Effects of Ranolazine on Torsades de Pointes Tachycardias in a Healthy Isolated Rabbit Heart Model
2014 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Effects of Ranolazine on Torsades de Pointes Tachycardias in a Healthy Isolated Rabbit Heart Model
Sossalla, S. T. ; Wallisch, N.; Toischer, K. ; Sohns, C.; Vollmann, D.; Seegers, J. & Luethje, L. et al. (2014)
Cardiovascular Therapeutics, 32(4) pp. 170-177. DOI: https://doi.org/10.1111/1755-5922.12078
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- Authors
- Sossalla, Samuel Tobias ; Wallisch, Nora; Toischer, Karl ; Sohns, Christian; Vollmann, Dirk; Seegers, Joachim; Luethje, Lars; Maier, Lars S. ; Zabel, Markus
- Abstract
- Purpose: Torsades de pointes (TdP) 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 Langendorff-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 EADs and induction of TdP. 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 mu mol/L did not cause additional induction of EADs and/or TdP but also did not significantly suppress arrhythmogenic triggers. The higher concentration of ranolazine (10 mu 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 EADs was reduced and an antitorsadogenic effect was seen. Conclusions: In the healthy isolated rabbit heart (where late INa is not elevated), ranolazine does not cause proarrhythmia but exerts antiarrhythmic effects in a dose-dependent manner against d-sotalol/low K-induced TdP. This finding-despite additional APD prolongation-supports the safety of a combined use of both drugs and merits clinical investigation.
- Issue Date
- 2014
- Journal
- Cardiovascular Therapeutics
- Project
- SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz - Working Group
- RG L. Maier (Experimentelle Kardiologie)
RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)
RG Toischer (Kardiales Remodeling) - ISSN
- 1755-5922; 1755-5914