Revisiting Antiarrhythmic Drug Therapy for Atrial Fibrillation: Reviewing Lessons Learned and Redefining Therapeutic Paradigms

Geng, Meng; Lin, Andrew; Nguyen, Thao P.

doi:10.3389/fphar.2020.581837

Cited by 40 publications

(33 citation statements)

References 219 publications

(468 reference statements)

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“…Besides vernakalant and amiodarone, both inhibiting TASK1 channels (Heijman et al, 2017), more selective inhibitors have been utilized to investigate the anti‐arrhythmic potential of K 2P channels in porcine models of AF (Table 1 and Figure 2). Doxapram, which is a I K2P blocker, is currently being investigated in a clinical trial for cardioversion of both paroxysmal and persistent non‐valvular AF (Geng et al, 2020).…”

Section: Anti‐arrhythmic Drugs In Large Animal Models Of Afmentioning

confidence: 99%

Anti‐arrhythmic investigations in large animal models of atrial fibrillation

Saljic

Jespersen

Buhl

2021

British J Pharmacology

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Atrial fibrillation (AF) constitutes an increasing health problem in the aging population. Animal models reflecting human phenotypes are needed to understand the mechanisms of AF, as well as to test new pharmacological interventions. In recent years, a number of large animal models, primarily pigs, goats, dog and horses have been used in AF research. These animals can to a certain extent recapitulate the human pathophysiological characteristics and serve as valuable tools in investigating new pharmacological interventions for treating AF. This review focuses on anti‐arrhythmic investigations in large animals. Initially, spontaneous AF in small and large mammals is discussed. This is followed by a short presentation of frequently used methods for inducing short‐ and long‐term AF. The major focus of the review is on anti‐arrhythmic compounds either frequently used in the human clinic (ranolazine, flecainide, vernakalant and amiodarone) or being promising new AF medicine candidates (IK,Ach, ISK,Ca and IK2P blockers). LINKED ARTICLES This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc

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Section: Anti‐arrhythmic Drugs In Large Animal Models Of Afmentioning

confidence: 99%

Anti‐arrhythmic investigations in large animal models of atrial fibrillation

Saljic

Jespersen

Buhl

2021

British J Pharmacology

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“…Its management involves drugs to modulate ion channels’ activity in cardiac cells. Most antiarrhythmic drugs (AADs) present nowadays in clinical practice possess a strong propensity for inducing ventricular arrhythmias coupled with systemic toxicity when used for long periods [ 2 ]. Additional efforts to develop novel drugs are needed [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…For example, amiodarone is one of the most effective antiarrhythmic drugs. Its action depends on a multi-target effect [ 2 ]. The advantages of a multi-channel blockade for AF are exemplified not only with a single-molecule blocker such as amiodarone but also with drug combinations [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach

et al. 2022

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Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Nav1.5 (and its current, INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD) as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We present a computational workflow for a flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of the flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the central cavity and consists of a hydrophobic patch and a polar region, involving residues from the S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment.

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“…Since existing anti-atrial fibrillation (AF) drugs have been known to block both atrial and ventricular ionic channels, adverse effects were largely induced by their ionic channel blockade in the ventricle, which may often blunt their therapeutic benefits for the atrial arrhythmias ( Geng et al, 2020 ). The ideal anti-AF drug should selectively improve the pathophysiology in the atria without affecting the electrophysiological profile of the ventricles.…”

Section: Introductionmentioning

confidence: 99%

Translational Studies on Anti-Atrial Fibrillatory Action of Oseltamivir by its in vivo and in vitro Electropharmacological Analyses

et al. 2021

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Oseltamivir has been shown to prolong the atrial conduction time and effective refractory period, and to suppress the onset of burst pacing-induced atrial fibrillation in vitro. To better predict its potential clinical benefit as an anti-atrial fibrillatory drug, we performed translational studies by assessing in vivo anti-atrial fibrillatory effect along with in vivo and in vitro electropharmacological analyses. Oseltamivir in intravenous doses of 3 (n = 6) and 30 mg/kg (n = 7) was administered in conscious state to the persistent atrial fibrillation model dogs to confirm its anti-atrial fibrillatory action. The model was prepared by tachypacing to the atria of chronic atrioventricular block dogs for > 6 weeks. Next, oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously administered to the halothane-anesthetized intact dogs to analyze its in vivo electrophysiological actions (n = 4). Finally, its in vitro effects of 10–1,000 μM on IK,ACh, IKur, IKr, INa and ICaL were analyzed by using cell lines stably expressing Kir3.1/3.4, KV1.5, hERG, NaV1.5 or CaV1.2, respectively (n = 3 for IK,ACh and IKr or n = 6 for IKr, INa and ICaL). Oseltamivir in doses of 3 and 30 mg/kg terminated the atrial fibrillation in 1 out of 6 and in 6 out of 7 atrial fibrillation model dogs, respectively without inducing any lethal ventricular arrhythmia. Its 3 and 30 mg/kg delayed inter-atrial conduction in a frequency-dependent manner, whereas they prolonged atrial effective refractory period in a reverse frequency-dependent manner in the intact dogs. The current assay indicated that IC50 values for IK,ACh and IKr were 160 and 231 μM, respectively, but 1,000 µM inhibited INa, ICaL and IKur by 22, 19 and 13%, respectively. The extent of INa blockade was enhanced at faster beating rate and more depolarized resting membrane potential. Oseltamivir effectively terminated the persistent atrial fibrillation, which may be largely due to the prolongation of the atrial effective refractory period and inter-atrial conduction time induced by IK,ACh and IKr inhibitions along with INa suppression. Thus, oseltamivir can exert a powerful anti-atrial fibrillatory action through its ideal multi-channel blocking property; and oseltamivir would become a promising seed compound for developing efficacious and safe anti-atrial fibrillatory drugs.

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Revisiting Antiarrhythmic Drug Therapy for Atrial Fibrillation: Reviewing Lessons Learned and Redefining Therapeutic Paradigms

Cited by 40 publications

References 219 publications

Anti‐arrhythmic investigations in large animal models of atrial fibrillation

Anti‐arrhythmic investigations in large animal models of atrial fibrillation

Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach

Translational Studies on Anti-Atrial Fibrillatory Action of Oseltamivir by its in vivo and in vitro Electropharmacological Analyses

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