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Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 July 2024) | Viewed by 17621

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Dr. Yosuke Okamoto

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Guest Editor

Department of Cell Physiology, Akita University Graduate School of Medicine, Akita, Japan
Interests: heart rhythm; cardiac arrhythmia; atrial fibrillation; ventricular arrhythmia; ion channel; heart transcriptome; adrenergic signaling pathway
Special Issues, Collections and Topics in MDPI journals

Dr. Kunichika Tsumoto

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Guest Editor

Department of Physiology II, Kanazawa Medical University, Uchinada, Japan
Interests: mathematical models; cardiomyocytes; action potential; conduction; cardiac arrhythmia; electrophysiology; bifurcation phenomena; nonlinear dynamical system

Special Issue Information

Dear Colleagues,

As is well known, heart disease is the leading cause of death worldwide. Arrhythmias play a significant role in the terminal manifestation of cardiac disease, including the failure of blood circulation due to ventricular arrhythmias and the highly mortal cerebral infarction associated with atrial arrhythmias. Thus, arrhythmia research has been a priority for many years because controlling arrhythmias directly contributes to controlling the prognosis of cardiac disease. Our research into the mechanisms of arrhythmias first requires an understanding of the sophisticated regulatory system of cardiac excitation, and arrhythmias are essentially a breakdown of the finely regulated cardiac excitation system. Because cardiac excitation is coupled with cardiac contraction, lethal biological problems are ultimately triggered. There are several classifications of arrhythmias, such as atrial and ventricular arrhythmias, and there are a variety of approaches, from nanoscale basic research to clinical, epidemiological studies, to elucidate the mechanisms of arrhythmogenesis for each arrhythmia type.

This Special Issue, “Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies”, will address novel insights into the molecular mechanisms of arrhythmias based on original work. Our interests range from basic research in structural biology, molecular biology, electrophysiology, pharmacology, and immunology, to clinical research in antiarrhythmic therapy, catheter ablation, and novel clinical devices, as long as the research questions involve the mechanisms of arrhythmogenesis.

Dr. Yosuke Okamoto
Dr. Kunichika Tsumoto
Guest Editors

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Keywords

ion channel
atrial fibrillation
cardiac sudden death
after-depolarization
mathematical model analysis
catheter ablation
antiarrhythmic drug
medical device

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Published Papers (10 papers)

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Research

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14 pages, 3580 KiB

Open AccessArticle

Enhanced Late I_Na Induces Intracellular Ion Disturbances and Automatic Activity in the Guinea Pig Pulmonary Vein Cardiomyocytes

by Taro Saito, Mahiru Suzuki, Aiko Ohba, Shogo Hamaguchi, Iyuki Namekata and Hikaru Tanaka

Int. J. Mol. Sci. 2024, 25(16), 8688; https://doi.org/10.3390/ijms25168688 - 9 Aug 2024

Viewed by 749

Abstract

The effects of enhanced late I_Na, a persistent component of the Na⁺ channel current, on the intracellular ion dynamics and the automaticity of the pulmonary vein cardiomyocytes were studied with fluorescent microscopy. Anemonia viridis toxin II (ATX- II), an enhancer of late I_Na, caused increases in the basal Na⁺ and Ca²⁺ concentrations, increases in the number of Ca²⁺ sparks and Ca²⁺ waves, and the generation of repetitive Ca²⁺ transients. These phenomena were inhibited by eleclazine, a blocker of the late I_Na; SEA0400, an inhibitor of the Na⁺/Ca²⁺ exchanger (NCX); H89, a protein kinase A (PKA) inhibitor; and KN-93, a Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These results suggest that enhancement of late I_Na in the pulmonary vein cardiomyocytes causes disturbance of the intracellular ion environment through activation of the NCX and Ca²⁺-dependent enzymes. Such mechanisms are probably involved in the ectopic electrical activity of the pulmonary vein myocardium. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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15 pages, 7223 KiB

Open AccessArticle

Eicosapentaenoic Acid Rescues Cav1.2-L-Type Ca²⁺ Channel Decline Caused by Saturated Fatty Acids via Both Free Fatty Acid Receptor 4-Dependent and -Independent Pathways in Cardiomyocytes

by Masaki Morishima, Pu Wang, Kosuke Horii, Kazuki Horikawa and Katsushige Ono

Int. J. Mol. Sci. 2024, 25(14), 7570; https://doi.org/10.3390/ijms25147570 - 10 Jul 2024

Cited by 1 | Viewed by 1849

Abstract

Dietary intake of omega-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA) exerts antiarrhythmic effects, although the mechanisms are poorly understood. Here, we investigated the possible beneficial actions of EPA on saturated fatty acid-induced changes in the L-type Ca²⁺ channel in cardiomyocytes. Cardiomyocytes were cultured with an oleic acid/palmitic acid mixture (OAPA) in the presence or absence of EPA. Beating rate reduction in cardiomyocytes caused by OAPA were reversed by EPA. EPA also retrieved a reduction in Cav1.2 L-type Ca²⁺ current, mRNA, and protein caused by OAPA. Immunocytochemical analysis revealed a distinct downregulation of the Cav1.2 channel caused by OAPA with a concomitant decrease in the phosphorylated component of a transcription factor adenosine-3′,5′-cyclic monophosphate (cAMP) response element binding protein (CREB) in the nucleus, which were rescued by EPA. A free fatty acid receptor 4 (FFAR4) agonist TUG-891 reversed expression of Cav1.2 and CREB mRNA caused by OAPA, whereas an FFAR4 antagonist AH-7614 abolished the effects of EPA. Excessive reactive oxygen species (ROS) accumulation caused by OAPA decreased Cav1.2 and CREB mRNA expressions, which was reversed by an ROS scavenger. Our data suggest that EPA rescues cellular Cav1.2-Ca²⁺ channel decline caused by OAPA lipotoxicity and oxidative stresses via both free fatty acid receptor 4-dependent and -independent pathways. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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18 pages, 7746 KiB

Open AccessArticle

Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton’s Tyrosine Kinase Inhibitor Acalabrutinib

by Yanan Zhao, Praloy Chakraborty, Julianna Tomassetti, Tasnia Subha, Stéphane Massé, Paaladinesh Thavendiranathan, Filio Billia, Patrick F. H. Lai, Husam Abdel-Qadir and Kumaraswamy Nanthakumar

Int. J. Mol. Sci. 2024, 25(11), 6207; https://doi.org/10.3390/ijms25116207 - 5 Jun 2024

Viewed by 1150

Abstract

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton’s tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague–Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca²⁺ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca²⁺ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca²⁺ leak and Ca²⁺ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca²⁺ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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18 pages, 3052 KiB

Open AccessArticle

Ionic Mechanisms of Propagated Repolarization in a One-Dimensional Strand of Human Ventricular Myocyte Model

by Yukiko Himeno, Yixin Zhang, Suzuka Enomoto, Hiroto Nomura, Natsuki Yamamoto, Shotaro Kiyokawa, Mirei Ujihara, Yuttamol Muangkram, Akinori Noma and Akira Amano

Int. J. Mol. Sci. 2023, 24(20), 15378; https://doi.org/10.3390/ijms242015378 - 19 Oct 2023

Cited by 1 | Viewed by 1245

Abstract

Although repolarization has been suggested to propagate in cardiac tissue both theoretically and experimentally, it has been challenging to estimate how and to what extent the propagation of repolarization contributes to relaxation because repolarization only occurs in the course of membrane excitation in normal hearts. We established a mathematical model of a 1D strand of 600 myocytes stabilized at an equilibrium potential near the plateau potential level by introducing a sustained component of the late sodium current (I_NaL). By applying a hyperpolarizing stimulus to a small part of the strand, we succeeded in inducing repolarization which propagated along the strand at a velocity of 1~2 cm/s. The ionic mechanisms responsible for repolarization at the myocyte level, i.e., the deactivation of both the I_NaL and the L-type calcium current (I_CaL), and the activation of the rapid component of delayed rectifier potassium current (I_Kr) and the inward rectifier potassium channel (I_K1), were found to be important for the propagation of repolarization in the myocyte strand. Using an analogy with progressive activation of the sodium current (I_Na) in the propagation of excitation, regenerative activation of the predominant magnitude of I_K1 makes the myocytes at the wave front start repolarization in succession through the electrical coupling via gap junction channels. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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17 pages, 2274 KiB

Open AccessArticle

The W101C KCNJ5 Mutation Induces Slower Pacing by Constitutively Active GIRK Channels in hiPSC-Derived Cardiomyocytes

by Anne Kayser, Sven Dittmann, Tomo Šarić, Giulia Mearini, Arie O. Verkerk and Eric Schulze-Bahr

Int. J. Mol. Sci. 2023, 24(20), 15290; https://doi.org/10.3390/ijms242015290 - 18 Oct 2023

Cited by 2 | Viewed by 1384

Abstract

Mutations in the KCNJ5 gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K⁺ (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K⁺ current (I_K,ACh). hiPSC-CMs with the W101C KCNJ5 mutation (hiPSC^W101C-CM) had a constitutively active I_K,ACh under baseline conditions; the application of carbachol was able to increase I_K,ACh, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSC^W101C-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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13 pages, 2066 KiB

Open AccessArticle

Selective Inhibition of Pulmonary Vein Excitability by Constitutively Active GIRK Channels Blockade in Rats

by Ian Findlay, Côme Pasqualin, Angèle Yu, Véronique Maupoil and Pierre Bredeloux

Int. J. Mol. Sci. 2023, 24(17), 13629; https://doi.org/10.3390/ijms241713629 - 4 Sep 2023

Cited by 1 | Viewed by 1040

Abstract

Pulmonary veins (PV) are the main source of ectopy, triggering atrial fibrillation. This study investigated the roles of G protein-coupled inwardly rectifying potassium (GIRK) channels in the PV and the left atrium (LA) of the rat. Simultaneous intracellular microelectrode recording from the LA and the PV of the rat found that in the presence or absence of acetylcholine, the GIRK channel blocker tertiapin-Q induced AP duration elongation in the LA and the loss of over-shooting AP in the PV, suggesting the presence of constitutively active GIRK channels in these tissues. Patch-clamp recordings from isolated myocytes showed that tertiapin-Q inhibited a basal inwardly rectified background current in PV cells with little effect in LA cells. Experiments with ROMK1 and KCa1.1 channel blockers ruled out the possibility of an off-target effect. Western blot showed that GIRK4 subunit expression was greater in PV cardiomyocytes, which may explain the differences observed between PV and LA in response to tertiapin-Q. In conclusion, GIRK channels blockade abolishes AP only in the PV, providing a molecular target to induce electrical disconnection of the PV from the LA. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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16 pages, 1941 KiB

Open AccessArticle

Bioinformatic Identification of Potential RNA Alterations on the Atrial Fibrillation Remodeling from Human Pulmonary Veins

by Wataru Igarashi, Daichi Takagi, Daigo Okada, Daiki Kobayashi, Miho Oka, Toshiro Io, Kuniaki Ishii, Kyoichi Ono, Hiroshi Yamamoto and Yosuke Okamoto

Int. J. Mol. Sci. 2023, 24(13), 10501; https://doi.org/10.3390/ijms241310501 - 22 Jun 2023

Cited by 2 | Viewed by 2198

Abstract

Atrial fibrillation (AF) is the most frequent persistent arrhythmia. Many genes have been reported as a genetic background for AF. However, most transcriptome analyses of AF are limited to the atrial samples and have not been evaluated by multiple cardiac regions. In this study, we analyzed the expression levels of protein-coding and long noncoding RNAs (lncRNAs) in six cardiac regions by RNA-seq. Samples were donated from six subjects with or without persistent AF for left atria, left atrial appendages, right atria, sinoatrial nodes, left ventricles, right ventricles, and pulmonary veins (PVs), and additional four right atrial appendages samples were collected from patients undergoing mitral valve replacement. In total, 23 AF samples were compared to 23 non-AF samples. Surprisingly, the most influenced heart region in gene expression by AF was the PV, not the atria. The ion channel-related gene set was significantly enriched upon analysis of these significant genes. In addition, some significant genes are cancer-related lncRNAs in PV in AF. A co-expression network analysis could detect the functional gene clusters. In particular, the cancer-related lncRNA, such as SAMMSON and FOXCUT, belong to the gene network with the cancer-related transcription factor FOXC1. Thus, they may also play an aggravating role in the pathogenesis of AF, similar to carcinogenesis. In the least, this study suggests that (1) RNA alteration is most intense in PVs and (2) post-transcriptional gene regulation by lncRNA may contribute to the progression of AF. Through the screening analysis across the six cardiac regions, the possibility that the PV region can play a role other than paroxysmal triggering in the pathogenesis of AF was demonstrated for the first time. Future research with an increase in the number of PV samples will lead to a novel understanding of the pathophysiology of AF. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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Review

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27 pages, 1506 KiB

Open AccessReview

Atrial Fibrillation and Underlying Structural and Electrophysiological Heterogeneity

by Satoshi Iwamiya, Kensuke Ihara, Giichi Nitta and Tetsuo Sasano

Int. J. Mol. Sci. 2024, 25(18), 10193; https://doi.org/10.3390/ijms251810193 - 23 Sep 2024

Viewed by 1508

Abstract

As atrial fibrillation (AF) progresses from initial paroxysmal episodes to the persistent phase, maintaining sinus rhythm for an extended period through pharmacotherapy and catheter ablation becomes difficult. A major cause of the deteriorated treatment outcome is the atrial structural and electrophysiological heterogeneity, which AF itself can exacerbate. This heterogeneity exists or manifests in various dimensions, including anatomically segmental structural features, the distribution of histological fibrosis and the autonomic nervous system, sarcolemmal ion channels, and electrophysiological properties. All these types of heterogeneity are closely related to the development of AF. Recognizing the heterogeneity provides a valuable approach to comprehending the underlying mechanisms in the complex excitatory patterns of AF and the determining factors that govern the seemingly chaotic propagation. Furthermore, substrate modification based on heterogeneity is a potential therapeutic strategy. This review aims to consolidate the current knowledge on structural and electrophysiological atrial heterogeneity and its relation to the pathogenesis of AF, drawing insights from clinical studies, animal and cell experiments, molecular basis, and computer-based approaches, to advance our understanding of the pathophysiology and management of AF. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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15 pages, 2954 KiB

Open AccessReview

Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk

by Kazuharu Furutani

Int. J. Mol. Sci. 2023, 24(22), 16261; https://doi.org/10.3390/ijms242216261 - 13 Nov 2023

Cited by 2 | Viewed by 2187

Abstract

Modulation of the human Ether-à-go-go-Related Gene (hERG) channel, a crucial voltage-gated potassium channel in the repolarization of action potentials in ventricular myocytes of the heart, has significant implications on cardiac electrophysiology and can be either antiarrhythmic or proarrhythmic. For example, hERG channel blockade is a leading cause of long QT syndrome and potentially life-threatening arrhythmias, such as torsades de pointes. Conversely, hERG channel blockade is the mechanism of action of Class III antiarrhythmic agents in terminating ventricular tachycardia and fibrillation. In recent years, it has been recognized that less proarrhythmic hERG blockers with clinical potential or Class III antiarrhythmic agents exhibit, in addition to their hERG-blocking activity, a second action that facilitates the voltage-dependent activation of the hERG channel. This facilitation is believed to reduce the proarrhythmic potential by supporting the final repolarizing of action potentials. This review covers the pharmacological characteristics of hERG blockers/facilitators, the molecular mechanisms underlying facilitation, and their clinical significance, as well as unresolved issues and requirements for research in the fields of ion channel pharmacology and drug-induced arrhythmias. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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12 pages, 657 KiB

Open AccessReview

The Role of TRPM4 in Cardiac Electrophysiology and Arrhythmogenesis

by Yaopeng Hu, Jiehui Cang, Keizo Hiraishi, Takayuki Fujita and Ryuji Inoue

Int. J. Mol. Sci. 2023, 24(14), 11798; https://doi.org/10.3390/ijms241411798 - 22 Jul 2023

Cited by 2 | Viewed by 2083

Abstract

The transient receptor potential melastatin 4 (TRPM4) channel is a non-selective cation channel that activates in response to increased intracellular Ca²⁺ levels but does not allow Ca²⁺ to pass through directly. It plays a crucial role in regulating diverse cellular functions associated with intracellular Ca²⁺ homeostasis/dynamics. TRPM4 is widely expressed in the heart and is involved in various physiological and pathological processes therein. Specifically, it has a significant impact on the electrical activity of cardiomyocytes by depolarizing the membrane, presumably via Na⁺ loading. The TRPM4 channel likely contributes to the development of cardiac arrhythmias associated with specific genetic backgrounds and cardiac remodeling. This short review aims to overview what is known so far about the TRPM4 channel in cardiac electrophysiology and arrhythmogenesis, highlighting its potential as a novel therapeutic target to effectively prevent and treat cardiac arrhythmias. Full article

(This article belongs to the Special Issue Cardiac Arrhythmia: Molecular Mechanisms and Therapeutic Strategies)

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