Classification of feline hypertrophic cardiomyopathy-associated gene variants according to the American College of Medical Genetics and Genomics guidelines.

Introduction: The correct labeling of a genetic variant as pathogenic is important as breeding decisions based on incorrect DNA tests can lead to the unwarranted exclusion of animals, potentially compromising the long-term health of a population. In human medicine, the American college of Medical Genetics (ACMG) guidelines provide a framework for variant classification. This study aims to apply these guidelines to six genetic variants associated with hypertrophic cardiomyopathy (HCM) in certain cat breeds and to propose a modified criterion for variant classification. Methods: Genetic samples were sourced from five cat breeds: Maine Coon, Sphynx, Ragdoll, Devon Rex, and British Short- and Longhair. Allele frequencies were determined, and in the subset with phenotypes available, odds ratios to determine the association with HCM were calculated. In silico evaluation followed with joint evidence and data from other publications assisting in the classification of each variant. Results: Two variants, MYBPC3:c.91G > C [A31P] and MYBPC3:c.2453C > T [R818W], were designated as pathogenic. One variant, MYH7:c.5647G > A [E1883K], was found likely pathogenic, while the remaining three were labeled as variants of unknown significance. Discussion: Routine genetic testing is advised solely for the MYBPC3:c.91G > C [A31P] in the Maine Coon and MYBPC3:c.2453C > T [R818W] in the Ragdoll breed. The human ACMG guidelines serve as a suitable foundational tool to ascertain which variants to include; however, refining them for application in veterinary medicine might be beneficial.

The Feline Cardiomyopathies: 3. Cardiomyopathies other than HCM.

PRACTICAL RELEVANCE: Although feline hypertrophic cardiomyopathy (HCM) occurs more commonly, dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular noncompaction (LVNC) and cardiomyopathy - nonspecific phenotype (NCM; formerly unclassified cardiomyopathy) are all recognized in domestic cats. PATIENT GROUP: Any adult domestic cat, of either sex and of any breed, can be affected. DIAGNOSTICS: The non-HCM cardiomyopathies are rarely suspected in subclinically affected cats, so most are first identified when a cat presents with signs of heart failure or systemic thromboembolic disease. The definitive clinical confirmatory test for these other feline cardiomyopathies is echocardiography. KEY FINDINGS: 'Cardiomyopathy - nonspecific phenotype' is a catch-all term that groups hearts with myocardial changes that either do not meet the criteria for any one type of cardiomyopathy (HCM, RCM, DCM, ARVC, LVNC) or meet the echocardiography criteria for more than one type. RCM is characterized by diastolic dysfunction due to fibrosis that results in a restrictive transmitral flow pattern on Doppler echocardiography and usually marked left or biatrial enlargement. DCM is characterized by decreased myocardial contractility and is rare in cats. When it occurs, it is seldom due to taurine deficiency. However, since taurine-deficient DCM is usually reversible, a diet history should be obtained, whole blood and plasma taurine levels should be measured and taurine should be supplemented in the diet if the diet is not commercially manufactured. ARVC should be suspected in adult cats with severe right heart enlargement and right heart failure (ascites and/or pleural effusion), especially if arrhythmia is present. Feline LVNC is rare; its significance continues to be explored. Treatment of the consequences of these cardiomyopathies (management of heart failure, thromboprophylaxis, treatment of systemic arterial thromboembolism) is the same as for HCM. CONCLUSIONS: While these other cardiomyopathies are less prevalent than HCM in cats, their clinical and radiographic presentation is often indistinguishable from HCM. Echocardiography is usually the only ante-mortem method to determine which type of cardiomyopathy is present. However, since treatment and prognosis are often similar for the feline cardiomyopathies, distinguishing among the cardiomyopathies is often not essential for determining appropriate therapy. AREAS OF UNCERTAINTY: The feline cardiomyopathies do not always fit into one distinct category. Interrelationships among cardiomyopathies in cats may exist and understanding these relationships in the future might provide critical insights regarding treatment and prognosis.

The Feline Cardiomyopathies: 1. General concepts.

PRACTICAL RELEVANCE: The feline cardiomyopathies are the most prevalent type of heart disease in adult domestic cats. Several forms have been identified (see Parts 2 and 3), with hypertrophic cardiomyopathy (HCM) being the most common. Clinically the cardiomyopathies are often indistinguishable. Cats with subclinical cardiomyopathy may or may not have characteristic physical examination findings (eg, heart murmur, gallop sound), or radiographic cardiomegaly. Cats with severe disease may develop signs of heart failure (eg, dyspnea, tachypnea) or systemic arterial thromboembolism (ATE; eg, pain and paralysis). Sudden death is possible. Treatment usually does not alter the progression from subclinical to clinical disease and often the treatment approach, once clinical signs are apparent, is the same regardless of the type of cardiomyopathy. However, differentiating cardiomyopathy from normal variation may be important prognostically. PATIENT GROUP: Domestic cats of any age from 3 months upward, of either sex and of any breed, can be affected. Mixed-breed cats are most commonly affected but certain breeds are disproportionately prone to developing HCM. DIAGNOSTICS: Subclinical feline cardiomyopathies may be suspected based on physical examination findings, thoracic radiographs and cardiac biomarker results but often the disease is clinically silent. The definitive clinical confirmatory test is echocardiography. Left heart failure (pulmonary edema and/or pleural effusion) is most commonly diagnosed radiographically, but point-of-care ultrasound and amino terminal pro-B-type natriuretic peptide (NT-proBNP) biomarker testing can also be useful, especially when the stress of taking radiographs is best avoided. KEY FINDINGS: Knowledge of pathophysiological mechanisms helps the practitioner identify the feline cardiomyopathies and understand how these diseases progress and how they manifest clinically (heart failure, ATE). Existing diagnostic tests have strengths and limitations, and being aware of these can help a practitioner deliver optimal recommendations regarding referral. CONCLUSIONS: Several types of feline cardiomyopathies exist in both subclinical (mild to severe disease) and clinical (severe disease) phases. Heart failure and ATE are the most common clinical manifestations of severe cardiomyopathy and are therapeutic targets regardless of the type of cardiomyopathy. The long-term prognosis is often guarded or poor once overt clinical manifestations are present. AREAS OF UNCERTAINTY: Some cats with presumed cardiomyopathy do not have echocardiographic features that fit the classic cardiomyopathies (cardiomyopathy - nonspecific phenotype). Although no definitive treatment is usually available, understanding how cardiomyopathies evolve remains worthy of investigation.

The Feline Cardiomyopathies: 2. Hypertrophic cardiomyopathy.

PRACTICAL RELEVANCE: Hypertrophic cardiomyopathy (HCM) is the most common form of feline cardiomyopathy observed clinically and may affect up to approximately 15% of the domestic cat population, primarily as a subclinical disease. Fortunately, severe HCM, leading to heart failure or arterial thromboembolism (ATE), only occurs in a small proportion of these cats. PATIENT GROUP: Domestic cats of any age from 3 months upward, of either sex and of any breed, can be affected. A higher prevalence in male and domestic shorthair cats has been reported. DIAGNOSTICS: Subclinical feline HCM may or may not produce a heart murmur or gallop sound. Substantial left atrial enlargement can often be identified radiographically in cats with severe HCM. Biomarkers should not be relied on solely to diagnose the disease. While severe feline HCM can usually be diagnosed via echocardiography alone, feline HCM with mild to moderate left ventricular (LV) wall thickening is a diagnosis of exclusion, which means there is no definitive test for HCM in these cats and so other disorders that can cause mild to moderate LV wall thickening (eg, hyperthyroidism, systemic hypertension, acromegaly, dehydration) need to be ruled out. KEY FINDINGS: While a genetic cause of HCM has been identified in two breeds and is suspected in another, for most cats the cause is unknown. Systolic anterior motion of the mitral valve (SAM) is the most common cause of dynamic left ventricular outflow tract obstruction (DLVOTO) and, in turn, the most common cause of a heart murmur with feline HCM. While severe DLVOTO is probably clinically significant and so should be treated, lesser degrees probably are not. Furthermore, since SAM can likely be induced in most cats with HCM, the distinction between HCM without obstruction and HCM with obstruction (HOCM) is of limited importance in cats. Diastolic dysfunction, and its consequences of abnormally increased atrial pressure leading to signs of heart failure, and sluggish atrial blood flow leading to ATE, is the primary abnormality that causes clinical signs and death in affected cats. Treatment (eg, loop diuretics) is aimed at controlling heart failure. Preventive treatment (eg, antithrombotic drugs) is aimed at reducing the risk of complications (eg, ATE). CONCLUSIONS: Most cats with HCM show no overt clinical signs and live a normal or near-normal life despite this disease. However, a substantial minority of cats develop overt clinical signs referable to heart failure or ATE that require treatment. For most cats with clinical signs caused by HCM, the long-term prognosis is poor to grave despite therapy. AREAS OF UNCERTAINTY: Genetic mutations (variants) that cause HCM have been identified in a few breeds, but, despite valiant efforts, the cause of HCM in the vast majority of cats remains unknown. No treatment currently exists that reverses or even slows the cardiomyopathic process in HCM, again despite valiant efforts. The search goes on.

Psychometric Properties of the Spanish Version of the Functional Evaluation of Cardiac Health Questionnaire "FETCH-Q™" for Assessing Health-related Quality of Life in Dogs with Cardiac Disease.

To evaluate the psychometric properties of the Spanish version of the "FETCH-Q™", 228 dogs with cardiovascular diseases were included. After forward and back translation of the original questionnaire, nonexperts, ethologists and veterinary colleagues evaluated the content's validity through feedback. For criteria validity, the total score was correlated with the heart disease/failure class. For construct validity, the overall quality of life of the dog and the results obtained in each question was correlated. The reliability of the questionnaire was assessed using the Cronbach's alpha coefficient. To evaluate the test-retest validity the intra-class correlation coefficient and Wilcoxon signed-rank test were used. A good agreement with the original questionnaire was evident. For construct validity, the questionnaire obtained r > 0.09 to < 0.82. The criterion validity was appropriate and the correlation was rho = 0.82, with an effect size of 0.55 (P < 0.05). Cronbach's alpha coefficient was (α = 0.89). The test-retest assessment revealed adequate repeatability (correlation coefficient = 0.87; P < .001). There was no difference in the owner responses to the questionnaire at baseline and 2 weeks later in dogs with stable cardiac disease (P > .05). This study supports the validity of psychometric properties of the Spanish version of the functional evaluation of cardiac health questionnaire "FETCHSV2-Q™" to assess Health-related Quality of Life in dogs with cardiovascular disease in clinical settings and research.

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 A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency.

Mutations in MYBPC3, the gene encoding cardiac myosin binding protein C (cMyBP-C), are a major cause of hypertrophic cardiomyopathy (HCM). While most mutations encode premature stop codons, missense mutations causing single amino acid substitutions are also common. Here we investigated effects of a single proline for alanine substitution at amino acid 31 (A31P) in the C0 domain of cMyBP-C, which was identified as a natural cause of HCM in cats. Results using recombinant proteins showed that the mutation disrupted C0 structure, altered sensitivity to trypsin digestion, and reduced recognition by an antibody that preferentially recognizes N-terminal domains of cMyBP-C. Western blots detecting A31P cMyBP-C in myocardium of cats heterozygous for the mutation showed a reduced amount of A31P mutant protein relative to wild-type cMyBP-C, but the total amount of cMyBP-C was not different in myocardium from cats with or without the A31P mutation indicating altered rates of synthesis/degradation of A31P cMyBP-C. Also, the mutant A31P cMyBP-C was properly localized in cardiac sarcomeres. These results indicate that reduced protein expression (haploinsufficiency) cannot account for effects of the A31P cMyBP-C mutation and instead suggest that the A31P mutation causes HCM through a poison polypeptide mechanism that disrupts cMyBP-C or myocyte function.

The genetic basis of hypertrophic cardiomyopathy in cats and humans.

Mutations in genes that encode for muscle sarcomeric proteins have been identified in humans and two breeds of domestic cats with hypertrophic cardiomyopathy (HCM). This article reviews the history, genetics, and pathogenesis of HCM in the two species in order to give veterinarians a perspective on the genetics of HCM. Hypertrophic cardiomyopathy in people is a genetic disease that has been called a disease of the sarcomere because the preponderance of mutations identified that cause HCM are in genes that encode for sarcomeric proteins (Maron and Maron, 2013). Sarcomeres are the basic contractile units of muscle and thus sarcomeric proteins are responsible for the strength, speed, and extent of muscle contraction. In people with HCM, the two most common genes affected by HCM mutations are the myosin heavy chain gene (MYH7), the gene that encodes for the motor protein ß-myosin heavy chain (the sarcomeric protein that splits ATP to generate force), and the cardiac myosin binding protein-C gene (MYBPC3), a gene that encodes for the closely related structural and regulatory protein, cardiac myosin binding protein-C (cMyBP-C). To date, the two mutations linked to HCM in domestic cats (one each in Maine Coon and Ragdoll breeds) also occur in MYBPC3 (Meurs et al., 2005, 2007). This is a review of the genetics of HCM in both humans and domestic cats that focuses on the aspects of human genetics that are germane to veterinarians and on all aspects of feline HCM genetics.

Fossa ovalis tear causing right to left shunting in a Cavalier King Charles Spaniel.

Left atrial tear is an infrequent sequela of severe mitral regurgitation due to myxomatous mitral valve degeneration. Interatrial septal tear due to mitral regurgitation causing a left-to-right shunt is uncommon. Right to left shunting secondary to acute interatrial septal tear is very rarely reported in the human literature, and has not been reported in the veterinary literature in a dog. This case describes the clinical, radiographic, echocardiographic, gross pathologic, and histopathologic features of a dog presented in acute respiratory distress secondary to acute onset right to left shunting through the interatrial septum. This was later documented to be due to a tear in the septum secondary to tricuspid regurgitation and pulmonary hypertension. The presence of an acquired right to left shunting atrial septal defect is of clinical and prognostic significance, and should be considered in cases of acute respiratory distress.

Evaluation of heart murmurs in chinchillas (Chinchilla lanigera): 59 cases (1996-2009).

OBJECTIVE: To determine the prevalence of heart murmurs in chinchillas (Chinchilla lanigera) and determine whether heart murmurs were associated with cardiac disease. DESIGN: Retrospective multi-institutional case series. ANIMALS: 260 chinchillas. PROCEDURES: Medical records of all chinchilla patients evaluated at the Tufts University Foster Hospital for Small Animals between 2001 and 2009, the University of California-Davis William R. Pritchard Veterinary Medical Teaching Hospital between 1996 and 2009, and the University of Wisconsin Veterinary Medical Teaching Hospital between 1998 and 2009 were reviewed. RESULTS: Prevalence of heart murmurs was 23% (59/260). Of 15 chinchillas with heart murmurs that underwent echocardiography, 8 had echocardiographic abnormalities, including dynamic right ventricular outflow tract obstruction, mitral regurgitation, hypertrophy of the left ventricle, tricuspid regurgitation, and hypovolemia. Echocardiographic abnormalities were approximately 29 times as likely (OR, 28.7) to be present in chinchillas with a murmur of grade 3 or higher than in chinchillas without a murmur. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that heart murmurs are common in chinchillas and that chinchillas with heart murmurs often have echocardiographic abnormalities, with valvular disease being the most common. On the basis of these results, we believe that echocardiography should be recommended for chinchillas with heart murmurs, especially older chinchillas with murmurs of grade 3 or higher. Further prospective studies are needed to accurately evaluate the prevalence of cardiac disease in chinchillas with heart murmurs.

Cardiovascular and respiratory effects of incremental doses of dopamine and phenylephrine in the management of isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy.

OBJECTIVE: To determine cardiopulmonary effects of incremental doses of dopamine and phenylephrine during isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy (HCM). ANIMALS: 6 adult cats with severe naturally occurring HCM. PROCEDURES: Each cat was anesthetized twice (once for dopamine treatment and once for phenylephrine treatment; treatment order was randomized). Hypotension was induced by increasing isoflurane concentration. Cardiopulmonary data, including measurement of plasma concentration of cardiac troponin I (cTnI), were obtained before anesthesia, 20 minutes after onset of hypotension, and 20 minutes after each incremental infusion of dopamine (2.5, 5, and 10 µg/kg/min) or phenylephrine (0.25, 0.5, and 1 µg/kg/min). RESULTS: Mean ± SD end-tidal isoflurane concentration for dopamine and phenylephrine was 2.44 ± 0.05% and 2.48 ± 0.04%, respectively. Cardiac index and tissue oxygen delivery were significantly increased after administration of dopamine, compared with results after administration of phenylephrine. Systemic vascular resistance index was significantly increased after administration of phenylephrine, compared with results after administration of dopamine. Oxygen consumption remained unchanged for both treatments. Systemic and pulmonary arterial blood pressures were increased after administration of both dopamine and phenylephrine. Acid-base status and blood lactate concentration did not change and were not different between treatments. The cTnI concentration increased during anesthesia and infusion of dopamine and phenylephrine but did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Dopamine and phenylephrine induced dose-dependent increases in systemic and pulmonary blood pressure, but only dopamine resulted in increased cardiac output. Hypotension and infusions of dopamine and phenylephrine caused significant increases in cTnI concentrations.