Electrophysiological characterization of omecamtiv mecarbil in an experimental whole heart model

Julian Wolfes (Münster)1, K. Neff (Münster)1, F. Doldi (Münster)1, F. K. Wegner (Münster)1, L. Eckardt (Münster)1, G. Frommeyer (Münster)1, C. Ellermann (Münster)1

1Universitätsklinikum Münster Klinik für Kardiologie II - Rhythmologie Münster, Deutschland



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. 


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. 


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. 


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.   

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