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Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment

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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 (31 December 2021) | Viewed by 48083

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Dr. Narcis Tribulova

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Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 84104 Bratislava, Slovakia
Interests: inflammation; redox disorder; heart diseases; arrhythmia substrate; cardiac connexin-43; Cx-hemichannels; antiarrhythmic mechanisms of tested agents; omega-3 fatty acids; melatonin
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Dr. Peter Hlivak

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President of the Slovak Society of Cardiology, Deputy Head of Department of Arrhythmias and Cardiac Pacing, National Cardiovascular Institute, Bratislava, Slovakia
Interests: non-invasive and invasive evaluation and treatment of all cardiac arrhythmias, catheter ablation of complex arrhythmias, atrial fibrillation, ventricular arrhythmias and arrhythmias in grown-up congenital heart diseases, sudden cardiac death, basic and translational research

Prof. Dr. Robert Hatala

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Director of Department of Arrhythmias and Cardiac Pacing, National Cardiovascular Institute, Bratislava, Slovakia
Interests: diagnostic and treatment of cardiac arrhythmias; sudden cardiac death; invasive and non-invasive electro-cardiology; interdisciplinary cardiology; basic sciences; biomedical engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you know, cardiac rhythm disorders, i.e., arrhythmias, are a permanent focus of experimental and clinical cardiologists. This is because of high impact on mortality and morbidity worldwide, despite the progress of treatment in the last decades. Both invasive and non-invasive approaches are still not efficient enough to prevent the occurrence and/or recurrence of cardiac arrhythmias, such as atrial fibrillation (AF) and ventricular fibrillation (VF). AF is most frequent arrhythmia, whose incidence increases along with the high risk of stroke. VF is often the cause of sudden cardiac death and sometimes even in patients with an implantable cardioverter-defibrillator. Taken together, it is challenging to address this topic on both bench and bedside molecular levels to understand better arrhythmogenesis, since it is conditio sine qua non to discover novel targets and approaches to fight cardiac arrhythmias.

This Special Issue “Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment” will cover a selection of recent research topics and updated review articles based on the molecular and cellular view on cardiac arrhythmias and their possible prevention.

Dr. Narcis Tribulova
Dr. Peter Hlivak
Prof. Dr. Robert Hatala
Guest Editors

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Keywords

Heart diseases
Sudden cardiac arrhythmic death
Atrial fibrillation
Channelopathies
Connexin-43/40
Fibrosis
Conduction disturbances
Triggered activity
Autonomic misbalance
Hormones misbalance
Novel antiarrhyhmic targets
Non-invasive treatment

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Related Special Issue

Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets in International Journal of Molecular Sciences (12 articles)

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Research

Jump to: Review

15 pages, 3982 KiB

Open AccessArticle

Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

by William A. Agudelo, Sebastian Ramiro Gil-Quiñones, Alejandra Fonseca, Alvaro Arenas, Laura Castro, Diana Carolina Sierra-Díaz, Manuel A. Patarroyo, Paul Laissue, Carlos F. Suárez and Rodrigo Cabrera

Int. J. Mol. Sci. 2021, 22(23), 12861; https://doi.org/10.3390/ijms222312861 - 28 Nov 2021

Cited by 2 | Viewed by 2870

Abstract

Congenital long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of the QT interval and T-wave abnormalities, caused, in most cases, by mutations in KCNQ1, KCNH2, and SCN5A. Although the predominant pattern of LQTS inheritance is autosomal dominant, compound heterozygous mutations in genes encoding potassium channels have been reported, often with early disease onset and more severe phenotypes. Since the molecular mechanisms underlying severe phenotypes in carriers of compound heterozygous mutations are unknown, it is possible that these compound mutations lead to synergistic or additive alterations to channel structure and function. In this study, all-atom molecular dynamic simulations of KCNQ1 and hERG channels were carried out, including wild-type and channels with compound mutations found in two patients with severe LQTS phenotypes and limited family history of the disease. Because channels can likely incorporate different subunit combinations from different alleles, there are multiple possible configurations of ion channels in LQTS patients. This analysis allowed us to establish the structural impact of different configurations of mutant channels in the activated/open state. Our data suggest that channels with these mutations show moderate changes in folding energy (in most cases of stabilizing character) and changes in channel mobility and volume, differentiating them from each other and from WT. This would indicate possible alterations in K⁺ ion flow. Hetero-tetrameric mutant channels showed intermediate structural and volume alterations vis-à-vis homo-tetrameric channels. These findings support the hypothesis that hetero-tetrameric channels in patients with compound heterozygous mutations do not necessarily lead to synergistic structural alterations. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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18 pages, 42510 KiB

Open AccessArticle

Sarcomeres Morphology and Z-Line Arrangement Disarray Induced by Ventricular Premature Contractions through the Rac2/Cofilin Pathway

by Yu-Sheng Lin, Tzu-Hao Chang, Wan-Chun Ho, Shun-Fu Chang, Yung-Lung Chen, Shih-Tai Chang, Huang-Chung Chen, Kuo-Li Pan and Mien-Cheng Chen

Int. J. Mol. Sci. 2021, 22(20), 11244; https://doi.org/10.3390/ijms222011244 - 18 Oct 2021

Cited by 3 | Viewed by 3353

Abstract

The most common ventricular premature contractions (VPCs) originate from the right ventricular outflow tract (RVOT), but the molecular mechanisms of altered cytoskeletons of VPC-induced cardiomyopathy remain unexplored. We created a RVOT bigeminy VPC pig model (n = 6 in each group). Echocardiography was performed. The histopathological alternations in the LV myocardium were analyzed, and next generation sequencing (NGS) and functional enrichment analyses were employed to identify the differentially expressed genes (DEGs) responsible for the histopathological alternations. Finally, a cell silencing model was used to confirm the key regulatory gene and pathway. VPC pigs had increased LV diameters in the 6-month follow-up period. A histological study showed more actin cytoskeleton disorganization and actin accumulation over intercalated disc, Z-line arrangement disarray, increased β-catenin expression, and cardiomyocyte enlargement in the LV myocardium of the VPC pigs compared to the control pigs. The NGS study showed actin cytoskeleton signaling, RhoGDI signaling, and signaling by Rho Family GTPases and ILK Signaling presented z-scores with same activation states. The expressions of Rac family small GTPase 2 (Rac2), the p-cofilin/cofilin ratio, and the F-actin/G-actin ratio were downregulated in the VPC group compared to the control group. Moreover, the intensity and number of actin filaments per cardiomyocyte were significantly decreased by Rac2 siRNA in the cell silencing model. Therefore, the Rac2/cofilin pathway was found to play a crucial role in the sarcomere morphology and Z-line arrangement disarray induced by RVOT bigeminy VPCs. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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14 pages, 1992 KiB

Open AccessArticle

Melatonin Prevents Early but Not Delayed Ventricular Fibrillation in the Experimental Porcine Model of Acute Ischemia

by Alena S. Tsvetkova, Olesya G. Bernikova, Natalya J. Mikhaleva, Darya S. Khramova, Alexey O. Ovechkin, Marina M. Demidova, Pyotr G. Platonov and Jan E. Azarov

Int. J. Mol. Sci. 2021, 22(1), 328; https://doi.org/10.3390/ijms22010328 - 30 Dec 2020

Cited by 12 | Viewed by 2501

Abstract

Antiarrhythmic effects of melatonin have been demonstrated ex vivo and in rodent models, but its action in a clinically relevant large mammalian model remains largely unknown. Objectives of the present study were to evaluate electrophysiological and antiarrhythmic effects of melatonin in a porcine model of acute myocardial infarction. Myocardial ischemia was induced by 40-min coronary occlusion in 25 anesthetized pigs. After ischemia onset, 12 animals received melatonin (4 mg/kg). 48 intramyocardial electrograms were recorded from left ventricular wall and interventricular septum (IVS). In each lead, activation time (AT) and repolarization time (RT) were determined. During ischemia, ATs and dispersion of repolarization (DOR = RTmax − RTmin) increased reaching maximal values by 3–5 and 20–25 min, respectively. Ventricular fibrillation (VF) incidence demonstrated no relations to redox state markers and was associated with increased DOR and delayed ATs (specifically, in an IVS base, an area adjacent to the ischemic zone) (p = 0.031). Melatonin prevented AT increase in the IVS base, (p < 0.001) precluding development of early VF (1–5 min, p = 0.016). VF occurrence in the delayed phase (17–40 min) where DOR was maximal was not modified by melatonin. Thus, melatonin-related enhancement of activation prevented development of early VF in the myocardial infarction model. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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14 pages, 1904 KiB

Open AccessArticle

Structural, Pro-Inflammatory and Calcium Handling Remodeling Underlies Spontaneous Onset of Paroxysmal Atrial Fibrillation in JDP2-Overexpressing Mice

by Mariana S. Parahuleva, Jens Kockskämper, Jacqueline Heger, Wolfram Grimm, Anna Scherer, Sarah Bühler, Julian Kreutz, Rainer Schulz and Gerhild Euler

Int. J. Mol. Sci. 2020, 21(23), 9095; https://doi.org/10.3390/ijms21239095 - 30 Nov 2020

Cited by 8 | Viewed by 2558

Abstract

Background: Cardiac-specific JDP2 overexpression provokes ventricular dysfunction and atrial dilatation in mice. We performed in vivo studies on JDP2-overexpressing mice to investigate the impact of JDP2 on the predisposition to spontaneous atrial fibrillation (AF). Methods: JDP2-overexpression was started by withdrawal of a doxycycline diet in 4-week-old mice. The spontaneous onset of AF was documented by ECG within 4 to 5 weeks of JDP2 overexpression. Gene expression was analyzed by real-time RT-PCR and Western blots. Results: In atrial tissue of JDP2 mice, besides the 3.6-fold increase of JDP2 mRNA, no changes could be detected within one week of JDP2 overexpression. Atrial dilatation and hypertrophy, combined with elongated cardiomyocytes and fibrosis, became evident after 5 weeks of JDP2 overexpression. Electrocardiogram (ECG) recordings revealed prolonged PQ-intervals and broadened P-waves and QRS-complexes, as well as AV-blocks and paroxysmal AF. Furthermore, reductions were found in the atrial mRNA and protein level of the calcium-handling proteins NCX, Cav1.2 and RyR2, as well as of connexin40 mRNA. mRNA of the hypertrophic marker gene ANP, pro-inflammatory MCP1, as well as markers of immune cell infiltration (CD68, CD20) were increased in JDP2 mice. Conclusion: JDP2 is an important regulator of atrial calcium and immune homeostasis and is involved in the development of atrial conduction defects and arrhythmogenic substrates preceding paroxysmal AF. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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Review

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24 pages, 2178 KiB

Open AccessReview

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

by Katarina Andelova, Barbara Szeiffova Bacova, Matus Sykora, Peter Hlivak, Miroslav Barancik and Narcis Tribulova

Int. J. Mol. Sci. 2022, 23(3), 1416; https://doi.org/10.3390/ijms23031416 - 26 Jan 2022

Cited by 28 | Viewed by 5403

Abstract

The prevention of cardiac life-threatening ventricular fibrillation and stroke-provoking atrial fibrillation remains a serious global clinical issue, with ongoing need for novel approaches. Numerous experimental and clinical studies suggest that oxidative stress and inflammation are deleterious to cardiovascular health, and can increase heart susceptibility to arrhythmias. It is quite interesting, however, that various cardio-protective compounds with antiarrhythmic properties are potent anti-oxidative and anti-inflammatory agents. These most likely target the pro-arrhythmia primary mechanisms. This review and literature-based analysis presents a realistic view of antiarrhythmic efficacy and the molecular mechanisms of current pharmaceuticals in clinical use. These include the sodium-glucose cotransporter-2 inhibitors used in diabetes treatment, statins in dyslipidemia and naturally protective omega-3 fatty acids. This approach supports the hypothesis that prevention or attenuation of oxidative and inflammatory stress can abolish pro-arrhythmic factors and the development of an arrhythmia substrate. This could prove a powerful tool of reducing cardiac arrhythmia burden. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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16 pages, 1601 KiB

Open AccessReview

Strain Echocardiography to Predict Postoperative Atrial Fibrillation

by Francisco Javier Sánchez, Esther Pueyo and Emiliano Raúl Diez

Int. J. Mol. Sci. 2022, 23(3), 1355; https://doi.org/10.3390/ijms23031355 - 25 Jan 2022

Cited by 5 | Viewed by 3533

Abstract

Postoperative atrial fibrillation (POAF) complicates 15% to 40% of cardiovascular surgeries. Its incidence progressively increases with aging, reaching 50% in octogenarians. This arrhythmia is usually transient but it increases the risk of embolic stroke, prolonged hospital stay, and cardiovascular mortality. Though many pathophysiological mechanisms are known, POAF prediction is still a hot topic of discussion. Doppler echocardiogram and, lately, strain echocardiography have shown significant capacity to predict POAF. Alterations in oxidative stress, calcium handling, mitochondrial dysfunction, inflammation, fibrosis, and tissue aging are among the mechanisms that predispose patients to the perfect “atrial storm”. Manifestations of these mechanisms have been related to enlarged atria and impaired function, which can be detected prior to surgery. Specific alterations in the atrial reservoir and pump function, as well as atrial dyssynchrony determined by echocardiographic atrial strain, can predict POAF and help to shed light on which patients could benefit from preventive therapy. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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21 pages, 3702 KiB

Open AccessReview

Calcium Signaling Silencing in Atrial Fibrillation: Implications for Atrial Sodium Homeostasis

by Aaron D. Kaplan, Humberto C. Joca, Liron Boyman and Maura Greiser

Int. J. Mol. Sci. 2021, 22(19), 10513; https://doi.org/10.3390/ijms221910513 - 29 Sep 2021

Cited by 12 | Viewed by 3468

Abstract

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting more than 33 million people worldwide. Despite important advances in therapy, AF’s incidence remains high, and treatment often results in recurrence of the arrhythmia. A better understanding of the cellular and molecular changes that (1) trigger AF and (2) occur after the onset of AF will help to identify novel therapeutic targets. Over the past 20 years, a large body of research has shown that intracellular Ca²⁺ handling is dramatically altered in AF. While some of these changes are arrhythmogenic, other changes counteract cellular arrhythmogenic mechanisms (Calcium Signaling Silencing). The intracellular Na⁺ concentration ([Na⁺])_i is a key regulator of intracellular Ca²⁺ handling in cardiac myocytes. Despite its importance in the regulation of intracellular Ca²⁺ handling, little is known about [Na⁺]_i, its regulation, and how it might be changed in AF. Previous work suggests that there might be increases in the late component of the atrial Na⁺ current (I_Na,L) in AF, suggesting that [Na⁺]_i levels might be high in AF. Indeed, a pharmacological blockade of I_Na,L has been suggested as a treatment for AF. Here, we review calcium signaling silencing and changes in intracellular Na⁺ homeostasis during AF. We summarize the proposed arrhythmogenic mechanisms associated with increases in I_Na,L during AF and discuss the evidence from clinical trials that have tested the pharmacological I_Na,L blocker ranolazine in the treatment of AF. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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27 pages, 549 KiB

Open AccessReview

Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation

by Daniela Baracaldo-Santamaría, Kevin Llinás-Caballero, Julián Miguel Corso-Ramirez, Carlos Martín Restrepo, Camilo Alberto Dominguez-Dominguez, Dora Janeth Fonseca-Mendoza and Carlos Alberto Calderon-Ospina

Int. J. Mol. Sci. 2021, 22(15), 8090; https://doi.org/10.3390/ijms22158090 - 28 Jul 2021

Cited by 21 | Viewed by 5274

Abstract

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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23 pages, 5198 KiB

Open AccessReview

Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models

by Jieyun Bai, Yaosheng Lu, Yijie Zhu, Huijin Wang, Dechun Yin, Henggui Zhang, Diego Franco and Jichao Zhao

Int. J. Mol. Sci. 2021, 22(14), 7681; https://doi.org/10.3390/ijms22147681 - 19 Jul 2021

Cited by 6 | Viewed by 3551

Abstract

Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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14 pages, 1869 KiB

Open AccessReview

The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment

by Caroline Pham, Noelia Muñoz-Martín and Elisabeth M. Lodder

Int. J. Mol. Sci. 2021, 22(12), 6422; https://doi.org/10.3390/ijms22126422 - 15 Jun 2021

Cited by 12 | Viewed by 5199

Abstract

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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17 pages, 4254 KiB

Open AccessReview

The Defibrillation Conundrum: New Insights into the Mechanisms of Shock-Related Myocardial Injury Sustained from a Life-Saving Therapy

by Nicolas Clementy, Alexandre Bodin, Arnaud Bisson, Ana-Paula Teixeira-Gomes, Sebastien Roger, Denis Angoulvant, Valérie Labas and Dominique Babuty

Int. J. Mol. Sci. 2021, 22(9), 5003; https://doi.org/10.3390/ijms22095003 - 8 May 2021

Cited by 8 | Viewed by 5582

Abstract

Implantable cardiac defibrillators (ICDs) are recommended to prevent the risk of sudden cardiac death. However, shocks are associated with an increased mortality with a dose response effect, and a strategy of reducing electrical therapy burden improves the prognosis of implanted patients. We review the mechanisms of defibrillation and its consequences, including cell damage, metabolic remodeling, calcium metabolism anomalies, and inflammatory and pro-fibrotic remodeling. Electrical shocks do save lives, but also promote myocardial stunning, heart failure, and pro-arrhythmic effects as seen in electrical storms. Limiting unnecessary implantations and therapies and proposing new methods of defibrillation in the future are recommended. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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17 pages, 891 KiB

Open AccessReview

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

by Tadashi Nakajima, Shuntaro Tamura, Masahiko Kurabayashi and Yoshiaki Kaneko

Int. J. Mol. Sci. 2021, 22(8), 3930; https://doi.org/10.3390/ijms22083930 - 10 Apr 2021

Cited by 5 | Viewed by 3344

Abstract

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine. Full article

(This article belongs to the Special Issue Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment)

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