Submit to Biomolecules Review for Biomolecules Propose a Special Issue

Journal Browser

► Journal Browser

Molecular Pathogenesis of Cardiac Arrhythmia

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 29720

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special issue Molecular Pathogenesis of Cardiac Arrhythmia book cover image

Share This Special Issue

Special Issue Editors

Dr. Yosuke Okamoto

E-Mail Website
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. Kyoichi Ono

E-Mail Website
Guest Editor

Department of Cell Physiology, Akita University Graduate School of Medicine, Akita, Japan
Interests: cardiac automaticity; analysis of cell and organ functions on the basis of electrophysilogical methods; cardiovascular physiology; ion channel; transporter

Special Issue Information

Dear Colleagues,

As is well known, sustainable heart contractions with a regular rhythm are essential for life. Thus, the processes underlying the heartbeat have long been a significant focus of science. To our knowledge, the human heart is the first functional organ that starts to beat at embryonic week four. Once the heart’s function is activated, the heart continues to pump out oxygenated blood and fuel for the rest of one’s life. Several transcription factors have been reported to engage in the development of the early heart. In adults, ion channels, Ca²⁺ handling, muscle fibers, and cell signaling networks are regarded as fundamental to cardiac physiology. Several recent studies have shown that epigenetic regulation and immunologic responses also impact heart functions. Generally, cooperation among tens of thousands of biomolecules plays a role in maintaining cardiovascular homeostasis, and disorders of the principal system can lead to severe illnesses. Arrhythmia, disturbances of cardiac beating, can be life-threatening or, occasionally, lethal. Ventricular arrhythmias cause sudden cardiac death, while supraventricular arrhythmias, such as atrial fibrillation, complicate cerebral embolism, heart failure, and dementia. Unsurprisingly, there has recently been increasing interest in translational studies on the pathophysiology of cardiac arrhythmia.

This Special Issue, “Molecular Pathogenesis of Cardiac Arrhythmia”, will address novel insights into arrhythmia’s molecular mechanism based on original work. Our interests cover molecular biology, biochemistry, regenerative medicine, electrophysiology, mathematical simulation, bioinformatics, epigenetics, proteomics, and immunology.

Dr. Yosuke Okamoto
Dr. Kyoichi Ono
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. Biomolecules 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 2700 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

atrial fibrillation
heart rhythm
sudden cardiac death
ventricular arrhythmia

Published Papers (11 papers)

Download All Papers

Editorial

Jump to: Research, Review

3 pages, 187 KiB

Open AccessEditorial

Molecular Pathogenesis of Cardiac Arrhythmia

by Yosuke Okamoto and Kyoichi Ono

Biomolecules 2022, 12(10), 1393; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12101393 - 29 Sep 2022

Viewed by 1221

Abstract

The heart is a necessary organ for sustaining life in mammals, and it is the first organ to function during early development [...] Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

Research

Jump to: Editorial, Review

19 pages, 2962 KiB

Open AccessArticle

Comparative Study of Transcriptome in the Hearts Isolated from Mice, Rats, and Humans

by Daigo Okada, Yosuke Okamoto, Toshiro Io, Miho Oka, Daiki Kobayashi, Suzuka Ito, Ryo Yamada, Kuniaki Ishii and Kyoichi Ono

Biomolecules 2022, 12(6), 859; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060859 - 20 Jun 2022

Cited by 4 | Viewed by 2538

Abstract

The heart is a significant organ in mammalian life, and the heartbeat mechanism has been an essential focus of science. However, few studies have focused on species differences. Accordingly, challenges remain in studying genes that have universal functions across species and genes that determine species differences. Here, we analyzed transcriptome data in mouse, rat, and human atria, ventricles, and sinoatrial nodes (SA) obtained from different platforms and compared them by calculating specificity measure (SPM) values in consideration of species differences. Among the three heart regions, the species differences in SA were the greatest, and we searched for genes that determined the essential characteristics of SA, which was SHOX2 in our criteria. The SPM value of SHOX2 was prominently high across species. Similarly, by calculating SPM values, we identified 3 atrial-specific, 11 ventricular-specific, and 17 SA-specific markers. Ontology analysis identified 70 cardiac region- and species-specific ontologies. These results suggest that reanalyzing existing data by calculating SPM values may identify novel tissue-specific genes and species-dependent gene expression. This study identified the importance of SHOX2 as an SA-specific transcription factor, a novel cardiac regional marker, and species-dependent ontologies. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

18 pages, 35190 KiB

Open AccessFeature PaperArticle

Preferential Expression of Ca²⁺-Stimulable Adenylyl Cyclase III in the Supraventricular Area, including Arrhythmogenic Pulmonary Vein of the Rat Heart

by Yosuke Okamoto, Naing Ye Aung, Masahiro Tanaka, Yuji Takeda, Daichi Takagi, Wataru Igarashi, Kuniaki Ishii, Mitsunori Yamakawa and Kyoichi Ono

Biomolecules 2022, 12(5), 724; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12050724 - 20 May 2022

Cited by 4 | Viewed by 2078

Abstract

Ectopic excitability in pulmonary veins (PVs) is the major cause of atrial fibrillation. We previously reported that the inositol trisphosphate receptor in rat PV cardiomyocytes cooperates with the Na⁺-Ca²⁺ exchanger to provoke ectopic automaticity in response to norepinephrine. Here, we focused on adenylyl cyclase (AC) as another effector of norepinephrine stimulation. RT-PCR, immunohistochemistry, and Western blotting revealed that the abundant expression of Ca²⁺-stimulable AC3 was restricted to the supraventricular area, including the PVs. All the other AC isotypes hardly displayed any region-specific expressions. Immunostaining of isolated cardiomyocytes showed an enriched expression of AC3 along the t-tubules in PV myocytes. The cAMP-dependent response of L-type Ca²⁺ currents in the PV and LA cells is strengthened by the 0.1 mM intracellular Ca²⁺ condition, unlike in the ventricular cells. The norepinephrine-induced automaticity of PV cardiomyocytes was reversibly suppressed by 100 µM SQ22536, an adenine-like AC inhibitor. These findings suggest that the specific expression of AC3 along t-tubules may contribute to arrhythmogenic automaticity in rat PV cardiomyocytes. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

14 pages, 1669 KiB

Open AccessArticle

Propofol, an Anesthetic Agent, Inhibits HCN Channels through the Allosteric Modulation of the cAMP-Dependent Gating Mechanism

by Morihiro Shimizu, Xinya Mi, Futoshi Toyoda, Akiko Kojima, Wei-Guang Ding, Yutaka Fukushima, Mariko Omatsu-Kanbe, Hirotoshi Kitagawa and Hiroshi Matsuura

Biomolecules 2022, 12(4), 570; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12040570 - 12 Apr 2022

Cited by 5 | Viewed by 2016

Abstract

Propofol is a broadly used intravenous anesthetic agent that can cause cardiovascular effects, including bradycardia and asystole. A possible mechanism for these effects is slowing cardiac pacemaker activity due to inhibition of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. However, it remains unclear how propofol affects the allosteric nature of the voltage- and cAMP-dependent gating mechanism in HCN channels. To address this aim, we investigated the effect of propofol on HCN channels (HCN4 and HCN2) in heterologous expression systems using a whole-cell patch clamp technique. The extracellular application of propofol substantially suppressed the maximum current at clinical concentrations. This was accompanied by a hyperpolarizing shift in the voltage dependence of channel opening. These effects were significantly attenuated by intracellular loading of cAMP, even after considering the current modification by cAMP in opposite directions. The differential degree of propofol effects in the presence and absence of cAMP was rationalized by an allosteric gating model for HCN channels, where we assumed that propofol affects allosteric couplings between the pore, voltage-sensor, and cyclic nucleotide-binding domain (CNBD). The model predicted that propofol enhanced autoinhibition of pore opening by unliganded CNBD, which was relieved by the activation of CNBD by cAMP. Taken together, these findings reveal that propofol acts as an allosteric modulator of cAMP-dependent gating in HCN channels, which may help us to better understand the clinical action of this anesthetic drug. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

13 pages, 1957 KiB

Open AccessArticle

Intracellular Ca²⁺-Mediated Mechanisms for the Pacemaker Depolarization of the Mouse and Guinea Pig Sinus Node Tissue

by Iyuki Namekata, Kento Jitsukata, Ayumi Fukuda, Ryosuke Odaka, Shogo Hamaguchi and Hikaru Tanaka

Biomolecules 2022, 12(3), 377; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12030377 - 28 Feb 2022

Cited by 3 | Viewed by 2205

Abstract

Intracellular Ca²⁺-mediated mechanisms for pacemaker depolarization were studied in sinus node tissue preparations from mice and guinea pigs. Microelectrode recordings revealed that the sinus node of the mouse, which had a higher beating rate, had a steeper slope of the pacemaker depolarization than that of the guinea pig. BAPTA and ryanodine, agents that interfere with intracellular Ca²⁺, significantly decreased the slope of the pacemaker depolarization in both species. In contrast, SEA0400, a specific inhibitor of the Na⁺-Ca²⁺ exchanger (NCX), as well as change to low Na⁺ extracellular solution, significantly decreased the slope in the mouse, but not in the guinea pig. Niflumic acid, a blocker of the Ca²⁺ activated Cl⁻ channel, decreased the slope in both species. Confocal microscopy revealed the presence of spontaneous Ca²⁺ oscillations during the interval between Ca²⁺ transients; such phenomenon was more pronounced in the mouse than in the guinea pig. Thus, although intracellular Ca²⁺-mediated mechanisms were involved in the pacemaker depolarization of the sinus node in both species, the NCX current was involved in the mouse but not in the guinea pig. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Graphical abstract

10 pages, 1426 KiB

Open AccessArticle

The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031

by Fumiya Tamura, Shintaro Sugimoto, Mana Sugimoto, Kazuho Sakamoto, Masahiko Yamaguchi, Takeshi Suzuki, Keiichi Fukuda, Masaki Ieda and Junko Kurokawa

Biomolecules 2021, 11(9), 1385; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11091385 - 20 Sep 2021

Cited by 2 | Viewed by 2576

Abstract

Inhibition of K⁺-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 residue F656 and increase the sensitivity of hERG blockade by E-4031. Although these studies suggested that clinically used synthetic estrogens with similar structures have the marked potential to alter hERG functions, the hERG interactions with synthetic estrogens have not been assessed. We therefore examined whether ethinylestradiol (EE2), a synthetic estrogen used in oral contraceptives, affects hERG function and blockade by drugs. Supratherapeutic concentrations of EE2 did not alter amplitudes or kinetics of the hERG currents elicited by train pulses at 20 mV (0.1 Hz). On the other hand, EE2 at therapeutic concentrations reduced the degree of hERG current suppression by E-4031. The administration of EE2 followed by E-4031 blockade reversed the current suppression, suggesting that the interaction of EE2 and E-4031 alters hERG at the drug-binding site. The effects of EE2 on hERG blockade raised the possibility that other estrogens, including synthetic estrogens, can alter hERG blockade by drugs that cause QT prolongation and ventricular arrhythmias. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

19 pages, 1868 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

by Ewan Douglas Fowler and Spyros Zissimopoulos

Biomolecules 2022, 12(8), 1030; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12081030 - 26 Jul 2022

Cited by 9 | Viewed by 2973

Abstract

The ryanodine receptor (RyR2) has a critical role in controlling Ca²⁺ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca²⁺ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca²⁺ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca²⁺ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na⁺/Ca²⁺ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

15 pages, 1409 KiB

Open AccessFeature PaperReview

Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes

by Mariko Omatsu-Kanbe, Ryo Fukunaga, Xinya Mi and Hiroshi Matsuura

Biomolecules 2022, 12(7), 896; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12070896 - 27 Jun 2022

Cited by 2 | Viewed by 1954

Abstract

In the adult mammalian heart, no data have yet shown the existence of cardiomyocyte-differentiable stem cells that can be used to practically repair the injured myocardium. Atypically shaped cardiomyocytes (ACMs) are found in cultures of the cardiomyocyte-removed fraction obtained from cardiac ventricles from neonatal to aged mice. ACMs are thought to be a subpopulation of cardiomyocytes or immature cardiomyocytes, most closely resembling cardiomyocytes due to their spontaneous beating, well-organized sarcomere and the expression of cardiac-specific proteins, including some fetal cardiac gene proteins. In this review, we focus on the characteristics of ACMs compared with ventricular myocytes and discuss whether these cells can be substitutes for damaged cardiomyocytes. ACMs reside in the interstitial spaces among ventricular myocytes and survive under severely hypoxic conditions fatal to ventricular myocytes. ACMs have not been observed to divide or proliferate, similar to cardiomyocytes, but they maintain their ability to fuse with each other. Thus, it is worthwhile to understand the role of ACMs and especially how these cells perform cell fusion or function independently in vivo. It may aid in the development of new approaches to cell therapy to protect the injured heart or the clarification of the pathogenesis underlying arrhythmia in the injured heart. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

33 pages, 2773 KiB

Open AccessFeature PaperReview

Bifurcations and Proarrhythmic Behaviors in Cardiac Electrical Excitations

by Kunichika Tsumoto and Yasutaka Kurata

Biomolecules 2022, 12(3), 459; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12030459 - 16 Mar 2022

Cited by 3 | Viewed by 4251

Abstract

The heart is a hierarchical dynamic system consisting of molecules, cells, and tissues, and acts as a pump for blood circulation. The pumping function depends critically on the preceding electrical activity, and disturbances in the pattern of excitation propagation lead to cardiac arrhythmia and pump failure. Excitation phenomena in cardiomyocytes have been modeled as a nonlinear dynamical system. Because of the nonlinearity of excitation phenomena, the system dynamics could be complex, and various analyses have been performed to understand the complex dynamics. Understanding the mechanisms underlying proarrhythmic responses in the heart is crucial for developing new ways to prevent and control cardiac arrhythmias and resulting contractile dysfunction. When the heart changes to a pathological state over time, the action potential (AP) in cardiomyocytes may also change to a different state in shape and duration, often undergoing a qualitative change in behavior. Such a dynamic change is called bifurcation. In this review, we first summarize the contribution of ion channels and transporters to AP formation and our knowledge of ion-transport molecules, then briefly describe bifurcation theory for nonlinear dynamical systems, and finally detail its recent progress, focusing on the research that attempts to understand the developing mechanisms of abnormal excitations in cardiomyocytes from the perspective of bifurcation phenomena. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

12 pages, 588 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Automatic Activity Arising in Cardiac Muscle Sleeves of the Pulmonary Vein

by Pierre Bredeloux, Come Pasqualin, Romain Bordy, Veronique Maupoil and Ian Findlay

Biomolecules 2022, 12(1), 23; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12010023 - 24 Dec 2021

Cited by 7 | Viewed by 2676

Abstract

Ectopic activity in the pulmonary vein cardiac muscle sleeves can both induce and maintain human atrial fibrillation. A central issue in any study of the pulmonary veins is their difference from the left atrial cardiac muscle. Here, we attempt to summarize the physiological phenomena underlying the occurrence of ectopic electrical activity in animal pulmonary veins. We emphasize that the activation of multiple signaling pathways influencing not only myocyte electrophysiology but also the means of excitation–contraction coupling may be required for the initiation of triggered or automatic activity. We also gather information regarding not only the large-scale structure of cardiac muscle sleeves but also recent studies suggesting that cellular heterogeneity may contribute to the generation of arrythmogenic phenomena and to the distinction between pulmonary vein and left atrial heart muscle. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

14 pages, 1176 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Physiological and Pathophysiological Roles of Mitochondrial Na⁺-Ca²⁺ Exchanger, NCLX, in Hearts

by Ayako Takeuchi and Satoshi Matsuoka

Biomolecules 2021, 11(12), 1876; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11121876 - 14 Dec 2021

Cited by 11 | Viewed by 2749

Abstract

It has been over 10 years since SLC24A6/SLC8B1, coding the Na⁺/Ca²⁺/Li⁺ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na⁺-Ca²⁺ exchange, a major Ca²⁺ efflux system in cardiac mitochondria. This molecular identification enabled us to determine structure–function relationships, as well as physiological/pathophysiological contributions, and our understandings have dramatically increased. In this review, we provide an overview of the recent achievements in relation to NCLX, focusing especially on its heart-specific characteristics, biophysical properties, and spatial distribution in cardiomyocytes, as well as in cardiac mitochondria. In addition, we discuss the roles of NCLX in cardiac functions under physiological and pathophysiological conditions—the generation of rhythmicity, the energy metabolism, the production of reactive oxygen species, and the opening of mitochondrial permeability transition pores. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Molecular Pathogenesis of Cardiac Arrhythmia

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (11 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI