Pharmacokinetics and pharmacodynamics of intravenous and oral apixaban in horses.

Large vessel and microvascular thrombi are common complications in systemically ill horses contributing to patient morbidity and mortality. Apixaban, an oral factor Xa inhibitor, shows excellent efficacy against stroke and deep vein thrombosis in humans. The purpose of this study was to determine serum apixaban concentrations and anti-factor Xa activity in horses after orally administered apixaban. Five horses received a single dose of intravenous (0.09 mg/kg) and oral (1 mg/kg) apixaban in a cross-over design. Serum apixaban concentrations and anti-Xa activity were measured serially via liquid chromatography-tandem mass spectrometry and a commercial assay, respectively, for 12 hr following oral administration. Apixaban was detected in all horses after both oral and intravenous administration. Oral administration yielded a mean maximum concentration of 60.3 ng/ml (59.4-111 ng/ml), mean time to maximum concentration of 0.5 hr (0.5-2), mean half-life of 6.2 hr (4.6-8.3), and mean oral bioavailability of 10% (3.8-17.4). After oral administration, anti-Xa activity had a strong positive relationship with serum apixaban and was best represented by a dose-response model with the following parameters: E0  = 5.00 ng/ml, EMAX  = 311 ng/mL, EC50  = 267 ng/ml, and n = 1.58. Anti-Xa activity was significantly higher 2 hr post-administration compared with baseline (p = .032). Despite low oral bioavailability, administration of 1 mg/kg oral apixaban, in healthy horses, achieves serum concentrations similar to those reported in humans. Apixaban has potential clinical utility in horses and warrants further investigation.

Detection of intra-cardiac thrombi and congestive heart failure in cats using computed tomographic angiography.

Arterial thromboembolism is a life-threatening condition in cats most commonly secondary to cardiac disease. Echocardiography is the reference standard to evaluate for presence of a thrombus. In humans, computed tomographic (CT) angiography is becoming widely used to detect left atrial thrombi precluding the use of sedation. The purpose of this prospective, controlled, methods comparison pilot study was threefold: (1) describe new CT angiography protocol used in awake cats with cardiac disease and congestive heart failure; (2) determine accuracy of continuous and dynamic acquisition CT angiography to identify and characterize cardiac thrombi from spontaneous echocardiographic contrast using transthoracic echocardiography as our reference standard; (3) identify known negative prognostic factors and comorbidities of the thorax that CT angiography may provide that complement or supersede echocardiographic examination. Fourteen cats with heart disease were recruited; 7 with thrombi and 7 with spontaneous echocardiographic contrast. Echocardiography and awake CT angiography were performed using a microdose of contrast. Six of 7 thrombi were identified on CT angiography as filling defects by at least one reviewer within the left auricle (n = 6) and right heart (n = 1). Highest sensitivity (71.4%) was in continuous phase and highest specificity (85.7%) was in dynamic studies with fair to moderate interobserver agreement (0.38 and 0.44). CT angiography identified prognostic cardiac information (left atrial enlargement, congestive heart failure, arterial thromboembolism) and comorbidities (suspected idiopathic pulmonary fibrosis, asthma). This study indicates CT angiography can readily identify cardiac thrombi, important prognostic information and comorbidities, and can be safely performed in cats with cardiac disease and congestive heart failure.

Cardiac Magnetic Resonance Imaging Detects Myocardial Abnormalities in Naturally Infected Dogs with Chronic Asymptomatic Chagas Disease.

Trypanosoma cruzi infection causes inflammation and fibrosis, resulting in cardiac damage in dogs. The objectives of this study were to describe cardiac magnetic resonance imaging (CMR) in naturally infected dogs with chronic Chagas disease and the frequency of abnormalities for CMR and cardiac diagnostic tests. Ten asymptomatic, client-owned dogs seropositive for T. cruzi were prospectively enrolled in an observational study evaluating echocardiography, ECG (standard and ambulatory), cardiac troponin I (cTnI), and CMR. Standard ECG measurements (3/10) and cTnI concentration (1/10) outside the reference range were uncommon. Ambulatory ECG abnormalities were documented more frequently (6/10 dogs) than with standard ECG and included ventricular arrhythmias (4), supraventricular premature beats (3), second-degree atrioventricular block (2), and sinus arrest (1). Echocardiographic abnormalities were documented in 6/10 dogs including mildly increased left ventricular internal dimension in diastole (1) and decreased right ventricular (RV) systolic function based on reductions in tricuspid annular plane systolic excursion (3) and RV S' (4). Abnormalities were detected with CMR in 7/10 dogs including delayed myocardial enhancement in 5 of which 2 also had increased extracellular volume, abnormal wall motion in 5, and loss of apical compact myocardium in 1. In conclusion, CMR abnormalities were common, and the results of this study suggest CMR can provide useful information in dogs with T. cruzi infection and may support naturally infected dogs for future clinical investigation as an animal model for Chagas disease.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio in Cats With Hypertrophic Cardiomyopathy.

Objective: To assess the prognostic value of neutrophil-to-lymphocyte ratio (NLR) for cardiac death in cats with hypertrophic cardiomyopathy. Study Design: Prospective observation study. Animals: Ninety-six client-owned cats. Methods: Complete blood count samples were collected from 38 healthy and 58 cats with hypertrophic cardiomyopathy (HCM), and the NLR ratios were analyzed. All cats had echocardiographic measurements performed on the same day as blood collection. Spearman rank correlation was used to assess the relationship between echocardiographic measurements and NLR. Long-term outcome data were obtained, and time to cardiac death and variables associated with cardiac death were analyzed using Kaplan-Meier survival curves and Cox proportional hazards models, respectively. Results: The NLR was significantly higher in cats with confirmed congestive heart failure. When evaluating HCM patients, cats in the third NLR tertile had a significantly higher risk of cardiac death with a hazard ratio of 10.26 (95% CI: 1.84-57.14; p = 0.0001) when compared with that of patients in the first tertile. NLR was significantly associated with echocardiographic measures of left atrial size, left auricular function, the presence of left atrial spontaneous echo contrast (SEC), and thrombus formation. Conclusions and Clinical Relevance: Increased NLR is a negative prognostic indicator in cats with HCM.

Comparison of in-hospital continuous electrocardiography versus recordable Holter monitoring in dogs with ventricular arrhythmias.

OBJECTIVE: Determine the agreement between nonrecordable continuous ECG and Holter monitoring at estimating arrhythmia severity in hospitalized dogs. DESIGN: Prospective, observational, cohort study. SETTING: University teaching hospital. ANIMALS: Ten dogs. INTERVENTIONS: Heart rates and rhythms were simultaneously monitored using nonrecordable cage-side continuous ECG and Holter monitoring. Continuous ECG was assessed by ICU technicians for 1 min every hour, and heart rate and rhythm were recorded. A modified Lown score was used to grade arrhythmia severity (Grade 0 = sinus; Grade 1 = single ventricular premature complexes; Grade 2 = accelerated idioventricular; Grade 3 = bigeminy/trigeminy; Grade 4 = couplets/triplets; Grade 5 = ventricular tachycardia or R on T). Holter data were analyzed by a board-certified cardiologist, and arrhythmia grade was assigned to the same 1-min time period reported by ICU technicians. A 1-h arrhythmia grade was also determined from Holter data and was reported as the highest grade noted during the previous hour. Cohen's weighted kappa analysis was used to compare the agreement of ICU and Holter grade during the same 1-min time period and to compare 1-min Holter grade with the prior hour Holter grade. MEASUREMENTS AND MAIN RESULTS: Weak agreement was found between ICU-reported grade and Holter grade (κ = 0.40), as well as weak agreement between 1-min Holter grade and hour Holter grade (κ = 0.39). CONCLUSIONS: Results of this study indicate that arrhythmia grades assessed by ICU technicians and hourly 1-min observations weakly agree with recordable Holter monitoring in hospitalized dogs with ventricular arrhythmias.

Cardiac extracellular volume fraction in cats with preclinical hypertrophic cardiomyopathy.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) allows for detection of fibrosis in hypertrophic cardiomyopathy (HCM) by quantification of the extracellular volume fraction (ECV). HYPOTHESIS/OBJECTIVES: To quantify native T1 mapping and ECV in cats. We hypothesize that native T1 mapping and ECV will be significantly increased in HCM cats compared with healthy cats. ANIMALS: Seventeen healthy and 12 preclinical HCM, age-matched, client-owned cats. METHODS: Prospective observational study. Tests performed included indirect blood pressure, CBC, biochemical analysis including total thyroid, urinalysis, transthoracic echocardiogram, and CMR. Cats were considered healthy if all tests were within normal limits and a diagnosis of HCM was determined by the presence of left ventricular concentric hypertrophy ≥6 mm on echocardiography. RESULTS: There were statistically significant differences in LV mass (healthy = 5.87 g, HCM = 10.3 g, P < .0001), native T1 mapping (healthy = 1122 ms, HCM = 1209 ms, P = .004), and ECV (healthy = 26.0%, HCM = 32.6%, P < .0001). Variables of diastolic function including deceleration time of early diastolic transmitral flow (DTE), ratio between peak velocity of early diastolic transmitral flow and peak velocity of late diastolic transmitral flow (E : A), and peak velocity of late diastolic transmitral flow (A wave) were significantly correlated with ECV (DTE; r = 0.73 P = .007, E : A; r = -0.75 P = .004, A wave; r = 0.76 P = .004). CONCLUSIONS AND CLINICAL IMPORTANCE: Quantitative assessment of cardiac ECV is feasible and can provide additional information not available using echocardiography.

Quantitative assessment of left ventricular volume and function by transthoracic and transesophageal echocardiography, ultrasound velocity dilution, and gated magnetic resonance imaging in healthy foals.

OBJECTIVE: To compare measurements of left ventricular volume and function derived from 2-D transthoracic echocardiography (2DE), transesophageal echocardiography (TEE), and the ultrasound velocity dilution cardiac output method (UDCO) with those derived from cardiac MRI (cMRI) in healthy neonatal foals. ANIMALS: 6 healthy 1-week-old Standardbred foals. PROCEDURES: Foals were anesthetized and underwent 2DE, TEE, and cMRI; UDCO was performed simultaneously with 2DE. Images acquired by 2DE included the right parasternal 4-chamber (R4CH), left apical 4- and 2-chamber (biplane), and right parasternal short-axis M-mode (M-mode) views. The longitudinal 4-chamber view was obtained by TEE. Measurements assessed included left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), ejection fraction, stroke volume (LVSV), cardiac output (CO), and cardiac index (CI). Bland-Altman analyses were used to compare measurements derived from biplane, R4CH, and M-mode images and UDCO with cMRI-derived measurements. Repeatability of measurements calculated by 3 independent reviewers was assessed by the intraclass correlation coefficient. RESULTS: Compared with cMRI, all 2DE and TEE modalities underestimated LVEDV and LVESV and overestimated ejection fraction, CO, and CI. The LVSV was underestimated by the biplane, R4CH, and TEE modalities and overestimated by UDCO and M-mode methods. However, the R4CH-derived LVSV, CO, and CI were clinically comparable to cMRI-derived measures. Repeatability was good to excellent for measures derived from the biplane, R4CH, M-mode, UDCO, and cMRI methods and poor for TEE-derived measures. CONCLUSIONS AND CLINICAL RELEVANCE: All assessed modalities yielded clinically acceptable measurements of LVEDV, LVESV, and function, but those measurements should not be used interchangeably when monitoring patient progress.

Effects of oral trazodone on echocardiographic and hemodynamic variables in healthy cats.

OBJECTIVES: The purpose of this study was to evaluate the effects of oral trazodone on echocardiographic variables, heart rate (HR) and blood pressure (BP) in healthy cats. METHODS: Client-owned domestic cats between 2 and 8 years of age were recruited. Cats were considered healthy based on physical examination, complete blood count, blood chemistry profile, urinalysis, total thyroxine concentration, non-invasive BP measurement by Doppler method and a screening transthoracic echocardiogram with simultaneous electrocardiogram. Echocardiographic variables assessed pre-trazodone and 90-120 mins post-trazodone (50 mg PO) included left ventricular internal diameter in systole and diastole, interventricular septal and left ventricular free-wall thickness in systole and diastole, left atrial size, left auricular function and left ventricular diastolic function assessed by spectral Doppler transmitral and pulmonary venous flow velocities, and tissue Doppler profiles. Mean echocardiographic and hemodynamic variables were calculated for pre- and post-trazodone examinations for each cat. Pre- and post-trazodone variables were analyzed with a paired t-test with significance set at P <0.05. RESULTS: Twelve healthy cats were evaluated. Trazodone was administered to all cats and a sedative effect was observed. There were no clinically significant differences in any echocardiographic variables post-trazodone administration. Systolic BP was significantly decreased after trazodone (P = 0.001) with no significant change in HR. CONCLUSIONS AND RELEVANCE: Trazodone did not alter echocardiographic variables, in a clinically relevant manner, in this group of healthy cats. Trazodone may aid in obtaining transthoracic echocardiograms without affecting HR or echocardiographic variables but may significantly lower BP in healthy cats.

Plasma and tissue angiotensin-converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a homologue of angiotensin-converting enzyme (ACE) and produces angiotensin peptides (APs), such as angiotensin 1-9 and 1-7 that are vasodilatory and natriuretic, and act to counterbalance angiotensin II. HYPOTHESIS: Evidence of ACE2 can be found in tissues and plasma of dogs. Equilibrium concentrations of renin angiotensin aldosterone system (RAAS) APs differ in dogs with heart disease compared to healthy dogs and recombinant human ACE2 (rhACE2) alters relative concentrations of APs. ANIMALS: Forty-nine dogs with and 34 dogs without heart disease. METHODS: Immunohistochemistry and assays for tissue and plasma ACE2 activity and equilibrium concentrations of plasma RAAS APs were performed. RESULTS: Immunolabeling for ACE2 was present in kidney and myocardial tissue. Median plasma ACE2 activity was significantly increased in dogs with congestive heart failure (CHF; 6.9 mU/mg; interquartile range [IQR], 5.1-12.1) as compared to control (2.2 mU/mg; IQR, 1.8-3.0; P = .0003). Plasma equilibrium analysis of RAAS APs identified significant increases in the median concentrations of beneficial APs, such as angiotensin 1-7, in dogs with CHF (486.7 pg/mL; IQR, 214.2-1168) as compared to those with preclinical disease (41.0 pg/mL; IQR, 27.4-45.1; P < .0001) or control (11.4 pg/mL; IQR, 7.1-25.3; P = .01). Incubation of plasma samples from dogs with CHF with rhACE2 increased beneficial APs, such as angiotensin 1-9 (preincubation, 10.3 pg/mL; IQR, 4.4-37.2; postincubation, 2431 pg/mL; IQR, 1355-3037; P = .02), while simultaneously decreasing maladaptive APs, such as angiotensin II (preincubation, 53.4 pg/mL; IQR, 28.6-226.4; postincubation, 2.4 pg/mL; IQR, 0.50-5.8; P = .02). CONCLUSIONS AND CLINICAL IMPORTANCE: Recognition of the ACE2 system expands the conventional view of the RAAS in the dog and represents an important potential therapeutic target.

Severe hyperkalemia presenting with wide-complex tachycardia in a puppy with acute kidney injury secondary to leptospirosis.

OBJECTIVE: To describe a case of hyperkalemia coinciding with wide-complex tachycardia (WCT) in a dog with acute kidney injury secondary to leptospirosis infection. CASE SUMMARY: An 11-week-old Golden Retriever-Standard Poodle cross puppy was referred for acute kidney injury and hepatopathy. WCT coinciding with marked hyperkalemia was identified on presentation. Tachycardia persisted until resolution of hyperkalemia. NEW OR UNIQUE INFORMATION PROVIDED: To our knowledge, this is the first report of severe hyperkalemia presenting with WCT in a dog. Hyperkalemia should be considered a differential for WCT in dogs.

Effect of oral administration of pimobendan in cats with heart failure.

OBJECTIVE: To determine the effect of PO administration of pimobendan on clinical and echocardiographic variables and survival time in cats with heart failure characterized by ventricular systolic dysfunction. DESIGN: Retrospective cohort study. ANIMALS: 27 client-owned cats (16 male and 11 female) with heart failure, treated with pimobendan (mean ± SD dosage, 0.26 ± 0.08 mg/kg [0.118 ± 0.036 mg/lb], PO, q 12 h). PROCEDURES: Information on medical history, laboratory results, diagnostic imaging findings, treatments received, and survival time were obtained from medical records of cats that received pimobendan because of cardiac disease. When possible, additional follow-up information was obtained through telephone interviews with referring veterinarians and owners. RESULTS: The mean ± SD age of all 27 cats was 8.9 ± 5.2 years. All cats had received several cardiac medications. Types of heart disease represented included unclassified cardiomyopathy (CM; n = 11 [41%]), dilated CM (8 [30%]), arrhythmogenic right ventricular CM (4 [15%]), congenital heart disease (3 [11 %]), and hypertrophic CM with regional hypokinesis (1 [4%]). All cats had ventricular systolic dysfunction. One cat with systolic anterior motion of the mitral valve became severely hypotensive after initial administration of pimobendan and was excluded from the survival analysis. Median survival time was 167 days (95% confidence interval, 32 to 339 days). CONCLUSIONS AND CLINICAL RELEVANCE: Pimobendan appeared to be well tolerated in cats with heart failure characterized by ventricular systolic dysfunction of various etiologies. Cats with systolic anterior motion of the mitral valve may develop systemic hypotension when treated with pimobendan. Additional studies are needed to establish dosages for pimobendan and its effects before it can be recommended for treatment of cats with CHF.