Effects of Ranolazine on Torsades de Pointes Tachycardias in a Healthy Isolated Rabbit Heart Model. Issue 4 (August 2014)

• Record Type: Journal Article
• Authors: Sossalla, Samuel; Wallisch, Nora; Toischer, Karl; Sohns, Christian; Vollmann, Dirk; Seegers, Joachim; Lüthje, Lars; Maier, Lars S.; Zabel, Markus
• Is Part Of: Cardiovascular therapeutics. Volume 32:Issue 4(2014:Aug.)
• Page Start: 170
• Page End: 177
• Publication Date: 2014-08
• Subjects: Cardiovascular pharmacology -- Periodicals; Cardiovascular agents -- Periodicals; Cardiovascular system -- Diseases -- Chemotherapy -- Periodicals; Cardiovascular Agents -- Periodicals; Cardiovascular Diseases -- drug therapy -- Periodicals; Agents cardiovasculaires -- Périodiques; Appareil cardiovasculaire -- Maladies -- Chimiothérapie -- Périodiques; 616.1005
• DOI: 10.1111/1755-5922.12078
• Languages: English
• ISSNs: 1755-5914

Abstract

<abstract abstract-type="main" id="cdr12078-abs-0001"> <title>Abstract</title> <sec id="cdr12078-sec-0001" sec-type="section"> <title>Purpose</title> <p>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 <italic>I</italic><sub>Na</sub> but also <italic>I</italic><sub>Kr</sub>. Aim of this study was to evaluate the effects of ranolazine in a validated isolated Langendorff‐perfused rabbit heart model.</p> </sec> <sec id="cdr12078-sec-0002" sec-type="section"> <title>Methods</title> <p>TdP was reproducibly induced with d‐sotalol (10<sup>−4</sup> 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.</p> </sec> <sec id="cdr12078-sec-0003" sec-type="section"> <title>Results</title> <p>D‐sotalol prolonged APD<sub>90</sub> and increased dispersion of APD<sub>90</sub>, simultaneously causing EADs and induction of TdP. The combination of d‐sotalol and two concentrations of ranolazine did not increase dispersion of ventricular APD<sub>90</sub> as compared to vehicle. Ranolazine at 5 <italic>μ</italic>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 <italic>μ</italic>mol/L) in combination with d‐sotalol caused further prolongation of APD<sub>90</sub>, at the same time reduction in APD<sub>90</sub> dispersion. In parallel, the incidence of EADs was reduced and an antitorsadogenic effect was seen.</p> </sec> <sec id="cdr12078-sec-0004" sec-type="section"> <title>Conclusions</title> <p>In the healthy isolated rabbit heart (where late <italic>I</italic><sub>Na</sub> 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.</p> </sec> </abstract>