Effects of Ranolazine on Torsades de Pointes Tachycardias in a Healthy Isolated Rabbit Heart Model

Purpose Torsades de pointes ( T d P ) tachycardias are triggered, polymorphic ventricular arrhythmias arising from early afterdepolarizations ( EADs ) and increased dispersion of repolarization. Ranolazine is a new agent which reduces pathologically elevated late I Na but also I Kr . Aim of this study was to evaluate the effects of ranolazine in a validated isolated L angendorff‐perfused rabbit heart model. Methods TdP was reproducibly induced with d‐sotalol (10 −4  mol/L) and low potassium ( K ) (1.0 mmol/L for 5 min, pacing at CL 1000 ms). In 10 hearts, ECG and 8 epi‐ and endocardial monophasic action potentials were recorded. Action potential duration ( APD ) was measured at 90% repolarization and dispersion defined as APD max–min. Results D‐sotalol prolonged APD 90 and increased dispersion of APD 90 , simultaneously causing EAD s and induction of T d P . The combination of d‐sotalol and two concentrations of ranolazine did not increase dispersion of ventricular APD 90 as compared to vehicle. Ranolazine at 5  μ mol/L did not cause additional induction of EAD s and/or T dP but also did not significantly suppress arrhythmogenic triggers. The higher concentration of ranolazine (10  μ mol/L) in combination with d‐sotalol caused further prolongation of APD 90 , at the same time reduction in APD 90 dispersion. In parallel, the incidence of EAD s was reduced and an antitorsadogenic effect was seen. Conclusions In the healthy isolated rabbit heart (where late I Na is not elevated), ranolazine does not cause proarrhythmia but exerts antiarrhythmic effects in a dose‐dependent manner against d‐sotalol/low K ‐induced T d P . This finding—despite additional APD prolongation—supports the safety of a combined use of both drugs and merits clinical investigation.