1Universitätsklinikum Münster Klinik für Kardiologie II - Rhythmologie Münster, Deutschland
Introduction:
Omecamtiv mecarbil represents a promising cardiac-specific myosin activator with a promising perspective to become a potential treatment alternative in the therapy of heart failure. The electrophysiological effects of omecamtiv mecarbil have been not yet been described. Therefore, we investigated omecamtiv mecarbil in a Langendorff model of the isolated rabbit heart.
Methods:
33 hearts from New Zealand White Rabbits were retrogradely perfused employing a Langendorff-setup. 24 hearts were used in two groups of a ventricular setup, and 9 hearts were used in an atrial setup.
Briefly summarized, in the ventricular experiments eight catheters were placed endo- and epicardially, thereby recording monophasic action potentials. Hearts were paced at seven different cycle lengths (300-900ms), thus obtaining cycle-length dependent action potential duration at 90% of repolarization (APD90), QT interval and dispersion of repolarization. Thereafter, bradycardic AV-blocked hearts were perfused with a hypokalemic solution to enhance the occurrence of triggered activity (early afterdepolarizations and torsade de pointes).
After generating baseline data, the hearts were assigned to two groups: In group 1, 12 hearts (n=12) were treated with 1 µM omecamtiv mecarbil (OM). Thereafter, 5 µM and 10µM OM were infused. Group 2 (n=12) was perfused with 100 µM sotalol followed by 5 µM OM. In the atrial group 3 (n=9) the hearts were perfused with 1µM isoproterenol acetylcholine (IsoACh) to raise atrial fibrillation (AF) inducibility followed by 5 µM OM.
Results:
Sole OM caused a shortening of ventricular APD and QT-interval whilst significant dispersion of repolarization was observed. The incidence of ventricular arrhythmias was increased under OM perfusion.
Perfusion with sotalol led to a significant increase in APD and QT-interval. Furthermore, significant dispersion of repolarization occurred. As a result of this the inducibility and spontaneous occurrence of VT episodes increased significantly. Additional perfusion with OM led to a further increase in APD, QT-interval and dispersion of repolarization. These changes were accompanied by a further raised arrhythmia susceptibility with significantly increased number of VT episodes and the spontaneous onset of Torsade de pointes tachycardias.
IsoACh caused a significant APD shortening accompanied by a significant increase in atrial conduction velocity and shortened refractory periods. In parallel, the incidence of AF episodes was significantly increased. The additional perfusion with OM caused a significant decrease of atrial conduction velocity followed by a significant suppression of AF episodes.
Conlcusion:
In summary, OM showed proarrhythmic effects at the ventricular level in this Langendorff model. At the atrial level, OM showed promising antiarrhythmic effects, which appeared similar to the modes of action of class I antiarrhythmic drugs.