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Mechanisms and Novel Therapeutic Approaches for Cardiac Arrhythmia

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 9178

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Special Issue Editors

Dr. István Koncz

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Guest Editor

Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School, University of Szeged, 6721 Szeged, Hungary
Interests: cellular electrophysiology; ion channels; action potentials; arrhythmias; acetylcholine; Purkinje fibers; J-wave syndromes; optical mapping

Dr. Arie O. Verkerk

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Co-Guest Editor

Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Interests: patch clamp; physiology; pacemakers; sodium channels; patch-clamp electrophysiology; electrophysiology; cardiology; patch-clamp techniques; channelopathies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We would like to draw your attention to a special issue of Biomedicines.

In this particular Special Issue, we aim to present recent advances in the understanding of cardiac arrhythmias and to introduce novel pharmacological and (clinical) treatments. Potential topics for this Special Issue, which is dealing with all aspects of cardiac arrhythmias, include, but are not limited to: acquired and inherited cardiac arrhythmias, ion channels and exchangers, intracellular Ca²⁺ homeostasis, impulse formation and conduction, animal and cell culture models, side effects of non-cardiac drugs, (non) cardiac modulatory factors in channelopathies disease severity, and treatment of arrhythmias. Contributions on arrhythmia treatments may focus on gene modulation, (new) blockers, and drugs involved in enhanced trafficking and expression.

Both reviews and original research articles are welcomed. We are looking forward to receiving your contributions.

Dr. István Koncz
Dr. Arie O. Verkerk
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

arrhythmias
whole heart
cardiomyocytes
ion channels
animal models
human induced pluripotent stem cell-derived cardiomyocytes

Published Papers (6 papers)

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Research

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22 pages, 3436 KiB

Open AccessArticle

The Action Potential Clamp Technique as a Tool for Risk Stratification of Sinus Bradycardia Due to Loss-of-Function Mutations in HCN4: An In Silico Exploration Based on In Vitro and In Vivo Data

by Arie O. Verkerk and Ronald Wilders

Biomedicines 2023, 11(9), 2447; https://doi.org/10.3390/biomedicines11092447 - 2 Sep 2023

Cited by 1 | Viewed by 1558

Abstract

These days, in vitro functional analysis of gene variants is becoming increasingly important for risk stratification of cardiac ion channelopathies. So far, such risk stratification has been applied to SCN5A, KCNQ1, and KCNH2 gene variants associated with Brugada syndrome and long QT syndrome types 1 and 2, respectively, but risk stratification of HCN4 gene variants related to sick sinus syndrome has not yet been performed. HCN4 is the gene responsible for the hyperpolarization-activated ‘funny’ current I_f, which is an important modulator of the spontaneous diastolic depolarization underlying the sinus node pacemaker activity. In the present study, we carried out a risk classification assay on those loss-of-function mutations in HCN4 for which in vivo as well as in vitro data have been published. We used the in vitro data to compute the charge carried by I_f (Q_f) during the diastolic depolarization phase of a prerecorded human sinus node action potential waveform and assessed the extent to which this Q_f predicts (1) the beating rate of the comprehensive Fabbri–Severi model of a human sinus node cell with mutation-induced changes in I_f and (2) the heart rate observed in patients carrying the associated mutation in HCN4. The beating rate of the model cell showed a very strong correlation with Q_f from the simulated action potential clamp experiments (R² = 0.95 under vagal tone). The clinically observed minimum or resting heart rates showed a strong correlation with Q_f (R² = 0.73 and R² = 0.71, respectively). While a translational perspective remains to be seen, we conclude that action potential clamp on transfected cells, without the need for further voltage clamp experiments and data analysis to determine individual biophysical parameters of I_f, is a promising tool for risk stratification of sinus bradycardia due to loss-of-function mutations in HCN4. In combination with an I_f blocker, this tool may also prove useful when applied to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) obtained from mutation carriers and non-carriers. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Cardiac Arrhythmia)

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13 pages, 2514 KiB

Open AccessArticle

Selective Inhibition of Cardiac Late Na⁺ Current Is Based on Fast Offset Kinetics of the Inhibitor

by Muhammad Naveed, Aiman Saleh A. Mohammed, Leila Topal, Zsigmond Máté Kovács, Csaba Dienes, József Ovári, Norbert Szentandrássy, János Magyar, Tamás Bányász, János Prorok, Norbert Jost, László Virág, István Baczkó, András Varró, Péter P. Nánási and Balázs Horváth

Biomedicines 2023, 11(9), 2383; https://doi.org/10.3390/biomedicines11092383 - 25 Aug 2023

Cited by 1 | Viewed by 773

Abstract

The present study was designed to test the hypothesis that the selectivity of blocking the late Na⁺ current (I_NaL) over the peak Na⁺ current (I_NaP) is related to the fast offset kinetics of the Na⁺ channel inhibitor. Therefore, the effects of 1 µM GS967 (I_NaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on I_NaL and I_NaP were compared in canine ventricular myocardium. I_NaP was estimated as the maximum velocity of action potential upstroke (V⁺_max). Equal amounts of I_NaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of I_NaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V⁺_max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of I_NaL over I_NaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of I_NaL over I_NaP is related to the fast offset kinetics of the Na⁺ channel inhibitor. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Cardiac Arrhythmia)

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11 pages, 2925 KiB

Open AccessArticle

I_Ks Activator ML277 Mildly Affects Repolarization and Arrhythmic Outcome in the CAVB Dog Model

by Joanne J. A. van Bavel, Henriëtte D. M. Beekman, Agnieszka Smoczyńska, Marcel A. G. van der Heyden and Marc A. Vos

Biomedicines 2023, 11(4), 1147; https://doi.org/10.3390/biomedicines11041147 - 11 Apr 2023

Cited by 1 | Viewed by 1015

Abstract

Long QT syndrome type 1 with affected I_Ks is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target I_Ks as antiarrhythmics. We examined the antiarrhythmic effect of I_Ks channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6–1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). I_Ks channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Cardiac Arrhythmia)

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13 pages, 4079 KiB

Open AccessArticle

The Anti-Epileptic Drugs Lamotrigine and Valproic Acid Reduce the Cardiac Sodium Current

by Lixia Jia, Arie O. Verkerk and Hanno L. Tan

Biomedicines 2023, 11(2), 477; https://doi.org/10.3390/biomedicines11020477 - 7 Feb 2023

Cited by 2 | Viewed by 1786

Abstract

Anti-epileptic drugs (AEDs) are associated with increased risk of sudden cardiac death. To establish whether gabapentin, lamotrigine, levetiracetam, pregabalin, and valproic acid reduce the Na_v1.5 current, we conducted whole-cell patch-clamp studies to study the effects of the five AEDs on currents of human cardiac Na_v1.5 channels stably expressed in HEK293 cells, and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. Lamotrigine and valproic acid exhibited inhibitory effects on the Na_v1.5 current in a concentration-dependent manner with an IC₅₀ of 142 ± 36 and 2022 ± 25 µM for lamotrigine and valproic acid, respectively. In addition, these drugs caused a hyperpolarizing shift of steady-state inactivation and a delay in recovery from inactivation. The changes on the Na_v1.5 properties were reflected by a reduction in AP upstroke velocity (43.0 ± 6.8% (lamotrigine) and 23.7 ± 10.6% (valproic acid) at 1 Hz) and AP amplitude; in contrast, AP duration was not changed. Gabapentin, levetiracetam, and pregabalin had no effect on the Na_v1.5 current. Lamotrigine and valproic acid reduce the Na_v1.5 current density and affect its gating properties, resulting in a decrease of the AP upstroke velocity. Gabapentin, levetiracetam, and pregabalin have no effects on the Na_v1.5 current. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Cardiac Arrhythmia)

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13 pages, 3198 KiB

Open AccessArticle

Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes

by Ching-Han Liu, Yao-Chang Chen, Yen-Yu Lu, Yung-Kuo Lin, Satoshi Higa, Shih-Ann Chen and Yi-Jen Chen

Biomedicines 2022, 10(11), 2727; https://doi.org/10.3390/biomedicines10112727 - 28 Oct 2022

Cited by 1 | Viewed by 1431

Abstract

Lithium intoxication induces Brugada-pattern ECG, ventricular arrhythmia, and sudden death with the predominant preference for the male over the female gender. This study investigated the mechanisms of gender difference in lithium-induced arrhythmogenesis. The ECG parameters were recorded in male and female rabbits before and after the intravenous administration of lithium chloride (LiCl) (1, 3, 10 mmol/kg). Patch clamps were used to study the sodium current (I_Na) and late sodium current (I_Na-late) in the isolated single male and female right ventricular outflow tract (RVOT) cardiomyocytes before and after LiCl. Male rabbits (n = 9) were more prone to developing lithium-induced Brugada-pattern ECG changes (incomplete right bundle branch block, ST elevation and QRS widening) with fatal arrhythmia (66.7% vs. 0%, p = 0.002) than in female (n = 7) rabbits at 10 mmol/kg (but not 1 or 3 mmol/kg). Compared to those in the female RVOT cardiomyocytes, LiCl (100 μM) reduced I_Na to a greater extent and increased I_Na-late in the male RVOT cardiomyocytes. Moreover, in the presence of ranolazine (the I_Na-late inhibitor, 3.6 mg/kg iv loading, followed by a second iv bolus 6.0 mg/kg administered 30 min later, n = 5), LiCl (10 mmol/kg) did not induce Brugada-pattern ECG changes (p < 0.005). The male gender is much predisposed to lithium-induced Brugada-pattern ECG changes with a greater impact on I_Na and I_Na-late in RVOT cardiomyocytes. Targeting I_Na-late may be a potential therapeutic strategy for Brugada syndrome-related ventricular tachyarrhythmia. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Cardiac Arrhythmia)

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Review

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22 pages, 2795 KiB

Open AccessReview

Towards Improved Human In Vitro Models for Cardiac Arrhythmia: Disease Mechanisms, Treatment, and Models of Atrial Fibrillation

by Carla Cofiño-Fabres, Robert Passier and Verena Schwach

Biomedicines 2023, 11(9), 2355; https://doi.org/10.3390/biomedicines11092355 - 23 Aug 2023

Cited by 2 | Viewed by 1558

Abstract

Heart rhythm disorders, arrhythmias, place a huge economic burden on society and have a large impact on the quality of life of a vast number of people. Arrhythmias can have genetic causes but primarily arise from heart tissue remodeling during aging or heart disease. As current therapies do not address the causes of arrhythmias but only manage the symptoms, it is of paramount importance to generate innovative test models and platforms for gaining knowledge about the underlying disease mechanisms which are compatible with drug screening. In this review, we outline the most important features of atrial fibrillation (AFib), the most common cardiac arrhythmia. We will discuss the epidemiology, risk factors, underlying causes, and present therapies of AFib, as well as the shortcomings and opportunities of current models for cardiac arrhythmia, including animal models, in silico and in vitro models utilizing human pluripotent stem cell (hPSC)-derived cardiomyocytes. Full article

(This article belongs to the Special Issue Mechanisms and Novel Therapeutic Approaches for Cardiac Arrhythmia)

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