Acute effects of intravenous dronedarone on electrocardiograms, hemodynamics and cardiac functions in anesthetized dogs

Abstract

Dronedarone is a class III antiarrhythmic that has been used for management of atrial fibrillation in humans, but limited information was found in dogs. The objective of this study was to determine the acute effects of escalating concentrations of dronedarone on electrocardiograms (ECG), hemodynamics and cardiac mechanics in healthy dogs. A total of 7 beagle dogs were anesthetized with isoflurane and instrumented to obtain lead II ECG, pressures at ascending aorta, right atrium, pulmonary artery and left ventricle, and left ventricular pressure-volume relationship. Five dogs were given vehicle and followed by escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg, 15 min for each dose), and two dogs were used as a vehicle-treated control. All parameters were measured at 15 min after the end of each dose. The results showed that all parameters in vehicle-treated dogs were unaltered. Dronedarone at 2.5 mg/kg significantly lengthened PQ interval (P<0.01), reduced cardiac output (P<0.01) and increased systemic vascular resistance (P<0.01). Dronedarone produced negative inotropy assessed by significantly lowered end-systolic pressure-volume relationship, preload recruitable stroke work, contractility index and dP/dtmax. It also impaired diastolic function by significantly increased end-diastolic pressure-volume relationship, tau and dP/dtmin. These results suggested that acute effects of dronedarone produced negative dromotropy, inotropy and lusitropy in anesthetized dogs. Care should be taken when given dronedarone to dogs, especially when the patients have impaired cardiac function.

Fig. 1.

Experimental procedure to study acute effects of escalating doses of dronedarone on electrocardiograms (ECG), hemodynamics and left ventricular functions in anesthetized dogs. RAP=right atrial pressure, PAP=pulmonary arterial pressure, LVP=left ventricular pressure, AoP=aortic pressure, CO=cardiac output, PVL=pressure-volume loop

Fig. 2.

Effects of escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg) versus vehicle-treated dogs measured at the same time-point on baseline adjusted PQ interval (A), QRS complex (B), QT and QTc intervals (C) and heart rate (D). Values were presented as mean ± standard error of means (SEM) in dronedarone-treated dogs (n=5), while those values in the vehicle-treated dogs were presented as an average of 2 dogs. * indicates P<0.05.

Fig. 3.

Effects of escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg) versus vehicle-treated dogs measured at the same time-point on baseline adjusted cardiac output (A), mean aortic pressure (B), pulmonary vascular resistance (PVR, C) and systemic vascular resistance (SVR, D). Values were presented as mean ± standard error of means (SEM) in dronedarone-treated dogs (n=5), while those values in the vehicle-treated dogs were presented as an average of 2 dogs. **indicates P<0.01.

Fig. 4.

Effects of cumulative doses of dronedarone (0.5, 1.5 and 4 mg/kg) versus vehicle-treated dogs measured at the same time-point on baseline adjusted stroke volume (SV, A), end-diastolic volume (EDV, B) and end-systolic volume (ESV, C). Values were presented as mean ± standard error of means (SEM) in dronedarone-treated dogs (n=5), while those values in the vehicle-treated dogs were presented as an average of 2 dogs. It can be noticed that acute dronedarone administration significantly reduced stroke volume, whereas the end-systolic volume was significantly increased. There is no significant change in end-diastolic volume. *indicates P<0.05.

Fig. 5.

Effects of escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg) versus vehicle-treated dogs measured at the same time-point on baseline adjusted introtropic indices, end-systolic pressure-volume relationship (ESPVR, A), preload recruitable stroke work (PRSW, B), contractility index (CI, C) and dP/dt_max (D). Values were presented as mean ± standard error of means (SEM) in dronedarone-treated dogs (n=5), while those values in the vehicle-treated dogs were presented as an average of 2 dogs. *indicates P<0.05, and **indicates P<0.01.

Fig. 6.

Representative left ventricular pressure-volume relationship in a single dog receiving vehicle and after administration of dronedarone (0.5 and 1.0 mg/kg) in isoflurane anesthetized dog. The slopes of the end-systolic pressure-volume relationship were fitted by linear.

Fig. 7.

Effects of escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg) versus vehicle-treated dogs measured at the same time-point on baseline adjusted lusitropic indices, end-diastolic pressure-volume relationship (EDPVR, A), tau (B) and dP/dt_min (C). Values were presented as mean ± standard error of means (SEM) in dronedarone-treated dogs (n=5), while those values in the vehicle-treated dogs were presented as an average of 2 dogs. *indicates P<0.05, and **indicates P<0.01.