Clinical Study of the Acute Effects of Intravenous Nifekalant on the Defibrillation Threshold in Patients With Persistent and Paroxysmal Atrial Fibrillation

Okishige, Kaoru; Uehara, Hiroki; Miyagi, Naoto; Nakamura, Kentarou; Azegami, Kouji; Wakimoto, Hirofumi; Ohba, Kageyuki; Hirao, Kazuyuki; Mitsuo, Shimabukuro; Isobe, Mistuaki

doi:10.1253/circj.72.76

Cited by 5 publications

(6 citation statements)

References 25 publications

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“…This is in agreement with the experimental findings of Hondeghem and Hoffmann in isolated rabbit hearts [ 29 ], and with documented Verapamil-induced SAN asystole [ 28 ] as well. An opposite effect on SASF is brought about in SAN-atrial cell pairs by the downregulation (−74%) of G Kr in order to simulate the action of pure anti- I Kr class III antiarrhythmic agents, like Dofetilide and Nifekalant [ 56 , 57 ]. In this case, the decrease of G Kr leads to (1) an increase in SASF, likely mediated by the coupling-induced greater increase in I f and in I CaL (Figures 7(b) and 8(a) ), (2) a decrease in conduction delay, and (3) a better entrainment of repolarization, all synergic with a reduced proneness to develop AF.…”

Section: Discussionmentioning

confidence: 99%

Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study

Cacciani

Zaniboni

2015

BioMed Research International

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Initiation and maintenance of atrial fibrillation (AF) is often associated with pharmacologically or pathologically induced bradycardic states. Even drugs specifically developed in order to counteract cardiac arrhythmias often combine their action with bradycardia and, in turn, with development of AF, via still largely unknown mechanisms. This study aims to simulate action potential (AP) conduction between sinoatrial node (SAN) and atrial cells, either arranged in cell pairs or in a one-dimensional strand, where the relative amount of SAN membrane is made varying, in turn, with junctional resistance. The source-sink relationship between the two membrane types is studied in control conditions and under different simulated chronotropic interventions, in order to define a safety factor for pacemaker-to-atrial AP conduction (SASF) for each treatment. Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent. Particularly interesting is the increase of SASF observed when downregulation G Kr, which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in I CaL. Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies.

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Section: Discussionmentioning

confidence: 99%

Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study

Cacciani

Zaniboni

2015

BioMed Research International

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“…[6][7][8]25 Models of enhanced propensity to AF because of reduced refractoriness provide a therapeutic rationale for prolonging atrial refractoriness. In clinical use, anti-arrhythmic drugs prolonging the APD have proven to be effective in many subjects with AF, 26 with potassium-channel-blocking class III drugs being the most effective (as well as classes IA and C) in conversion to or maintenance of sinus rhythm, 27,28 and even in improving the electrical defibrillation efficacy in patients with persistent AF. 26 Because APD-shortening has been identified as a proarrhythmic factor, we hypothesized that genetic manipulation leading to the prolongation of atrial APD (and thus prolonging the AERP) should have a protective effect against atrial arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Effect of a Dominant Negative Kv4.2 Loss-of-Function Mutation Eliminating Ito,f on Atrial Refractoriness and Atrial Fibrillation in Mice

Odening

Nerbonne²,

Bode

et al. 2009

Circ J

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he most common arrhythmia in humans is atrial fibrillation (AF), with increasing prevalence and incidence with aging. 1 Electrical remodeling resulting in a shortening of the atrial action potential duration (APD) and of the atrial effective refractory period (AERP) is known to promote AF, 2 whereas drug-induced prolongation of APD and the AERP reduces its occurrence. [3][4][5] Recent evidence suggests that mutations in the genes responsible for voltage-gated K + -channels play an important role in the subset of human patients with familial AF. 6-8 These mutations lead to a shortening of the APD and AERP by a gain of function in IKs or IK1 and thereby facilitate AF.In line with these findings in humans with familial AF, transgenic mice overexpressing Kir2.1, which leads to augmentation of the IK1 current, show a shortening of APD and AERP, as well as an increase in the occurrence of spontaneous AF. 9 Spontaneous AF was also demonstrated in transgenic mouse models with atrial fibrosis because of either the expression of a constitutively-active form of transforming growth factor (TGF)-β1 10 or an overexpression of tumor necrosis factor (TNF)-α, 11 even in the absence of changes in the APD. 10 Similarly, targeted deletion of connexin40 (Cx40 -/-) slowed atrial and atrioventricular (AV) conduction, and increased vulnerability to AF 12 after transesophageal stimulation.Interestingly, in the TNF-α heart failure mouse model, the incidence of spontaneous and inducible AF increases with age, predominantly in males, 11 indicating a similar influence of age and gender as seen in human patients.In experimental studies, the feasibility of inducing AF using in vivo programmed stimulation has been demonstrated in mice; in wild-type (WT) animals, transvenous electrophysiological (EP) studies showed that after administration of the parasympathetic drug carbachol, which is known to facilitate AF and hence is used as standard model for AF induction, the majority (>70%) of animals had AF induced. 13 Several mutations protect against pacing-induced AF: in an IKACh knock-out mouse model, AF was inducible after carbachol only in WT animals, but not in knock-out mice. 14 In another mouse model, the overexpression of HERG markedly reduced AF inducibility after carbachol administration, despite shortening of the APD, predominantly at slow heart rates, presumably because of a prolonged post-repolarization refractoriness, an increased repolarization reserve and the lack of electrical alternans. 15 Genetic alterations of the atria that either shorten the APD and AERP (eg, by augmenting potassium currents such as IKs or IK1) or manipulations that slow atrial conduction (Cx40 -/-or TGF-β1/TNF-α overexpression) lead to increased vulnerability for AF in mice, and both the elimi-

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“…Nifekalant, a novel class III AAD, is mainly used to treat ventricular arrhythmias and its therapeutic dose ranges from 0.3 to 0.5 mg/kg, as recommended by the European Resuscitation Council Guidelines and International Consensus on Cardiopulmonary Resuscitation 6‐9 . More recently, nifekalant has been used in the treatment of atrial arrhythmia and cardioversion of AF and atrial flutter 10‐13 . Compared with traditional AADs, such as quinidine, propafenone and amiodarone, nifekalant is a new agent for instant cardioversion of persistent AF, and its prevalence of AF termination after administration during the procedure was approximately 64.6% 14 .…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9] More recently, nifekalant has been used in the treatment of atrial arrhythmia and cardioversion of AF and atrial flutter. [10][11][12][13] Compared with traditional AADs, such as quinidine, propafenone and amiodarone, nifekalant is a new agent for instant cardioversion of persistent AF, and its prevalence of AF termination after administration during the procedure was approximately 64.6%. 14 Nevertheless, the efficacy and safety of different doses of nifekalant for the rapid cardioversion of persistent AF during RFCA has not been tested in randomized controlled trials (RCTs), and guidelines provide no clear consensus regarding the preferred dose recommended.…”

mentioning

confidence: 99%

Comparison of the efficacy and safety of different doses of nifekalant in the instant cardioversion of persistent atrial fibrillation during radiofrequency ablation

Zhai

Xia

et al. 2020

Basic Clin Pharma Tox

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Nifekalant has been used in the treatment of atrial arrhythmia recently. However, there is no consensus on the preferable nifekalant dose to treat atrial fibrillation (AF). The purpose of this study was to explore efficacy and safety of different doses of nifekalant in the cardioversion of persistent AF. The study was a single‐centre, randomized controlled trial. All subjects received nifekalant or placebo intravenously, and the nifekalant was given at the dosage of 0.3, 0.4 or 0.5 mg/kg. Primary efficacy end‐point: compared with 0.3 mg group, the rate of cardioversion to sinus rhythm from AF in 0.4 and 0.5 mg group was higher. The 0.4 and 0.5 mg/kg doses were associated with a similar magnitude of efficacy (P > .05). Secondary efficacy end‐point: termination rates of AF in the group of 0.4 mg and 0.5 mg were higher than 0.3 mg. Primary safety end‐point: the rate of Torsades de Pointes or ventricular fibrillation was numerically lower in the 0.4 mg group than 0.5 mg group (P = .02). Secondary safety end‐point: The rates of the majority of other common drug‐related adverse events in the group of 0.5 and 0.4 mg were higher than the 0.3 mg group. A 0.4 mg/kg dose of intravenous nifekalant may be recommended during the radiofrequency ablation for persistent AF considering the benefit‐risk profile.

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Clinical Study of the Acute Effects of Intravenous Nifekalant on the Defibrillation Threshold in Patients With Persistent and Paroxysmal Atrial Fibrillation

Cited by 5 publications

References 25 publications

Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study

Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study

In Vivo Effect of a Dominant Negative Kv4.2 Loss-of-Function Mutation Eliminating Ito,f on Atrial Refractoriness and Atrial Fibrillation in Mice

Comparison of the efficacy and safety of different doses of nifekalant in the instant cardioversion of persistent atrial fibrillation during radiofrequency ablation

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