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Cells
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Mechanisms Driving Electropathology in Cardiac Arrhythmias
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Mechanisms Driving Electropathology in Cardiac Arrhythmias

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 April 2023) | Viewed by 4643

Special Issue Editors

Prof. Dr. Bianca Brundel

E-Mail Website
Guest Editor
Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands
Interests: molecular & cellular biology; proteostasis; pharmacology; atrial fibrillation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Natasja de Groot

E-Mail Website1 Website2
Guest Editor
Department of Cardiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
Interests: cardiac mapping; mechanism of cardiac arrhythmias; signal recording- and processing technologies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Emerging research findings indicate a key role for electropathology to drive cardiac arrhythmias, including the most common tachyarrhythmia atrial fibrillation. Electropathology is defined as electrical conduction disorders, and consequently contractile dysfunction, that are caused by molecular changes in atrial tissue, that drive structural changes (including myolysis, dilatation and fibrosis) and arrhythmia initiation and perpetuation (Brundel et. al. 2022).

To improve cardiac arrhythmia therapy and diagnostics, research is increasingly focused on dissection of the molecular mechanisms driving these diseases and the correlation with electrical properties of the atria, e.g. signal morphology or patterns of activation. In this special issue, we aim to present evidence from experimental and clinical studies on cardiac arrhythmias, that indicate key pathways in which molecular changes may occur. These pathways include, but are not limited to:

  • protein homeostasis (protesostasis)
  • stress signaling routes
  • inflammasome activation

Derailment of these pathways may result in impairment of cardiomyocyte calcium handling, complex patterns of electrical activation and contractile dysfunction. Importantly, key modulators within these pathways may also represent potential druggable and (bio-electrical) diagnostic targets and therefore may aid in achieving mechanism-based and personalized AF management.

We are pleased to invite you as a recognized expert in the field to contribute original articles, communications, and reviews covering mechanisms driving electropathology in cardiac arrhythmias.

Prof. Dr. Bianca Brundel
Prof. Dr. Natasja de Groot
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. Cells is an international peer-reviewed open access semimonthly 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

  • cardiac arrhythmia
  • electropathology
  • proteostasis
  • molecular mechanism
  • contractile function

Published Papers (4 papers)

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Research

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17 pages, 8072 KiB  
Article
A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome
by Jia Song, Jiao Wu, Dexter J. Robichaux, Tingting Li, Shuyue Wang, Maria J. Arredondo Sancristobal, Bingning Dong, Dobromir Dobrev, Jason Karch, Sandhya S. Thomas and Na Li
Cells 2024, 13(2), 108; https://doi.org/10.3390/cells13020108 - 05 Jan 2024
Viewed by 1094
Abstract
High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome [...] Read more.
High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and Aim2−/− mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not in the Aim2−/−-HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca2+-release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in Aim2−/− mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca2+-release in atrial myocytes. These data suggest that HPD creates a substrate conducive to AF development by activating the AIM2-inflammasome, which is associated with mitochondrial oxidative stress along with proarrhythmic SR Ca2+-release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations. Full article
(This article belongs to the Special Issue Mechanisms Driving Electropathology in Cardiac Arrhythmias)
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12 pages, 1255 KiB  
Article
Long-Term Alcohol-Activated c-Jun N-terminal Kinase Isoform 2 Preserves Cardiac Function but Drives Ca2+-Triggered Arrhythmias
by Nikola Ricchiuti, Kurtis Chenoweth, Xianlong Gao, Dan J. Bare, Jiajie Yan and Xun Ai
Cells 2023, 12(18), 2233; https://doi.org/10.3390/cells12182233 - 08 Sep 2023
Viewed by 851
Abstract
Long-term alcohol consumption leads to cardiac arrhythmias including atrial fibrillation (AF), the most common alcohol-related arrhythmia. While AF significantly increases morbidity and mortality in patients, it takes years for an alcoholic individual undergoing an adaptive status with normal cardiac function to reach alcoholic [...] Read more.
Long-term alcohol consumption leads to cardiac arrhythmias including atrial fibrillation (AF), the most common alcohol-related arrhythmia. While AF significantly increases morbidity and mortality in patients, it takes years for an alcoholic individual undergoing an adaptive status with normal cardiac function to reach alcoholic cardiomyopathy. The underlying mechanism remains unclear to date. In this study, we assessed the functional role of JNK2 in long-term alcohol-evoked atrial arrhythmogenicity but preserved cardiac function. Wild-type (WT) mice and cardiac-specific JNK2dn mice (with an overexpression of inactive dominant negative (dn) JNK2) were treated with alcohol (2 g/kg daily for 2 months; 2 Mo). Confocal Ca2+ imaging in the intact mouse hearts showed that long-term alcohol prolonged intracellular Ca2+ transient decay, and increased pacing-induced Ca2+ waves, compared to that of sham controls, while cardiac-specific JNK2 inhibition in JNK2dn mice precluded alcohol-evoked Ca2+-triggered activities. Moreover, activated JNK2 enhances diastolic SR Ca2+ leak in 24 h and 48 h alcohol-exposed HL-1 atrial myocytes as well as HEK-RyR2 cells (inducible expression of human RyR2) with the overexpression of tGFP-tagged active JNK2-tGFP or inactive JNK2dn-tGFP. Meanwhile, the SR Ca2+ load and systolic Ca2+ transient amplitude were both increased in ventricular myocytes, along with the preserved cardiac function in 2 Mo alcohol-exposed mice. Moreover, the role of activated JNK2 in SR Ca2+ overload and enhanced transient amplitude was also confirmed in long-term alcohol-exposed HL-1 atrial myocytes. In conclusion, our findings suggest that long-term alcohol-activated JNK2 is a key driver in preserved cardiac function, but at the expense of enhanced cardiac arrhythmogenicity. Modulating JNK2 activity could be a novel anti-arrhythmia therapeutic strategy. Full article
(This article belongs to the Special Issue Mechanisms Driving Electropathology in Cardiac Arrhythmias)
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Review

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23 pages, 1420 KiB  
Review
Role of Genetic Variation in Transcriptional Regulatory Elements in Heart Rhythm
by Timo Jonker, Phil Barnett, Gerard J. J. Boink and Vincent M. Christoffels
Cells 2024, 13(1), 4; https://doi.org/10.3390/cells13010004 - 19 Dec 2023
Viewed by 988
Abstract
Genetic predisposition to cardiac arrhythmias has been a field of intense investigation. Research initially focused on rare hereditary arrhythmias, but over the last two decades, the role of genetic variation (single nucleotide polymorphisms) in heart rate, rhythm, and arrhythmias has been taken into [...] Read more.
Genetic predisposition to cardiac arrhythmias has been a field of intense investigation. Research initially focused on rare hereditary arrhythmias, but over the last two decades, the role of genetic variation (single nucleotide polymorphisms) in heart rate, rhythm, and arrhythmias has been taken into consideration as well. In particular, genome-wide association studies have identified hundreds of genomic loci associated with quantitative electrocardiographic traits, atrial fibrillation, and less common arrhythmias such as Brugada syndrome. A significant number of associated variants have been found to systematically localize in non-coding regulatory elements that control the tissue-specific and temporal transcription of genes encoding transcription factors, ion channels, and other proteins. However, the identification of causal variants and the mechanism underlying their impact on phenotype has proven difficult due to the complex tissue-specific, time-resolved, condition-dependent, and combinatorial function of regulatory elements, as well as their modest conservation across different model species. In this review, we discuss research efforts aimed at identifying and characterizing-trait-associated variant regulatory elements and the molecular mechanisms underlying their impact on heart rate or rhythm. Full article
(This article belongs to the Special Issue Mechanisms Driving Electropathology in Cardiac Arrhythmias)
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16 pages, 1040 KiB  
Review
Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses
by Fabries G. Huiskes, Esther E. Creemers and Bianca J. J. M. Brundel
Cells 2023, 12(18), 2242; https://doi.org/10.3390/cells12182242 - 09 Sep 2023
Viewed by 1212
Abstract
Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that [...] Read more.
Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that drive electrical conduction disorders and AF (i.e., electropathology). Insights into AF-induced transcriptomic alterations may aid in a deeper understanding of electropathology. Specifically, RNA sequencing (RNA-seq) facilitates transcriptomic analyses and discovery of differences in gene expression profiles between patient groups. In the last decade, various RNA-seq studies have been conducted in atrial tissue samples of patients with AF versus controls in sinus rhythm. Identified differentially expressed molecular pathways so far include pathways related to mechanotransduction, ECM remodeling, ion channel signaling, and structural tissue organization through developmental and inflammatory signaling pathways. In this review, we provide an overview of the available human AF RNA-seq studies and highlight the molecular pathways identified. Additionally, a comparison is made between human RNA-seq findings with findings from experimental AF model systems and we discuss contrasting findings. Finally, we elaborate on new exciting RNA-seq approaches, including single-nucleotide variants, spatial transcriptomics and profiling of different populations of total RNA, small RNA and long non-coding RNA. Full article
(This article belongs to the Special Issue Mechanisms Driving Electropathology in Cardiac Arrhythmias)
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