Hypertrophic cardiomyopathy in a dog: a systematic diagnostic approach.

A seven-year-old female neutered Parson Russel terrier was referred for syncopal episodes. An electrocardiogram revealed paroxysmal atrial flutter followed by periods of sinus arrest, suggesting sick sinus syndrome. Echocardiography showed severe biventricular wall thickening (hypertrophic cardiomyopathy (HCM) phenotype) with no signs of fixed or dynamic left ventricular outflow tract obstruction. Blood pressure, abdominal ultrasound, serum total thyroxin and thyroid-stimulating hormone, and insulin-like growth factor-1 were all within normal limits. Cardiac troponin I was elevated (1.7 ng/mL, ref<0.07). Serological tests for common infectious diseases were negative. A 24-h Holter confirmed that the syncopal episodes were associated with asystolic pauses (sinus arrest after runs of atrial flutter) ranging between 8.5 and 9.6 s. Right ventricular endomyocardial biopsies (EMB) were performed at the time of pacemaker implantation to assess for storage or infiltrative diseases that mimic HCM in people. Histological analysis of the EMB revealed plurifocal inflammatory infiltrates with macrophages and lymphocytes (CD3+ > 7/mm2) associated with myocyte necrosis, but no evidence of myocyte vacuolisation or infiltrative myocardial disorders. These findings were compatible with myocardial ischaemic injury or acute lymphocytic myocarditis. Molecular analysis of canine cardiotropic viruses were negative. The dog developed refractory congestive heart failure and was euthanised 16 months later. Cardiac post-mortem examination revealed cardiomyocyte hypertrophy and disarray with diffuse interstitial and patchy replacement fibrosis, and small vessel disease, confirming HCM. We described a systemic diagnostic approach to an HCM phenotype in a dog, where a diagnosis of HCM was reached by excluding HCM phenocopies.

Aortic annular plane systolic excursion in cats with hypertrophic cardiomyopathy.

BACKGROUND: Impairment of left ventricular (LV) longitudinal function is an early marker of systolic dysfunction in hypertrophic cardiomyopathy (HCM). Aortic annular plane systolic excursion (AAPSE) is a measure of LV longitudinal function in people that has not been evaluated in cats. HYPOTHESIS: Aortic annular plane systolic excursion is lower in cats with HCM compared to control cats, and cats in stage C have the lowest AAPSE. ANIMALS: One hundred seventy-five cats: 60 normal, 61 HCM stage B and 54 HCM stage C cats. MATERIALS: Multicenter retrospective case-control study. Electronic medical records from 4 referral hospitals were reviewed for cats diagnosed with HCM and normal cats. HCM was defined as LV wall thickness ≥6 mm and normal cats ≤5 mm. M-mode bisecting the aorta in right parasternal short-axis view was used to measure AAPSE. RESULTS: Aortic annular plane systolic excursion was lower in HCM cats compared to normal cats (3.9 ± 0.9 mm versus 4.6 ± 0.9 mm, P < .001) and was lowest in HCM stage C (2.4 ± 0.6 mm, P < .001). An AAPSE <2.9 mm gave a sensitivity of 83% (95% CI 71%-91%) and specificity of 92% (95% CI 82%-97%) to differentiate HCM stage C from stage B. AAPSE correlated with mitral annular plane systolic excursion (r = .6 [.4-.7], P < .001), and atrial fractional shortening (r = .6 [.5-.7], P < .001), but showed no correlation with LV fractional shortening. CONCLUSIONS AND CLINICAL IMPORTANCE: Aortic annular plane systolic excursion is an easily acquired echocardiographic variable and might be a new measurement of LV systolic performance in cats with HCM.

Echocardiographic and hemodynamic effects of alfaxalone or dexmedetomidine based sedation protocols in cats with hypertrophic cardiomyopathy: a pilot study.

OBJECTIVE: To report the effects of alfaxalone and dexmedetomidine based sedation protocols on echocardiographic and hemodynamic variables in cats with hypertrophic cardiomyopathy (HCM) during sedation and inhalational anesthesia. STUDY DESIGN: Prospective, randomized, experimental study. ANIMALS: A group of 10 client-owned cats with subclinical HCM. METHODS: Cats were administered one of two sedative intramuscular combinations: protocol ABM (alfaxalone 2 mg kg-1, butorphanol 0.4 mg kg-1, midazolam 0.2 mg kg-1; n = 5) or protocol DBM (dexmedetomidine 8 µg kg-1, butorphanol 0.4 mg kg-1, midazolam 0.2 mg kg-1; n = 5). General anesthesia was induced with intravenous alfaxalone and maintained with isoflurane in oxygen. Echocardiographic variables and noninvasive arterial blood pressures were obtained before sedation, following sedation, and during inhalational anesthesia. Sedation scores and alfaxalone induction dose requirements were recorded. Descriptive statistics are reported for cardiovascular variables. RESULTS: During sedation, echocardiographic and hemodynamic variables remained within normal limits with protocol ABM, whereas protocol DBM was characterized by bradycardia, low cardiac index and elevated blood pressure. During isoflurane anesthesia, both protocols demonstrated similar hemodynamic performance, with heart rates of 98 ± 12 and 89 ± 11 beats min-1, cardiac index values of 68 ± 17 and 47 ± 13 mL min-1 kg-1 and Doppler blood pressures of 72 ± 15 and 79 ± 20 mmHg with protocols ABM and DBM, respectively. A reduction in myocardial velocities were also observed during atrial and ventricular contraction with both protocols during isoflurane anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: An alfaxalone based protocol offered hemodynamic stability during sedation in cats with HCM; however, both dexmedetomidine and alfaxalone based protocols resulted in clinically relevant hemodynamic compromise during isoflurane anesthesia. Further studies are required to determine optimal sedative and anesthetic protocols in cats with HCM.

Isolated discrete upper septal thickening in a non-referral cat population of senior and young cats.

INTRODUCTION/OBJECTIVES: Discrete upper septal thickening (DUST) is a phenotype of elderly people. The cardiac phenotype in senior cats has been incompletely described. We aimed to characterize the echocardiographic phenotype of senior cats, specifically to determine prevalence of DUST and hypertrophic cardiomyopathy (HCM). ANIMALS: One hundred and forty-nine healthy, normotensive cats. MATERIALS AND METHODS: Prospective cross-sectional study. Senior (≥9 years) and young (<6 years) cats were recruited from non-referral population. We defined DUST as an isolated basilar septal bulge, and HCM as left ventricular wall thickness ≥6 mm. An interventricular septum ratio (basal-to-mid septal thickness ratio) was calculated. We assessed for associations between clinical and echocardiographic variables and DUST. Data are presented as mean (±SD), median (range), or frequency (percentage). RESULTS: One-hundred and two senior and 47 young cats were enrolled. Aortoseptal angle (AoSA) was steeper in senior cats (137° (±14.5) vs. 145° (±12.3) in young cats, P=0.002). Eighteen cats had DUST (18/149, 12%), fourteen senior, and four young cats (P=0.4). Cats with DUST had steeper AoSA (125° (±8.3) vs. 142° (±13.7), P<0.0001) and higher interventricular septum ratio (1.4 (1.2-2.0) vs. 1.0 (0.7-1.8)). Univariable analysis showed decreased odds of DUST with greater AoSA (OR 0.9, P<0.0001), age was not associated with DUST. Twenty-nine senior cats had HCM (28.4%). DISCUSSION/CONCLUSIONS: Prevalence of DUST was 12%. There was no association between age and DUST. Smaller/steeper AoSA was the main factor associated with DUST. There was a high prevalence of HCM in this senior population.

Cardiomyopathy associated 5 (CMYA5) implicated as a genetic risk factor for radial hemimelia in Siamese cats.

OBJECTIVES: The present study aimed to determine the inheritance pattern and genetic cause of congenital radial hemimelia (RH) in cats. METHODS: Clinical and genetic analyses were conducted on a Siamese cat family (n = 18), including two siblings with RH. Radiographs were obtained for the affected kittens and echocardiograms of an affected kitten and sire. Whole genome sequencing was completed on the two cases and the parents. Genomic data were compared with the 99 Lives Cat Genome data set of 420 additional domestic cats with whole genome and whole exome sequencing data. Variants were considered as homozygous in the two cases of the siblings with RH and heterozygous in the parents. Candidate variants were genotyped by Sanger sequencing in the extended pedigree. RESULTS: Radiographs of the female kitten revealed bilateral absence of the radii and bowing of the humeri, while the male kitten showed a dysplastic right radius. Echocardiography suggested the female kitten had restrictive cardiomyopathy with a positive left atrial-to-aortic root ratio (LA:Ao = 1.83 cm), whereas hypertrophic cardiomyopathy was more likely in the sire, showing diastolic dysfunction using tissue Doppler imaging (59.06 cm/s). Twenty-two DNA variants were unique and homozygous in the affected kittens and heterozygous in the parents. Seven variants clustered in one chromosomal region, including two frameshift variants in cardiomyopathy associated 5 (CMYA5) and five variants in junction mediating and regulatory protein, P53 cofactor (JMY ), including a missense and an in-frame deletion. CONCLUSIONS AND RELEVANCE: The present study suggested an autosomal recessive mode of inheritance with variable expression for RH in the Siamese cat family. Candidate variants for the phenotype were identified, implicating their roles in bone development. These genes should be considered as potentially causal for other cats with RH. Siamese cat breeders should consider genetically testing their cats for these variants to prevent further dissemination of the suspected variants within the breed.

Serum C-terminal telopeptide of Type-I collagen (CTx) concentration and myocardial hyperechogenicity in cats with hypertrophic cardiomyopathy.

Objective: This study sought to determine the serum concentrations of C-terminal telopeptide of Type-I collagen (CTx), a marker of collagen degradation, in a hospital population of cats with hypertrophic cardiomyopathy (HCM). The study also evaluated the prevalence of myocardial hyperechogenicity of the left ventricle (LV) in the same cats. Animals and procedure: Cats brought to a university veterinary cardiology service entered the study when they had an echocardiographic diagnosis of HCM; echocardiographically normal cats served as controls. Serum CTx concentrations were assessed using ELISA. Results: There was no difference in serum CTx concentrations between cats with HCM and controls (HCM: median 0.248 ng/mL, controls: median 0.253 ng/mL; P = 0.4). Significantly more cats with HCM (60%) showed echocardiographic LV myocardial hyperechogenicity compared to normal controls (17%; P = 0.0057), but serum CTx concentrations were not different between these 2 groups. Conclusion and clinical relevance: These results indicate that, as in human patients with HCM and in contrast to earlier feline studies, there was no evidence of enhanced collagen degradation indicated by serum CTx concentrations in cats with HCM compared to normal controls.

Concentration sérique de télopeptide C-terminal du collagène de Type I (CTx) et hyperéchogénicité myocardique chez des chats atteints de cardiomyopathie hypertrophique. Objectif: Le premier objectif de cette étude était d'évaluer le taux sérique d'un marqueur de dégradation de collagène, soit le télopeptide C-terminal du collagène de Type-I (CTx), chez les chats atteints de cardiomyopathie hypertrophique (CMH). Le deuxième objectif était d'évaluer la prévalence de l'hyperéchogénicité du myocarde du ventricule gauche chez ces mêmes chats. Animaux et procédures: Les chats participant à l'étude avaient été présentés pour soins à un service de cardiologie vétérinaire universitaire, et ces chats avaient un diagnostic échocardiographique soit de CMH, soit d'aucune lésion cardiaque (groupe témoin). Le taux sérique de CTx a été évalué de façon immuno-enzymatique par ELISA. Résultats: Les résultats n'ont démontré aucune différence entre le taux sérique de CTx chez les chats atteint de CMH et le taux sérique de CTx chez les chats sans lésion cardiaque (CMH : médiane, 0,248 ng/mL; groupe témoin : médiane, 0,253 ng/mL; P = 0,4). Plus de chats atteints de CMH (60 %) que de chats dans le groupe témoin (17 %) ont démontré une hyperéchogénicité du myocarde du ventricule gauche à l'échocardiographie (P = 0,0057), quoique les taux sériques de CTx n'étaient pas différents entre ces 2 groupes. Conclusion et signification clinique: Ces résultats n'indiquent aucune augmentation de la dégradation de collagène chez les chats atteints de CMH, ce qui s'apparente aux résultats provenant d'études antérieures de la CMH chez l'humain mais non pas à ceux provenant d'études de la CMH féline.(Traduit par les auteurs).

Heart failure in a cat due to hypertrophic cardiomyopathy phenotype caused by chronic uncontrolled hyperthyroidism.

A 16-year-old castrated male Persian cat was presented with weight loss, anorexia and dyspnoea. Tachycardia and tachypnoea were observed upon presentation. The cat was previously diagnosed with hyperthyroidism and left ventricular hypertrophy and received methimazole, but was subsequently not followed up and treated appropriately. Thoracic radiography revealed mild pleural effusion, interstitial lung pattern, moderate cardiomegaly and moderate-to-severe dilation of the pulmonary artery and pulmonary vein. On echocardiography, the left ventricular hypertrophy, identified earlier, shoed partial regression. Therefore, the previous myocardial hypertrophy was diagnosed as a hypertrophic cardiomyopathy phenotype related to hyperthyroidism. ST-segment elevation was identified on electrocardiography, and the thyroid profile examination revealed increased total thyroxine and free thyroxine and decreased thyroid-stimulating hormone levels, suggesting myocardial injury and uncontrolled hyperthyroidism, respectively. In addition, normal N-terminal pro-B-type natriuretic peptide and high cardiac troponin I levels were found. Based on these findings, the observed congestive heart failure was considered as a sequel of myocardial injury caused by uncontrolled hyperthyroidism. Clinical signs resolved after intravenous administration of furosemide and butorphanol, oxygen supply and thoracocentesis. Furosemide and pimobendan were additionally administered, and the cat was discharged. This case demonstrates that myocardial damage due to chronic uncontrolled hyperthyroidism may cause heart failure in cats.

Clinical findings using echocardiography and plasma cardiac troponin I and pathological findings in dogs with hypertrophic cardiomyopathy: A retrospective study.

Background: Hypertrophic cardiomyopathy (HCM) is considered rare in dogs, and there is a lack of clinical data. Cardiac troponin I (cTnI) is a biomarker of cardiomyocyte damage and necrosis and can be used to diagnose cat and human HCM. Aim: We investigated whether the presence of cTnI in clinical data can be used in conjunction with echocardiography to diagnose canine HCM. Methods: This study comprised client-owned dogs with clinical evidence of concentric hypertrophy on echocardiographic images, serum total thyroxine levels of ≤5 µg/dl, systolic blood pressure of ≤180 mmHg, and absence of aortic stenosis. All cases were necropsied. Results: Cardiomyocyte hypertrophy (mean diameter, 18.3 ± 1.8 µm), myocardial fiber disarray (70%), interstitial fibrosis (80%), and small vessel disease (100%) were assessed. In dogs with HCM, the left ventricles were concentric, almost symmetrical, and hypertrophied above the aortic diameter. The end-diastolic interventricular septum normalized to body weight [intraventricular septal thickness in diastole (IVSDN)] was 0.788 [interquartile range (IQR), 0.7-0.92], which exceeded the normal range (5%-95%, IQR: 0.33-0.52). In total, 70% of the dogs with HCM had syncope and dyspnea, and all dogs had high cTnI levels (median, 3.94 ng/ml), exceeding the upper limit of normal (0.11 ng/ml) and indicating cardiomyocyte damage. IVSDN and serum cTnI levels were correlated (ρ = 0.839, p = 0.01). Conclusion: Ventricular wall thickening and high serum cTnI levels can provide a presumptive diagnosis of HCM and prompt the initiation of treatment or additional diagnostic investigations.

Radiographic findings of cardiopulmonary structures can predict hypertrophic cardiomyopathy and congestive heart failure in cats.

OBJECTIVE: This study aimed to find the radiographic characteristics for the detection of hypertrophic cardiomyopathy (HCM) and congestive heart failure (CHF) in cats. ANIMALS: Healthy cats (n = 35) and HCM cats with (21) and without (22) CHF. METHODS: On radiography, the cardiac size using vertebral heart score, left atrium enlargement (LAE), and dilation of the pulmonary vessels were assessed. The sensitivity and specificity of the radiographic characteristics regarding LAE were evaluated with the echocardiographic left atrium to aortic root ratio as a reference. RESULTS: In HCM cats, cardiomegaly, LAE, and dilation of the caudal pulmonary artery were found compared with those in healthy cats. The LAE could be predicted using the elevation of the carina with 94.12% specificity but 17.5% sensitivity. When CHF developed, LAE and dilation of the caudal pulmonary vein (PV) were significantly different compared with those in HCM cats without CHF. The distal side of the summated shadow made by the right caudal PV with the ninth rib in HCM cats with CHF was significantly larger than that in HCM cats without CHF and a cut-off value of 5.35 mm was drawn with 75% sensitivity and 100% specificity. CLINICAL RELEVANCE: Although there was an overlapping of radiographic findings between healthy and HCM cats, radiographic assessment of LAE can be useful for predicting HCM and the distal side of the summated shadow made by the right caudal PV with the ninth rib can predict CHF in HCM cats.

Hypertrophic Cardiomyopathy-Advances in Imaging and Diagnostic Strategies.

Hypertrophic cardiomyopathy (HCM) is the most important and prevalent cardiac disease in cats. Due to the highly variable nature of HCM, a multimodal approach including physical examination, genetic evaluation, cardiac biomarkers, and imaging are all essential elements to appropriate and timely diagnosis. These foundational elements are advancing rapidly in veterinary medicine. Newer biomarkers such as galectin-3 are currently being researched and advances in tissue speckle-tracking and contrast-enhanced echocardiography are readily available. Advanced imaging techniques, such as cardiac MRI, are providing previously unavailable information about myocardial fibrosis and paving the way for enhanced diagnostic capabilities and risk-stratification in cats with HCM.

Galectin-3 as a novel biomarker in cats with hypertrophic cardiomyopathy.

INTRODUCTION/OBJECTIVES: Galectin-3 (Gal-3) is a circulating biomarker of fibrosis. In humans, increased Gal-3 is predictive of myocardial fibrosis and adverse cardiac events. The aim of this study was to evaluate the potential for Gal-3 as a cardiac biomarker in cats with hypertrophic cardiomyopathy (HCM). MATERIALS AND METHODS: Eighty cats were enrolled (25 healthy cats with normal hearts, 35 with HCM American College of Veterinary Internal Medicine (ACVIM) stage B, and 21 with HCM ACVIM stage C). Each cat received a full echocardiogram, health panel, and total thyroxin level. Galectin-3 levels were measured for each enrolled patient. Troponin I and N-terminal pro-brain natriuretic peptide (NT-proBNP) were obtained for the majority of cats. Additionally, 17 ACVIM stage B cats underwent cardiac-gated magnetic resonance (CMR) imaging to assess myocardial extracellular volume (ECV), a noninvasive measure of myocardial fibrosis. RESULTS: Galectin-3 levels are increased in cats with HCM ACVIM stage B and C compared to healthy cats; however, no significant differences were detected between ACVIM stage B and ACVIM stage C cats. In HCM-affected cats, Galectin-3 showed statistically significant correlations with left atrial dimensions, left atrial:aorta ratio, and CMR-derived ECV. Quantitative NT-proBNP showed excellent discrimination between all groups and troponin I was able to discriminate between ACVIM stage C and normal cats, but not between other groups. CONCLUSIONS: Circulating Gal-3 levels are increased in cats with HCM and is positively correlated with left atrial dimensions and ECV in affected cats. Further studies evaluating the relationship between Gal-3, myocardial fibrosis, and clinical outcomes are warranted.

Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial.

OBJECTIVE: Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM. ANIMALS: 43 client-owned cats with subclinical HCM. METHODS: Cats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA. RESULTS: No demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups. CLINICAL RELEVANCE: Results demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.

Systolic third sound associated with systolic anterior motion of the mitral valve in cats with obstructive hypertrophic cardiomyopathy.

BACKGROUND: Third heart sounds in cats frequently are associated with hypertrophic cardiomyopathy (HCM) but their exact characterization and timing within the cardiac cycle remains unknown. OBJECTIVES: Characterize third heart sounds in cats by phonocardiography and test the ability of 3 observers with different levels of experience and training to recognize third systolic heart sounds in cats. ANIMALS: Fifty client-owned cats of different breeds presented for heart screening. METHODS: Cats were prospectively assessed using an electronic stethoscope (with digital recording) and then underwent full conventional echocardiographic examination. Audio recordings were blindly assessed in a random order by 3 observers: the cardiologist who collected clinical data, as well as a trained and an untrained junior veterinarian. Cohen's kappa coefficients were calculated to quantify agreement between the opinion of each observer and the echocardiography results (considered the gold standard). RESULTS: Twenty cats had a third systolic sound on phonocardiography and an obstructive HCM phenotype with systolic anterior motion of the mitral valve (SAM) on echocardiography. Agreement with echocardiography was very good for the experienced cardiologist, substantial for the trained junior veterinarian, and poor for the untrained junior veterinarian (kappa of 0.92, 0,64, and 0.08, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: We describe here a new auscultatory abnormality in cats with obstructive HCM. It could help a trained non-cardiologist veterinarian in suspecting obstructive HCM in cats based on auscultation only.

Comparative cardiac macroscopic and microscopic study in cats with hyperthyroidism vs. cats with hypertrophic cardiomyopathy.

Hyperthyroidism is considered the most common endocrinopathy in middle-aged and old cats. The increased level of thyroid hormones influences many organs, including the heart. Cardiac functional and structural abnormalities in cats with hyperthyroidism have indeed been previously described. Nonetheless, myocardial vasculature has not been subjected to analysis. Also, no comparison with hypertrophic cardiomyopathy has been previously described. Although it has been shown that clinical alterations resolve after the treatment of hyperthyroidism, no detailed data have been published on the cardiac pathological or histopathological image of field cases of hyperthyroid cats that received pharmacological treatment. The aim of this study was to evaluate the cardiac pathological changes in feline hyperthyroidism and to compare them to alterations present in cardiac hypertrophy due to hypertrophic cardiomyopathy in cats. The study was conducted on 40 feline hearts divided into three groups: 17 hearts from cats suffering from hyperthyroidism, 13 hearts from cats suffering from idiopathic hypertrophic cardiomyopathy and 10 hearts from cats without cardiac or thyroid disease. A detailed pathological and histopathological examination was performed. Cats with hyperthyroidism showed no ventricular wall hypertrophy in contrast to cats with hypertrophic cardiomyopathy. Nonetheless, histological alterations were similarly advanced in both diseases. Moreover, in hyperthyroid cats more prominent vascular alterations were noted. In contrast to hypertrophic cardiomyopathy, the histological changes in hyperthyroid cats involved all ventricular walls and not mainly the left ventricle. Our study showed that despite normal cardiac wall thickness, cats with hyperthyroidism show severe structural changes in the myocardium.

Hypertrophic cardiomyopathy in purpose-bred cats with the A31P mutation in cardiac myosin binding protein-C.

We sought to establish a large animal model of inherited hypertrophic cardiomyopathy (HCM) with sufficient disease severity and early penetrance for identification of novel therapeutic strategies. HCM is the most common inherited cardiac disorder affecting 1 in 250-500 people, yet few therapies for its treatment or prevention are available. A research colony of purpose-bred cats carrying the A31P mutation in MYBPC3 was founded using sperm from a single heterozygous male cat. Cardiac function in four generations was assessed by periodic echocardiography and measurement of blood biomarkers. Results showed that HCM penetrance was age-dependent, and that penetrance occurred earlier and was more severe in successive generations, especially in homozygotes. Homozygosity was also associated with progression from preclinical to clinical disease. A31P homozygous cats represent a heritable model of HCM with early disease penetrance and a severe phenotype necessary for interventional studies aimed at altering disease progression. The occurrence of a more severe phenotype in later generations of cats, and the occasional occurrence of HCM in wildtype cats suggests the presence of at least one gene modifier or a second causal variant in this research colony that exacerbates the HCM phenotype when inherited in combination with the A31P mutation.

Presence of known feline ALMS1 and MYBPC3 variants in a diverse cohort of cats with hypertrophic cardiomyopathy in Japan.

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats with a suspected genetic origin. Previous studies have identified five HCM-associated variants in three genes (Myosin binding protein C3: MYBPC3 p.A31P, p.A74T, p.R820W; Myosin heavy chain 7: MYH7 p.E1883K; Alstrom syndrome protein 1: ALMS1 p.G3376R). These variants are considered breed-specific, with the exception of MYBPC3 p.A74T, and have rarely been found in other breeds. However, genetic studies on HCM-associated variants across breeds are still insufficient because of population and breed bias caused by differences in genetic background. This study investigates the ubiquitous occurrence of HCM-associated genetic variants among cat breeds, using 57 HCM-affected, 19 HCM-unaffected, and 227 non-examined cats from the Japanese population. Genotyping of the five variants revealed the presence of MYBPC3 p.A31P and ALMS1 p.G3376R in two (Munchkin and Scottish Fold) and five non-specific breeds (American Shorthair, Exotic Shorthair, Minuet, Munchkin and Scottish Fold), respectively, in which the variants had not been identified previously. In addition, our results indicate that the ALMS1 variants identified in the Sphynx breed might not be Sphynx-specific. Overall, our results suggest that these two specific variants may still be found in other cat breeds and should be examined in detail in a population-driven manner. Furthermore, applying genetic testing to Munchkin and Scottish Fold, the breeds with both MYBPC3 and ALMS1 variants, will help prevent the development of new HCM-affected cat colonies.

Circulating neutrophil extracellular traps in cats with hypertrophic cardiomyopathy and cardiogenic arterial thromboembolism.

BACKGROUND: Cats with hypertrophic cardiomyopathy (HCM) are at risk of cardiogenic arterial thromboembolism (CATE). Neutrophil extracellular traps (NETs) may be a potential biomarker and therapeutic target for cardiomyopathy in cats. HYPOTHESIS/OBJECTIVES: Characterize NETs in cats with HCM or CATE. We hypothesized that circulating NETs assessed in the form of cell-free DNA (cfDNA) and citrullinated histone H3 (citH3) are increased in cats with HCM and CATE and associated with reported predisposing factors for thrombus formation. ANIMALS: Eighty-five cats including client-owned cats with HCM and CATE and staff- and student-owned clinically healthy cats without HCM. METHODS: After echocardiographic evaluations, NETs were measured as cfDNA and citH3. RESULTS: Cats with CATE had significant increases in cfDNA (11.2 ng/µL; interquartile range [IQR], 8.1 to 29.6) compared to those without HCM (8.2 ng/µL; IQR, 5.7 to 11.7 µL; P = .01) and were responsible for 75% to 83% of cases with cfDNA fragments sized 100 to 2000 base pairs. Citrullinated histone 3, detected in 52% of cats with HCM (31.1 ng/mL; IQR, 16.9 to 29.8), was significantly lower than in those with CATE (48.2 ng/mL; IQR, 34.2 to 60.2; P = .007). The citH3 concentrations correlated significantly with reported risk factors of CATE, such as left atrial auricular velocity. CONCLUSIONS AND CLINICAL IMPORTANCE: Neutrophil extracellualr traps, especially citH3, are increased in cats with HCM and CATE. They may serve as a novel therapeutic target and biomarker of thrombosis in cats with HCM.

Thin and hypokinetic myocardial segments in cats with cardiomyopathy.

INTRODUCTION/OBJECTIVES: Thin and hypokinetic myocardial segments (THyMS) represent adverse ventricular (LV) remodeling in human hypertrophic cardiomyopathy. We describe the echocardiographic features and outcome in cats with THyMS, and in a subpopulation, the echocardiographic phenotype before LV wall thinning was detected (pre-THyMS). ANIMALS: Eighty client-owned cats. MATERIALS AND METHODS: Retrospective multicenter study. Clinical records were searched for cats with THyMS, defined as LV segment(s) with end-diastolic wall thickness (LVWT) <3 mm and hypokinesis in the presence of ≥one LV segment(s) with LVWT >4 mm and normal wall motion. When available, echocardiograms pre-THyMS were assessed. Survival time was defined as time from first presentation with THyMS to death. RESULTS: Mean thickest LV wall segment (MaxLVWT) was 6.1 mm (95% CI 5.8-6.4 mm) and thinnest (MinLVWT) was 1.7 mm (95% CI 1.6-1.9 mm). The LV free wall was affected in 74%, apex in 13% and septum in 5%. Most cats (85%) presented with heart failure and/or arterial thromboembolism. Median circulating troponin I concentration was 1.4 ng/mL ([range 0.07-180 ng/mL]). Prior echocardiography results were available for 13/80 cats, a mean of 2.5 years pre-THyMS. In segments subsequently undergoing thinning, initial MaxLVWT measured 6.7 mm (95% CI 5.8-7.7 mm) vs. 1.9 mm (95% CI 1.5-2.4 mm) at last echocardiogram (P<0.0001). Survival data were available for 56/80 cats, median survival time after diagnosing THyMS was 153 days (95% CI 83-223 days). Cardiac histopathology in one cat revealed that THyMS was associated with severe transmural scarring. CONCLUSIONS: Cats with THyMS had advanced cardiomyopathy and a poor prognosis.

QT interval instability and QRS interval dispersion in healthy cats and cats with a hypertrophic cardiomyopathy phenotype.

OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats. Electrocardiographic (ECG) analysis can help with the diagnosis of HCM and also in the investigation of the secondary consequences of the disease. This study investigated ECG markers of QT interval variability (total instability [TI], short-term instability [STI], long-term instability [LTI], QT variance [QTv]), mean QT interval (QTa) and QT interval corrected for heart rate (QTac), as well as the duration (QRSd) and dispersion (QRSv) of the QRS interval in healthy cats and in those with HCM. METHODS: Data were collected from 63 domestic cats: 40 in the control group and 23 in the HCM group. Fifty consecutive QT intervals were recorded for all cats and then QTa, QTac, QTv, TI, LTI and STI were calculated. QRSd and QRSv were also obtained for all animals. A Mann-Whitney U-test was used for group comparison. Receiver operating characteristic curves were plotted to evaluate the sensitivity and specificity of all markers for HCM. Logistic regression analysis was performed to assess the risks of cats having HCM, based on the studied indexes. RESULTS: QTa (P <0.01), QTac (P <0.01), QRSd (P <0.01) and STI (P = 0.02) were higher in the HCM group. QTa >158.8 ms, QTac >27.4 ms and QRSd >0.045 s had an accuracy of 77.4%, 68.2% and 80.9%, respectively, in detecting HCM. Logistic regression showed that cats with QTa >158 ms, QTac >27.4 ms and QRSd >0.045 s had a 1.58-, 1,23- and 6.5-fold higher risk, respectively, of developing HCM. CONCLUSIONS AND RELEVANCE: Cats with HCM had higher ventricular instability as assessed by STI and showed a prolongation of the QT and QRS intervals via the QTa, QTac and QRSd markers. These markers show potential as ancillary screening tools for identifying the presence of HCM.

Deep learning-based diagnosis of feline hypertrophic cardiomyopathy.

Feline hypertrophic cardiomyopathy (HCM) is a common heart disease affecting 10-15% of all cats. Cats with HCM exhibit breathing difficulties, lethargy, and heart murmur; furthermore, feline HCM can also result in sudden death. Among various methods and indices, radiography and ultrasound are the gold standards in the diagnosis of feline HCM. However, only 75% accuracy has been achieved using radiography alone. Therefore, we trained five residual architectures (ResNet50V2, ResNet152, InceptionResNetV2, MobileNetV2, and Xception) using 231 ventrodorsal radiographic images of cats (143 HCM and 88 normal) and investigated the optimal architecture for diagnosing feline HCM through radiography. To ensure the generalizability of the data, the x-ray images were obtained from 5 independent institutions. In addition, 42 images were used in the test. The test data were divided into two; 22 radiographic images were used in prediction analysis and 20 radiographic images of cats were used in the evaluation of the peeking phenomenon and the voting strategy. As a result, all models showed > 90% accuracy; Resnet50V2: 95.45%; Resnet152: 95.45; InceptionResNetV2: 95.45%; MobileNetV2: 95.45% and Xception: 95.45. In addition, two voting strategies were applied to the five CNN models; softmax and majority voting. As a result, the softmax voting strategy achieved 95% accuracy in combined test data. Our findings demonstrate that an automated deep-learning system using a residual architecture can assist veterinary radiologists in screening HCM.