Ranolazine Prevents Levosimendan-Induced Atrial Fibrillation

Abstract

Objectives: Levosimendan is a calcium sensitizer that is used as positive inotropic drug in acute decompensated heart failure. An increased incidence of atrial fibrillation after levosimendan-treatment was observed in clinical and experimental studies. Due to the limited range of antiarrhythmic drugs, the aim of the present study was to assess potential antiarrhythmic effects of ranolazine in levosimendan-pretreated isolated rabbit hearts. Methods: Twelve rabbit hearts were excised and retrogradely perfused employing the Langendorff setup. Left and right atrial catheters were used to record monophasic action potentials and to obtain cycle length-dependent atrial action potential durations (aAPD₉₀) and effective refractory periods (aERP). After obtaining baseline data, 0.5 µmol/L levosimendan was infused. Subsequently, 10 µmol/L ranolazine was administered. Results: Infusion of levosimendan led to a reduction of aAPD₉₀ (–9 ms, p < 0.05) and aERP (–13 ms, p < 0.05). Additional treatment with ranolazine prolonged aAPD₉₀ (+23 ms, p < 0.01) and aERP (+30 ms, p < 0.05). Under baseline conditions, a predefined pacing protocol induced 77 episodes of atrial fibrillation. Infusion of levosimendan enhanced the vulnerability to atrial fibrillation (132 episodes, p = 0.14). Further treatment with ranolazine had a significant antiarrhythmic effect (61 episodes, p < 0.05). Conclusions: In this study, ranolazine seems to prevent atrial fibrillation in levosimendan-pretreated hearts. Underlying mechanism is a prolongation of atrial repolarization and aERP.

Antiarrhythmic Effect of Ranolazine in Combination with Selective NCX-Inhibition in an Experimental Model of Atrial Fibrillation

“…Ranolazine is an FDA-approved antianginal agent with already known antiarrhythmic effects on the ventricular and atrial level in this [ 16 , 17 ] model, experimental models of other groups [ 9 ] and clinical trials [ 18 ].…”

Challenges and Opportunities for Therapeutic Targeting of Calmodulin Kinase II in Heart

“…Late Na + current, through the actions of the sodium Ca 2+ exchanger, may impact intracellular Ca 2+ , contributing to further activation of CaMKII as well as driving the incidence of arrhythmogenic DADs. Ranolazine has been used successfully in rodents and large animals to block these changes and prevent the development of hypertrophy, HF, and arrhythmias (Rastogi et al, 2008;Figueredo et al, 2011;Glynn et al, 2015;Liang et al, 2016;Ellermann et al, 2018;Nie et al, 2019). However, results from clinical trials have been mixed with data supporting that ranolazine is safe with questionable efficacy in preventing AF recurrence (RAFAELLO trial), ventricular tachycardia (VT) or ventricular fibrillation (VF) following implantation of cardioverter defibrillator (RAID trial), or improving functional capacity in hypertrophic cardiomyopathy (RESTYLE-HCM trial) (De Ferrari et al, 2015;Bengel et al, 2017;Olivotto et al, 2018;Zareba et al, 2018).…”

Latest Insights into Mechanisms behind Atrial Cardiomyopathy: It Is Not always about Ventricular Function

“…Intracellular Ca 2+ homeostasis and subsequent contractility efficiency rely upon phosphorylation processes, which, in AF, are pathologically altered. Some recent studies have shown that levosimendan increases cerebral blood flow, decreases NT-proBNP (an indirect marker of adverse atrial remodeling), and improves atrial pump function on echocardiography; however, it also increases the occurrence of AF in these patients, an undesired effect attenuated by concomitant treatment with ranolazine, an inhibitor of the late inward sodium current [55]. Some very recent reports were focused on unravelling the pleiotropic, cardiovascular protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel class of oral hypoglycemic medication that showed very promising results in the treatment of HF.…”