Abstract 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 P2RY:A236G variant.
Subvalvular aortic stenosis (SAS) and valvular pulmonic stenosis (PS) are two of the most common congenital heart diseases of dogs. The aim of this study was to determine the prevalence and mode of inheritance of these congenital heart diseases in a large veterinary teaching hospital population. Case records of dogs presented to the University of California Davis, Veterinary Medical Teaching Hospital (UCD VMTH) between January 2008 to December 2017 were reviewed retrospectively and pedigree information was obtained when available. There were 259 unique SAS and 336 unique PS cases diagnosed during the study period. The prevalence of SAS was 0.3% of overall hospital admissions and 4.7% for all dogs seen by the cardiology service. The prevalence for PS was 0.41% of overall hospital admissions and 6.1% of dogs seen by the cardiology service. Bullmastiffs and Newfoundlands had the greatest prevalence (6.59% and 4.46% respectively) and odds ratio (52.43 and 34.73 respectively) for SAS. Bulldogs and French Bulldogs had the greatest prevalence (4.8% and 2.7% respectively) and odds ratio (13.32 and 7.52 respectively) for PS. The identified prevalence of SAS and PS is higher than previously reported. Pedigree analysis in SAS affected Bullmastiffs, Golden Retrievers, and Rottweilers suggested an autosomal recessive pattern of inheritance. The mode of inheritance for PS in Bulldogs, also appears to be autosomal recessive. The results of this study can be used to inform future selection of breeding pairs and genetic studies aimed at reducing the prevalence of these common congenital heart diseases.
Abstract Background Prior studies have suggested that pimobendan is associated with several positive effects in cats, including improved survival in cats with congestive heart failure and improved left atrial function in research colony cats with hypertrophic cardiomyopathy (HCM) and normal cats. However, there is still a paucity of pharmacodynamic data refuting or supporting the use of pimobendan in a clinical cat population. This clinical trial aimed to evaluate the pharmacodynamic effects and tolerability of a single dose of pimobendan in cats with HCM. Echocardiograms and Doppler-derived systolic blood pressures were performed in 21 client-owned cats with subclinical HCM at baseline and 90-min after oral administration of 1.25 mg of pimobendan (Vetmedin). Seven additional cats were evaluated post-placebo administration to account for intra-day variability. Results Heart rate, systolic blood pressure, and murmur grade were not significantly different between baseline and post-pimobendan evaluations. Left auricular blood flow velocity, left atrial size, and left ventricular fractional shortening were not significantly different between baseline and post-pimobendan evaluations. Mean (± standard deviation) tissue Doppler peak systolic velocity of the mitral annulus was significantly higher following pimobendan (7.4 cm/s ± 1.5 vs 8.5 ± 1.6; p = 0.02). Median (min, max) left-ventricular outflow tract maximum velocity was significantly higher following pimobendan [1.9 m/sec (1.5, 3.4) vs 2.6 m/sec (2.0, 4.0); p = 0.01]. Mean right-ventricular outflow tract maximum velocity was also significantly higher following pimobendan (1.5 m/s ± 0.51 vs 2.0 ± 0.53; p = 0.004). Mean left atrial fractional shortening was significantly higher following pimobendan (28% ± 6 vs 32% ± 7; p = 0.02). No adverse events were observed following pimobendan administration. Right ventricular outflow tract velocity was significantly higher following placebo in control cats (1.02 ± 0.21 versus 1.31 ± 0.31; p = 0.01). No other significant differences were detected. Conclusions In client-owned cats with HCM, pimobendan acutely increased left atrial function and mildly increased left ventricular systolic function. Left ventricular outflow tract velocity was increased after pimobendan. Pimobendan was well tolerated in the acute setting in cats with HCM. The findings of this prospective, acute-dosing study confirm previous findings in research animals and retrospective analyses and suggest that chronic dosing studies are safe and warranted.
Introduction A surge in Food and Drug Administration (FDA) consumer complaints identified concerns that legume-rich, grain-free diets were associated with nutritionally-mediated dilated cardiomyopathy (DCM). Golden retrievers represent the most reported breed affected by this condition and previous studies documented the disease is responsive to dietary change and taurine supplementation. Although dietary findings across cases are compelling, prospective studies with control groups are lacking. The role of diet in developing taurine deficiency and echocardiographic changes consistent with DCM in healthy dogs is unknown. Objectives We hypothesized that golden retrievers eating non-traditional diets are at a higher risk of having taurine deficiency and nutritionally-mediated DCM compared with those eating traditional commercial diets. We aimed to compare taurine concentrations and echocardiographic indices of systolic function between golden retrievers in each diet group and elucidate associations between diet and these variables. Additionally, we aimed to generate breed-specific reference intervals for whole blood and plasma taurine concentrations. Animals 86 golden retrievers. Methods Golden retrievers eating traditional or non-traditional diets were evaluated and diet history, taurine concentrations and echocardiographic data were collected. Dietary features, taurine concentrations and echocardiographic findings were compared between diet groups. Relative risks were calculated for the likelihood of echocardiographic abnormalities and taurine deficiency in each diet group. Breed-specific reference intervals were constructed for taurine concentrations in dogs from the traditional diet group. Results Golden retrievers eating non-traditional diets had significantly lower taurine concentrations and more frequent systolic dysfunction. Breed specific reference intervals are higher than previously reported across breeds. Conclusions Non-traditional diets, which were typically grain-free and contained legumes in this study, were significantly associated with and have increased relative risk for the identification of taurine deficiency and echocardiographic abnormalities consistent with nutritionally-mediated DCM. These findings were identifiable in the absence of clinical signs and support the findings of multiple previous studies and the ongoing FDA investigation.
Introduction: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular (LV) hypertrophy in the absence of known causes. HCM can be due to genetic mutations that affect sarcomeric proteins, leading to myocardial hypercontractility. HCM is often complicated by left ventricular outflow tract obstruction (LVOTO) and patients may be at greater risk of cardiovascular death. Medications targeted to address the pathophysiology of HCM and ameliorate LVOTO are needed. CK-3773274 (CK-274) is a novel small molecule cardiac myosin inhibitor that reduces myocardial contractility in vitro and in vivo . Cats have naturally occurring HCM commonly complicated by LVOTO and are an excellent large animal model for investigation of HCM therapeutics. In this study, we aim to characterize the pharmacodynamic effect of a single oral dose of CK-274 on cardiac function in cats with hypertrophic cardiomyopathy and LVOTO. Methods: Eight purpose-bred cats with naturally occurring HCM and LVOTO due to the A31P mutation in cardiac myosin binding protein C (cMyBP-C) were included in a randomized, controlled, crossover study. Cats were randomized to receive vehicle, 0.3 mg/kg, or 1 mg/kg CK-274 treatment, and received echocardiograms at baseline, 6, 24, and 48 hours post-treatment. All cats were crossed over to all treatment groups. Results: CK-274 (1 mg/kg) reduced mean LV fractional shortening at 6, 24 and 48 hours post-treatment (mean reduction 13.6%, p=0.03; 15.4%, p=0.01; 11.6% p=0.02, respectively). CK-274 (1 mg/kg) increased LV systolic internal dimension at 6 and 24-hours post-treatment (mean increase 0.21 cm, p=0.046; 0.25 cm, p=0.03), and did not affect LV diastolic internal dimension. LVOT peak pressure gradient was reduced with CK-274 (0.3 mg/kg) treatment [median pressure gradient at baseline 27.1 mmHg (IQR 18.3-33.3) vs 24 hours post-drug, 7.3 mmHg (IQR 14.2-19.7) p=0.01]. Heart rate did not change for any treatment group over time. No differences were noted following vehicle administration at any time point. Conclusion: In HCM affected cats with the cMyBP-C A31P mutation, the cardiac myosin inhibitor CK-274 is well tolerated at the studied doses and caused dose-related changes in LV systolic function and reductions in LVOT peak pressure gradient.
Avian species have varying analgesic responses to opioid drugs. Some of this variability could be due to extrinsic factors such as administration route or dose. However, intrinsic factors such as gene expression or polymorphic differences in opioid receptors may be important components.The objectives of this study were to determine the relative gene expression and polymorphisms present for mu and kappa opioid receptors (OPRM1 and OPRK1) in the cerebrum, brainstem, spinal cord, and footpad of cockatiels and pigeons.Tissue biopsies were obtained from 11 adult cockatiels (6 male and 5 female) and 11 adult pigeons (6 male and 5 female). RNA was extracted and qPCR was performed to determine the level of gene expression for OPRM1 and OPRK1 relative to a reference gene phosphoglycerate kinase 1 (PGK1) using the ΔΔCt method. Sanger sequencing was performed to identify polymorphisms, if present.There were higher expression levels of OPRM1 compared to OPRK1 in all tissues examined regardless of species (p < 0.001, FDR p < 0.001) Cockatiels had less OPRK1 expression in the cerebrum compared to pigeons (p = 0.005, FDR p = 0.004). Cockatiels had more OPRM1 expression in the brainstem (p = 0.045, FDR p = 0.029), but less OPRM1 expression in the footpad compared to pigeons (p = 0.029, FDR p = 0.021). No other significant differences in OPRM1 or OPRK1 expression were identified across species. Two missense polymorphisms were identified in OPRK1; none were found in OPRM1.The differential expression of opioid receptors between cockatiels and pigeons could have implications for variability in analgesic response between these two species.
Atrial fibrillation (AF) is the most common arrhythmia in dogs. The Irish Wolfhound breed has a high prevalence of AF making them an ideal breed to investigate possible genetic contributions to this disease. The aim of this study was to perform a heritability analysis in North American Irish Wolfhounds using phenotype data from cardiac screenings performed between 2000 and 2019 in order to determine how much of this disease can be attributed to genetics compared to environmental causes. The second aim was to determine the disease mode of inheritance to help inform prevention and breeding practices.There were 327 Irish Wolfhounds diagnosed with AF and 136 Irish Wolfhounds over 8 years of age without AF. The estimated mean (95% confidence interval) heritability of AF in Irish Wolfhounds was 0.69 (0.50-0.86). The pedigree was consistent with a dominant mode of inheritance.Results of this study indicate a strong genetic contribution to AF in Irish Wolfhounds and suggest that future research to identify causative genetic mutations is warranted.
