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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.

Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac disease in cats and lacks efficacious preclinical pharmacologic intervention, prompting investigation of novel therapies. Genetic mutations encoding sarcomeric proteins are implicated in the development of HCM and small molecule myosin inhibitors are an emerging class of therapeutics designed to target the interaction of actin and myosin to alleviate the detrimental effects of inappropriate contractile protein interactions. The purpose of this study was to characterize the pharmacodynamic effects of a single oral dose of the novel cardiac myosin inhibitor aficamten (CK-274) on cardiac function in purpose bred cats with naturally occurring A31P MYBPC3 mutation and a clinical diagnosis of HCM with left ventricular outflow tract obstruction (LVOTO). Five purpose bred cats were treated with aficamten (2 mg/kg) or vehicle and echocardiographic evaluations were performed at 0, 6, 24, and 48 h post-dosing. High dose aficamten (2 mg/kg) reduced left ventricular fractional shortening (LVFS%) by increasing the LV systolic internal dimension (LVIDs) and reduced isovolumic relaxation time (IVRT) compared with baseline without significant adverse effects. The marked reduction in systolic function and reduced IVRT coupled with an increased heart rate in treated cats, suggest a lower dose may be optimal. Further studies to determine optimal dosing of aficamten are indicated.

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease in humans and cats and lacks efficacious pharmacologic interventions in the preclinical phase of disease. LV outflow tract obstruction (LVOTO) is commonly observed in HCM-affected patients and is a primary driver of heart failure symptoms and reduced quality of life. Novel small-molecule cardiac myosin inhibitors target actin-myosin interactions to alleviate overactive protein interactions. A prospective, randomized, controlled cross-over study was performed to evaluate pharmacodynamic effects of two doses (0.3 and 1 mg/kg) of a next-in-class cardiac myosin inhibitor, aficamten (CK-3773274, CK-274), on cardiac function in cats with the A31P MYBPC3 mutation and oHCM. Dose-dependent reductions in LV systolic function, LVOT pressure gradient, and isovolumetric relaxation times compared to baseline were observed. Promising beneficial effects of reduced systolic function warrant further studies of this next-in-class therapeutic to evaluate the benefit of long-term administration in this patient population.

A two-week-old female llama cria was brought to the UC Davis Large Animal Hospital for evaluation of a cardiac murmur and suspected syncopal episodes. A grade IV/VI left basilar continuous murmur was present on cardiac auscultation. Echocardiography revealed a left-to-right shunting patent ductus arteriosus (PDA), mild left ventricular enlargement, scant pericardial effusion, and a suspected persistent left cranial vena cava. The PDA was successfully closed with an Amplatz canine duct occluder. Mild mitral regurgitation was present on echocardiography performed 7 d following PDA occlusion. No syncopal episodes were observed in hospital prior to or following PDA occlusion. At approximately 1 mo following PDA closure, a grade I/VI left apical systolic murmur was present and the cria's body condition was improved. Key clinical message: Patent ductus arteriosus closure is achievable in New World camelids using interventional cardiology which provides a minimally invasive treatment option for valuable or companion animals. Since interventional cardiac catheterization is commonly performed in small animal species, veterinary cardiologists are well-equipped to apply these skills to camelids.

Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. It is frequently used in cats with hypertrophic cardiomyopathy (HCM) to prevent thromboembolic complications. However, significant interpatient variability of the response to clopidogrel therapy has been suspected. In this study, we assessed the impact of single nucleotide polymorphisms (SNPs) within ADP receptor (P2RY1, P2RY12) and cytochrome P450 isoenzyme (CYP2C41) genes on platelet inhibition by clopidogrel administration in cats with HCM. Forty-nine cats completed the study, and blood samples were obtained before and after clopidogrel therapy to assess the degree of platelet inhibition based on flow cytometry and whole blood platelet aggregometry. Plasma concentrations of clopidogrel metabolites were measured after the last dose of clopidogrel. Whole blood platelet aggregometry revealed a significant reduction of platelet inhibition by clopidogrel in cats with the P2RY1:A236G and the P2RY12:V34I variants. The association with the P2RY1:A236G variant and clopidogrel resistance remained significant after adjustment for multiple comparisons. This study demonstrated that a genetic polymorphism in the P2RY1 gene altered response to clopidogrel therapy and suggests that clinicians may consider alternative or additional thromboprophylactic therapy in cats with the P2RY1:A236G variant.

BackgroundVelocity ratio, velocity time integral (VTI) ratio, and pulmonary valve area indexed to body surface area (iPVA) are methods of assessment of pulmonary valve stenosis (PS) severity that are less dependent on blood flow. Studies evaluating these methods are limited.ObjectivesTo determine the effects of butorphanol, atenolol, and balloon valvuloplasty (BV) on velocity ratio, VTI ratio, iPVA, mean PG, and max PG.AnimalsTwenty-seven dogs with PS (max PG >50 mm Hg).MethodsProspective study. All dogs underwent an echocardiogram at baseline, 5-minutes after administration of butorphanol (0.2-0.25 mg/kg IV), and 2-to-4 weeks after atenolol (1-1.5 mg/kg q12h). Twenty-one of these were evaluated 24-hours after BV.ResultsThere were no significant differences (P > .05) amongst any of the methods of assessment of PS severity after butorphanol. After atenolol, mean (SD) of mean (57.0 [21.0] mm Hg) and max PG (93.1 [33.8] mm Hg) were significantly decreased (P ≤ .047) compared with baseline (65.2 [26.2] mm Hg and 108 [44.4] mm Hg, respectively). After atenolol, there were no significant (P ≥ .12) differences in velocity ratio (0.29 [0.09]), VTI ratio (0.18 [0.05]), or iPVA (0.43 [0.16] cm2 /m2 ) compared with baseline (0.30 [0.09], 0.19 [0.09], 0.44 [0.17] cm2 /m2 , respectively).Conclusions and clinical importanceAtenolol might reduce mean and max PG but does not alter less flow-dependent methods of assessment of PS severity (velocity ratio, VTI ratio, and iPVA) in dogs with PS. Results support an integrative approach to assessment of PS severity that includes less flow-dependent methods, particularly in states of altered flow or right ventricular function.

BackgroundSotalol is a commonly used antiarrhythmic drug that may alter ventricular function.ObjectiveTo determine the effect of sotalol on echocardiographic indices of ventricular systolic function in dogs with ventricular arrhythmias.AnimalsThirty-five client-owned dogs with ventricular arrhythmias.MethodsDogs with ventricular arrhythmias (n = 27) had an echocardiogram and 5-minute ECG performed at baseline and 2-4 hours post-sotalol (2-2.5 mg/kg PO once). Eight additional dogs underwent the same protocol but did not receive sotalol (within-day variability controls). Left ventricular (LV) internal dimension at end-systole normalized to bodyweight (LVIDs_N), LV ejection fraction (LV EF), LV shortening area, LV fractional shortening, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic myocardial velocity were evaluated as indices of systolic function.ResultsAll indices except TAPSE had mild decreases in systolic function post-sotalol (all P ≤ .0007) compared with baseline but only the percent change in LVIDs_N and LV EF were significantly (P ≤ .0079) different from the percent change of the same indices in control dogs. Sinus heart rate, ventricular premature complexes/5-minutes, and arrhythmia grade also were decreased post-sotalol (all P ≤ .01) compared with baseline when assessed by a 5-minutes ECG. No dog experienced an adverse event post-sotalol, including dogs with systolic dysfunction or atrial enlargement.Conclusions and clinical importanceA single dose of sotalol may cause a mild decrease in LV systolic function in dogs with ventricular arrhythmias. Sotalol appears to be well tolerated, even in dogs with atrial enlargement or systolic dysfunction.

A cat was evaluated for an acute-onset of right pelvic limb paresis. Thoracic radiographs revealed normal cardiac size and tortuous pulmonary arteries. Abdominal ultrasound identified a heartworm (HW) extending from the caudal abdominal aorta into the right external iliac artery and right femoral artery. The cat was HW-antigen positive. Echocardiography revealed a HW within the right branch of the main pulmonary artery and evidence of pulmonary hypertension. An agitated-saline contrast echocardiogram revealed a small right to left intracardiac shunt at the level of the atria. Surgical removal of the HW was performed with no substantial postoperative complications. There was return of blood flow and improved motor function to the limb. The cat remains mildly paretic on the affected limb with no other clinical signs.

Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac disease in cats and lacks efficacious preclinical pharmacologic intervention, prompting investigation of novel therapies. Genetic mutations encoding sarcomeric proteins are implicated in the development of HCM and small molecule myosin inhibitors are an emerging class of therapeutics designed to target the interaction of actin and myosin to alleviate the detrimental effects of inappropriate contractile protein interactions. The purpose of this study was to characterize the pharmacodynamic effects of a single oral dose of the novel cardiac myosin inhibitor aficamten (CK‐274) on cardiac function in purpose bred cats with naturally occurring A31P MYBPC3 mutation and a clinical diagnosis of HCM with left ventricular outflow tract obstruction (LVOTO). Five purpose bred cats were treated with aficamten (2 mg/kg) or vehicle and echocardiographic evaluations were performed at 0, 6, 24, and 48 h post‐dosing. High dose aficamten (2 mg/kg) reduced left ventricular fractional shortening (LVFS%) by increasing the LV systolic internal dimension (LVIDs) and reduced isovolumic relaxation time (IVRT) compared with baseline without significant adverse effects. The marked reduction in systolic function and reduced IVRT coupled with an increased heart rate in treated cats, suggest a lower dose may be optimal. Further studies to determine optimal dosing of aficamten are indicated. [ABSTRACT FROM AUTHOR]

Background: Sotalol is a commonly used antiarrhythmic drug that may alter ventricular function. Objective: To determine the effect of sotalol on echocardiographic indices of ventricular systolic function in dogs with ventricular arrhythmias. Animals: Thirty‐five client‐owned dogs with ventricular arrhythmias. Methods: Dogs with ventricular arrhythmias (n = 27) had an echocardiogram and 5‐minute ECG performed at baseline and 2‐4 hours post‐sotalol (2‐2.5 mg/kg PO once). Eight additional dogs underwent the same protocol but did not receive sotalol (within‐day variability controls). Left ventricular (LV) internal dimension at end‐systole normalized to bodyweight (LVIDs_N), LV ejection fraction (LV EF), LV shortening area, LV fractional shortening, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic myocardial velocity were evaluated as indices of systolic function. Results: All indices except TAPSE had mild decreases in systolic function post‐sotalol (all P ≤ .0007) compared with baseline but only the percent change in LVIDs_N and LV EF were significantly (P ≤ .0079) different from the percent change of the same indices in control dogs. Sinus heart rate, ventricular premature complexes/5‐minutes, and arrhythmia grade also were decreased post‐sotalol (all P ≤ .01) compared with baseline when assessed by a 5‐minutes ECG. No dog experienced an adverse event post‐sotalol, including dogs with systolic dysfunction or atrial enlargement. Conclusions and Clinical Importance: A single dose of sotalol may cause a mild decrease in LV systolic function in dogs with ventricular arrhythmias. Sotalol appears to be well tolerated, even in dogs with atrial enlargement or systolic dysfunction. [ABSTRACT FROM AUTHOR]

A cat was evaluated for an acute‐onset of right pelvic limb paresis. Thoracic radiographs revealed normal cardiac size and tortuous pulmonary arteries. Abdominal ultrasound identified a heartworm (HW) extending from the caudal abdominal aorta into the right external iliac artery and right femoral artery. The cat was HW‐antigen positive. Echocardiography revealed a HW within the right branch of the main pulmonary artery and evidence of pulmonary hypertension. An agitated‐saline contrast echocardiogram revealed a small right to left intracardiac shunt at the level of the atria. Surgical removal of the HW was performed with no substantial postoperative complications. There was return of blood flow and improved motor function to the limb. The cat remains mildly paretic on the affected limb with no other clinical signs. [ABSTRACT FROM AUTHOR]