Late Na+Current Inhibition by Ranolazine Reduces Torsades de Pointes in the Chronic Atrioventricular Block Dog Model

Antoons, Gudrun; Oros, Avram; Beekman, Jet D.M.; Engelen, Markus A.; Houtman, Marien J C; Belardinelli, Luiz; Štengl, Milan; Vos, Marc A.

doi:10.1016/j.jacc.2009.10.033

Cited by 90 publications

(90 citation statements)

References 34 publications

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“…Our results are in keeping with experimental findings, in which the I NaL blocker ranolazine, effectively suppresses EADs from ventricular myocytes from failing hearts [18,23]. Furthermore, during conditions of reduced repolarization reserve, in which outward K + currents are inhibited by drugs or by diseases, results of experimental studies [21][22][23]62] have unmasked the role of endogenous or enhanced I NaL in exerting proarrhythmic effects. This is in agreement with the results of our simulations, and provides evidence of this effect in HF.…”

Section: Important Role Of I Nal During Heart Failure and Clinical Imsupporting

confidence: 89%

Influence of heart failure on nucleolar organization and protein expression in human hearts

Roselló‐Lletí¹,

Rivera²,

Cortés³

et al. 2012

Biochemical and Biophysical Research Communications

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Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na + current (I NaL ) is relevant and is currently under investigation. In this study we examined the role of I NaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I NaL . A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I NaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I NaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca 2+ transient. A mechanistic investigation of intracellular Na + accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na + / K + pump, the Na + /Ca 2+ exchanger and I NaL . The results of the simulations also showed that in failing myocytes, the enhancement of I NaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I NaL prolong APD and alter Ca 2+ transient facilitating the development of early afterdepolarizations. An enhanced I NaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca 2+ ] i homeostasis of failing myocytes.

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Section: Important Role Of I Nal During Heart Failure and Clinical Imsupporting

confidence: 89%

Influence of heart failure on nucleolar organization and protein expression in human hearts

Roselló‐Lletí¹,

Rivera²,

Cortés³

et al. 2012

Biochemical and Biophysical Research Communications

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“…For example, I Na block by lidocaine attenuated the incidence of TdP by almokalant in rabbits without influencing the almokalant-induced QT prolongation. 19 Similar effects have been shown in the chronic AVB dog after dofetilide-induced TdP both with lidocaine and the novel I Na-Late blocker ranolazine, 20 although in the latter study multiple ventricular ectopic beats were not completely abolished. In the same animal model, Oros et al 21 showed a robust antiarrhythmic effect of both flunarizine and verapamil against dofetilide-induced TdP.…”

supporting

confidence: 61%

Reduced Ventricular Proarrhythmic Potential of the Novel Combined Ion-Channel Blocker AZD1305 Versus Dofetilide in Dogs With Remodeled Hearts

Johnson

Jong

Crijns

et al. 2012

Circ: Arrhythmia and Electrophysiology

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Background-AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling. Methods and Results-AZD1305 was administered to anesthetized mongrel dogs before and Ͼ2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective I Kr blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison.

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“…Specifically, ranolazine showed to reduce the dofetilide‐ or clofilium‐induced torsades de pointes episodes in experimental models 28, 29. Additionally, ranolazine can reduce the torsades de pointes liability of agents that prolong the QT interval 30.…”

Section: Discussionmentioning

confidence: 99%

Impact of ranolazine on ventricular arrhythmias – A systematic review

Bazoukis

Tse

Letsas

et al. 2018

Journal of Arrhythmia

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Ranolazine is a new medication for the treatment of refractory angina. However, except its anti‐anginal properties, it has been found to act as an anti‐arrhythmic. The aim of our systematic review is to present the existing data about the impact of ranolazine in ventricular arrhythmias. We searched MEDLINE and Cochrane databases as well clinicaltrials.gov until September 1, 2017 to find all studies (clinical trials, observational studies, case reports/series) reported data about the impact of ranolazine in ventricular arrhythmias. Our search revealed 14 studies (3 clinical trials, 2 observational studies, 8 case reports, 1 case series). These data reported a beneficial impact of ranolazine in ventricular tachycardia/fibrillation, premature ventricular beats, and ICD interventions in different clinical settings. The existing data highlight the anti‐arrhythmic properties of ranolazine in ventricular arrhythmias.

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Late Na+Current Inhibition by Ranolazine Reduces Torsades de Pointes in the Chronic Atrioventricular Block Dog Model

Abstract: Despite down-regulation of I(NaL) in remodeled cAVB hearts, ranolazine is antiarrhythmic against drug-induced TdP. The antiarrhythmic effects are reflected in concomitant changes of BVR.

Cited by 90 publications

References 34 publications

Influence of heart failure on nucleolar organization and protein expression in human hearts

Influence of heart failure on nucleolar organization and protein expression in human hearts

Reduced Ventricular Proarrhythmic Potential of the Novel Combined Ion-Channel Blocker AZD1305 Versus Dofetilide in Dogs With Remodeled Hearts

Impact of ranolazine on ventricular arrhythmias – A systematic review

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