathy (DCM), unclassified cardiomyopathy (UCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), and we recommend retaining these categories (with the exception of UCM) as a basic framework, while acknowledging their limitations. For example, in some cats, the cardiac phenotype changes over time, because of disease progression, comorbidities or unknown factors.
We propose a classification of cardiomyopathies in cats based on structural and functional characteristics, or phenotype. The phenotypic categories include cats with cardiomyopathy of both known causes (eg, hyperthyroidism, sarcomeric gene mutation) and unknown causes (most cats with a cardiomyopathy phenotype). Until an underlying cause is sought, a cat is said to have a "hypertrophic cardiomyopathy phenotype" or a "dilated cardiomyopathy phenotype" (according to the cardiac morphology and function). If no underlying cause is found, a cat is said to have "hypertrophic cardiomyopathy (HCM)" or "dilated cardiomyopathy (DCM)," as appropriate. The proposed classification therefore does not define specific disease entities, but phenotypic categories instead. The description in any individual cat can be further refined by details of cause when known. Thus, a cat with left ventricular (LV) hypertrophy and hyperthyroidism is said to have an HCM phenotype in conjunction with hyperthyroidism.
Some cats have myocardial disease that does not fit well into any category. Rather than describe these cases as having "unclassified cardiomyopathy," according to the proposed classification these cats should be described as having cardiomyopathy with a "nonspecific phenotype." This term always should be accompanied by a description of Hypertrophic cardiomyopathy (HCM) Diffuse or regional increased LV wall thickness with a nondilated LV chamber.

Restrictive cardiomyopathy (RCM)
Endomyocardial form Characterized macroscopically by prominent endocardial scar that usually bridges the interventricular septum and LV free wall, and may cause fixed, mid-LV obstruction and often apical LV thinning or aneurysm; LA or biatrial enlargement is generally present.
Myocardial form Normal LV dimensions (including wall thickness) with LA or biatrial enlargement Dilated cardiomyopathy (DCM) LV systolic dysfunction characterized by progressive increase in ventricular dimensions, normal or reduced LV wall thickness, and atrial dilatation.
Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular cardiomyopathy (ARVC) or dysplasia (ARVD) Severe RA and RV dilatation and often, RV systolic dysfunction and RV wall thinning. The left heart may also be affected. Arrhythmias and right-sided congestive heart failure are common.
Nonspecific phenotype A cardiomyopathic phenotype that is not adequately described by the other categories; the cardiac morphology and function should be described in detail the morphologic and functional features to characterize the phenotype in more detail.

| Staging cardiomyopathies in cats
For describing the clinical impact of cardiomyopathy in affected cats, we propose a staging system adapted from the American Heart Association (AHA) and American College of Veterinary Internal Medicine (ACVIM) heart disease staging systems [8][9][10] ( Figure 2), with the aim of providing a framework for prognostication and therapeutic decision-making. Stage

| PREVALENCE AND NATURAL HISTORY
The most common type of cardiomyopathic phenotype is HCM and thus it is the major focus in these guidelines, but other phenotypes will be addressed separately where appropriate. Hypertrophic cardiomyopathy has an estimated prevalence of approximately 15% in the general cat population. [12][13][14][15][16] In older cats, the prevalence is much higher, with up to 29% reported affected, even when cats with hypertension and hyperthyroidism are excluded. 15 17,18,21 Less is known about risk factors for sudden cardiac death, but these might include a history of syncope, ventricular arrhythmias, LA enlargement, and regional LV wall hypokinesis. 11

| History
The history is unremarkable in many cats with cardiomyopathy, particularly those with HCM. The most common presenting sign is labored breathing, 17 although some cats only show nonspecific signs such as hiding or inappetence. Congestive heart failure appears to be the most common cause of respiratory distress in cats. 46,47 Paresis or paralysis associated with ATE is also a common presenting sign, 17 with syncope being less common. 19 In some cats with cardiomyopathy, sudden death may occur with no premonitory signs. 18

| Subclinical cardiomyopathy
A parasternal systolic heart murmur has been reported in up to 80% of cats with subclinical HCM, compared with 30%-45% of healthy cats without HCM. [14][15][16][17] Third heart sounds such as gallop sounds have been reported in 2.6%-19% of cats with subclinical HCM and are seldom present in healthy cats. 15 Arrhythmias also can be associated with cardiomyopathies. 48,49 Many affected cats have no auscultatory abnormality. 15,42 Further investigations are recommended if a heart murmur is detected in any cat (LOE medium). 15,42 A loud systolic murmur (grade 3-4/6) is more common in cats with HCM than in normal cats, but an increase in heart murmur intensity over time does not necessarily indicate the presence or worsening of disease. A palpable thrill (grade 5-6/6 murmur) seldom is associated with cardiomyopathy in cats and is more likely to be associated with a congenital malformation. Cats with more advanced disease (or those with restrictive or dilated phenotypes) may not have an audible murmur. 13,21,42,50 Auscultation of a gallop sound or an arrhythmia is more likely to be associated with cardiomyopathy, although differentiation of a gallop sound from other third heart sounds or a bigeminal rhythm can be challenging.

| Cardiomyopathy associated with CHF
Tachypnea, labored breathing or both are the typical historical and physical examination findings in cats with left heart failure. Compared with cats that have subclinical HCM, a gallop sound or an audible arrhythmia are more common in cats with CHF, and murmurs are less common. 13,21,43 In one study, cats presented to first opinion practices for evaluation of respiratory distress with respiratory rates >80 breaths/min, gallop sounds, rectal temperatures <37.5 C or heart rates >200 bpm were more likely to have CHF than other causes of dyspnea. 47 Pulmonary crackles can be heard when pulmonary edema is present, and breath sounds are often diminished ventrally when pleural effusion is present, together with paradoxical breathing. 51

| Radiography
Cardiomyopathy might be suspected when severe cardiomegaly is present radiographically, when a left auricular bulge is present on dorsoventral/ventrodorsal radiographic views, or both. 52,53 Thoracic radiography is insensitive for identification of mild or moderate cardiac changes associated with cardiomyopathy, and in some cats the cardiac silhouette may appear normal even when disease is severe enough to cause CHF. 54 Furthermore, it is difficult to identify the cardiomyopathy phenotype from the shape of the cardiac silhouette, and the classic "valentine-shaped" heart is not specific for HCM, as previously thought. 55,56 Although radiography is considered the gold standard for confirming the presence of cardiogenic pulmonary edema, if radiographs cannot be obtained safely consideration should be given to delaying thoracic radiography (LOE low). In contrast to dogs, the radiographic pattern associated with cardiogenic pulmonary edema in cats is highly variable. 52 if CHF is the cause of respiratory distress (LOE high). 58

| NT-proBNP
The quantitative feline-specific NT-proBNP assay using plasma or pleural fluid has good diagnostic accuracy for discriminating between cats with cardiac and noncardiac causes of respiratory distress (LOE high), 59-64 but it is not recommended for guiding therapeutic decisionmaking in cats with respiratory distress because of the delay in receiving test results from an external laboratory. Instead, a point-of-care NT-proBNP assay provides rapid results while maintaining reasonable diagnostic accuracy in discriminating between cardiac and noncardiac causes of respiratory distress, and should be considered when pointof-care ultrasound examination is not available (LOE medium). 58,65 The point-of-care assay can be used on plasma or pleural fluid, 64 75,76 In addition, cTnI also might be considered for its prognostic value, because an increased circulating cTnI concentration is associated with increased risk of cardiovascular death independent of LA size (LOE high). 77

| Electrocardiography
The sensitivity of a 6-lead ECG for detecting LV hypertrophy or LA enlargement is low, 13

| Thyroxine measurement
Hyperthyroidism is common in older cats, and is associated with auscultatory abnormalities (murmur, gallop, arrhythmias), cardiac remodeling (LV hypertrophy or increased cardiac chamber diameters), and in some cases, CHF or ATE. [95][96][97][98] Hyperthyroid cats with severe LV hypertrophy are sometimes seen, but this association is suspected to be the result of hyperthyroidism exacerbating preexisting mild to moderate HCM (LOE low). It is recommended that serum thyroxine concentrations be measured in all cats ≧6 years of age with abnormal cardiac auscultation findings with or without LV hypertrophy on an echocardiogram (LOE low).

| Echocardiography
Echocardiography is the gold standard test for diagnosis of cardiomyopathies in cats. Indications for echocardiography are listed in Table 4. Qualitative assessment as for standard of care Note: "Focused point-of-care" scan: an abbreviated echocardiographic examination conducted because of patient instability, because the operator has limited training in echocardiography, or both; "standard of care" scan: an echocardiographic examination that includes the content considered to be standard by a trained, competent observer; "best practice" scan: an echocardiographic examination conducted by a cardiologist with particular expertise in echocardiography. IVSd  recommended that a standard of care examination include a qualitative evaluation of SEC and regional wall motion abnormalities (Table 5) (Table 5). 58 It is recommended that this examination be followed by a best practice examination or at least a standardof-care examination once the cat is more stable, using the protocol suggested for cats with suspected cardiomyopathy.

| Approach to the diagnosis of subclinical cardiomyopathy
Cats with subclinical cardiomyopathy can be difficult to identify. Cardiac evaluation should be considered for cats with a suspicious history or physical examination findings that include a gallop sound, murmur, or arrhythmia, and in cats judged to be at high risk of CHF if subjected to interventions such as anesthesia or IV fluid therapy (LOE low; Table 4). Echocardiography is currently the most accurate clinical test for diagnosis of cardiomyopathy in cats, and is also the best technique for estimating prognosis, but is highly user-dependent. 99 However, with appropriate training and experience, focused point-of-care echocardiography is feasible in first opinion (general) practice and can be used to improve the accuracy of cardiomyopathy diagnosis by nonspecialist practitioners, particularly in cats with more advanced disease. 42 It is recommended that focused point-of-care echocardiography be undertaken only after appropriate training and practice 42,99 (LOE high) and a point-of-care examination should be followed at a later time point with a standard echocardiographic examination to characterize the phenotype.
When echocardiography is unavailable, evaluation of NT-proBNP concentrations may be considered. Circulating NT-proBNP concentrations increase with increasing clinical severity of cardiomyopathy in groups of cats, but overlap precludes using NT-proBNP to categorize individual cats into mild, moderate, and severe groups. 69 The measurement of NT-proBNP can be considered as an initial screening test for identifying advanced cardiomyopathy. Normal NT-pro-BNP results do not assure that a cat is free of cardiomyopathy, especially when mild heart disease is present, nor do they guarantee that a cat will remain free of cardiomyopathy later in life. They do however indicate a low likelihood of cardiomyopathy that is immediately, clinically harmful. Therefore, in a cat suspected of cardiomyopathy, follow-up echocardiography still should be considered, even if initial NT-proBNP results are within normal reference intervals (LOE low). It is recommended that a positive NT-proBNP test always be followed by an echocardiographic examination.
In older cats with heart murmurs, gallop sounds or arrhythmias, it is recommended that serum T4 concentration and blood pressure be measured (LOE high). Echocardiography also should be considered (LOE low).

| Approach to diagnosis in cats with suspected CHF
Physical examination findings of tachypnea, labored breathing, respiratory crackles, hypothermia, and a gallop sound are highly suggestive of CHF, 47  There is no evidence that DLVOTO is associated with increased morbidity or mortality in cats, and atenolol has not been shown to have any effect on the 5-year survival rate in cats with subclinical HCM. 116 However, atenolol is expected to decrease DLVOTO gradient and heart rate, 117 and may be considered in cats with stage B1 cardiomyopathy and severe DLVOTO, provided it can be administered consistently (LOE low).

| Stage B2 cardiomyopathy
Cats with stage B2 HCM have an increased risk of developing CHF or ATE. Primary prevention of ATE in cats with subclinical cardiomyopathy has not been studied, but thromboprophylaxis is recommended when known risk factors for ATE are present. 11,106 Clopidogrel was more effective than aspirin in cats that had survived a previous ATE episode, 118 and no other randomized, controlled studies have been reported. Clopidogrel therefore is recommended in cats considered at risk of ATE (moderate to severe LA enlargement, low LA FS%, low LA appendage velocities, SEC; LOE medium). Clopidogrel does not eliminate the risk of ATE, and thus other antithrombotic drugs can be considered in addition to clopidogrel in cats believed to be at very high risk of ATE (eg, clopidogrel plus aspirin, clopidogrel plus a PO factor Xa inhibitor, or clopidogrel plus aspirin plus a PO factor Xa inhibitor; LOE low).
Cats with stage B2 cardiomyopathy should be monitored for progression of disease and development of clinical signs, but the effects of stress caused by reexamination also should be taken into consideration. If a stage B2 cat is reexamined, attention to appropriate handling and minimizing stressful stimuli is important. If these measures are (or are likely to be) insufficient, PO administration of appropriate pharmaceuticals, 119,120 synthetic feline pheromone application [121][122][123] or both can be considered (LOE medium). Once the LA is moderately to severely enlarged and antithrombotic treatment is started, management is unlikely to change until clinical signs develop, but at a minimum, it is recommended that owners monitor the cat's resting or sleeping respiratory rate 124 (LOE medium).
In 2 randomized, placebo-controlled studies, neither an angiotensin converting enzyme (ACE) inhibitor (ramipril) nor spironolactone had any effect on LV mass or diastolic function in cats with subclinical HCM, but study populations were small and limited to cats of a single breed that had heritable cardiomyopathy. 125,126 Similarly, benazepril had no effect on time to treatment failure compared to placebo in a randomized placebo-controlled study that included cats with subclinical heart disease. 127 No studies have been reported of pimobendan use in cats with subclinical cardiomyopathy.
Ventricular ectopy is common in cats with HCM 48,49 and ARVC 48,128 and is associated with sudden death in people with these cardiomyopathies. 80,129,130 Treatment options in cats are limited, but atenolol has been shown to decrease ventricular ectopy in cats with HCM. 117 It is recommended that cats with complex ventricular ectopy be treated with atenolol (6.25 mg/cat q12h PO) or sotalol (10-20 mg/ cat q12h PO; LOE low). Markedly increased heart rate is observed in a minority of cats with atrial fibrillation (AF), 83

| Management of ATE
Most cats with ATE presented to first opinion practice are euthanized. 136 This approach is justifiable In terms of the cat's welfare and generally poor prognosis, but if analgesia is adequate and favorable prognostic factors are present (eg, normothermia, only 1 limb affected, absence of CHF), 136,137 an attempt at treatment can be considered provided the owner is fully informed of the risks and overall poor prognosis.
Analgesia is a priority for management of acute ATE in the first 24 hours, and treatment with a mu opioid agonist such as fentanyl, hydromorphone, or methadone is recommended (LOE low). Anticoagulant treatment is recommended using low-molecular-weight heparin (LMWH) or unfractionated heparin, or a PO factor Xa inhibitor, which should be started as soon as possible (LOE low). Thrombolytic treatment is not recommended for cats with ATE (LOE high). [138][139][140] If CHF is present with ATE, management with furosemide and oxygen is recommended as necessary (LOE high), but it is important to note that pain also can cause tachypnea, and this should not be mistaken for the presence of CHF. It is recommended that clopidogrel be started as soon as the cat can tolerate PO medications, with an initial loading dose of 75 mg PO (LOE low) followed by 18.75 mg PO q24h (LOE high). Heparin can be replaced by a PO factor Xa inhibitor in combination with clopidogrel (LOE low).

| Post-ATE
Reexamination is recommended 3-7 days after discharge from the hospital, as well as 1-2 weeks after the ATE event. Evaluation should include assessment of the distal limbs for evidence of necrosis, electrolyte status, appetite, and treatment compliance, as well as the degree of improvement in neuromuscular function. Resolution of lower motor neuron dysfunction can take weeks or months in some cats, 141 and reexamination should be considered every 1-3 months, considering the effects of stress in the individual cat. It is recommended that the owner continue to monitor resting or sleeping respiratory rate.

| CONCLUSIONS
Cardiomyopathies in cats are a heterogeneous group of myocardial disorders of mostly unknown etiology and with potentially life-threatening consequences. However, it is possible to identify cats at high risk of adverse events. In this consensus statement, we have outlined an approach to diagnosis and treatment that should be accessible to general practitioners as well as specialists. We make several new recommendations: cardiomyopathy classification should be focused on phenotype, but staging is more important for management than type of cardiomyopathy. Echocardiography is a very powerful tool that can provide valuable information, but even a simple focused point-of-care ultrasound examination can be performed by nonspecialist practitioners to identify cats at high risk of CHF or ATE, or those already presenting with CHF.
Evidence-based recommendations are provided on diagnosis and treatment of cardiomyopathies according to stage.

OFF-LABEL ANTIMICROBIAL DECLARATIONS
Authors declare no off-label use of antimicrobials.

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Authors declare no IACUC or other approval was needed.

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