Comparison of the effects of ivabradine and atenolol on heart rate and echocardiographic variables of left heart function in healthy cats

Background: Ivabradine is a novel negative chronotropic drug used for treatment of ischemic heart disease in people. Little is known about its effects and safety in cats. Hypothesis/Objectives: Ivabradine is not inferior to atenolol with regard to clinical tolerance, heart rate (HR) reduction, and effects on cardiac function in healthy, lightly sedated cats. Animals: Ten healthy laboratory cats. Methods: Physical examination, systolic blood pressure measurement, and transthoracic echocardiography were performed in all cats at baseline and after oral administration (4 weeks each) of ivabradine (0.3 mg/kg q12h) and atenolol (6.25 mg/cat q12h; 1.0–1.7 mg/kg) in a prospective, double‐blind, randomized, active‐control, fully crossed study. A priori noninferiority margins for the effects of ivabradine compared with atenolol were set at 50% (f= 0.5) based on predicted clinical relevance, observer measurement variability, and in agreement with FDA guidelines. Variables were compared by use of 2‐way repeated measures ANOVA. Results: Ivabradine was clinically well tolerated with no adverse events observed. HR (ivabradine, P < .001; atenolol, P < .001; ivabradine versus atenolol, P= .721) and rate‐pressure product (RPP) (ivabradine, P < .001; atenolol, P= .001; ivabradine versus atenolol, P= .847) were not different between treatments. At the dosages used, ivabradine demonstrated more favorable effects than atenolol on echocardiographic indices of left ventricular (LV) systolic and diastolic function and left atrial performance. Conclusions and Clinical Importance: Ivabradine is not inferior to atenolol with regard to effects on HR, RPP, LV function, left atrial performance, and clinical tolerance. Clinical studies in cats with hypertrophic cardiomyopathy are needed to validate these findings.     

Effects of sedation on echocardiographic variables of left atrial and left ventricular function in healthy cats

Although sedation is frequently used to facilitate patient compliance in feline echocardiography, the effects of sedative drugs on echocardiographic variables have been poorly documented. This study investigated the effects of two sedation protocols on echocardiographic indices in healthy cats, with special emphasis on the assessment of left atrial size and function, as well as left ventricular diastolic performance. Seven cats underwent echocardiography (transthoracic two-dimensional, spectral Doppler, color flow Doppler and tissue Doppler imaging) before and after sedation with both acepromazine (0.1 mg/kg IM) and butorphanol (0.25 mg/kg IM), or acepromazine (0.1 mg/kg IM), butorphanol (0.25 mg/kg IM) and ketamine (1.5 mg/kg IV). Heart rate increased significantly following acepromazine/butorphanol/ketamine (mean ± SD of increase, 40 ± 26 beats/min) and non-invasive systolic blood pressure decreased significantly following acepromazine/butorphanol (mean ± SD of decrease, 12 ± 19 mmHg). The majority of echocardiographic variables were not significantly different after sedation compared with baseline values. Both sedation protocols resulted in mildly decreased left ventricular end-diastolic dimension and mildly increased left ventricular end-diastolic wall thickness. This study therefore failed to demonstrate clinically meaningful effects of these sedation protocols on echocardiographic measurements, suggesting that sedation with acepromazine, butorphanol and/or ketamine can be used to facilitate echocardiography in healthy cats.     

Pharmacokinetics of oral ivabradine in healthy cats

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for the measurement of the novel heart rate-lowering drug ivabradine and its major metabolite, S-18982, was cross-validated in the plasma of eight healthy cats. Plasma concentrations were then determined after single and repeated oral administration of ivabradine. Individual plasma concentrations versus time from each cat were used in compartmental analysis using the commercially available software WinNonlin. Both ivabradine and S-18982 reached their maximum concentrations of 103.33 and 3.86 ng/mL within 1 h. Following repeated administration, areas under the plasma concentration-time curves for ivabradine and S-18982 did not significantly increase. Two-compartmental and one-compartmental models with first-order input and elimination provided the best fit to the data for ivabradine and S-18982, respectively. Both models were combined to produce a single 4-compartment model characterizing ivabradine and S-18982 pharmacokinetics. The results of this study indicate that repeated oral doses of ivabradine produced plasma drug concentrations suitable for 12-h dosing intervals in healthy cats. Furthermore, the analytical assay and combined ivabradine/S-18982 model provide tools for further evaluation of ivabradine pharmacokinetics and pharmacodynamics in future studies in cats.     

丙泊酚对比格犬DR心脏形态及超声心动图左心室功能的影响

丙泊酚是兽医临床上常用的一种短效麻醉药或镇静药。本试验基于胸部DR和超声心动图检查,结合心电图描记及血压测量,探究临床推荐镇静剂量的丙泊酚对比格犬心脏形态及左心室功能的影响。对8只成年比格犬以2.5mg/kg、0.4mg/s经静脉泵注丙泊酚,分别在给药前及给药后0,5,10,20和30 min拍摄背腹位(DV)、腹背位(VD)、左侧卧位(LL)和右侧卧位(RL)共4个体位胸部DR片,采用超声心动图法测量给药前、后左心室功能相关参数,实时描记心电图并监测血压。结果显示,通过胸部DR测量出比格犬椎体心脏比分(vertebral heart score,VHS)在LL(9.7±0.2)和RL(9.8±0.3)时差异不显著(P0.05)。与给药前相比,给药后比格犬心脏短轴和VHS在10,20和30min显著减少(P0.01);心胸宽比在20,30 min显著减小(P0.01或P0.05);左心室舒张末期容积(EDV)、每搏输出量(SV)、缩短分数(FS)和射血分数(EF)均显著下降(P0.01或P0.05)。试验表明临床推荐镇静剂量的丙泊酚可引起成年比格犬心脏形态显著改变,左心室功能显著降低。     

Effects of vagal maneuvers on heart rate and Doppler variables of left ventricular filling in healthy cats

BackgroundEvaluation of left ventricular (LV) diastole is clinically important in cats with heart disease. Diastolic dysfunction is a main characteristic of feline cardiomyopathy and is associated with clinical signs and poor outcome. Numerous echocardiographic indices characterizing LV diastole exist, of which Doppler variables of transmitral flow and mitral annular motion are used most often. However, rapid heart rate (HR), a common finding in cats examined in the veterinary hospital environment, may cause summation of flow waves limiting interpretation of diastolic function.ObjectiveTo evaluate the effects of vagal maneuvers (gentle eyeball pressure and nasal planum massage) on HR and Doppler variables of LV diastolic filling.AnimalsTwenty-four healthy client-owned cats with summated transmitral flow waves at baseline.MethodsProspective observational study. Transthoracic echocardiography was performed and Doppler transmitral and mitral annular tissue Doppler velocities recorded both before and during vagal maneuvers. Data were compared using a paired t-test.ResultsApplication of vagal maneuvers temporarily decreased HR in all cats (mean reduction ± SD; 42 ± 22 bpm). The duration of HR reduction (<5 s, 5–10 s, and >10–15 s) was evenly distributed among groups (8 cats in each). Summated Doppler transmitral flow and mitral annular tissue velocity waves were separated during vagal maneuvers in 71% and 72% of cats, respectively. No adverse effects were observed.ConclusionsVagal maneuvers may be utilized as a simple non-pharmacologic tool in the Doppler evaluation of LV diastolic function in healthy cats.     

Radiographic measurement of vertebral heart size in healthy stray cats

The aims of this study were to determine vertebral heart size (VHS) in stray cats and to compare different radiographic views. This study was performed on 50 adult stray cats. All cats were short-haired and non-obese and were considered to be healthy based on physical examination and electrocardiography. Left and right lateral, dorsoventral and ventrodorsal radiographs were taken. The long and short axes of the heart were measured in millimetres. The thoracic vertebral length spanned by each dimension was measured caudally from the fourth thoracic vertebra. Mean+/-SD and the correlation coefficient between the measurements were calculated with standard statistical software. The sum of the long and short axes of the heart expressed as VHS was 7.3+/-0.49 vertebrae in right lateral, 7.3+/-0.55 vertebrae in left lateral, 7.5+/-0.68 vertebrae in dorsoventral and 7.5+/-0.53 vertebrae in ventrodorsal. The differences between right and left lateral as well as dorsoventral and ventrodorsal views were not significant (P>0.05). Absolute measurements and vertebral heart scale values were slightly smaller than those reported in the literature for mixed population of cats. It is, therefore, important to take the breed in to account.     

Effects of saffan on cardiopulmonary function in healthy cats.

The effects of saffan on cardiopulmonary function were evaluated in eight healthy adult cats. Measured values were cardiac output by thermodilution, heart rate by electrocardiogram, arterial blood gases, respiratory rate and systolic, diastolic and mean arterial blood pressures by arterial catheterization. Calculated values included cardiac index, stroke volume and systemic vascular resistance. Statistical analysis employed paired t-tests comparing pre saffan anesthetic induction and post saffan anesthetic parameters over a 120 minute time sequence. Thirty min after saffan induction, significant depression in cardiac output was evident while stroke volume was significantly depressed at 45 and 60 min, systolic blood pressure at 15 min and respiratory rate at 5, 10 and 15 min. No significant changes occurred in cardiac index, heart rate, arterial blood gases, diastolic and mean arterial blood pressure or systemic vascular resistance. It was concluded that saffan causes significant depression of cardiopulmonary function in normal adult cats.     

Pharmacodynamic effects of ivabradine, a negative chronotropic agent, in healthy cats

Objective

To determine the pharmacodynamic effects of oral ivabradine in cats.

Animals

Eight healthy, adult domestic short hair cats.

Methods

Each cat underwent four study periods of 24 h, receiving either one dose of placebo or ivabradine (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) in a single-blind randomized crossover study. Clinical tolerance was assessed hourly for the first 8 h, at 12 h, and at the end of the 24-h study period. Heart rate and blood pressure were monitored continuously for 18–24 h via radiotelemetry after each treatment. Response to stress (acoustic startle) was studied before (t = 0) and after treatment (t = 4 h). Statistical comparisons were made using a linear mixed models and 1-way and 2-way repeated measures ANOVA.

Results

Heart rate (min⁻¹) decreased significantly (P < 0.05) in a dose-dependent manner with peak negative chronotropic effects observed 3 h after ivabradine (mean ± SD; placebo, 144 ± 20; ivabradine 0.1 mg/kg, 133 ± 22; ivabradine 0.3 mg/kg, 112 ± 20; and ivabradine 0.5 mg/kg, 104 ± 11). Heart rate (min⁻¹) was still reduced (P < 0.05) 12 h after ivabradine (0.3 mg/kg; 128 ± 18 and 0.5 mg/kg; 124 ± 16) compared to placebo (141 ± 21). The tachycardic response to acoustic startle was significantly (P < 0.01) blunted at all 3 doses of ivabradine. Myocardial oxygen consumption estimated by the rate-pressure product was significantly reduced (P < 0.05) for all doses of ivabradine. No effect of ivabradine on systolic, diastolic, and mean blood pressure was identified and no clinically discernable side effects were observed.

Conclusion

These findings indicate that a single oral dose of ivabradine predictably lowers heart rate, blunts the chronotropic response to stress, and is clinically well tolerated in healthy cats. This makes ivabradine potentially interesting in the treatment of feline heart disease where ischemia is of pathophysiologic importance.     

Two-dimensional echocardiographic estimates of left atrial function in healthy dogs and dogs with myxomatous mitral valve disease

Objectives

To provide reference intervals for 2-dimensional linear and area-based estimates of left atrial (LA) function in healthy dogs and to evaluate the ability of estimates of LA function to differentiate dogs with subclinical myxomatous mitral valve disease (MMVD) and similarly affected dogs with congestive heart failure (CHF).

Methods and reliability of echocardiographic assessment of left atrial size and mechanical function in horses

OBJECTIVE: To assess the feasibility, describe the techniques, and determine the reliability of transthoracic echocardiography for characterization of left atrial (LA) size and LA mechanical function in horses. ANIMALS: 6 healthy adult horses. PROCEDURES: Repeated echocardiographic examinations were performed independently by 2 observers in standing, unsedated horses by use of 2-dimensional echocardiography, pulsed-wave flow Doppler, and tissue Doppler imaging (TDI) techniques. Test reliability was determined by estimating measurement variability, within-day interobserver variability, and between-day inter- and intraobserver variability of all echocardiographic variables. Variability was expressed as the coefficient of variation (CV) and the absolute value below which the difference between 2 measurements will lie with 95% probability. RESULTS: Most echocardiographic variables of LA size had low overall variability (CV, < 15%). Among the 2-dimensional indices of LA mechanical function, area-based and volume-based ejection phase indices had moderate between-day variability (CV usually < 25%). Transmitral Doppler flow indices were characterized by low to high between-day variability (CV, 6% to 35%). The TDI wall motion velocities had high between-day variability (CV, > 25%), whereas most TDI-derived time intervals had low variability (CV, < 15%). CONCLUSIONS AND CLINICAL RELEVANCE: LA size and mechanical function can be reliably assessed in standing, unsedated horses by use of 2-dimensional echocardiography, transmitral blood flow velocity profiles, and analyses of LA wall motion by use of TDI. These results may provide useful recommendations for echocardiographic assessment of LA size and function in horses.     

Prevalence of echocardiographic evidence of cardiac disease in apparently healthy cats with murmurs

The objective of this prospective study was to determine the prevalence of echocardiographic evidence of heart disease in apparently healthy cats with heart murmurs. Thirty-two privately owned domestic cats were examined. All cats were considered healthy on the basis of history and physical examination, except for the finding of a heart murmur on auscultation. Cats on any medications (besides regular flea, tick and heartworm preventative) or that were pregnant or lactating were excluded from this study. The prevalence of echocardiographic evidence of heart disease in this population of cats was 53%. Therefore, identification of a heart murmur on routine physical examination in apparently healthy cats warrants further investigation.     

Measurement of M-mode echocardiographic parameters in healthy adult Maine Coon cats

OBJECTIVE: To determine reference values for M-mode echocardiographic parameters in nonsedated healthy adult Maine Coon cats and compare those values with data reported for nonsedated healthy adult domestic cats. DESIGN: Prospective study. ANIMALS: 105 healthy adult Maine Coon cats. PROCEDURE: Over a 3-year period, M-mode echocardiographic examinations (involving a standard right parasternal transthoracic technique) were performed on Maine Coon cats as part of prebreeding evaluations; values of M-mode parameters in healthy individuals were collected, and mean values were calculated for comparison with those reported for healthy adult domestic cats. RESULTS: The mean +/- SD weight of Maine Coon cats was significantly greater than that of domestic cats. Mean values of left ventricular internal dimension at end diastole and end systole (LVIDd and LVIDs, respectively), interventricular septal thickness at end systole (IVSs), left ventricular posterior wall thickness at end systole (LVPWs), left atrial dimension at end systole (LADs), and aortic root dimension (Ao) in Maine Coon cats differed significantly from values in healthy domestic cats. The greatest differences detected between the 2 groups involved values of LVIDd, LADs, and Ao. Linear regression analysis revealed a weak but significant correlation between weight and each of LVIDd, LVPWs, IVSs, Ao, LADs, and left ventricular posterior wall thickness at end diastole. CONCLUSIONS AND CLINICAL RELEVANCE: Values of several M-mode echocardiographic parameters in Maine Coon cats differ from those reported for domestic cats; these differences should be considered during interpretation of echocardiographic findings to distinguish between cardiac health and disease in this breed.     

Evaluation of plasma C-terminal atrial natriuretic peptide in healthy cats and cats with heart disease

BACKGROUND: The clinical implications of evaluating C-terminal atrial natriuretic peptide (ANP) concentration in cats are still controversial. HYPOTHESIS: The objective of this study was to investigate the relationship between plasma C-terminal ANP concentration and left atrial pressure (LAP) in healthy cats with volume overload (study 1), and to compare plasma C-terminal ANP in normal cats and cats with cardiomyopathy (study 2). ANIMALS: Five healthy adult cats were used in study 1, and clinically healthy cats (n=8) and cats with cardiomyopathy (n=14) were used in study 2. METHODS: In study 1, cats were anesthetized and given acetated Ringer's solution (100 mL/kg/h for 60 minute) via the cephalic vein. Hemodynamic measurements and blood samples, collected from the jugular vein, were performed at 10-min intervals. In study 2, blood samples from normal cats and cats with cardiomyopathy were collected from the cephalic vein. The plasma C-terminal ANP concentration was determined by radioimmunoassay for human alpha-ANP. RESULTS: In study 1, volume overload significantly increased the C-terminal ANP concentration and LAP from baseline. The C-terminal ANP concentration was strongly correlated with the mean LAP. In study 2, age, E wave velocity, and the ratios of the left atrium to aorta were significantly higher in the cats with cardiomyopathy compared with the normal cats. The C-terminal ANP concentration was significantly higher in the cats with cardiomyopathy compared with the normal cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that the measurement of plasma C-terminal ANP in cats may provide additional information for the diagnosis of heart disease.