The left atrium plays an important role in the modulation of left ventricular filling through 3 phasic functions: a reservoir function (expansion associated with inflow of blood from the pulmonary veins during ventricular systole), a conduit function (passage of blood from the pulmonary veins to the left ventricle during ventricular diastole), and a booster pump function (augmentation of left ventricular filling during atrial contraction).1 In humans with various cardiac diseases including dilated cardiomyopathy and mitral regurgitation, there is a correlation between left atrial dysfunction and the severity of cardiac disease2–4 or the occurrence of cardiovascular events.5
Left atrial phasic function can be assessed simply and noninvasively with echocardiography. In human medicine, common methods for evaluation of left atrial phasic function are based on the calculation of left atrial phasic sizes (areas and volumes), pulsed-wave Doppler evaluation of transmitral and pulmonary venous flow, and tissue Doppler imaging.6–8
A novel technique that uses 2-D speckle tracking echocardiography has been developed to calculate left atrial phasic sizes on the basis of time–left atrial area or volume curve analysis. With this technique, left atrial wall movement throughout the cardiac cycle can be automatically tracked in 2-D echocardiographic images to automatically and precisely produce a time–left atrial area or volume curve.9,10 Results of a study11 performed by our laboratory group indicate that this technique is a repeatable and reproducible method for evaluation of left atrial phasic function in healthy dogs. Additionally, indices of left atrial reservoir and booster pump functions determined by this technique are associated with survival times for dogs with chronic mitral valve disease.12
Before indices of left atrial phasic function determined from time–left atrial area curve analysis can be used to evaluate disease severity or guide treatments for dogs with cardiac disease, it is necessary to understand how each index is influenced by cardiovascular drugs. To our knowledge, basic information on the effects of cardiovascular drugs on indices of left atrial phasic function in healthy dogs is lacking. The purpose of the study reported here was to investigate the effects of 4 cardiovascular drugs (positive and negative inotropes, an inodilator, and a vasopressor) on the left atrial phasic function of healthy dogs.
Materials and Methods
Animals
Nine Beagles (3 males and 6 females; age, 1 to 3 years; body weight, 9.5 to 13.0 kg) that were part of a research colony owned by our laboratory were included in the study. All dogs were determined to be healthy with no cardiac abnormalities on the basis of results of a physical examination, ECG, and standard echocardiographic examinations (including M-mode and pulsed-wave and color-flow Doppler imaging) performed prior to study initiation. All procedures were approved by the Laboratory Animal Experimentation Committee of the Graduate School of Veterinary Medicine at Hokkaido University.
Study protocol
Each dog was administered 1 cardiovascular drug (dobutamine hydrochloride, esmolol hydrochloride, milrinone lactate, or phenylephrine hydrochloride) on an experimental day, and there was at least 14 days between experimental days. Each drug was given to 6 dogs; however, some dogs did not receive all 4 drugs because they were involved in other experiments and were unavailable on 1 or more experimental days (eg, dobutamine and esmolol were administered to dogs 1, 2, 3, 4, 5, and 6, and milrinone and phenylephrine were administered to dogs 4, 5, 6, 7, 8, and 9).
Each dog was sedated with propofola (3 to 6 mg/kg, IV bolus to effect, followed by a CRI of 0.4 to 0.6 mg/kg/min). The CRI of propofol was adjusted as necessary to maintain sedation and spontaneous breathing. The dog was positioned in left or right lateral recumbency as necessary. Systolic, diastolic, and mean arterial blood pressures were monitored noninvasively with an oscillometric technique.b Heart rate was monitored by an ECG-equipped (lead II) ultrasonographic unit.c Baseline echocardiographic measurements were obtained after blood pressure and heart rate stabilized, which was approximately 5 minutes after initiation of the propofol infusion. Then the designated cardiovascular drug was administered, and the hemodynamic variables were allowed to stabilize (approx 20 to 30 minutes after initiation of propofol administration) before the echocardiographic examination was repeated. Dogs were allowed to recover from sedation following completion of the second echocardiographic examination.
Cardiovascular drugs
Dobutamined (5.0 μg/kg/min), esmolole (500 μg/kg/min), and phenylephrinef (2.0 μg/kg/min) were administered IV as CRIs.13–15 Milrinoneg (25 μg/kg) was administered as a slow IV bolus for 5 minutes, followed by a CRI of 0.5 μg/kg/min.16,17 All doses were determined on the basis of results of preliminary studies conducted by our laboratory group.
Conventional echocardiography
All echocardiographic examinations were performed with a commercially available ultrasonographic devicec equipped with a 3- to 7-MHz sector probeh and continuous ECG recording. Echocardiographic measurements were made irrespective of the respiratory phase. All data were stored digitally and analyzed off-line by 1 observer (TO). The mean of 3 consecutive cardiac cycles was calculated for all variables including those obtained by 2-D speckle tracking echocardiography.
From the right parasternal short-axis view, M-mode variables of the left ventricle including LVIDd and LVIDs were obtained, and left ventricular fractional shortening was calculated. Pulsed-wave Doppler echocardiography was used to measure the transmitral flow velocity, with the sample volume positioned at the tip of the mitral valve leaflets from the left apical 4-chamber view. Peak velocities of the early diastolic transmitral flow wave (E wave) and late diastolic transmitral flow wave (A wave) were measured, and the ratio of the peak velocity of the E wave to the peak velocity of the A wave was calculated. The stroke volume was calculated by multiplying the time velocity integral, which was measured by tracing the Doppler aortic flow profile from the left apical 5-chamber view, by the luminal area of the aorta, which was calculated by tracing the aortic lumen on the right parasternal transverse view.18,19 The cardiac output was then calculated by multiplying the stroke volume by the heart rate during evaluation of the Doppler aortic flow profile. Pulsed-wave Doppler velocities of myocardial motion were also recorded from the left apical view with the sample volume positioned at the septal mitral annulus.13 Variables included the peak myocardial velocities during systole (S’ wave), early diastole (E’ wave), and late diastole (A’ wave). The ratio of the peak velocity of the E’ wave to the peak velocity of the A’ wave and ratio of the peak velocity of the E wave to the peak velocity of the E’ wave were also calculated.
2-D speckle tracking echocardiography
With the dog positioned in left lateral recumbency, an apical 4-chamber view was obtained by second harmonic grayscale imaging, with the frequency, depth, and sector width adjusted for frame-rate optimization (117 to 154 frames/s). An ECG trace (lead II) was recorded simultaneously with echocardiographic imaging. The echocardiographic images were analyzed with off-line softwarei in accordance with methods described in previous studies.11,12 A frame corresponding to the time of the peak R wave on the ECG was selected as an indicator of left ventricular end-diastole, and the endocardium of the left atrium was manually traced in that frame. The area of the left atrium was then automatically calculated by the software in each subsequent frame throughout the cardiac cycle to derive a time–left atrial area curve (Figure 1). The tracking quality was assessed visually. If the tracking quality was unsatisfactory (ie, the blood-tissue border was not tracked), manual tracing of the endocardium was repeated. The LAAmax, LAAp, and LAAmin for the left atrium were determined by the software. Variables used as indicators of the left atrial phasic function were calculated9,11,20 as follows (Figure 2):
A representative computer-generated time–left atrial area curve for a single cardiac cycle of a healthy 3-year-old Beagle prior to administration of a cardiovascular drug (baseline). Software was used to automatically calculate the area of the left atrium in each frame throughout the cycle and derive the time–left atrial area curve. Time (in seconds) is on the x-axis, and left atrial area (in cm2) is on the y-axis. The simultaneously recorded ECG for the cardiac cycle appears below the curve. EAact = Active emptying area. EApass = Passive emptying area. EAtotal = Total emptying area.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.702
A representative computer-generated time–left atrial area curve for a single cardiac cycle of a healthy 3-year-old Beagle prior to administration of a cardiovascular drug (baseline). Software was used to automatically calculate the area of the left atrium in each frame throughout the cycle and derive the time–left atrial area curve. Time (in seconds) is on the x-axis, and left atrial area (in cm2) is on the y-axis. The simultaneously recorded ECG for the cardiac cycle appears below the curve. EAact = Active emptying area. EApass = Passive emptying area. EAtotal = Total emptying area.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.702
A representative computer-generated time–left atrial area curve for a single cardiac cycle of a healthy 3-year-old Beagle prior to administration of a cardiovascular drug (baseline). Software was used to automatically calculate the area of the left atrium in each frame throughout the cycle and derive the time–left atrial area curve. Time (in seconds) is on the x-axis, and left atrial area (in cm2) is on the y-axis. The simultaneously recorded ECG for the cardiac cycle appears below the curve. EAact = Active emptying area. EApass = Passive emptying area. EAtotal = Total emptying area.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.702
Schematic representation of the time–left atrial area curve (top) generated during a single cardiac cycle (represented as an ECG tracing; bottom) in a healthy dog. Measurements of the left atrial area are indicated. From the onset of ventricular systole, the atrial area progressively increases, reaching its maximal dimension at ventricular end-systole. After mitral valve opening, the atrial area rapidly decreases during early ventricular diastole. During diastasis, the left atrial area remains constant or is slightly increased. At the end of diastasis, atrial contraction begins, which causes the atrial area to decrease to its minimal dimension. MVC = Mitral valve closure. MVO = Mitral valve opening. (From 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. Reprinted with permission.) See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.702
Schematic representation of the time–left atrial area curve (top) generated during a single cardiac cycle (represented as an ECG tracing; bottom) in a healthy dog. Measurements of the left atrial area are indicated. From the onset of ventricular systole, the atrial area progressively increases, reaching its maximal dimension at ventricular end-systole. After mitral valve opening, the atrial area rapidly decreases during early ventricular diastole. During diastasis, the left atrial area remains constant or is slightly increased. At the end of diastasis, atrial contraction begins, which causes the atrial area to decrease to its minimal dimension. MVC = Mitral valve closure. MVO = Mitral valve opening. (From 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. Reprinted with permission.) See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.702
Schematic representation of the time–left atrial area curve (top) generated during a single cardiac cycle (represented as an ECG tracing; bottom) in a healthy dog. Measurements of the left atrial area are indicated. From the onset of ventricular systole, the atrial area progressively increases, reaching its maximal dimension at ventricular end-systole. After mitral valve opening, the atrial area rapidly decreases during early ventricular diastole. During diastasis, the left atrial area remains constant or is slightly increased. At the end of diastasis, atrial contraction begins, which causes the atrial area to decrease to its minimal dimension. MVC = Mitral valve closure. MVO = Mitral valve opening. (From 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. Reprinted with permission.) See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 76, 8; 10.2460/ajvr.76.8.702
where EAtotal, EApass, and EAact represent the total, passive, and active emptying areas, respectively, of the left atrium. The total emptying area and fractional area change were calculated as indicators of the reservoir function, whereas the passive emptying area and fractional area change were determined as indicators of the conduit function. The active emptying area and fractional area change were calculated as indicators of the booster pump function.
Statistical analysis
Normal distribution of the data was confirmed by means of a Shapiro-Wilk test. A commercially available statistical software programj was used to develop a mixed linear model, with state (baseline vs after drug administration), drug (dobutamine, esmolol, milrinone, or phenylephrine), and the interaction between state and drug included as categorical fixed effects and dog identification included as a random effect. The effects of state and drug on the values of the measured variables were assessed with the F test. For each drug, pairwise comparisons of measurements between baseline and after drug administration were performed by calculation of the least squares means and use of the Bonferroni correction to account for multiple comparisons. For all analyses, values of P < 0.05 were considered significant.
Results
Hemodynamic (Table 1), conventional echocardiographic (Table 2), and left atrial phasic function (Table 3) indices before (baseline) and after administration of dobutamine, esmolol, milrinone, and phenylephrine were summarized. There was a significant (P < 0.05) interaction between state (baseline or after drug administration) and drug for all variables, except the peak velocity of the myocardial A’ wave, ratio of the peak velocity of the E’ wave to the peak velocity of the A’ wave, ratio of the peak velocity of the E wave to the peak velocity of the E’ wave, LAAmin, passive emptying area, and passive and active fractional area changes.
Least squares mean values (95% confidence interval) for hemodynamic variables for 6 healthy adult Beagles before (baseline) and after administration of dobutamine (5.0 μg/kg/min, CRI), esmolol (500 μg/kg/min, CRI), milrinone (25 μg/kg, slow IV bolus for 5 minutes followed by 0.5 μg/kg/min, CRI), or phenylephrine (2.0 μg/kg/min, CRI).
| Variable | Drug | Baseline | After drug administration |
|---|---|---|---|
| Heart rate (beats/min) | Dobutamine | 99 (88–109) | 89 (79–100) |
| Esmolol | 105 (94–115) | 110 (99–120) | |
| Milrinone | 94 (83–105) | 101 (90–111) | |
| Phenylephrine | 99 (89–110) | 62 (51–72)* | |
| Systolic arterial pressure (mm Hg) | Dobutamine | 102 (92–112) | 121 (111–132)* |
| Esmolol | 118 (107–128) | 103 (92–113) | |
| Milrinone | 105 (95–116) | 92 (81–102) | |
| Phenylephrine | 107 (97–118) | 133 (123–144)* | |
| Diastolic arterial pressure (mm Hg) | Dobutamine | 48 (41–55) | 59 (51–66) |
| Esmolol | 56 (48–63) | 46 (38–53) | |
| Milrinone | 48 (41–58) | 41 (33–48) | |
| Phenylephrine | 54 (46–61) | 81 (73–88)* | |
| Mean arterial pressure (mm Hg) | Dobutamine | 73 (64–82) | 88 (79–97)* |
| Esmolol | 88 (79–97) | 72 (63–81)* | |
| Milrinone | 76 (67–85) | 67 (58–76) | |
| Phenylephrine | 78 (69–87) | 109 (100–118)* |
Each dog was administered 1 cardiovascular drug on an experimental day, and there was at least a 14-day interval between experimental days. Each drug was administered to 6 dogs; however, some dogs did not receive all 4 drugs.
Value differs significantly (P < 0.05) from the corresponding baseline value.
Least squares mean values (95% confidence interval) for conventional echocardiographic variables for the dogs of Table 1.
| Variable | Drug | Baseline | After drug administration |
|---|---|---|---|
| LVIDd (mm) | Dobutamine | 30.4 (28.7–32.1) | 31.9 (30.2–33.6) |
| Esmolol | 30.1 (28.4–31.8) | 31.3 (29.6–33.0) | |
| Milrinone | 32.0 (30.3–33.7) | 28.6 (26.9–30.3)* | |
| Phenylephrine | 31.2 (29.5–32.9) | 34.6 (32.9–36.3)* | |
| LVIDs (mm) | Dobutamine | 23.3 (21.3–25.3) | 20.3 (18.3–22.3)* |
| Esmolol | 22.1 (20.1–24.1) | 25.4 (23.4–27.4)* | |
| Milrinone | 23.1 (21.1–25.1) | 18.7 (16.7–20.7)* | |
| Phenylephrine | 22.6 (20.6–24.6) | 27.6 (25.6–29.6)* | |
| Left ventricular fractional shortening (%) | Dobutamine | 23.5 (19.0–28.0) | 36.2 (31.7–40.7)* |
| Esmolol | 26.9 (22.4–31.4) | 18.6 (14.1–23.1)* | |
| Milrinone | 27.9 (23.4–32.4) | 35.2 (30.7–39.7)* | |
| Phenylephrine | 27.7 (23.2–32.2) | 20.0 (15.5–24.5)* | |
| Stroke volume (mL) | Dobutamine | 27.7 (22.8–32.6) | 35.8 (30.9–40.7)* |
| Esmolol | 28.3 (23.6–33.0) | 22.5 (17.8–27.2)* | |
| Milrinone | 27.1 (22.4–31.8) | 24.1 (19.4–28.8) | |
| Phenylephrine | 26.4 (21.7–31.1) | 26.4 (21.7–31.1) | |
| Cardiac output (L/min) | Dobutamine | 2.79 (2.38–3.19) | 3.44 (3.04–3.84)* |
| Esmolol | 3.01 (2.62–3.39) | 2.52 (2.13–2.91)* | |
| Milrinone | 2.59 (2.20–2.98) | 2.27 (1.88–2.66) | |
| Phenylephrine | 2.43 (2.04–2.82) | 1.78 (1.40–2.17)* | |
| E wave (m/s) | Dobutamine | 0.72 (0.64–0.80) | 0.90 (0.82–0.98)* |
| Esmolol | 0.69 (0.61–0.77) | 0.62 (0.54–0.70) | |
| Milrinone | 0.70 (0.62–0.78) | 0.67 (0.59–0.75) | |
| Phenylephrine | 0.61 (0.53–0.69) | 0.58 (0.50–0.66) | |
| A wave (m/s) | Dobutamine | 0.47 (0.40–0.54) | 0.64 (0.57–0.70)* |
| Esmolol | 0.49 (0.42–0.55) | 0.47 (0.40–0.53) | |
| Milrinone | 0.47 (0.40–0.54) | 0.40 (0.33–0.46) | |
| Phenylephrine | 0.48 (0.41–0.54) | 0.34 (0.27–0.41)* | |
| E:A ratio | Dobutamine | 1.61 (1.34–1.88) | 1.47 (1.20–1.74) |
| Esmolol | 1.48 (1.20–1.75) | 1.34 (1.07–1.61) | |
| Milrinone | 1.52 (1.25–1.79) | 1.71 (1.44–1.98) | |
| Phenylephrine | 1.28 (1.01–1.55) | 1.78 (1.50–2.05)* | |
| E’ wave (cm/s) | Dobutamine | 5.0 (4.0–6.1) | 7.4 (6.4–8.4)* |
| Esmolol | 5.5 (4.5–6.6) | 4.7 (3.7–5.7) | |
| Milrinone | 6.2 (5.1–7.2) | 6.2 (5.2–7.2) | |
| Phenylephrine | 5.8 (4.8–6.8) | 5.6 (4.6–6.6) | |
| A’ wave (cm/s) | Dobutamine | 4.9 (4.0–5.9) | 6.1 (5.2–7.0) |
| Esmolol | 5.3 (4.4–6.3) | 5.3 (4.3–6.2) | |
| Milrinone | 5.1 (4.1–6.0) | 4.2 (3.3–5.1) | |
| Phenylephrine | 4.7 (3.7–5.6) | 4.4 (3.5–5.3) | |
| S’ wave (cm/s) | Dobutamine | 7.5 (6.4–8.5) | 10.2 (9.2–11.3)* |
| Esmolol | 8.0 (7.0–9.0) | 5.9 (4.9–6.9)* | |
| Milrinone | 7.0 (5.9–8.0) | 8.7 (7.7–9.8)* | |
| Phenylephrine | 6.9 (5.9–7.9) | 4.5 (3.5–5.5)* | |
| E':A'ratio | Dobutamine | 1.12 (0.97–1.27) | 1.12 (0.97–1.27) |
| Esmolol | 1.09 (0.94–1.24) | 0.96 (0.81–1.11) | |
| Milrinone | 1.19 (1.04–1.34) | 1.33 (1.18–1.48) | |
| Phenylephrine | 1.19 (1.04–1.34) | 1.20 (1.05–1.35) | |
| E:E’ ratio | Dobutamine | 13.9 (11.7–16.2) | 13.4 (11.1–15.7) |
| Esmolol | 12.7 (10.5–15.0) | 13.3 (11.0–15.6) | |
| Milrinone | 12.5 (10.2–14.7) | 12.1 (9.8–14.3) | |
| Phenylephrine | 11.5 (9.2–13.7) | 11.0 (8.7–13.3) |
A wave = Peak velocity of late diastolic transmitral flow. A’ wave = Peak myocardial velocity during late diastole. E:A ratio = Ratio of peak velocity of the E wave to the peak velocity of the A wave. E':A’ ratio = Ratio of the peak velocity of the E’ wave to the peak velocity of the A’ wave. E:E’ = Ratio of the peak velocity of the E wave to the peak velocity of the E’ wave. E wave = Peak velocity of early diastolic transmitral flow. E’ wave = Peak myocardial velocity during early diastole. S’ wave = Peak myocardial velocity during systole.
See Table 1 for remainder of key.
Least squares mean values (95% confidence interval) for left atrial phasic function indices obtained by 2-D speckle tracking echocardiography for the dogs of Table 1.
| LAAmax (cm2) | Dobutamine | 5.71 (4.83–6.59) | 6.94 (6.05–7.82)* |
|---|---|---|---|
| Esmolol | 5.65 (4.77–6.54) | 5.42 (4.53–6.30) | |
| Milrinone | 5.66 (4.77–6.54) | 5.07 (4.18–5.95) | |
| Phenylephrine | 5.35 (4.47–6.23) | 6.44 (5.56–7.32) | |
| LAAp (cm2) | Dobutamine | 3.95 (3.31–4.59) | 4.69 (4.05–5.33) |
| Esmolol | 4.07 (3.43–4.71) | 4.08 (3.44–4.72) | |
| Milrinone | 4.40 (3.76–5.04) | 3.87 (3.24–4.51) | |
| Phenylephrine | 4.15 (3.51–4.79) | 5.16 (4.52–5.80)* | |
| LAAmin (cm2) | Dobutamine | 2.83 (2.34–3.32) | 3.07 (2.58–3.56) |
| Esmolol | 3.01 (2.52–3.50) | 3.03 (2.54–3.52) | |
| Milrinone | 3.18 (2.68–3.66) | 2.82 (2.33–3.31) | |
| Phenylephrine | 3.18 (2.69–3.66) | 3.79 (3.30–4.28) | |
| Emptying area (cm2) | |||
| Total | Dobutamine | 2.88 (2.37–3.39) | 3.87 (3.36–4.38)* |
| Esmolol | 2.64 (2.14–3.15) | 2.39 (1.88–2.89) | |
| Milrinone | 2.48 (1.98–2.99) | 2.25 (1.74–2.75) | |
| Phenylephrine | 2.17 (1.67–2.68) | 2.65 (2.14–3.15) | |
| Passive | Dobutamine | 1.72 (1.38–2.06) | 2.20 (1.86–2.55) |
| Esmolol | 1.54 (1.19–1.88) | 1.29 (0.95–1.64) | |
| Milrinone | 1.29 (0.95–1.95) | 1.24 (0.90–1.58) | |
| Phenylephrine | 1.25 (0.91–1.59) | 1.33 (0.99–1.67) | |
| Active | Dobutamine | 1.14 (0.85–1.43) | 1.64 (1.35–1.93)* |
| Esmolol | 1.08 (0.79–1.37) | 1.07 (0.78–1.36) | |
| Milrinone | 1.22 (0.92–1.51) | 1.03 (0.74–1.32) | |
| Phenylephrine | 0.95 (0.66–1.24) | 1.34 (1.05–1.63) | |
| Fractional area change (%) | |||
| Total | Dobutamine | 50.2 (46.3–54.1) | 56.3 (52.5–60.2)* |
| Esmolol | 45.9 (42.0–49.8) | 43.1 (39.2–46.9) | |
| Milrinone | 44.4 (40.5–48.2) | 44.0 (40.1–47.8) | |
| Phenylephrine | 41.7 (37.8–45.5) | 41.8 (37.9–45.6) | |
| Passive | Dobutamine | 30.2 (26.6–33.7) | 32.1 (28.6–35.6) |
| Esmolol | 26.8 (23.3–30.4) | 23.5 (20.0–27.0) | |
| Milrinone | 23.3 (19.8–26.9) | 24.0 (20.5–27.5) | |
| Phenylephrine | 23.4 (19.8–26.9) | 20.9 (17.4–24.5) | |
| Active | Dobutamine | 28.2 (23.5–32.9) | 35.3 (30.6–40.0) |
| Esmolol | 25.8 (21.1–30.5) | 25.3 (20.6–30.0) | |
| Milrinone | 27.6 (22.9–32.3) | 26.4 (21.7–31.1) | |
| Phenylephrine | 23.9 (19.2–28.6) | 26.3 (21.6–31.0) |
See Table 1 for key.
Following administration of dobutamine, systolic and mean arterial pressure, left ventricular fractional shortening, stroke volume, cardiac output, peak velocities of the transmitral E and A waves, myocardial E’ and S’ waves, LAAmax, total and active emptying areas, and total fractional area change were significantly increased from baseline values. Conversely, the heart rate did not change significantly after dobutamine administration, whereas the LVIDs was significantly decreased from baseline.
Following administration of esmolol, heart rate, left atrial phasic function indices, transmitral E and A wave velocities, and myocardial E’ and A’ waves did not differ significantly from baseline values. Mean arterial pressure, cardiac output, stroke volume, left ventricular fractional shortening, and peak velocity of the myocardial S’ wave were significantly decreased and LVIDs was significantly increased from baseline values after esmolol administration.
Following administration of milrinone, there were no significant changes in heart rate; systolic, diastolic, and mean arterial pressures; or any of the left atrial phasic function indices. Left ventricular internal diameters at end diastole and end systole were significantly decreased, whereas left ventricular fractional shortening and the velocity of the myocardial S’ wave were significantly increased, compared with baseline values.
Following administration of phenylephrine, systolic, diastolic, and mean arterial pressures; LAAp; LVIDd; LVIDs; and the ratio of the peak velocity of the E wave to the peak velocity of the A wave were significantly increased from baseline values. Conversely, heart rate, cardiac output, left ventricular fractional shortening, and velocities of the transmitral A wave and myocardial S’ wave were significantly decreased from baseline values. The left atrial emptying areas and fractional area were not altered significantly after phenylephrine administration.
Discussion
Results of the present study indicated that echocardiographic measurements of left atrial phasic function did not change in parallel with those of the left ventricle and were fairly stable following the administration of dobutamine, esmolol, milrinone, or phenylephrine. To our knowledge, this was the first study conducted in healthy dogs to evaluate the effects of various cardiovascular drugs on left atrial phasic function indices as measured by 2-D speckle tracking echocardiography of the left atrium.
The 4 drugs used in the present study were chosen because they are commonly used in veterinary practice and have different mechanisms of action, which allowed us to elucidate the effects of each drug on left atrial phasic function indices and investigate the potential usefulness of those indices for guiding treatment decisions in clinically ill dogs. Dobutamine is a predominantly β1 adrenergic receptor agonist with positive inotropic and lusitropic effects and is used for the treatment of dogs with cardiogenic shock or acute pulmonary edema caused by chronic mitral valve disease or dilated cardiomyopathy.21 Milrinone is a phosphodiesterase inhibitor with positive inotropic and lusitropic effects and vasodilatory activity (an inodilator),16,21–23 which can be administered IV. Inodilators such as pimobendan are used to treat dogs with congestive heart failure, cardiogenic shock associated with mitral valve disease, or dilated cardiomyopathy.21 Esmolol is an ultra–short-acting, selective β1 adrenergic receptor anagonist with negative inotropic and lusitropic effects13,14,24–27 and was selected because its effects were expected to contrast with those of dobutamine. Phenylephrine is an α1 adrenergic receptor agonist with vasoconstrictive effects28 and was selected because its effects were expected to contrast with those of milrinone.
Changes in the 3 left atrial phasic functions are determined by cardiovascular factors other than intrinsic left atrial inotropy and lusitropy. The reservoir function is modulated by left ventricular contraction that leads to descent of the left ventricular base, right ventricular systolic pressure that is transmitted through the pulmonary circulation, and intrinsic left atrial intrinsic relaxation and chamber stiffness.1,6 The conduit function is modulated by left ventricular relaxation and the early diastolic pressure gradient between the left ventricle and atrium.6 The booster pump function is modulated by left ventricular compliance and end-diastolic pressure (ie, left atrial after-load) and left atrial intrinsic contractility.6 Additionally, an increase in the blood volume of venous return (ie, left atrial preload) will enhance all 3 left atrial phasic functions,6,24,29 and it is possible that drug-induced changes in left atrial intrinsic contractility and relaxation will not affect the indices of left atrial phasic function.
In the dogs of the present study, administration of dobutamine caused a significant increase in indices of left atrial reservoir and booster pump functions in a manner similar to that observed in healthy humans,30,31 whereas administration of esmolol caused no significant change in left atrial phasic function, which was similar to the effects of esmolol administration to healthy cats.32 This discrepancy in the effects of dobutamine and esmolol on left atrial phasic function could have several explanations. The negative inotropic and lusitropic effects of esmolol could have been offset by a compensatory response to drug-induced hypotension, which resulted in baroreflex-mediated vasoconstriction and an increase in venous return.33 Also, healthy dogs have fewer β-adrenergic receptors in the left atrium than in the left ventricle34; thus, the negative inotropic and lusitropic effects of esmolol on the left atrium might have been inadequate to cause a significant decrease in left atrial function, especially in the presence of the concurrent drug-induced effects on the left ventricle.
To our knowledge, prior to the present study, the effect of milrinone on left atrial function indices had not been investigated in healthy humans or animals. Although milrinone, like dobutamine, has positive inotropic and lusitropic actions,16,21–23 its administration did not significantly affect left atrial phasic function in the dogs of the present study. It is possible that milrinone-induced vasodilation16 caused a decrease in venous return and left atrial preload, which counteracted the drug's positive inotropic and lusitropic effects.6,24,29 Indeed, in the present study, a decrease in venous return following milrinone administration was supported by a decrease in LVIDd.
Similar to milrinone, administration of phenylephrine did not significantly affect left atrial phasic function in the dogs of the present study. However, phenylephrine had the opposite effect of milrinone on left ventricular function. Contrary to milrinone, phenylephrine might have suppressive effects on left atrial contractility and lusitropy in addition to its vasoconstrictive effect. A phenylephrine-induced increase in systemic blood pressure could impair left ventricular systolic function, which in turn could adversely affect left atrial reservoir function. Impairment of left ventricular contractility may have adverse effects on left ventricular relaxation because of a reduction in suction effects, which then impairs conduit function.35–37 Additionally, booster pump function may be adversely affected when left ventricular end-diastolic pressure increases subsequent to an increase in venous return associated with vasoconstriction and a baroreflex-mediated decrease in heart rate.1,6,24,28,29 In the present study, LVIDd was significantly increased from its baseline value following phenylephrine administration, which suggested that the increase in venous return associated with phenylephrine-induced vasoconstriction and the subsequent decrease in heart rate might augment all 3 left atrial phasic functions.6,24,29,35 Thus, it is likely that the opposing effects of phenylephrine administration on left atrial phasic function counterbalanced each other in the present study.
Results of the present study suggested that indices of left atrial phasic function obtained by time–left atrial area curve analysis were less sensitive than were indices of left ventricular function for monitoring the efficacy of inotropic and lusitropic drugs. However, the present study involved only healthy dogs. It is possible that our findings cannot be extrapolated to dogs with clinical cardiac disease associated with sympathetic activation and parasympathetic withdrawal or volume overload,23,38 and monitoring left atrial phasic function indices could provide useful guidance for the adjustment of cardiovascular drug doses in those dogs. Indeed, results of another study39 indicate that administration of an inodilator improves left atrial reservoir and booster pump functions in human patients with cardiac failure.
The present study had several limitations. Invasive cardiovascular procedures were not performed; left atrial pressure-volume loop analysis, an invasive procedure that is the gold standard for evaluation of left atrial phasic function, might have detected changes in left atrial intrinsic properties. Assumptions regarding venous return were made solely on the basis of echocardiographic variables. Also, the sample size was small, and not all dogs were available to receive all 4 cardiovascular drugs, which might have led to a type-2 error. The effects of sedation on cardiac function could not be eliminated, and the study did not include a placebo, or control, treatment in which dogs were sedated for echocardiographic examination without concurrent administration of a cardiovascular drug. We sedated the dogs with propofol because the level of sedation could be easily adjusted to minimize its effect on autonomic activity and mental status; however, propofol can impair left atrial and ventricular contractility and lusitropy40,41 and cause vasodilation, which results in a reduction in preload.41 Therefore, the positive inotropic and lusitropic and vasoconstrictive effects of the cardiovascular drugs used in the present study might have been partially counterbalanced by the concurrent administration of propofol.
In the present study, left atrial phasic function indices obtained by time–left atrial area curve analysis were fairly stable and did not parallel changes in left ventricular function indices following administration of dobutamine, esmolol, milrinone, or phenylephrine to healthy propofol-sedated dogs. Further investigations of dogs with clinical cardiac disease are warranted to elucidate the effects of those 4 cardiovascular drugs on left atrial phasic function indices.
Acknowledgments
Supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.
ABBREVIATIONS
| CRI | Constant rate infusion |
| LAAmax | Maximum area of the left atrium at ventricular end-systole |
| LAAmin | Minimum area of the left atrium at ventricular end-diastole |
| LAAp | Area of the left atrium at onset of the P wave on the ECG |
| LVIDd | Left ventricular internal diameter at end-diastole |
| LVIDs | Left ventricular internal diameter at end-systole |
Footnotes
Propofol Mylan, Mylan Inc, Canonsburg, Pa.
BSM-5192, Nihon Kohden Co, Tokyo, Japan.
HI VISION Preirus, Hitachi Aloka Medical Ltd, Tokyo, Japan.
Dobutrex, Shionogi & Co Ltd, Osaka, Japan.
Brevibloc, Maruishi Pharmaceutical Co Ltd, Osaka, Japan.
Neosynesin Kowa, Kowa Pharmaceutical Co Ltd, Tokyo, Japan.
Milrinone, Takata Seiyaku Co Ltd, Tokyo, Japan.
EUP-S52, Hitachi Aloka Medical Ltd, Tokyo, Japan.
Left Atrial Tracking, Hitachi Aloka Medical Ltd, Tokyo, Japan.
JMP Pro, version 10.0, SAS Institute Inc, Cary, NC.
References
1. 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.
2. 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.
3. D'Andrea A, Caso P, Romano S, et al. Association between left atrial myocardial function and exercise capacity in patients with either idiopathic or ischemic dilated cardiomyopathy: a two-dimensional speckle strain study. Int J Cardiol 2009; 132: 354–363.
4. Cameli M, Lisi M, Giacomin E, et al. Chronic mitral regurgitation: left atrial deformation analysis by two-dimensional speckle tracking echocardiography. Echocardiography 2011; 28: 327–334.
5. Cameli M, Lisi M, Focardi M, et al. Left atrial deformation analysis by speckle tracking echocardiography for prediction of cardiovascular outcomes. Am J Cardiol 2012; 110: 264–269.
6. Roşca M, Lancellotti P, Popescu BA, et al. Left atrial function: pathophysiology, echocardiographic assessment, and clinical applications. Heart 2011; 97: 1982–1989.
7. Leung DY, Boyd A, Ng AA, et al. Echocardiographic evaluation of left atrial size and function: current understanding, pathophysiologic correlates, and prognostic implications. Am Heart J 2008; 156: 1056–1064.
8. Baron Toaldo M, Guglielmini C, Diana A, et al. Feasibility and reproducibility of echocardiographic assessment of regional left atrial deformation and synchrony by tissue Doppler ultrasonographic imaging in healthy dogs. Am J Vet Res 2014; 75: 59–66.
9. Huang G, Zhang L, Xie M, et al. Assessment of left atrial function in diabetes mellitus by left atrial volume tracking method. J Huazhong Univ Sci Technolog Med Sci 2010; 30: 819–823.
10. Mori M, Kanzaki H, Amaki M, et al. Impact of reduced left atrial functions on diagnosis of paroxysmal atrial fibrillation: results from analysis of time-left atrial volume curve determined by two-dimensional speckle tracking. J Cardiol 2011; 57: 89–94.
11. 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.
12. 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.
13. Nagueh SF, Sun H, Kopelen HA, et al. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 2001; 37: 278–285.
14. Hori Y, Kanai K, Nakao R, et al. Assessing diastolic function with Doppler echocardiography using a novel index: ratio of the transmitral early diastolic velocity to pulmonary diastolic velocity. J Vet Med Sci 2008; 70: 359–366.
15. Swamy G, Kuiper J, Gudur MS, et al. Continuous left ventricular ejection monitoring by aortic pressure waveform analysis. Ann Biomed Eng 2009; 37: 1055–1068.
16. Sato N, Asai K, Okumura S, et al. Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure. Am J Physiol 1999; 276: H1699–H1705.
17. Takahashi S, Fujii Y, Hoshi T, et al. Milrinone attenuates the negative inotropic effects of landiolol in halothane-anesthetized dogs. Can J Anaesth 2003; 50: 830–834.
18. Boon JA. Evaluation of size, function, and hemodynamics. In: Boon JA, ed. Veterinary echocardiography. 2nd ed. Ames, Iowa: Wiley-Blackwell, 2011; 153–266.
19. Uehara Y, Koga M, Takahashi M. Determination of cardiac output by echocardiography. J Vet Med Sci 1995; 57: 401–407.
20. Shin MS, Kim BR, Oh KJ, et al. Echocardiographic assessments of left atrial strain and volume in healthy patients and patients with mitral valvular heart disease by tissue Doppler imaging and 3-dimensional echocardiography. Korean Circ J 2009; 39: 280–287.
21. Fuentes VL. Inotropes: inodilators. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 7th ed. St Louis: Saunders, 2010; 1202–1207.
22. Yano M, Kohno M, Ohkusa T, et al. Effect of milrinone on left ventricular relaxation and Ca2+ uptake function of cardiac sarcoplasmic reticulum. Am J Physiol Heart Circ Physiol 2000; 279: H1898–H1905.
23. Nakayama T, Nishijima Y, Miyamoto M, et al. Effects of 4 classes of cardiovascular drugs on ventricular function in dogs with mitral regurgitation. J Vet Intern Med 2007; 21: 445–450.
24. Wang YP, Takenaka K, Sakamoto T, et al. Effects of volume loading, propranolol, and heart rate changes on pump function and systolic time intervals of the left atrium in open-chest dogs. Acta Cardiol 1993; 48: 245–262.
25. Hori Y, Kunihiro S, Kanai K, et al. The relationship between invasive hemodynamic measurements and tissue Dopplerderived myocardial velocity and acceleration during isovolumic relaxation in healthy dogs. J Vet Med Sci 2009; 71: 1419–1425.
26. Gordon SG. Beta blocking agents. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 7th ed. St Louis: Saunders, 2010; 1207–1211.
27. Colucci WS, Parker JD. Effects of beta-adrenergic agents on systolic and diastolic myocardial function in patients with and without heart failure. J Cardiovasc Pharmacol 1989; 14(suppl 5):S28–S37.
28. Ettinger SJ. Therapy of arrhythmias. In: Ettinger SJ, Feldman EC, eds. Textbook of veterinary internal medicine. 7th ed. St Louis: Saunders, 2010; 1225–1236.
29. Hondo T, Okamoto M, Kawagoe T, et al. Effects of volume loading on pulmonary venous flow and its relation to left atrial functions. Jpn Circ J 1997; 61: 1015–1020.
30. Moyssakis I, Papadopoulos DP, Kelepeshis G, et al. Left atrial systolic reserve in idiopathic vs. ischaemic-dilated cardiomyopathy. Eur J Clin Invest 2005; 35: 355–361.
31. 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.
32. Riesen SC, Schober KE, Smith DN, et al. Effects of ivabradine on heart rate and left ventricular function in healthy cats and cats with hypertrophic cardiomyopathy. Am J Vet Res 2012; 73: 202–212.
33. Iskandrian AS, Bemis CE, Hakki AH, et al. Effects of esmolol on patients with left ventricular dysfunction. J Am Coll Cardiol 1986; 8: 225–231.
34. Baker SP, Boyd HM, Potter LT. Distribution and function of beta-adrenoceptors in different chambers of the canine heart. Br J Pharmacol 1980; 68: 57–63.
35. Vandenberg BF, Kieso RA, Fox-Eastham K, et al. Effect of age on diastolic left ventricular filling at rest and during inotropic stimulation and acute systemic hypertension: experimental studies in conscious Beagles. Am Heart J 1990; 120: 73–81.
36. Sarnoff SJ, Mitchell JH. The regulation of the performance of the heart. Am J Med 1961; 30: 747–771.
37. Hoit BD, Shao Y, Gabel M, et al. Influence of loading conditions and contractile state on pulmonary venous flow. Validation of Doppler velocimetry. Circulation 1992; 86: 651–659.
38. López-Alvarez J, Boswood A, Moonarmart W, et al. Longitudinal electrocardiographic evaluation of dogs with degenerative mitral valve disease. J Vet Intern Med 2014; 28: 393–400.
39. 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.
40. Kehl F, Kress TT, Mraovic B, et al. Propofol alters left atrial function evaluated with pressure-volume relations in vivo. Anesth Analg 2002; 94: 1421–1426.
41. Puttick RM, Diedericks J, Sear JW, et al. Effect of graded infusion rates of propofol on regional and global left ventricular function in the dog. Br J Anaesth 1992; 69: 375–381.
