Introduction
The benzimidazole-pyridazinone derivative pimobendan induces vasodilation and increases myocardial contractility through inhibition of phosphodiesterase 3.1 Additionally, pimobendan increases intracellular sensitivity to calcium in the cardiac contractile apparatus, further contributing to its inotropic effect.2 Pimobendan has been increasingly used in the management of dogs with MMVD,3 and oral administration of pimobendan reduces LA size in dogs with MMVD,4–6 reduces LA pressure in dogs with surgically induced mitral regurgitation,7 and improves the prognosis for dogs with MMVD and cardiomegaly regardless of the presence or absence of clinical signs of heart disease.4,8,9
The LA plays an integral role in cardiac performance by modulating LV filling through 3 phasic functions as follows: reservoir (expansion associated with inflow of blood from the pulmonary veins during ventricular systole), conduit (passage of blood from the pulmonary veins to the LV during early ventricular diastole), and booster pump (augmentation of LV filling during atrial systole).10 Because echocardiography is simple and noninvasive, it has been widely used to assess these LA phasic functions.11, 12 Left atrial strain and SR describe longitudinal deformation of the LA myocardium and can be evaluated by use of 2-D STE, a novel angle-independent technique based on tracking the movement of natural acoustic markers (speckles) present on standard 2-D images. In dogs, 2-D STE enables deformation and volumetric analyses of the LA with adequate repeatability.13–16 Of clinical relevance is that decreased LA booster pump function, indicated by fractional area change, is the most important prognostic factor for dogs with MMVD.11 Also, LA strain indices that correspond to reservoir and booster pump functions decrease with progression of MMVD15,17,18 and predict the onset of congestive heart failure better than does LA size.17, 18
An IV formulation of pimobendan may be administered for the initial management of dogs with acute congestive heart failure,3 and on the basis of the known actions of pimobendan, pimobendan may improve LA and LV function. However, studies regarding the effects of pimobendan on the phasic functions of the LA in healthy dogs are lacking. Therefore, the objective of the study presented here was to determine the short-term effects of IV administration of pimobendan on STE-derived indices of LA function in healthy dogs.
Materials and Methods
Animals
Six Beagles (4 males and 2 females; age, 1 to 2 years; body weight, 8.9 to 12.2 kg) that were part of a research colony owned by the authors’ laboratory were included in the study. All dogs were confirmed to be healthy on the basis of the results of complete physical, ECG, and conventional echocardiographic examinations. The study protocol was approved by the Laboratory Animal Experimentation Committee of the Graduate School of Veterinary Medicine at Hokkaido University (approval No. 15-0087).
Study protocol
The dogs were administered atropine sulfate (0.05 mg/kg, SC), cefazolin sodium hydrate (20 mg/kg, IV), and heparin sodium (100 U/kg, IV) prior to induction of anesthesia with propofol (6 mg/kg, IV) and orotracheal intubation. Anesthesia was maintained with 1.75% to 2.0% isoflurane in 100% oxygen, and the dogs were placed on mechanical ventilation. End-tidal partial pressure of carbon dioxide and, as measured by pulse oximetry, hemoglobin oxygen saturation were monitored and maintained between 35 and 45 mm Hg and > 95%, respectively. Lactated Ringer solution was infused through a catheter in one of the cephalic veins at a rate of 5 mL/kg/h. A 24-gauge over-the-needle catheter was inserted into the left or right dorsal pedal artery for direct monitoring of arterial blood pressure. Heart rate and arterial blood pressure were monitored by use of a polygraph instrument.a A 6F introducer sheathb was inserted percutaneously into the right jugular vein, and a 5F Swan-Ganz catheterc was then advanced into the pulmonary artery with the aid of fluoroscopy. The catheter was connected to the polygraph instrument.
After a 10-minute stabilization period, baseline hemodynamic and echocardiographic indices were determined. Then, 0.15 mg of pimobendand/kg was administered IV; this dose was selected on the basis of the drug manufacturer's recommendation. After 15 minutes had elapsed, hemodynamic and echocardiographic indices were again determined. This time point was selected on the basis of the results of a preliminary study, in which pimobendan exerted significant hemodynamic effects within 15 minutes of its administration (data not shown). After determining the postdrug hemodynamic and echocardiographic indices, anesthesia was discontinued and the dogs were allowed to recover.
Evaluation of hemodynamic indices
Mechanical ventilation was briefly paused during measurement of the hemodynamic indices. Systolic, mean, and diastolic arterial blood pressures, pulmonary arterial pressure, right atrial pressure, and PCWP were measured over 3 consecutive cardiac cycles, and their mean values were determined. Pulmonary arterial and right atrial pressures were measured by use of the distal and proximal ports of the Swan-Ganz catheter, respectively. The PCWP was measured when the balloon near the tip of the Swan-Ganz catheter was inflated to be wedged in a branch of the pulmonary artery. Then, cardiac output was determined by use of the thermodilution technique as follows: a 5-mL bolus of cold saline (0.9% NaCl) solution was injected into the right atrium through the proximal port of the Swan-Ganz catheter, the temperature of the pulmonary arterial blood was recorded by a thermistor at the catheter tip, and then a temperature-time curve for the pulmonary artery was obtained for the calculation of cardiac output. Stroke volume was calculated by dividing cardiac output by heart rate. Mean cardiac output and mean stroke volume were calculated from 3 measurements. Systemic vascular resistance was derived according to the following equation: (mean arterial pressure – right atrial pressure)/cardiac output.
Conventional echocardiography
One of the authors (KN) experienced with echocardiography examined all dogs with an ultrasound unite equipped with a 3- to 7-MHz sector probe.f Dogs were positioned in right and left lateral recumbency during the examination, and a lead II ECG trace was simultaneously recorded. All echocardiographic indices were measured when the dogs were in the expiratory phase of respiration. The LA-to-aortic root ratio was obtained from the right parasternal short axis view on the first frame after the closure of the aortic valve. Conventional M-mode echocardiographic indices (LV internal diameter at end-diastole, LV internal diameter at end-systole, and fractional shortening) were also obtained from the right parasternal short axis view, and then the values for these indices were normalized to body weight as previously described.19 From the left apical 4-chamber view, pulsed-wave Doppler echocardiography was performed to measure the peak early and late diastolic mitral inflow velocities. Tissue Doppler echocardiography was performed to measure the peak velocities at the septal mitral annulus during systole, early diastole, and late diastole. The ratio of the peak early diastolic mitral inflow velocity to the late diastolic mitral inflow velocity and the ratio of the peak early diastolic mitral inflow velocity to the early diastolic mitral annular velocity were calculated. Left ventricular ejection fraction was determined with the single plane Simpson method from the left apical 4-chamber view. The images obtained by tissue Doppler echocardiography were also used to obtain isovolumic contraction time, isovolumic relaxation time, and ejection time. The Tei index was then calculated as follows20: (isovolumic contraction time + isovolumic relaxation time)/ejection time.
2-D STE
From the left apical 4-chamber view, a minimum of 3 cine loops with 3 consecutive cardiac cycles each (total of 9 cardiac cycles) were acquired during the end-expiratory phase of respiration for performing STE of the LA; the depth and sector width were minimized to increase frame rates (between 151 and 247 frames/s). Cine loops were stored digitally for later off-line analysis. One of the authors (SM) selected 3 cardiac cycles for which the endocardium of the LA could be clearly seen and analyzed LALS and SR by use of semi-automated analytic softwareg designed for LV analysis. A frame corresponding to the time of the peak R wave on the ECG was selected as an indicator of LV end-diastole. The endocardial surface of the LA was manually traced in that frame by use of the point-and-click technique, and the epicardial surface of the LA was automatically traced by the software, thus creating a region of interest that covered the full thickness of the LA myocardium. The software then divided the myocardium of the LA into 6 segments and tracked the motion of these segments throughout a cardiac cycle, but tracking quality was visually inspected and the region of interest was manually adjusted if necessary. The software generated LALS and SR curves for each of the 6 segments; then, the software generated LALS and SR curves of the average of all 6 segments (global LALS and SR; Figure 1). On the global LALS curve, LALS during ventricular end-diastole (LALSmin) was defined as the zero reference (ie, the baseline length of the myocardium), and LALS was measured at the time of maximum strain during ventricular systole (LALSmax) and the time before atrial systole (LALSa). Left atrial longitudinal strain during ventricular systole was an indicator of reservoir function, εE was an indicator of conduit function, and εA was an indicator of booster pump function. These 3 phasic functions were calculated as follows16:
Representative global LALS (A; solid line) and SR (B; solid line) curves and LA time-volume curves (dashed lines) obtained with 2-D STE for a healthy adult Beagle. A—From the global LALS curve, LALSmin, LALSmax, and LALSa were used to calculate εS, εE, and εA. B—From the global SR curve, the SR during ventricular systole (positive peak, SRs), the SR during early ventricular diastole (first negative peak, SRe), and the SR during atrial systole (second negative peak, SRa) were determined as indicators of LA reservoir, conduit, and booster pump function, respectively.
Citation: American Journal of Veterinary Research 82, 10; 10.2460/ajvr.82.10.795
Representative global LALS (A; solid line) and SR (B; solid line) curves and LA time-volume curves (dashed lines) obtained with 2-D STE for a healthy adult Beagle. A—From the global LALS curve, LALSmin, LALSmax, and LALSa were used to calculate εS, εE, and εA. B—From the global SR curve, the SR during ventricular systole (positive peak, SRs), the SR during early ventricular diastole (first negative peak, SRe), and the SR during atrial systole (second negative peak, SRa) were determined as indicators of LA reservoir, conduit, and booster pump function, respectively.
Citation: American Journal of Veterinary Research 82, 10; 10.2460/ajvr.82.10.795
Representative global LALS (A; solid line) and SR (B; solid line) curves and LA time-volume curves (dashed lines) obtained with 2-D STE for a healthy adult Beagle. A—From the global LALS curve, LALSmin, LALSmax, and LALSa were used to calculate εS, εE, and εA. B—From the global SR curve, the SR during ventricular systole (positive peak, SRs), the SR during early ventricular diastole (first negative peak, SRe), and the SR during atrial systole (second negative peak, SRa) were determined as indicators of LA reservoir, conduit, and booster pump function, respectively.
Citation: American Journal of Veterinary Research 82, 10; 10.2460/ajvr.82.10.795
On the global SR curve, LA SR was measured at 3 points as follows: the positive peak during ventricular systole, the first negative peak during early ventricular diastole, and the second negative peak during atrial systole.16
Simultaneous to the generation of LALS and SR curves, LA time-volume curves were autogenerated by use of the monoplane area-length method. From these curves, maximum LA volume during ventricular systole, LA volume immediately prior to atrial systole, and minimum LA volume during ventricular end-diastole were measured. The total, passive, and active FVC of the LA, indicators of LA reservoir, conduit, and booster pump function, respectively, were calculated as by use of the following equations11:
The mean of 3 representative cardiac cycles was calculated for all STE-derived indices.
Statistical analysis
Each measurement is presented as median and interquartile (25th to 75th percentile) range. Normality of continuous data was determined by use of the Shapiro-Wilk test. Pairs of pre- and postdrug indices were compared by use of the paired t test for parametric data and the Wilcoxon signed rank test for nonparametric data. All statistical analyses were performed with commercial software.h Values of P < 0.05 were considered significant.
Results
Hemodynamic indices at baseline and after IV administration of pimobendan are summarized (Table 1). Following pimobendan administration, stroke volume and cardiac output significantly increased, compared with baseline, whereas systemic vascular resistance significantly decreased. Heart rate and all pressure indices did not significantly differ from those at baseline.
Median (interquartile [25th to 75th percentile] range) for various hemodynamic indices for 6 healthy anesthetized Beagles obtained before (baseline) and 15 minutes after IV administration of 0.15 mg of pimobendan/kg.
| Index | Baseline | After drug | P value† |
|---|---|---|---|
| HR (beats/min) | 99 (89–117) | 104 (98–110) | 0.613 |
| SAP (mm Hg) | 93.0 (82.8–103.3) | 94.0 (87.3–100.8) | 0.669 |
| MAP (mm Hg) | 58.5 (54.8–61.5) | 59.0 (54.0–62.5) | 0.911 |
| DAP (mm Hg) | 46.5 (43.0–47.8) | 46.5 (42.0–49.5) | 0.842 |
| PAP (mm Hg) | 9.5 (9.0–10.8) | 10.5 (10.0–11.0) | 0.275 |
| PCWP (mm Hg) | 4.0 (3.0–5.0) | 4.5 (3.0–6.0) | 0.732 |
| RAP (mm Hg) | 1.5 (0.3–2.0) | 0.5 (0.0–1.0) | 0.235 |
| SV (mL/beat) | 18.7 (15.7–25.3) | 24.0 (23.0–30.2) | 0.013 |
| CO (L/min) | 1.9 (1.9–2.2) | 2.6 (2.4–3.0) | < 0.001 |
| SVR (Wood units) | 28.0 (25.7–30.3) | 23.0 (20.4–25.9) | 0.003 |
CO = Cardiac output. DAP = Diastolic arterial pressure. HR = Heart rate. MAP = Mean arterial pressure. PAP = Pulmonary arterial pressure. RAP = Right atrial pressure. SAP = Systolic arterial pressure. SV = Stroke volume. SVR = Systemic vascular resistance.
Values of P < 0.05 indicate significant difference in the indices between those obtained at baseline and those after IV administration of pimobendan.
Conventional echocardiographic indices at baseline and after pimobendan administration are summarized (Table 2). Pimobendan significantly shortened isovolumic contraction time and lengthened ejection time, consequently significantly decreasing the Tei index. Values for the other conventional echocardiographic indices did not significantly differ between baseline and after drug administration.
Median (interquartile [25th to 75th percentile] range) for indices obtained through conventional echocardiography for 6 healthy anesthetized Beagles before (baseline) and 15 minutes after IV administration of 0.15 mg of pimobendan/kg.
| Index | Baseline | After drug | P value* |
|---|---|---|---|
| LA:Ao ratio | 1.34 (1.26–1.35) | 1.37 (1.27–1.48) | 0.063 |
| LVIDdN | 1.49 (1.28–1.52) | 1.50 (1.49–1.53) | 0.166 |
| LVIDsN | 0.98 (0.95–1.10) | 1.05 (1.01–1.09) | 0.722 |
| FS (%) | 23.3 (16.8–29.5) | 27.9 (25.0–31.4) | 0.241 |
| EF (%) | 44.9 (44.0–46.3) | 48.5 (37.7–55.9) | 0.449 |
| E wave (cm/s) | 74.0 (68.5–81.3) | 76.1 (66.2–87.4) | 0.593 |
| A wave (cm/s) | 38.6 (35.1–42.1) | 42.9 (39.7–46.1) | 0.525 |
| E:A ratio | 1.78 (1.59–2.14) | 1.86 (1.71–1.96) | 0.747 |
| S′ wave (cm/s) | 7.5 (5.8–8.3) | 7.2 (5.9–7.9) | 0.586 |
| E′ wave (cm/s) | 6.3 (5.9–6.8) | 8.3 (6.7–9.3) | 0.174 |
| A′ wave (cm/s) | 4.7 (3.6–6.3) | 4.6 (3.7–5.3) | 0.684 |
| E:E′ ratio | 12.2 (10.9–14.1) | 9.5 (8.9–10.1) | 0.563 |
| IVCT (ms) | 47 (43–59) | 28 (25–32) | 0.016 |
| ET (ms) | 180 (173–183) | 200 (190–202) | 0.032 |
| IVRT (ms) | 46 (42–55) | 49 (39–65) | 0.395 |
| Tei index | 0.53 (0.50–0.57) | 0.37 (0.35–0.47) | 0.016 |
A wave = Peak velocity of late diastolic transmitral flow. A′ wave = Peak velocity of late diastolic mitral annular motion. E:A ratio = Ratio of the peak velocity of the E wave to the peak velocity of the A wave. E:E′ ratio = Ratio of the peak velocity of the E wave to the peak velocity of the E′ wave. EF = Ejection fraction. ET = Ejection time. E wave = Peak velocity of early diastolic transmitral flow. E′ wave = Peak velocity of early diastolic mitral annular motion. FS = Fractional shortening. IVCT = Isovolumic contraction time. IVRT = Isovolumic relaxation time. LA:Ao = Ratio of LA to aortic root. LVIDdN = Body-weight normalized left ventricular internal diameter at end-diastole. LVIDsN = Body-weight normalized left ventricular internal diameter at end-systole. S′ wave= Peak velocity of systolic mitral annular motion.
Values of P < 0.05 indicate significant difference in the indices between those obtained at baseline and those after IV administration of pimobendan.
Among the LA STE-derived indices, the booster pump function indices εA and LA-FVCactive significantly increased after pimobendan administration (Table 3). Second negative peak SR during atrial systole decreased by a median of 45.6% between the values at baseline and after pimobendan administration, but this decrease was not significant. The indices of reservoir function; εS, positive peak SR during ventricular systole, and LA-FVCtotal; and of conduit function; εE, first negative peak SR during early ventricular diastole, and LA-FVCpassive; did not significantly differ between baseline and postdrug administration.
Median (interquartile [25th to 75th percentile] range) for indices obtained through LA STE for 6 healthy anesthetized Beagles before (baseline) and after IV administration of 0.15 mg of pimobendan/kg.
| Index | Baseline | After drug | P value* |
|---|---|---|---|
| LAVmax (mL) | 13.4 (12.2 to 14.8) | 12.4 (10.7 to 14.7) | 0.883 |
| LAVp (mL) | 9.9 (8.8 to 10.6) | 9.6 (8.0 to 9.9) | 0.799 |
| LAVmin (mL) | 8.1 (7.4 to 8.8) | 7.5 (6.7 to 7.6) | 0.787 |
| εS (%) | 18.8 (15.8 to 22.1) | 21.7 (18.0 to 24.5) | 0.145 |
| εE (%) | 15.1 (12.4 to 16.0) | 13.4 (10.4 to 16.1) | 0.818 |
| εA (%) | 5.4 (3.5 to 7.3) | 7.5 (6.2 to 8.7) | 0.011 |
| SRs (/s) | 1.11 (0.96 to 1.18) | 1.39 (1.27 to 1.55) | 0.158 |
| SRe (/s) | –2.72 (–3.02 to–2.48) | –2.30 (–2.89 to–1.95) | 0.155 |
| SRa (/s) | –1.03 (–1.24 to–0.96) | –1.50 (–1.69 to–1.08) | 0.077 |
| LA-FVCtotal (%) | 42.1 (38.4 to 43.7) | 43.1 (38.8 to 47.9) | 0.295 |
| LA-FVCpassive (%) | 29.7 (27.8 to 32.8) | 30.8 (27.0 to 34.8) | 0.652 |
| LA-FVCactive (%) | 14.7 (13.4 to 16.3) | 20.6 (15.0 to 22.7) | 0.014 |
LAVmax = Maximum left atrial volume. LAVmin = Minimum left atrial volume. LAVp = Left atrial volume before atrial systole. SRa = Second negative peak SR during atrial systole. SRe = First negative peak strain rate during early ventricular diastole. SRs = Positive peak SR during ventricular systole.
Values of P < 0.05 indicate significant difference in the indices between those obtained at baseline and those after IV administration of pimobendan.
Discussion
The present study revealed that the IV administration of pimobendan significantly improved STE-derived LA indices of booster pump function, whereas indices of LA reservoir and conduit functions were not significantly changed following drug administration. Booster pump function of the LA assessed by εA and LA-FVCactive increased significantly following pimobendan administration but the peak velocity of late diastolic mitral annular motion, another index of LA booster pump function, did not significantly change following pimobendan administration. This peak velocity may be less sensitive to changes in the inotropic state than STE-derived indices of booster pump function. During late ventricular diastole, active atrial systole augments LV filling. This function is modulated by LA preload (ie, LA volume before atrial systole) and afterload (ie, LV compliance and end-diastolic pressure) as well as intrinsic LA contractility.10 Because IV administration of pimobendan decreases LV end-diastolic pressure in healthy dogs and dogs with pacing-induced heart failure,21–23 decreased LA afterload noted for the dogs in the present study may have contributed to the improvement in LA booster pump function. Pimobendan administration may also have increased LA contractility by phosphodiesterase 3 inhibition and calcium sensitization. Although the effects of pimobendan on LA contractility have not been reported, levosimendan, an inodilator with a similar mechanism of action to pimobendan, increases the isometric force in the electrically driven LA of guinea pigs.24 Administration of the β-adrenergic agonist dobutamine to healthy dogs increases the active LA emptying area, an indicator of LA booster pump function.25 These results suggest that the efficacy of inotropic drugs may be related to improved LA booster pump function.
In contrast, pimobendan did not alter the indices of LA reservoir function in the present study. This result is inconsistent with the results of studies25, 26 that included an evaluation of dobutamine but is consistent with the results of a study25 that included an evaluation of the phosphodiesterase 3 inhibitor milrinone. The reservoir function of the LA is modulated by LV contraction through the descent of the LV base during systole, by right ventricular systolic pressure transmitted through the pulmonary circulation, and by properties of the LA (ie, relaxation and chamber stiffness).10, 27 Following pimobendan administration to the dogs in the present study, LV systolic function improved, indicated by significantly shortened isovolumic contraction time, prolonged ejection time, and increased stroke volume and cardiac output. Improved LV systolic function may have positively influenced LA reservoir function, but vasodilation may have decreased venous return and LA preload, counteracting the positive effects (on LV systolic function) of pimobendan. Because both milrinone and pimobendan exert vasodilatory effects through phosphodiesterase 3 inhibition,1, 28 such counteractivity is possible for the results of both past and present studies.25
The present study showed that the indices of LA conduit function were not significantly altered by pimobendan administration. During early ventricular diastole, the LA passively transfers blood from the pulmonary veins to the LV. Left atrial conduit function is modulated by LV relaxation and the early diastolic pressure gradient between the LV and the LA.10 Administration of dobutamine, esmolol, milrinone, and phenylephrine also do not alter the LA conduit function as assessed by fractional area change in healthy dogs.25 These results suggest that LA conduit function is relatively stable following administration of inotropic and lusitropic drugs.
In the present study, PCWP, a surrogate for LA pressure, did not significantly change following pimobendan administration. Reduction of LA pressure is a desirable goal for drugs used to manage left-sided congestive heart failure.7 In dogs with propranolol-induced myocardial depression and mildly elevated PCWP, various doses of pimobendan (0.03, 0.1, and 0.3 mg/kg, IV) markedly decreased PCWP in a dose-dependent manner.29 Thus, pimobendan may decrease LA pressure in dogs with heart disease and increased LA pressure, compared with healthy dogs.
In dogs with MMVD17, 18 and in people with various heart diseases,30–32 linked to the development of congestive heart failure is LA booster pump dysfunction, such that it may increase LA pressure and decrease LV preload. Thus, the positive effect of pimobendan on LA booster pump function may help to normalize hemodynamic indices in and improve the clinical status of dogs with congestive heart failure. In people with acute heart failure secondary to ischemic cardiomyopathy, a 24-hour IV infusion of the inodilator levosimendan increases LA FVC through all 3 phasic functions.33 Levosimendan not only improves LV systolic function but also LV diastolic function and filling pressure.33 Improvements in LV diastolic function and loading condition may positively affect the indices of LA conduit and booster pump function.33 In contrast, long-term oral administration of pimobendan to dogs with preclinical MMVD does not alter LA function as assessed by fractional changes in LA diameter and volume.34 In that study,34 the intervals between baseline and follow-up examinations were relatively long (median of 4 months) and progression of MMVD may have offset the potential beneficial effect of pimobendan on LA function. Additional studies are needed to validate whether the results of the present study may be extrapolated to dogs with clinical MMVD, which may be associated with increased LA volume loading or LA degeneration (eg, interstitial fibrosis, chronic inflammation, or fatty replacement).35
The present study has several limitations. First, invasive assessments of the intrinsic properties of LA and LV to characterize changes in the indices of the 3 LA phasic functions were not performed. Second, the duration of action and the effects of different doses of pimobendan were not investigated; rather, the effects of only 1 dose of pimobendan were evaluated at only 1 time point. Third, the small sample size limited the statistical power to detect differences between pre- and postdrug measurements. Fourth, the effects of general anesthesia on cardiac function and vascular tone could not be eliminated, and a placebo group in which dogs were anesthetized but did not receive pimobendan was not included. Isoflurane may impair myocardial contractility and relaxation in the LA and LV36 and may also cause vasodilation.37 Propofol may also reduce LA and LV contractility and cause vasodilation.36, 38 As a result, systemic arterial pressure was relatively low despite that the dogs received IV fluid therapy. In contrast, preanesthetic medication with atropine may inhibit cardiac vagal tone and consequently may increase LA and LV contractility.39 The effects of pimobendan on the 3 LA phasic functions may have been modulated by these agents.
The present study revealed that IV administration of pimobendan improved LA booster pump function as assessed by 2-D STE in healthy anesthetized Beagles. Indices of LA reservoir and conduit function were not significantly altered by pimobendan. The improvement in LA booster pump function may be one reason that pimobendan is clinically effective for various heart diseases in dogs.
Acknowledgments
Funded in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science (No. 19K06422).
The authors declare that there were no conflicts of interest.
Abbreviations
| εA | Left atrial longitudinal strain during atrial systole |
| εE | Left atrial longitudinal strain during early ventricular diastole |
| εS | Left atrial longitudinal strain during ventricular systole |
| FVC | Fractional volume change |
| LA | Left atrium |
| LALS | Left atrial longitudinal strain |
| LV | Left ventricle |
| MMVD | Myxomatous mitral valve disease |
| PCWP | Pulmonary capillary wedge pressure |
| SR | Strain rate |
| STE | Speckle-tracking echocardiography |
Footnotes
RMC-4000, Nihon Kohden Corp, Tokyo, Japan.
Fast-Cath hemostasis introducers, St Jude Medical Inc, Minnetonka, Minn.
Edwards Lifesciences Corp, Irvine, Calif.
Vetmedin Injectable Solution, Boehringer Ingelheim Pty Ltd, Ingelheim am Rhein, Rheinland-Pfalz, Germany.
Artida, Canon Medical Systems Corp, Utsunomiya, Tochigi, Japan.
PST-50BT, Canon Medical Systems Corp, Utsunomiya, Tochigi, Japan.
UltraExtend, version 3.10, Canon Medical Systems Corp, Utsunomiya, Tochigi, Japan.
JMP Pro, version 13.1.0, SAS Institute Inc, Cary, NC.
References
- 1. ↑
Boyle KL, Leech E. A review of the pharmacology and clinical uses of pimobendan. J Vet Emerg Crit Care (San Antonio) 2012;22:398–408.
- 2. ↑
Fujino K, Sperelakis N, Solaro RJ. Sensitization of dog and guinea pig heart myofilaments to Ca2+ activation and the inotropic effect of pimobendan: comparison with milrinone. Circ Res 1988;63:911–922.
- 3. ↑
Keene BW, Atkins CE, Bonagura JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med 2019;22:1127–1140.
- 4. ↑
Lombard CW, Jöns O, Bussadori CM. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc 2006;42:249–261.
- 5.
Häggström J, Lord PF,Höglund K, et al. Short-term hemodynamic and neuroendocrine effects of pimobendan and benazapril in dogs with myxomatous mitral valve disease and congestive heart failure. J Vet Intern Med 2013;27:1452–1462.
- 6. ↑
Boswood A, Gordon SG, Häggström J, et al. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with preclinical myxomatous mitral valve disease receiving pimobendan or placebo: the EPIC study. J Vet Intern Med 2018;32:72–85.
- 7. ↑
Suzuki S, Fukushima R, Ishikawa T, et al. The effect of pimobendan on left atrial pressure in dogs with mitral valve regurgitation. J Vet Intern Med 2011;25:1328–1333.
- 8. ↑
Häggström J, Boswood A, O’Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. J Vet Intern Med 2008;22:1124–1135.
- 9. ↑
Boswood A, Häggström J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study–a randomized clinical trial. J Vet Intern Med 2016;30:1765–1779.
- 10. ↑
Roşca M, Lancellotti P, Popescu BA, et al. Left atrial function: pathophysiology, echocardiographic assessment, and clinical applications. Heart 2011;97:1982–1989.
- 11. ↑
Nakamura K, Osuga T, Morishita K, et al. Prognostic value of left atrial function in dogs with chronic mitral valvular heart disease. J Vet Intern Med 2014;28:1746–1752.
- 12. ↑
Höllmer M, Willesen JL, Tolver A, et al. Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease. J Vet Cardiol 2017;19:24–34.
- 13. ↑
Osuga T, Nakamura K, Lim SY, et al. Repeatability and reproducibility of measurements obtained via two-dimensional speckle tracking echocardiography of the left atrium and time-left atrial area curve analysis in healthy dogs. Am J Vet Res 2013;74:864–869.
- 14.
Caivano D, Rishniw M, Patata V, et al. Left atrial deformation and phasic function determined by 2-dimensional speckle tracking echocardiography in healthy dogs. J Vet Cardiol 2016;18:146–155.
- 15. ↑
Baron Toaldo M, Romito G, Guglielmini C, et al. Assessment of left atrial deformation and function by 2-dimensional speckle tracking echocardiography in healthy dogs and dogs with myxomatous mitral valve disease. J Vet Intern Med 2017;31:641–649.
- 16. ↑
Dermlim A, Nakamura K, Morita T, et al. The repeatability and left atrial strain analysis obtained via speckle tracking echocardiography in healthy dogs. J Vet Cardiol 2019;23:69–80.
- 17. ↑
Nakamura K, Kawamoto S, Osuga T, et al. Left atrial strain at different stages of myxomatous mitral valve disease in dogs. J Vet Intern Med 2017;31:316–325.
- 18. ↑
Caivano D, Rishniw M, Birettoni F, et al. Left atrial deformation and phasic function determined by two-dimensional speckle-tracking echocardiography in dogs with myxomatous mitral valve disease. J Vet Cardiol 2018;20:102–114.
- 19. ↑
Cornell CC, Kittleson MD, Della Torre P, et al. Allometric scaling of M-mode cardiac measurements in normal adult dogs. J Vet Intern Med 2004;18:311–321.
- 20. ↑
Hori Y, Kunihiro S, Hoshi F, et al. Comparison of the myocardial performance index derived by use of pulsed Doppler echocardiography and tissue Doppler imaging in dogs with volume overload. Am J Vet Res 2007;68:1177–1182.
- 21. ↑
Hori Y, Taira H, Nakajima Y, et al. Inotropic effects of a single intravenous recommended dose of pimobendan in healthy dogs. J Vet Med Sci 2019;81:22–25.
- 22.
Pagel PS, Hettrick DA, Warltier DC. Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol 1996;119:609–615.
- 23. ↑
Ohte N, Cheng CP, Suzuki M, et al. The cardiac effects of pimobendan (but not amrinone) are preserved at rest and during exercise in conscious dogs with pacing-induced heart failure. J Pharmacol Exp Ther 1997;282:23–31.
- 24. ↑
Bokník P, Neumann J, Kaspareit G, et al. Mechanisms of the contractile effects of levosimendan in the mammalian heart. J Pharmacol Exp Ther 1997;280:277–283.
- 25. ↑
Osuga T, Nakamura K, Morita T, et al. Effects of various cardiovascular drugs on indices obtained with two-dimensional speckle tracking echocardiography of the left atrium and time-left atrial area curve analysis in healthy dogs. Am J Vet Res 2015;76:702–709.
- 26. ↑
Ahtarovski KA, Iversen KK, Lønborg JT, et al. Left atrial and ventricular function during dobutamine and glycopyrrolate stress in healthy young and elderly as evaluated by cardiac magnetic resonance. Am J Physiol Heart Circ Physiol 2012;303:H1469–H1473.
- 27. ↑
Barbier P, Solomon SB, Schiller NB, et al. Left atrial relaxation and left ventricular systolic function determine left atrial reservoir function. Circulation 1999;100:427–436.
- 28. ↑
Fujimoto S. Effects of pimobendan, its active metabolite UD-CG 212, and milrinone on isolated blood vessels. Eur J Pharmacol 1994;265:159–166.
- 29. ↑
van Meel JC, Diederen W. Hemodynamic profile of the cardiotonic agent pimobendan. J Cardiovasc Pharmacol 1989;14:S1–S6.
- 30. ↑
Dernellis JM, Stefanadis CI, Zacharoulis AA, et al. Left atrial mechanical adaptation to long-standing hemodynamic loads based on pressure-volume relations. Am J Cardiol 1998;81:1138–1143.
- 31.
Roşca M, Popescu BA, Beladan CC, et al. Left atrial dysfunction as a correlate of heart failure symptoms in hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2010;23:1090–1098.
- 32. ↑
Imanishi J, Tanaka H, Sawa T, et al. Association of left atrial booster-pump function with heart failure symptoms in patients with severe aortic stenosis and preserved left ventricular ejection fraction. Echocardiography 2015;32:758–767.
- 33. ↑
Duygu H, Nalbantgil S, Ozerkan F, et al. Effects of levosimendan on left atrial functions in patients with ischemic heart failure. Clin Cardiol 2008;31:607–613.
- 34. ↑
Sarcinella F, Neves J, Maddox TW, et al. Effect of pimobendan on left atrial function in dogs with preclinical myxomatous mitral valve disease. Open Vet J 2020;9:375–383.
- 35. ↑
Lee J, Mizuno M, Mizuno T, et al. Pathologic manifestations on surgical biopsy and their correlation with clinical indices in dogs with degenerative mitral valve disease. J Vet Intern Med 2015;29:1313–1321.
- 36. ↑
Pagel PS, Kehl F, Gare M, et al. Mechanical function of the left atrium: new insights based on analysis of pressure-volume relations and Doppler echocardiography. Anesthesiology 2003;98:975–994.
- 37. ↑
McCallum JB, Stekiel TA, Bosnjak ZJ, et al. Does isoflurane alter mesenteric venous capacitance in the intact rabbit? Anesth Analg 1993;76:1095–1105.
- 38. ↑
Wouters PF, Van de Velde MA, Marcus MA, et al. Hemodynamic changes during induction of anesthesia with eltanolone and propofol in dogs. Anesth Analg 1995;81:125–131.
