New Advances in Antiarrhythmic Drugs

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 15 November 2024 | Viewed by 7645

Special Issue Editor


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Guest Editor
1. Department of Physiology, University of Debrecen, 4032 Debrecen, Hungary
2. Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, 4032 Debrecen, Hungary
Interests: antiarrhythmic drugs; ion channel blockers; cardiac action potential; new drug targets; new actions of antiarrhythmics; old drug combinations for cardiac arrhythmias

Special Issue Information

Dear Colleagues,

Cardiac arrhythmias are a major cause of death. The background of these arrhythmias ultimately involves the dysfunction of sarcolemmal ion channels. The reasons for the dysfunction can be several, starting from mutations in the channels themselves, continuing through their trafficking problems, and ending up with malfunction in their regulation, often due to ion homeostasis problems occurring on the basis of many cardiac diseases. Furthermore, problems with intracellular proteins or channels might also lead to cardiac arrhythmogenesis.

The treatment of these life-threatening arrhythmias involves not only electrical interventions but also the use of ion channel modulators. It is long known, that these modulators may carry a serious risk of proarrhythmia. Some ion channels are mainly located to certain parts of the myocardium (being for instance atrial-specific) giving place for specific targeting of certain cardiac diseases. Moreover, as our knowledge increases about non-major cardiac channels (e.g., channels of TRP group, Ca2+-activated selective and non-selective channels, mechanosensitive channels) more and more candidates emerge as a pharmacological target of cardiac arrhythmias.

The journal Pharmaceuticals invites both reviews and original articles related to cardiac arrhythmias. The goal of the Special Issue is to summarize the recent findings of the field, as well as to elucidate possible future targets and directions. Topics of the Special Issue include, but are not limited to, new drug targets; new actions of antiarrhythmics; newer, more selective compounds; old drug combinations for cardiac arrhythmias. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Norbert Szentandrássy
Guest Editor

Manuscript Submission Information

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Keywords

  • antiarrhythmic drugs
  • ion channel blockers
  • cardiac action potential
  • sudden cardiac death
  • cardiac arrhythmia
  • proarrhythmic action

Published Papers (5 papers)

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Research

9 pages, 1039 KiB  
Article
Impact of Body Mass Index in the Cardioverter Efficacy of Amiodarone in Persistent Atrial Fibrillation
by Carmen Ligero, Pau Riera, Amine El-Amrani, Victor Bazan, José M. Guerra, Silvia Herraez, Xavier Viñolas and Josep M. Alegret
Pharmaceuticals 2024, 17(6), 693; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17060693 - 28 May 2024
Viewed by 361
Abstract
Background: Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some implications of body fat composition in its pharmacokinetics and pharmacodynamics. However, no clinical studies have described its implications for clinical [...] Read more.
Background: Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some implications of body fat composition in its pharmacokinetics and pharmacodynamics. However, no clinical studies have described its implications for clinical efficacy. Methods: We studied 878 patients with persistent atrial fibrillation (AF) treated with a regimen of amiodarone and referred to electrical cardioversion (ECV), included prospectively in two Spanish registries. We analyzed the influence of body mass index (BMI), as well as overweight and obesity, in the efficacy of amiodarone for achieving pharmacologic cardioversion to sinus rhythm (SR) before ECV. Results: A total of 185 patients (21.1%) reverted to SR before ECV. Patients who reverted to SR had a lower BMI than those who did not revert (27.45 ± 4.36 kg/m2 vs. 29.11 ± 4.09 kg/m2; p < 0.001). We observed a progressively lower probability of reverting to SR in overweight and obese patients (normal weight 28.3%, overweight 21.3%, obesity 13.1%; p < 0.001). In the logistic regression, BMI (kg/m2) adjusted for other related variables remained as the main factor inversely related to reversion to SR (OR = 0.904 × kg/m2); CI 75% 0.864–0.946). Conclusions: We observed a negative relationship between an increased BMI and the efficacy of amiodarone for reversion to SR, suggesting a negative clinical impact of excess body fat in its efficacy. Full article
(This article belongs to the Special Issue New Advances in Antiarrhythmic Drugs)
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14 pages, 2998 KiB  
Article
Conductance Changes of Na+ Channels during the Late Na+ Current Flowing under Action Potential Voltage Clamp Conditions in Canine, Rabbit, and Guinea Pig Ventricular Myocytes
by Balázs Horváth, Zsigmond M. Kovács, Csaba Dienes, József Óvári, Norbert Szentandrássy, János Magyar, Tamás Bányász, András Varró and Péter P. Nánási
Pharmaceuticals 2023, 16(4), 560; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16040560 - 7 Apr 2023
Viewed by 1192
Abstract
Late sodium current (INa,late) is an important inward current contributing to the plateau phase of the action potential (AP) in the mammalian heart. Although INa,late is considered as a possible target for antiarrhythmic agents, several aspects of this current remained [...] Read more.
Late sodium current (INa,late) is an important inward current contributing to the plateau phase of the action potential (AP) in the mammalian heart. Although INa,late is considered as a possible target for antiarrhythmic agents, several aspects of this current remained hidden. In this work, the profile of INa,late, together with the respective conductance changes (GNa,late), were studied and compared in rabbit, canine, and guinea pig ventricular myocytes using the action potential voltage clamp (APVC) technique. In canine and rabbit myocytes, the density of INa,late was relatively stable during the plateau and decreased only along terminal repolarization of the AP, while GNa,late decreased monotonically. In contrast, INa,late increased monotonically, while GNa,late remained largely unchanged during the AP in guinea pig. The estimated slow inactivation of Na+ channels was much slower in guinea pig than in canine or rabbit myocytes. The characteristics of canine INa,late and GNa,late were not altered by using command APs recorded from rabbit or guinea pig myocytes, indicating that the different shapes of the current profiles are related to genuine interspecies differences in the gating of INa,late. Both INa,late and GNa,late decreased in canine myocytes when the intracellular Ca2+ concentration was reduced either by the extracellular application of 1 µM nisoldipine or by the intracellular application of BAPTA. Finally, a comparison of the INa,late and GNa,late profiles induced by the toxin of Anemonia sulcata (ATX-II) in canine and guinea pig myocytes revealed profound differences between the two species: in dog, the ATX-II induced INa,late and GNa,late showed kinetics similar to those observed with the native current, while in guinea pig, the ATX-II induced GNa,late increased during the AP. Our results show that there are notable interspecies differences in the gating kinetics of INa,late that cannot be explained by differences in AP morphology. These differences must be considered when interpreting the INa,late results obtained in guinea pig. Full article
(This article belongs to the Special Issue New Advances in Antiarrhythmic Drugs)
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18 pages, 2316 KiB  
Article
ABT-333 (Dasabuvir) Increases Action Potential Duration and Provokes Early Afterdepolarizations in Canine Left Ventricular Cells via Inhibition of IKr
by Zsigmond Máté Kovács, József Óvári, Csaba Dienes, János Magyar, Tamás Bányász, Péter P. Nánási, Balázs Horváth, Adam Feher, Zoltan Varga and Norbert Szentandrássy
Pharmaceuticals 2023, 16(4), 488; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16040488 - 25 Mar 2023
Viewed by 1469
Abstract
ABT-333 (dasabuvir) is an antiviral agent used in hepatitis C treatment. The molecule, similarly to some inhibitors of hERG channels, responsible for the delayed rectifier potassium current (IKr), contains the methanesulfonamide group. Reduced IKr current leads to long QT syndrome [...] Read more.
ABT-333 (dasabuvir) is an antiviral agent used in hepatitis C treatment. The molecule, similarly to some inhibitors of hERG channels, responsible for the delayed rectifier potassium current (IKr), contains the methanesulfonamide group. Reduced IKr current leads to long QT syndrome and early afterdepolarizations (EADs), therefore potentially causing life-threatening arrhythmias and sudden cardiac death. Our goal was to investigate the acute effects of ABT-333 in enzymatically isolated canine left ventricular myocardial cells. Action potentials (APs) and ion currents were recorded with a sharp microelectrode technique and whole-cell patch clamp, respectively. Application of 1 μM ABT-333 prolonged the AP in a reversible manner. The maximal rates of phases 0 and 1 were irreversibly decreased. Higher ABT-333 concentrations caused larger AP prolongation, elevation of the early plateau potential, and reduction of maximal rates of phases 0, 1, and 3. EADs occurred in some cells in 3–30 μM ABT-333 concentrations. The 10 μM ABT-333-sensitive current, recorded with AP voltage clamp, contained a late outward component corresponding to IKr and an early outward one corresponding to transient outward potassium current (Ito). ABT-333 reduced hERG-channel-mediated ion current in a concentration-dependent, partially reversible manner with a half-inhibitory concentration of 3.2 μM. As the therapeutic plasma concentration of ABT-333 is 1 nM, the arrhythmic risk of ABT-333 is very low, even in the case of drug overdose. Full article
(This article belongs to the Special Issue New Advances in Antiarrhythmic Drugs)
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22 pages, 4334 KiB  
Article
Drug Candidate BGP-15 Prevents Isoproterenol-Induced Arrhythmias and Alters Heart Rate Variability (HRV) in Telemetry-Implanted Rats
by Brigitta Bernat, Rita Erdelyi, Laszlo Fazekas, Greta Garami, Reka Maria Szekeres, Barbara Takacs, Mariann Bombicz, Balazs Varga, Fruzsina Sarkany, Arnold Peter Raduly, Dana Diana Romanescu, Zoltan Papp, Attila Toth, Zoltan Szilvassy, Bela Juhasz and Daniel Priksz
Pharmaceuticals 2023, 16(3), 359; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16030359 - 26 Feb 2023
Cited by 1 | Viewed by 1882
Abstract
Multi-target drug candidate BGP-15 has shown cardioprotective and antiarrhythmic actions in diseased models. Here, we investigated the effects of BGP-15 on ECG and echocardiographic parameters, heart rate variability (HRV), and arrhythmia incidence in telemetry-implanted rats, under beta-adrenergic stimulation by isoproterenol (ISO). In total, [...] Read more.
Multi-target drug candidate BGP-15 has shown cardioprotective and antiarrhythmic actions in diseased models. Here, we investigated the effects of BGP-15 on ECG and echocardiographic parameters, heart rate variability (HRV), and arrhythmia incidence in telemetry-implanted rats, under beta-adrenergic stimulation by isoproterenol (ISO). In total, 40 rats were implanted with radiotelemetry transmitters. First, dose escalation studies (40–160 mg/kg BGP-15), ECG parameters, and 24 h HRV parameters were assessed. After, rats were divided into Control, Control+BGP-15, ISO, and ISO+BGP-15 subgroups for 2 weeks. ECG recordings were obtained from conscious rats, arrhythmias and HRV parameters were assessed, and echocardiography was carried out. ISO-BGP-15 interaction was also evaluated on an isolated canine cardiomyocyte model. BGP-15 had no observable effects on the ECG waveforms; however, it decreased heart rate. HRV monitoring showed that BGP-15 increased RMSSD, SD1, and HF% parameters. BGP-15 failed to counteract 1 mg/kg ISO-induced tachycardia, but diminished the ECG of ischemia and suppressed ventricular arrhythmia incidence. Under echocardiography, after low-dose ISO injection, BGP-15 administration lowered HR and atrial velocities, and increased end-diastolic volume and ventricle relaxation, but did not counteract the positive inotropic effects of ISO. Two weeks of BGP-15 treatment also improved diastolic function in ISO-treated rats. In isolated cardiomyocytes, BGP-15 prevented 100 nM ISO-induced aftercontractions. Here, we show that BGP-15 increases vagally mediated HRV, reduces arrhythmogenesis, enhances left ventricle relaxation, and suppresses the aftercontractions of cardiomyocytes. As the drug is well tolerated, it may have a clinical value in preventing fatal arrhythmias. Full article
(This article belongs to the Special Issue New Advances in Antiarrhythmic Drugs)
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15 pages, 2000 KiB  
Article
A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5
by Szilvia Déri, Teodóra Hartai, László Virág, Norbert Jost, Alain J. Labro, András Varró, István Baczkó, Stanley Nattel and Balázs Ördög
Pharmaceuticals 2022, 15(12), 1550; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15121550 - 13 Dec 2022
Viewed by 1744
Abstract
Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac [...] Read more.
Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current IKs. While mutant LQT5 KCNE1 variants are known to inhibit IKs amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged IKs amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of IKs channels minimizes the inhibitory effects of LQT5 KCNE1 variants on IKs amplitudes, while current deactivation is accelerated. Such changes recapitulate IKs properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the IKs ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the IKs channel complex that regulates IKs function in cardiomyocytes and modifies the development of the LQT5 phenotype. Full article
(This article belongs to the Special Issue New Advances in Antiarrhythmic Drugs)
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