Hypertrophic cardiomyopathy is the most common heart disease in cats and is characterized by LV hypertrophy, myofiber disarray, myocardial fibrosis, intramural coronary arterial narrowing, and myocardial ischemia, which are all factors that compromise diastolic LV function.1–3 Treatment of cats with subclinical HCM remains controversial but has been directed at relieving obstruction of the LV outflow tract, improving LV diastolic function, and preventing arterial thromboembolism and sudden cardiac death. β-Adrenoreceptor antagonists and, less frequently, calcium channel antagonists have been used in the management of subclinical HCM in cats.4–8 However, concerns have been raised regarding potential adverse effects of these drugs in cats, including lethargy, inappetence, salivation, weight loss, and reduced LA function.4–8 β-Adrenoreceptor antagonists may also be contraindicated in congestive heart failure and cats with allergic airway disease, hypotension, and arterial thromboembolism.4–8
Several prognostic indicators have been proposed in cats with HCM, including LV diastolic function, LA size, and HR,1,9 which is a major determinant of myocardial oxygen consumption.10 Tachycardia is poorly tolerated in humans with HCM. Consequences of tachycardia can include reduced LV filling, decreased myocardial perfusion, and increased myocardial oxygen demand with worsening of preexisting diastolic dysfunction and myocardial ischemia.10 Evidence in human patients with HCM suggests that ischemia is a major contributor to clinical signs, disease progression, and fatal outcome. Furthermore, ischemia can be present in asymptomatic patients with HCM, with syncope and sudden cardiac death caused by ischemia, rather than a primary arrhythmogenic substrate.11 The association between ischemia, cellular calcium overload, and LV diastolic dysfunction is established. Hence, pharmacological modulation of HR is important in the treatment of pathological conditions characterized by a mismatch between oxygen supply and demand of the myocardium, such as coronary artery disease, systemic hypertension, and heart failure,12–15 and may also be important for management of HCM.
Recent advances related to the molecular basis of cardiac pacemaker function and the physiology of associated ion channels have led to novel approaches in the selective control of HR.16,17 One such cellular target is the pacemaker funny current (If) of the sinoatrial node. To date, several If inhibitors have been studied but only ivabradine has been approved for clinical use in human patients with ischemic heart disease.17
To the authors' knowledge, the hemodynamic effects of ivabradine have not yet been studied in cats. Therefore, the objectives of the study reported here were to evaluate the acute effects of ivabradine on HR, LV function, and LA performance by use of catheter-based and echocardiographic techniques and to investigate the effects of sympathetic stimulation on central hemodynamics under the influence of a β-adrenoreceptor antagonist (esmolol) and ivabradine in healthy cats (controls) and in cats with subclinical HCM under general anesthesia. We hypothesized that ivabradine would have minimal effects on LV and LA function but would significantly blunt positive chronotropic responses induced by catecholamine administration.
Materials and Methods
Animals—Subjects included 6 healthy domestic shorthair cats (controls) from 2 to 6 years of age (body weight, 3.7 to 5.0 kg) and 6 domestic shorthair cats with idiopathic symmetric or asymmetric LV hypertrophy. Cats with hypertrophy were classified as affected by HCM as defined by an end-diastolic dimension of the interventricular septum or the LV posterior wall > 6 mm determined via 3 or more echocardiographic examinations.2,18,19 Cats with HCM were 3 to 8 years old and weighed 2.8 to 8.3 kg. These cats were acquired from a commercial vendora (n = 8) or from an in-house research colony. Three of the cats with HCM were male, and the other 9 cats were female.
The study protocol was reviewed and approved by the Animal Care and Use Committee and the Institutional Review Board of the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University. All animals were treated in compliance with the National Institutes of Health guidelines on the care and use of laboratory animals.
Anesthesia, instrumentation, and hemodynamic measurements—Following sedation with acepromazineb (0.025 mg/kg, IM) and butorphanolc (0.25 mg/kg, IM), each cat was anesthetized with propofold (5 mg/kg, IV) and intubated. Anesthesia was maintained with isofluranee (0.5 to 2.0%) in 100% oxygen by use of mechanical ventilation with a tidal volume of 10 to 15 mL/kg and a respiratory frequency of 12 breaths/min. The cats were positioned in left lateral recumbency on a fluoroscopy table designed to allow echocardiographic examinations during cardiac catheterization. Drugs and fluids were infused into the right cephalic vein as boluses or at a constant rate by use of syringe pumps.f Cefazoling (20 mg/kg, IV) was administered immediately before and 90 minutes and 8 hours after induction of anesthesia. Heparinh (100 U/kg, IV) was administered once after completion of instrumentation. The right external jugular vein and the right carotid artery were surgically exposed according to standard techniques, and 2% lidocainei was infiltrated to provide additional local anesthesia. A 3F, high-fidelity, dual-micromanometer–tipped catheterj,k was advanced into the LV through the right carotid artery under fluoroscopic guidance and positioned to simultaneously record LV and aortic pressures. Digital sampling rate for the micromanometer catheter was 500 samples/s. As described,20 the transducers were placed in a water bath for 30 minutes, balanced at atmospheric pressure, and calibrated against a mercury manometer prior to use. A 5F, flow-directed, fluid-filled, thermistor-tipped catheterl connected to a pressure transducer and a CO computerm was positioned in the pulmonary artery via the right external jugular vein. The proximal catheter port was positioned in the right atrium or cranial vena cava, the thermistor in the main pulmonary artery, and the distal tip in the main or proximal left or right pulmonary artery branch. This catheter was used to measure pulmonary artery pressures and CO by thermodilution. For measurement of CO, a 1-mL bolus of saline (0.9% NaCl) solutionn was rapidly injected into the right atrium through the proximal port of the pulmonary artery catheter. Body temperature of the cats was monitored from the thermistor of the Swan-Ganz catheter and maintained with a circulating warm water blanket and an external warming unit. Body temperature, ECG, HR, LV pressures, aortic pressures, and pulmonary artery pressures were monitored continuously and recorded simultaneously during each treatment period. Cardiac output was measured at end-expiration during each intervention simultaneously with echocardiographic recordings.20
Echocardiography—Each cat underwent repeated transthoracic 2-D echocardiography, spectral and color Doppler echocardiography, and pulsed-wave tissue Doppler imaging echocardiography by use of digital probes with a transducer array with a nominal frequency of 5.0 to 7.0 MHz.o Recordings for tissue Doppler imaging and 2-D strain analyses were made at end-expiration. Echocardiography was performed by a single operator (SCR). Data were stored digitally, and echocardiographic data analysis was performed offline by use of a commercial analysis software package.p The mean of 3 cardiac cycles was calculated for each variable measured. A simultaneous 1-lead ECG was recorded.
Right parasternal long- and short-axis and left apical long-axis imaging views were acquired to allow for optimal recording of the LA, LV, transmitral and pulmonary venous flow, LA appendage flow, aortic outflow, IVRT, and tissue Doppler-derived velocity of the lateral mitral annulus.20–22 All Doppler-derived velocity measurements were performed from the left apical 4-chamber view. Two-dimensional and M-mode variables of the LV and LA were obtained as described.20–23 Ejection fraction was measured by use of the modified Simpson method (single plane) from a left apical transducer site.24 Left atrial size was assessed from the right parasternal long-axis view.21,22 In addition, FAC of the LA and LA shortening fraction were calculated.21,22 Left atrial appendage flow was obtained from a left apical tilted 3-chamber view and with a sample volume of 3 to 5 mm placed in the proximal third of the appendage.21,22 Pulmonary venous flow was obtained from the left apical 4-chamber view with minimized low-velocity filtering and with a sample volume of 5 mm placed 2 to 4 mm within the pulmonary vein. Transmitral flow was recorded with a sample volume of 5 mm placed between the tips of the opened mitral valve leaflets. Peak velocities of early diastolic transmitral flow wave (E wave) and late diastolic transmitral flow wave (A wave), deceleration time of the E wave, and A wave duration were measured. Fused E and A waves were measured, but data were excluded from final statistical analysis. The ratio of peak velocity of E wave (in m/s) to IVRT (in s) was calculated and reported as a dimensionless number.
Pulsed-wave Doppler-derived velocities of myocardial motion were also recorded from the left apical view.25 The Doppler gain was minimized to generate a clear tissue signal with minimum background noise. Frame rate was optimized (> 160 frames/s) by narrowing the tissue Doppler imaging sector. A sample volume of 5 mm was placed at the lateral mitral annulus, and the peak systolic and early and late diastolic velocities were measured. The ratio of peak velocity of E wave to early diastolic motion of the lateral mitral annulus was calculated. Data were excluded from statistical analysis when early and late diastolic motion waves of the lateral mitral annulus were fused.
The LV was imaged in a right parasternal midventricular short-axis plane for quantification of peak systolic radial strain, peak systolic and early and late diastolic radial strain rate, and global peak systolic and early and late diastolic circumferential strain rate, all recorded at end-expiration. Care was taken to obtain a frame rate between 60 and 200 frames/s (depending on HR) with the sector width and image depth optimized. The offline analysis of strain was obtained by use of a 2-D speckle-tracking method as described in dogs.26 In brief, aortic valve opening and closure were defined on the basis of the pulsed-wave aortic outflow signal. Once a suitable 2-D image was identified, the LV endocardium was manually traced in systole or diastole and an optimal region of interest was then chosen for automated determination of myocardial deformation by use of speckle tracking. Radial strain, radial strain rate, and circumferential strain rate were determined as the mean of 6 corresponding myocardial segments.26
Hemodynamic interventions—After baseline measurements were obtained, 4 treatments (esmolol,q Esm+Dob,r ivabradine,s and Iva+Dob) were studied. A 10- to 20-minute period was allowed for hemodynamic stabilization between each study period. Once HR was stable, hemodynamic variables and echocardiographic data were acquired simultaneously, with data collection taking approximately 15 minutes for each treatment period. The ultrashort-acting β-adrenoreceptor antagonist (esmolol) was administered (1 to 6 loading doses of 200 μg/kg, followed by 1 to 4 doses of 400 μg/kg each administered slowly over 1 minute, IV, followed by constant rate infusion of 200 to 600 μg/kg/min, IV) to reduce HR. Once HR reduction was achieved, the dosage of esmolol was maintained at 200 to 400 μg/kg/min, and measurements were performed after hemodynamic stabilization. When HR reduction as desired was not achieved, as in some cats, measurements were performed when no further effects on hemodynamic variables (eg, rate of LV pressure increase, LV pressures, and aortic pressures) were observed despite increasing doses of esmolol. Thereafter, administration of esmolol was continued (200 to 400 μg/kg/min, IV) and dobutamine (5.0 μg/kg/min, IV) was administered to study the effects of sympathoadrenergic stimulation during β-adreneoreceptor blockade (Esm+Dob). Following data collection, Esm+Dob was discontinued and HR, LV pressure, and aortic pressure were allowed to return to near baseline. A single bolus of ivabradines (0.3 mg/kg, IV) was then administered. The dose of ivabradine was selected on the basis of the results of a dose-finding study in healthy cats performed by use of 24-hour radiotelemetric recording method and was similar to doses used in dogs and humans.t Ivabradine used for injection (0.2 mg/mL) was reconstituted by adding sterile water to 1- and 2-mg vials of ivabradine hydrochloride immediately before administration, and the solution was injected through a diposable microfilter device.u Finally, dobutamine (5.0 μg/kg/min, IV) was administered to study the effects of sympathoadrenergic stimulation under the influence of ivabradine (Iva+Dob).
At the conclusion of the experiment, drug administration was stopped, all catheters and monitoring equipment were removed, the cannulated vessels were ligated, skin incisions were surgically closed, and the cats were closely observed until they were extubated and completely recovered from anesthesia. Butorphanol (0.35 mg/kg, SC) was administered every 8 hours for postoperative control of pain. Subsequently, the cats were transferred back to their original study protocol and were later placed in adoption homes.
Hemodynamic data—Pressures,v–x CO,m echocardiographicp data, and a single lead ECG were simultaneously recorded and stored digitally for subsequent analyses. Pressures were measured from the digitized recordings at end-expiration. Catheter-derived variables included HR, LV systolic pressure, LV EDP, aortic systolic pressure, aortic diastolic pressure, +dP/dtmax, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, and mean pulmonary artery pressure. Left ventricular EDP was defined as the LV pressure immediately preceding the onset of LV contraction. The LV relaxation time constant (tau) was calculated by the method of Weiss et al27 assuming a zero asymptote.
Cardiac output was determined with a commercial CO computer.m The mean of 5 measurements with a maximum variance of 15% was used as the determination for each study period. Left ventricular enddiastolic and end-systolic wall stress was calculated by use of a cylindrical model10,28 as 1.36 × (LV pressure × D/2h), where D is the maximum internal short-axis diameter and h is wall thickness of the LV. Considering that some cats with HCM had asymmetric LV hypertrophy, 2h was calculated as the sum of the thickness of the intraventricular septum and the LV posterior wall. The rate-pressure product was calculated as an estimate of myocardial oxygen consumption as LV systolic pressure × HR.29
Statistical analysis—Statistical analysis was performed by use of commercially available software.y,z All data were graphically evaluated, and descriptive statistics were calculated for all variables. Data are reported as mean and SD, unless stated otherwise. Normal distribution of variables was determined by use of the Kolmogorov-Smirnov test. To identify differences among treatments and between controls and cats with HCM, a 2-way repeated-measures ANOVA was used with cardiac status (HCM and control) and animal as within-subject factors and 3 of the treatment periods (baseline, esmolol, and ivabradine) as between-subject factors. If significant (P < 0.05) differences were identified, a Holm-Sidak test was used for pairwise comparisons. If statistical assumptions for the use of 2-way repeated-measures ANOVA were not met, linear mixed-effects models and change scores30 were used for group comparisons. The models included fixed effects of diagnosis (HCM and control) and treatment stage, the interaction of these 2 factors, and the baseline measure as a covariate.
In addition, changes of variables induced by dobutamine (Esm+Dob vs esmolol, Iva+Dob vs ivabradine, Esm+Dob minus esmolol, and Iva+Dob minus ivabradine) were compared by use of a 2-way repeated-measures ANOVA with Holm-Sidak post hoc analyses. Finally, univariate and multiple linear regression analyses and logistic regression were used to identify associations between tau and the independent variables of HR, CI, +dP/dtmax, LV systolic pressure, LV EDP, and treatment by use of pooled data. For all analyses, values of P ≤ 0.05 were considered significant.
Results
Cats with HCM and control cats were not significantly different with regard to age and body weight. Mean ± SD HR, hemodynamic data, and echocardiographic variables of cats of both groups were summarized (Tables 1–4). At baseline, only CI, pulmonary artery systolic pressure, thickness of the intraventricular septum in diastole, peak velocity of E wave, and S:D differed significantly between groups. Although HR (P = 0.19), tau (P = 0.09), rate-pressure product (P = 0.26), and IVRT (P = 0.21) appeared to be higher and end-systolic wall stress (P = 0.17), end-diastolic wall stress (P = 0.21), and peak velocity of early diastolic motion of the lateral mitral annulus (P = 0.08) appeared to be lower in cats with HCM, compared with controls, the observed differences did not attain significance. Data on the significant changes induced by dobutamine with regard to HR and selected variables of LV and LA function were summarized (Table 5).
Heart rate and invasively derived indices of LV systolic and diastolic function measured under 5 hemodynamic conditions in 6 control cats and 6 cats with HCM.
| Variable | Group | Baseline | Esmolol | Esm+Dob | Ivabradine | Iva+Dob |
|---|---|---|---|---|---|---|
| HR (beats/min) | Control | 129 ± 23 | 132 ± 17 | 160 ± 20b | 101 ± 12a | 108 ± 16 |
| HCM | 147 ± 30 | 135 ± 37 | 164 ± 28b | 99 ± 6a | 122 ± 18c | |
| LVSP (mm Hg) | Control | 79 ± 9 | 78 ± 11 | 104 ± 17b | 87 ± 16 | 110 ± 23c |
| HCM | 82 ± 14 | 77 ± 16 | 102 ± 27b | 84 ± 23 | 118 ± 40c | |
| LV EDP (mm Hg) | Control | 7.8 ± 3.9 | 9.8 ± 3.2 | 12.7 ± 3.2b | 12.9 ± 3.2a | 16.8 ± 4.5c |
| HCM | 7.7 ± 2.8 | 7.2 ± 3.2 | 11.9 ± 3.0b | 11.8 ± 4.7a | 16.7 ± 5.0c | |
| AoSP (mm Hg) | Control | 82 ± 6 | 77 ± 10 | 102 ± 18b | 86 ± 15 | 108 ± 22c |
| HCM | 81 ± 15 | 78 ± 16 | 102 ± 29b | 85 ± 24 | 111 ± 40c | |
| AoDP (mm Hg) | Control | 57 ± 7 | 52 ± 9 | 53 ± 16 | 51 ± 11 | 52 ± 12 |
| HCM | 62 ± 14 | 59 ± 15 | 61 ± 22 | 55 ± 17 | 63 ± 20 | |
| PASP (mm Hg) | Control | 15.2 ± 3.7 | 15.3 ± 1.7 | 27.4 ± 4.9b | 17.7 ± 3.3 | 26.5 ± 4.4c |
| HCM | 11.0 ± 2.7* | 12.6 ± 2.0 | 22.6 ± 3.8*b | 15.4 ± 3.7a | 23.2 ± 6.2c | |
| PADP (mm Hg) | Control | 11.3 ± 2.4 | 10.9 ± 2.8 | 19.5 ± 7.0b | 11.2 ± 3.3 | 15.2 ± 2.9c |
| HCM | 8.1 ± 4.4 | 10.5 ± 1.8 | 17.2 ± 3.8b | 11.0 ± 4.1 | 16.1 ± 5.3c | |
| PAPmean (mm Hg) | Control | 13.4 ± 2.9 | 13.3 ± 1.8 | 23.5 ± 5.5b | 14.9 ± 2.8 | 20.8 ± 2.9c |
| HCM | 9.7 ± 3.5 | 11.2 ± 1.7 | 20.0 ± 3.6b | 13.2 ± 3.6 | 19.8 ± 5.7c | |
| +dP/dtmax (mm Hg/s) | Control | 2,098 ± 430 | 1,712 ± 246a | 2,687 ± 1,089 | 1,954 ± 430 | 3,107 ± 1,092c |
| HCM | 2,101 ± 661 | 1,569 ± 391a | 2,449 ± 1,311 | 1,488 ± 343a | 3,456 ± 1,627c | |
| Tau (ms) | Control | 30 ± 3 | 31 ± 3 | 24 ± 5b | 31 ± 4 | 26 ± 3c |
| HCM | 34 ± 7 | 34 ± 7 | 29 ± 8b | 38 ± 5a | 26 ± 4c | |
| Stroke volume (mL) | Control | 3.5 ± 0.8 | 3.5 ± 0.6 | 4.1 ± 0.6 | 4.0 ± 0.8a | 5.2 ± 0.9c |
| HCM | 2.8 ± 1.0 | 2.7 ± 0.8 | 3.5 ± 1.2b | 3.2 ± 0.8 | 4.5 ± 1.2c | |
| CO (L/min) | Control | 0.44 ± 0.07 | 0.46 ± 0.05 | 0.66 ± 0.11b | 0.41 ± 0.11 | 0.56 ± 0.15c |
| HCM | 0.39 ± 0.11 | 0.34 ± 0.05* | 0.56 ± 0.18b | 0.31 ± 0.07*a | 0.55 ± 0.20c | |
| Cl (mL/kg/min) | Control | 99.9 ± 15.3 | 103.9 ± 14.4 | 149.5 ± 20.6b | 93.8 ± 27.6 | 129.0 ± 40.1c |
| HCM | 69.6 ± 17.8* | 63.2 ± 19.0* | 100.6 ± 31.3*b | 57.2 ± 19.1* | 99.6 ± 33.2c | |
| End systolic wall stress (g/cm2) | Control | 70.1 ± 18.5 | 88.3 ± 19.6 | 73.6 ± 27.3 | 73.6 ± 16.4 | 62.8 ± 13.3c |
| HCM | 54.8 ± 25.6 | 57.3 ± 27.8 | 57.8 ± 36.9 | 65.0 ± 34.9 | 66.6 ± 35.3 | |
| End diastolic wall stress (g/cm2) | Control | 15.2 ± 7.8 | 20.9 ± 6.4a | 28.4 ± 6.8b | 27.9 ± 7.4a | 36.1 ± 10.4c |
| HCM | 9.8 ± 3.4 | 9.7 ± 5.3* | 17.3 ± 8.8*b | 19.7 ± 10.7a | 28.2 ± 11.3c | |
| Rate-pressure product (mm Hg/min) | Control | 10,146 ± 1,750 | 10,179 ± 1,752 | 16,690 ± 3,828b | 8,720 ± 1,630 | 11,677 ± 2,367 |
| HCM | 12,140 ± 3,659 | 10,781 ± 5,047 | 16,961 ± 6,231b | 8,429 ± 2,513a | 14,794 ± 5,968c |
Values are expressed as mean ± SD.
For this variable and hemodynamic condition, the value in cats with HCM differed significantly (P < 0.05) from the value in control cats.
AoDP = Aortic diastolic pressure. AoSP = Aortic systolic pressure. LVSP = Leftventricular systolic pressure. PADP = Pulmonary artery diastolic pressure. PAPmean = Mean pulmonary artery pressure. PASP = Pulmonary artery systolic pressure. Tau = Left ventricular relaxation time constant.
Within a row, values for esmolol and ivabradine differ significantly (P < 0.05) from baseline.
Within a row, values for Esm+Dob differ significantly (P < 0.05) from esmolol.
Within a row, values for Iva+Dob differ significantly (P < 0.05) from ivabradine.
Echocardiographically derived 2-D and M-mode indices of LV and LA function measured under 5 hemodynamic conditions in 6 control cats and 6 cats with HCM.
| Variable | Group | Baseline | Esmolol | Esm+Dob | Ivabradine | Iva+Dob |
|---|---|---|---|---|---|---|
| IVSd (mm) | Control | 4.7 ± 0.1 | 4.7 ± 0.3 | 4.6 ± 0.3 | 4.6 ± 0.2 | 4.7 ± 0.2 |
| HCM | 6.8 ± 1.5* | 6.8 ± 1.2* | 6.8 ± 1.3* | 6.7 ± 1.5* | 6.4 ± 1.6* | |
| LVIDd (mm) | Control | 13.4 ± 0.6 | 14.4 ± 1.3 | 14.7 ± 0.9 | 14.4 ± 0.4 | 14.9 ± 0.9 |
| HCM | 12.1 ± 2.8 | 11.9 ± 2.9* | 12.1 ± 4.1 | 13.9 ± 1.6a | 14.1 ± 1.7 | |
| LVPWd (mm) | Control | 4.8 ± 0.4 | 4.5 ± 0.2 | 4.3 ± 0.5 | 4.5 ± 0.3 | 4.7 ± 0.3 |
| HCM | 6.1 ± 1.8 | 6.1 ± 1.6 | 6.1 ± 1.7* | 5.7 ± 1.5 | 5.7 ± 1.6 | |
| Fractional shortening (%) | Control | 38 ± 10 | 33 ± 10 | 52 ± 12b | 42 ± 7 | 58 ± 6c |
| HCM | 39 ± 17 | 37 ± 16 | 50 ± 16b | 41 ± 7 | 54 ± 7c | |
| Ejection fraction (%) | Control | 64 ± 4 | 53 ± 5a | 68 ± 6b | 71 ± 4 | 79 ± 4c |
| HCM | 62 ± 12 | 53 ± 14a | 68 ± 12b | 67 ± 4 | 77 ± 5c | |
| FAC (%) | Control | 41 ± 10 | 39 ± 5 | 52 ± 5b | 50 ± 8a | 55 ± 4 |
| HCM | 39 ± 7 | 36 ± 6 | 46 ± 8b | 46 ± 3a | 52 ± 4c | |
| Maximum LA anteroposterior dimension (cm) | Control | 1.4 ± 0.2 | 1.5 ± 0.1 | 1.6 ± 0.2 | 1.6 ± 0.1a | 1.6 ± 0.2 |
| HCM | 1.5 ± 0.1 | 1.5 ± 0.2 | 1.5 ± 0.1 | 1.5 ± 0.1 | 1.7 ± 0.2c | |
| LA shortening fraction (%) | Control | 23 ± 6 | 21 ± 5 | 31 ± 3b | 26 ± 5 | 32 ± 4 |
| HCM | 22 ± 6 | 21 ± 4 | 28 ± 4b | 25 ± 4 | 32 ± 6c |
IVSd = Thickness of the intraventricular septum in diastole. LVIDd = Left ventricular internal dimension in diastole. LVPWd = Thickness of the LV posterior wall in diastole.
See Table 1 for remainder of key.
Doppler-derived echocardiographic indices of LV and LA function measured under 5 hemodynamic conditions in 6 control cats and 6 cats with HCM.
| Variable | Group | Baseline | Esmolol | Esm+Dob | Ivabradine | Iva+Dob |
|---|---|---|---|---|---|---|
| Peak E (m/s) | Control | 0.61 ± 0.12 | 0.60 ± 0.05 | 0.84 ± 0.12 | 0.64 ± 0.15 | 0.76 ± 0.12 |
| HCM | 0.50 ± 0.05* | 0.51 ± 0.09 | 0.67 ± 0.06 | 0.51 ± 0.17 | 0.69 ± 0.19 | |
| MV DecTE (ms) | Control | 63 ± 13 | 61 ± 10 | 45 ± 15 | 60 ± 8 | 59 ± 11 |
| HCM | 77 ± 10 | 75 ± 7 | 66 ± 11 | 71 ± 12 | 57 ± 12 | |
| Peak A (m/s) | Control | 0.37 ± 0.11 | 0.39 ± 0.10 | 0.50 ± 0.02 | 0.41 ± 0.13 | 0.58 ± 0.14 |
| HCM | 0.36 ± 0.05 | 0.38 ± 0.09 | 0.36 ± 0.13 | 0.34 ± 0.07 | 0.53 ± 0.10 | |
| Peak E: Peak A | Control | 1.81 ± 0.72 | 1.66 ± 0.64 | 1.70 ± 0.22 | 1.71 ± 0.76 | 1.36 ± 0.33 |
| HCM | 1.41 ± 0.18 | 1.46 ± 0.66 | 1.99 ± 0.83 | 1.50 ± 0.44 | 1.33 ± 0.43 | |
| IVRT (ms) | Control | 63 ± 11 | 64 ± 17 | 45 ± 13b | 57 ± 10 | 47 ± 12 |
| HCM | 75 ± 15 | 85 ± 23* | 68 ± 12*b | 78 ± 16* | 63 ± 20c | |
| Peak E:IVRT | Control | 9.9 ± 1.9 | 9.9 ± 3.0 | 18.3 ± 6.7b | 11.5 ± 4.0 | 16.7 ± 3.8c |
| HCM | 6.8 ± 1.7 | 6.5 ± 2.7 | 10.7 ± 3.8*b | 7.1 ± 3.6* | 12.3 ± 5.5c | |
| S:D | Control | 1.09 ± 0.84 | 0.81 ± 0.34 | 0.96 ± 0.41 | 0.73 ± 0.15 | 1.03 ± 0.37 |
| HCM | 1.80 ± 0.89* | 1.45 ± 0.52 | 1.57 ± 0.63* | 1.18 ± 0.40 | 1.47 ± 0.90 | |
| Peak AR (m/s) | Control | 0.18 ± 0.05 | 0.17 ± 0.06 | 0.22 ± 0.04 | 0.14 ± 0.06 | 0.24 ± 0.08 |
| HCM | 0.18 ± 0.08 | 0.15 ± 0.06 | 0.28 ± 0.21 | 0.12 ± 0.03 | 0.26 ± 0.18c | |
| A:AR duration | Control | 0.78 ± 0.13 | 0.78 ± 0.10 | 0.91 ± 0.06 | 0.71 ± 0.07 | 0.76 ± 0.08 |
| HCM | 0.91 ± 0.24 | 1.02 ± 0.30 | 1.07 ± 0.30 | 0.92 ± 0.23 | 0.83 ± 0.09 | |
| Peak LAA (m/s) | Control | 0.43 ± 0.17 | 0.32 ± 0.07 | 0.51 ± 0.10b | 0.37 ± 0.10 | 0.57 ± 0.13c |
| HCM | 0.44 ± 0.16 | 0.39 ± 0.12 | 0.54 ± 0.19b | 0.34 ± 0.08 | 0.63 ± 0.14c |
A:AR duration = Ratio of the duration of the late diastolic transmitral flow wave to the duration of the late diastolic pulmonary vein atrial reversal wave. MV DecTE = Deceleration time of the early diastolic transmitral flow wave. Peak A = Peak velocity of late diastolic transmitral flow. Peak AR = Peak velocity of the late diastolic pulmonary vein atrial reversal wave. Peak E = Peak velocity of early diastolic transmitral flow. Peak LAA = Peak velocity of LA appendage flow.
See Table 1 for remainder of key.
Tissue velocity imaging and speckle tracking-derived indices of systolic and diastolic LV function measured under 5 hemodynamic conditions in 6 control cats and 6 cats with HCM.
| Variable | Group | Baseline | Esmolol | Esm+Dob | Ivabradine | Iva+Dob |
|---|---|---|---|---|---|---|
| Peak Ea (cm/s) | Control | 7.25 ± 0.62 | 7.84 ± 1.78 | 10.47 ± 3.33 | 9.73 ± 3.09a | 10.88 ± 1.99 |
| HCM | 6.20 ± 1.41 | 5.58 ± 1.05 | 7.87 ± 1.02 | 6.75 ± 2.29*a | 8.73 ± 2.47c | |
| Peak Aa (cm/s) | Control | 4.13 ± 0.73 | 3.62 ± 0.62 | 5.23 ± 1.14 | 5.13 ± 1.97 | 7.75 ± 1.69c |
| HCM | 3.23 ± 1.41 | 3.28 ± 1.13 | 4.90 ± 2.04 | 4.42 ± 1.95 | 6.52 ± 1.85c | |
| Peak E: Peak Ea | Control | 8.44 ± 1.40 | 8.03 ± 1.35 | 8.47 ± 2.46 | 6.74 ± 1.08 | 7.15 ± 1.44 |
| HCM | 8.91 ± 2.24 | 9.76 ± 1.91 | 8.89 ± 0.63 | 7.70 ± 1.11 | 7.84 ± 0.44 | |
| Circ SrR Peak S (1/s) | Control | 1.73 ± 0.17 | 1.74 ± 0.34 | 1.86 ± 0.37 | 1.63 ± 0.44 | 2.10 ± 0.20c |
| HCM | 1.64 ± 0.53 | 1.55 ± 0.42 | 1.54 ± 0.40 | 1.56 ± 0.31 | 2.63 ± 0.62*c | |
| Circ SrR Peak E (1/s) | Control | 1.96 ± 0.67 | 2.50 ± 0.69 | 2.08 ± 0.49 | 2.36 ± 0.47 | 2.09 ± 0.63 |
| HCM | 1.48 ± 0.01 | 1.76 ± 1.07 | 2.58 ± 0.65 | 2.39 ± 0.86 | 2.62 ± 1.59 | |
| Circ SrR Peak A (1/s) | Control | 0.87 ± 0.40 | 0.86 ± 0.45 | 1.09 ± 0.20 | 0.74 ± 0.45 | 1.06 ± 0.54 |
| HCM | 0.41 ± 0.16 | 0.79 ± 0.49 | 1.34 ± 0.39 | 0.83 ± 0.33 | 1.17 ± 0.54 | |
| Peak radial systolic strain rate (1/s) | Control | 2.31 ± 0.34 | 2.03 ± 0.49 | 2.85 ± 0.98b | 1.94 ± 0.18 | 3.13 ± 0.61c |
| HCM | 2.19 ± 0.41 | 1.95 ± 0.53 | 2.48 ± 0.75 | 1.85 ± 0.27 | 3.44 ± 1.32c | |
| Peak radial early diastolic strain rate (1/s) | Control | 2.70 ± 0.22 | 3.12 ± 1.15 | 3.75 ± 0.59 | 3.26 ± 1.13 | 3.32 ± 0.94 |
| HCM | 2.06 ± 0.28 | 1.92 ± 0.41 | 3.69 ± 0.67 | 2.94 ± 1.20 | 4.01 ± 1.81c | |
| Peak radial late diastolic strain rate (1/s) | Control | 1.29 ± 0.32 | 1.41 ± 0.22 | 1.60 ± 0.64 | 0.98 ± 0.27 | 1.84 ± 0.70c |
| HCM | 1.16 ± 0.50 | 1.39 ± 0.96 | 2.16 ± 1.09 | 1.28 ± 0.53 | 2.07 ± 0.94c | |
| Peak radial systolic strain (%) | Control | 42.2 ± 10.3 | 44.1 ± 18.7 | 44.2 ± 13.2 | 38.7 ± 4.6 | 51.8 ± 12.7c |
| HCM | 32.3 ± 9.7 | 27.6 ± 8.9* | 39.2 ± 12.8 | 37.1 ± 7.7 | 48.3 ± 10.3c |
Circ SrR peak A = Global late diastolic circumferential strain rate. Circ SrR peak E = Global early diastolic circumferential strain rate. Circ SrR peak S = Global systolic circumferential strain rate. Peak Aa = Peak velocity of late diastolic motion of the lateral mitral annulus. Peak Ea = Peak velocity of early diastolic motion of the lateral mitral annulus.
See Tables 1 and 3 for remainder of key.
Comparison of absolute changes induced by dobutamine when administered concurrently with esmolol or ivabradine in 6 control cats and 6 cats with HCM.
| Variable | Group | Esm+Dob | Iva+Dob | P value |
|---|---|---|---|---|
| HR (beats/min) | Control | 28 ± 16 | 7 ± 8 | 0.034 |
| HCM | 29 ± 21 | 23 ± 17 | NS | |
| +dP/dtmax (mm Hg/s) | Control | 975 ± 1,172 | 1,153 ± 980 | 0.568 |
| HCM | 880 ± 1,063 | 1,968 ± 1,398 | 0.044 | |
| Tau (ms) | Control | −7 ± 2 | −6 ± 6 | NS |
| HCM | −5 ± 5 | −12 ± 6* | 0.019 | |
| Ejection fraction (%) | Control | 15 ± 4 | 8 ± 8 | 0.02 |
| HCM | 15 ± 8 | 10 ± 5 | 0.044 | |
| FAC (%) | Control | 14 ± 6 | 5 ± 6 | 0.030 |
| HCM | 10 ± 7 | 6 ± 6 | NS | |
| Circ SrR Peak S (1/s) | Control | 0.11 ± 0.28 | 0.47 ± 0.30 | NS |
| HCM | −0.01 ± 0.68 | 1.07 ± 0.39* | 0.002 |
Within a row, P values refer to comparison of the 2 treatments (Esm+Dob and Iva+Dob).
NS = Not significant.
See Tables 1 and 4 for remainder of key.
Effects of ivabradine on HR and rate-pressure product—Diagnosis (HCM or control) did not have a fixed effect on HR (P = 0.61), whereas treatment (P < 0.001) and baseline values (P < 0.001) did. Compared with baseline, HR was significantly (P < 0.001) reduced by ivabradine in cats with HCM and control cats, whereas the negative chronotropic effect of esmolol did not reach significance (HCM, P = 0.44; control, P = 0.59). Administration of dobutamine increased HR in cats with HCM when given concurrently with esmolol or ivabradine. However, the mean and maximum HR observed during Esm+Dob (164 and 204 beats/min) were significantly (P < 0.001) higher, compared with the mean and maximum HR observed during Iva+Dob (122 and 140 beats/min; Tables 1 and 5). Similar observations were made in control cats, although dobutamine did not significantly increase HR during Iva+Dob in this group. Mean ± SD relative change of HR, compared with baseline, in cats with HCM and control cats were −12 ± 25% and 3 ± 13% for esmolol, 12 ± 19% and 24 ± 15% for Esm+Dob, −33 ± 4% and −22 ± 10%, for ivabradine, and −17 ± 12% and −16 ± 12% for Iva+Dob, respectively.
With regard to the rate-pressure product, diagnosis (HCM or control; P = 0.79) and baseline characteristics (P = 0.24) did not have a fixed effect on outcome, whereas treatment (P < 0.001) did. In contrast to esmolol (P = 0.40), ivabradine significantly (P < 0.001) reduced the rate-pressure product in cats with HCM.
Effects of ivabradine on variables of LV contractility and LV systolic function—Diagnosis (HCM vs control; P = 0.39) and baseline values (P = 0.19) did not have a fixed effect on +dP/dtmax, whereas treatment (P < 0.001) did. Both ivabradine and esmolol decreased +dP/dtmax in cats with HCM (P < 0.001), whereas in control cats, only esmolol (P = 0.005) but not ivabradine (P = 0.45) caused a decrease of +dP/dtmax (Table 1). Dobutamine administered simultaneously with esmolol or ivabradine increased +dP/dtmax in both HCM and control cats, with a significant (P = 0.044) difference in absolute change between groups (Tables 1 and 5).
Overall, cats with HCM had lower CI, compared with controls (Table 1), although significance was only reached at baseline and with esmolol and ivabradine for CI. Stroke volume was not different between treatment groups and disease groups (esmolol, P = 0.62; ivabradine, P = 0.088). Stroke volume increased after dobutamine and was not different between cats with HCM and controls.
In terms of echocardiographic changes, LV ejection fraction was not affected by ivabradine, whereas esmolol decreased ejection fraction in both groups (Table 2). Segmental myocardial analysis performed by use of 2-D speckle tracking techniques revealed that systolic strain indices were not significantly affected by ivabradine or esmolol in both groups. However, in contrast to Esm+Dob, most of the radial and circumferential systolic strain and strain rate indices were significantly increased during Iva+Dob in HCM and control cats with only global systolic circumferential strain rate significantly different between cats with HCM and controls (Table 4). Cats with HCM had a larger increase of global systolic circumferential strain rate at Iva+Dob, compared with Esm+Dob, than did control cats (Table 5).
Effects of ivabradine on variables of LV diastolic function—Diagnosis (HCM or control) did not have a fixed effect on tau (P = 0.183), whereas treatment (P < 0.001) and baseline values (P < 0.001) did. Tau was slightly prolonged (mean, 4 milliseconds) after administration of ivabradine in cats with HCM (HCM, P < 0.009; control, P = 0.61) in contrast to tau after administration of esmolol (P > 0.05; Table 1). Dobutamine administered simultaneously with esmolol or ivabradine decreased tau in both groups. However, there was a significant (P = 0.019) difference in the magnitude of mean decrease of tau with Iva+Dob, compared with Esm+Dob, in cats with HCM (Table 5). Moreover, there was a significant (P = 0.029) difference in the mean reduction of tau with Iva+Dob between cats with HCM (mean, −12 milliseconds) and controls (mean, −6 milliseconds). Multivariate logistic regression analysis revealed that tau could be predicted from a combination of +dP/dtmax (P < 0.001), animal (P = 0.001), treatment (P = 0.039), and LV EDP (P = 0.011) in cats with HCM. By use of forward stepwise regression, a cumulative R2 of 0.51 was determined for step 1 (+dP/dtmax; R2 = 0.37) and step 2 (animal, change of R2 = 0.14; cumulative R2 = 0.51; P < 0.001) with a power of 0.997 at α = 0.05. Heart rate did not enter the final prediction model. In control cats, multivariate logistic regression analysis revealed that tau could be predicted from a combination of HR (P = 0.009), animal (P = 0.028), and treatment (P = 0.047). By use of forward stepwise regression, a cumulative R2 of 0.55 was determined for step 1 (HR, R2 = 0.19) and step 2 (treatment, change of R2 = 0.22), and step 3 (animal, change of R2 = 0.41; cumulative R2 = 0.55; P < 0.001) with a power of 0.998 at α = 0.05.
Overall, IVRT was prolonged in cats with HCM, compared with controls, with significance observed for Esm+Dob, ivabradine, and Iva+Dob (Table 3). Neither ivabradine nor esmolol affected IVRT in either group, compared with baseline. Ivabradine, but not esmolol, increased peak velocity of early diastolic motion of the lateral mitral annulus in both groups (P < 0.05), compared with baseline. Mean increase in early diastolic motion of the lateral mitral annulus was 8% in cats with HCM and 34% in control cats after ivabradine. There were no significant differences of 2-D strain-derived indices of LV diastolic function between the 2 groups (Table 4).
Variables of LV compliance—Left ventricular EDP (HCM, P = 0.006; control, P < 0.001) and end-diastolic wall stress (HCM, P = 0.001; control, P = 0.01; Table 1) were significantly increased with ivabradine in both groups of cats. Overall, calculated end-diastolic wall stress was lower in cats with HCM, compared with control cats, although significance was only observed for esmolol and Esm+Dob. Left ventricular EDP and end-diastolic wall stress increased under the influence of dobutamine in all treatment groups with no significant difference evident between HCM and control groups. Doppler variables of early LV compliance (deceleration time of the E wave) and late LV compliance (ratio of the duration of the A wave to the duration of the late diastolic pulmonary vein atrial reversal wave) were unaffected by treatment or disease group.
Variables of LV filling and LV filling pressure—At baseline and during Esm+Dob, S:D was significantly (P = 0.045) different between HCM and controls. Ivabradine did not affect peak velocity of E wave, ratio of peak velocity of E and A waves, or S:D in either group (Table 3). Ivabradine significantly increased LV EDP by a mean of 4.2 mm Hg in cats with HCM and by a mean of 4.9 mm Hg in the control group (Table 1). Dobutamine significantly increased LV EDP and pulmonary artery diastolic pressure during Esm+Dob and Iva+Dob at a comparable magnitude in both groups with no difference between HCM and control cats (LV EDP, HCM P = 0.93 and control P = 0.59; pulmonary artery diastolic pressure, HCM P = 0.50 and control P = 0.07, respectively). Similar to LV EDP, the ratio of peak velocity of early diastolic transmitral flow to IVRT was increased for Esm+Dob and Iva+Dob.
Effects of ivabradine on variables of LA function—In contrast to control cats, maximum LA anteroposterior dimension was not increased in cats with HCM after administration of ivabradine (Table 2). Although esmolol did not change LA FAC, ivabradine increased FAC in both HCM (P = 0.045) and control (P = 0.009) groups. Peak velocity of the late diastolic pulmonary vein atrial reversal wave, peak velocity of LA appendage flow, peak velocity of late diastolic motion of the lateral mitral annulus, and circumferential and radial strain variables derived at atrial contraction were not significantly altered by ivabradine. Dobutamine led to a significant increase of FAC, LA shortening fraction, and peak velocity of LA appendage flow in both groups during Esm+Dob and Iva+Dob, whereas peak velocity of the A wave increased, albeit not significantly (P = 0.056), for Iva+Dob, compared with Esm+Dob, in cats with HCM (Tables 3–5).
Discussion
Results of this study indicated that IV administration of ivabradine decreased HR and the rate-pressure product in anesthetized cats with HCM. Left ventricular systolic and diastolic function as well as LA performance were either unchanged or minimally affected by ivabradine. Tachycardia induced by dobutamine was significantly blunted by ivabradine but not by esmolol at the dosages studied, indicating that the negative chronotropic activity of ivabradine was maintained under resting conditions and sympathetic stimulation.
Previous studies have established the selective HR-reducing effect of ivabradine in various species, including rats, pigs, dogs, and humans, administered IV31–35 and PO.36 Although ivabradine reduces HR at rest and during exercise,32–34,36 only limited information is available regarding its negative chronotropic effects during stress or enhanced sympathoadrenergic activity. Control of HR could be important in management of HCM, considering the anecdotal evidence that stress and tachycardia may contribute to clinical signs, disease progression, and fatal outcome.3,37
In the present study, we investigated the effects of IV-administered ivabradine on HR in anesthetized cats with HCM with and without sympathetic stimulation. The mean reduction of HR in cats with HCM observed after ivabradine administration was 33% relative to baseline. Heart rate was still reduced by 17%, compared with baseline, during dobutamine infusion in these cats. These results are in accordance with previous studies31–35 in dogs and humans in which subjects were studied at rest and during exercise and could have important clinical implications. In contrast to esmolol, ivabradine decreased HR consistently and maximum HR observed after dobutamine did not exceed 140 beats/min in any of the cats studied. Thus, results suggested that the negative chronotropic effect of ivabradine in the setting of sympathetic stimulation is more pronounced than that of a moderately high dose of esmolol in anesthetized cats with HCM. However, during ivabradine infusion, the sinus rate was still responsive to dobutamine. Complete suppression of the HR response to sympathetic stimulation is undesirable, considering a higher HR is needed during stress and exercise. It should be emphasized that we did not critically evaluate dose responses of either ivabradine or esmolol in this study, and it is likely that different dosages of either esmolol or ivabradine could have blunted the HR response to dobutamine in a similar manner.
The effects of ivabradine on myocardial perfusion and oxygen consumption were not directly measured in the present study. However, HR was determined, rate-pressure product calculated,38–41 and systolic and diastolic wall stress estimated.10,28 Systolic wall stress was not different among treatments or between cat groups, whereas calculated end-diastolic wall stress was lower in cats with HCM during treatments with esmolol and Esm+Dob, compared with controls. In contrast to previous studies10,28 in healthy dogs, we found a significant increase in diastolic wall stress following administration of ivabradine in both groups because of an increase of LV EDP and LV end-diastolic dimension. Increased diastolic wall stress in combination with hypertrophy may favor the development of myocardial ischemia, especially in the subendocardium.42 However, the increase in end-diastolic wall stress was low and the consequences would likely be balanced by the concurrent reduction of HR and the rate-pressure product in cats with HCM. Both HR and rate-pressure product decreased with administration of ivabradine, indicating a lower myocardial oxygen demand.38–41 Studies in awake cats with HCM are needed to further elucidate the clinical importance of increased LV end-diastolic wall stress after administration of ivabradine.
As expected, LV contractility decreased under the influence of esmolol in all cats. Similar observations were identified in cats with HCM after administration of ivabradine; however, other variables of systolic function (eg, fractional shortening, ejection fraction, and radial and circumferential strain rate and radial strain) were not altered. This finding is in contrast to those of previous studies31–34 in healthy laboratory dogs and in dogs with coronary artery ligation in which no significant changes in inotropic state were observed after administration of ivabradine. In the present study, mean reduction of HR after administration of ivabradine was 33% in cats with HCM and 22% in control cats. Thus, the decrease of LV +dP/dtmax observed in cats with HCM could simply be related to the negative staircase effect, as suggested.32 According to Colin et al,10,28 the presence of an intrinsic effect of ivabradine on myocardial contractility is unlikely and was not believed to directly decrease LV +dP/dtmax in cats with HCM. Although the mechanism for the mild decrease of LV contractility could not be determined, this observation may indeed be of benefit for cats with HCM and LV outflow obstruction. More than 50% of cats with HCM have dynamic obstruction of the LV outflow tract,19 and negative inotropy is a well-known mechanism for relief of the obstruction.4–6 In contrast, none of the variables characterizing LV systole were decreased in control cats after administration of ivabradine, indicating preserved LV systolic performance in this group, a finding consistent with previous reports.31–34
Left ventricular diastolic function has been characterized conceptually by 2 components: relaxation and compliance.20 Relaxation may be quantified by tau, the time constant of isovolumic relaxation.43 Assessment of ventricular relaxation has clinical value, especially in cats with HCM in which abnormal relaxation is a characteristic feature. Ventricular relaxation in normal hearts is affected by β-adrenergic receptor blockade and improved by sympathetic activation.27,44,45 Heart rate may influence tau directly via the reversed relaxation-frequency relationship.46 However, only small and clinically nonrelevant changes were observed after abrupt changes in HR from 120 to 170 beats/min in healthy dogs.46,47 Our data suggested a mild prolongation of tau in cats with HCM after ivabradine administration (mean, 4 milliseconds). This finding is in contrast to previous studies31–34 in healthy dogs and dogs with reduced coronary perfusion and may be related to experimental design (eg, effects of anesthetic drugs, duration of anesthesia, mild hypothermia, or sequence of drug administration) or the mild decrease in LV contractility found after administration of ivabradine. In accordance with previous observations in healthy anesthetized cats,20 there was a significant linear association between LV +dP/dtmax and tau in cats with HCM. Left ventricular +dP/dtmax was a major determinant of tau in the present study, confirming that systolic and diastolic function are closely related.21,48 Because regression analysis did not reveal an association between HR and tau in cats with HCM, the pure HR-decreasing effects of ivabradine could not explain the prolongation of tau. Other estimates of ventricular relaxation suggested improvement (early diastolic motion of the lateral mitral annulus) or no change in relaxation (IVRT and variables of regional relaxation from strain analysis) in cats with HCM. In contrast, tau was unchanged after administration of ivabradine in control cats. This discrepancy between groups deserves further study to determine its cause.
Sympathetic stimulation achieved a more profound decrease in tau in cats with HCM when administered simultaneously with ivabradine, compared with esmolol. This suggested an enhanced positive lusitropic effect of dobutamine when administered with ivabradine. In addition to tau, other estimates of ventricular relaxation, such as IVRT, peak velocity of early diastolic motion of the lateral mitral annulus, and radial strain rate-derived peak velocity of E wave also improved during administration of Iva+Dob, compared with ivabradine alone. This effect may be of benefit in cats with HCM in situations characterized by sympathetic stimulation, including stress and excitement.
Treatment with ivabradine resulted in a significant increase in LV EDP and LV end-diastolic wall stress in cats with HCM and control cats. These observations are in contrast to results of previous studies10,34 performed in healthy dogs at rest. However, in the same studies10,34 during exercise, ivabradine also led to an increase of LV EDP and LV end-diastolic wall stress. The mild increase of LV EDP may be explained by the concept of preload reserve, a mechanism by which filling pressure increases in response to blunted HR response to maintain CO.28 This was confirmed by normalization of the increased LV EDP and end-diastolic wall stress after administration of ivabradine in humans by use of atrial pacing.28,49 The significant increase of LV internal dimension in diastole found in the present study strengthens this assumption. Other variables related to LV compliance and LV filling, including deceleration time of the E wave, ratio of the duration of the A wave to the duration of the late diastolic pulmonary vein atrial reversal wave, peak velocity of E wave, ratio of peak velocity of E and A waves, ratio of peak velocity of E wave to early diastolic motion of the lateral mitral annulus, and S:D, were not significantly altered by administration of ivabradine in cats of either group. We conclude from these findings that a mild increase of preload caused by the negative chronotropic effects of ivabradine may lead to the increase of LV EDP and LV end-diastolic wall stress observed in anesthetized cats with HCM as well as control cats. The clinical importance of such observations needs to be determined.
Left atrial performance and LA size were not significantly altered after treatment with ivabradine, supporting the concept that If inhibition does not affect LA function and size in anesthetized cats with HCM. Because of the design of the present study, only acute and possibly only marked changes could have been detected with the known effects of anesthesia on LA function,50 potentially complicating interpretation of the results. Therefore, to further elucidate the effects of If inhibitors and β-adrenoreceptor antagonists on LA function, long-term studies in awake cats are needed to address this issue. As expected, sympathetic stimulation induced with dobutamine led to an augmentation of LA performance with all treatments and in all groups.
Certain limitations of this study should be emphasized. First, sex was not equally balanced between groups. The diagnosis of HCM was made by use of 2-D echocardiographic evaluation of wall thickness and generally accepted decision thresholds. However, LV wall thickness may be affected by factors other than idiopathic myocardial growth, and histologic studies needed for a definitive diagnosis were not performed. In addition, the number of cats in each group was small, rendering the study underpowered to detect smaller differences between groups or among treatments. We did not measure LA or LV pressure-volume loops, which are usually considered the gold standard for assessing compliance and LV contractile function. The order of drug administration was not randomized because of the long-lasting hemodynamic and HR-reducing effects of ivabradine. Furthermore, the resultant HR responses for the esmolol versus the ivabradine treatments were not similar and the possible influence of HR on outcome variables, although not evident, cannot be completely discounted. It should be emphasized that although high doses of esmolol (> 500 μg/kg/min) were administered, a significant reduction of HR, compared with baseline, was observed only in some cats. Despite the apparent inefficacy of esmolol with regard to HR reduction, a decrease in +dP/dtmax was evident in all cats, similar to the negative inotropic effect of ivabradine. Observers were not unaware of the pharmacological interventions during the studies. However, to reduce the effects of observer bias on interpretation of data, images and recordings were coded during data analysis, making observers unaware of animal and treatment during measurement of data. Repeatability of echocardiographic and hemodynamic measurements was not specifically addressed. However, previous data reported from our laboratory revealed clinically acceptable reproducibility of most variables determined.21,48 Because of the study design, the effects of anesthesia on cardiac function and possible interactions with the effects of the drugs could not be eliminated. Therefore, caution is advised when extrapolating the findings to conscious cats. Finally, evaluation of various doses of esmolol and ivabradine and the use of a separate treatment arm for dobutamine would have provided further valid information.
This study revealed that ivabradine (0.3 mg/kg, IV) reduced HR significantly with only minimal effects on LV and LA function in anesthetized cats with HCM. Ivabradine also blunted the positive chronotropic response to dobutamine in healthy cats and cats with HCM but did not eliminate responsiveness to catecholamines, which may be important for response to physiologic stress. These results are promising for potential clinical use of ivabradine in cats. Further studies of oral administration of ivabradine in awake cats with HCM are needed to clinically validate these findings.
ABBREVIATIONS
| CI | Cardiac index |
| CO | Cardiac output |
| +dP/dtmax | Maximum rate of left ventricular pressure rise |
| EDP | End-diastolic pressure |
| Esm+Dob | Concurrent administration of esmolol and dobutamine |
| FAC | Fractional area change |
| HCM | Hypertrophic cardiomyopathy |
| HR | Heart rate |
| Iva+Dob | Concurrent administration of ivabradine and dobutamine |
| IVRT | Isovolumic relaxation time |
| LA | Left atrium |
| LV | Left ventricle |
| S:D | Ratio of peak velocity of systolic pulmonary vein flow to peak velocity of diastolic pulmonary vein flow |
Liberty Research Inc, Waverly, NY.
Acepromazine maleate injection, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.
Torbugesic, Fort Dodge Laboratories, Fort Dodge, Iowa.
PropoFlo, Abbott Laboratories, North Chicago, Ill.
Isoflurane, Abbott Laboratories, North Chicago, Ill.
Medfusion 2010i syringe pump, Medexine, Duluth, Ga.
Cefazolin, Sandoz Inc, Princeton, NJ.
Heparin Sodium, APP Pharmaceuticals LLC, Schaumburg, Ill.
Lidocaine HCL 2%, Abbott Laboratories, Chicago, Ill.
Model SPC-751 Millar Micro-tip catheter pressure transducer, Millar Instruments Inc, Houston, Tex.
Model TCB-600 control unit, Millar Instruments Inc, Houston, Tex.
Arrows Thermodilution Balloon catheter, model AI-07165, Arrow International Inc, Reading, Pa.
Cardiomax III, Columbus Instruments, Columbus, Ohio.
Baxter Healthcare Corp, Deerfield, Ill.
Vivid 7 Vantage, GE Medical Systems, Milwaukee, Wis.
EchoPac software package, version BT06, GE Medical Systems, Milwaukee, Wis.
Esmolol HCL, Bedford Laboratories, Bedford, Ohio.
Dobutamine, Hosperia Inc, Lake Forrest, Ill.
Ivabradine HCL, Franck's Pharmacy, Ocala, Fla.
Cober RE, Schober KE, Buffington CAT, et al. Effects of ivabradine, a selective If channel inhibitor, on heart rate in healthy cats (abstr). J Vet Intern Med 2010;24:695.
Puradisc Syringe Filter, Whatman International Ltd, Maidstone, Kent, England.
DATAQ work station, DATAQ Instruments Inc, Akron, Ohio.
WINDAQ/200, Windows Acquisition and Analysis Software, DATAQ Instruments Inc, Akron, Ohio.
Advanced CODAS, DATAQ Instruments Inc, Akron, Ohio.
SigmaStat, version 3.5, SPSS Inc, Chicago, Ill.
PC SAS, version 9.2, SAS Institute Inc, Cary, NC.
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