ijms-logo

Journal Browser

Journal Browser

Special Issue "Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets"

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 November 2019).

Special Issue Editors

Dr. Narcis Tribulova
E-Mail
Guest Editor
Center of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Bratislava, Slovakia
Interests: heart diseases; arrhythmia substrate; cardiac connexin-43; malignant arrhythmia prevention; omega-3 fatty acids; melatonin; benefits of healthy life style in fighting of cardiac arrhythmias
Prof. Dr. Robert Hatala
E-Mail
Guest Editor
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 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 “Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets” 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
Prof. Dr. Robert Hatala
Guest Editor

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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • 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

Published Papers (7 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle
Suppression of β1-Adrenoceptor Autoantibodies is Involved in the Antiarrhythmic Effects of Omega-3 Fatty Acids in Male and Female Hypertensive Rats
Int. J. Mol. Sci. 2020, 21(2), 526; https://doi.org/10.3390/ijms21020526 - 14 Jan 2020
Abstract
The arrhythmogenic potential of β1-adrenoceptor autoantibodies (β1-AA), as well as antiarrhythmic properties of omega-3 in heart diseases, have been reported while underlying mechanisms are poorly understood. We aimed to test our hypothesis that omega-3 (eicosapentaenoic acid-EPA, docosahexaenoic acid-DHA) may inhibit matrix metalloproteinase (MMP-2) [...] Read more.
The arrhythmogenic potential of β1-adrenoceptor autoantibodies (β1-AA), as well as antiarrhythmic properties of omega-3 in heart diseases, have been reported while underlying mechanisms are poorly understood. We aimed to test our hypothesis that omega-3 (eicosapentaenoic acid-EPA, docosahexaenoic acid-DHA) may inhibit matrix metalloproteinase (MMP-2) activity to prevent cleavage of β1-AR and formation of β1-AA resulting in attenuation of pro-arrhythmic connexin-43 (Cx43) and protein kinase C (PKC) signaling in the diseased heart. We have demonstrated that the appearance and increase of β1-AA in blood serum of male and female 12-month-old spontaneously hypertensive rats (SHR) was associated with an increase of inducible ventricular fibrillation (VF) comparing to normotensive controls. In contrast, supplementation of hypertensive rats with omega-3 for two months suppressed β1-AA levels and reduced incidence of VF. Suppression of β1-AA was accompanied by a decrease of elevated myocardial MMP-2 activity, preservation of cardiac cell membrane integrity and Cx43 topology. Moreover, omega-3 abrogated decline in expression of total Cx43 as well as its phosphorylated forms at serine 368 along with PKC-ε, while decreased pro-fibrotic PKC-δ levels in hypertensive rat heart regardless the sex. The implication of MMP-2 in the action of omega-3 was also demonstrated in cultured cardiomyocytes in which desensitization of β1-AR due to permanent activation of β1-AR with isoproterenol was prevented by MMP-2 inhibitor or EPA. Collectively, these data support the notion that omega-3 via suppression of β1-AA mechanistically controlled by MMP-2 may attenuate abnormal of Cx43 and PKC signaling; thus, abolish arrhythmia substrate and protect rats with an advanced stage of hypertension from malignant arrhythmias. Full article
Show Figures

Figure 1

Open AccessArticle
Association Between Antiarrhythmic, Electrophysiological, and Antioxidative Effects of Melatonin in Ischemia/Reperfusion
Int. J. Mol. Sci. 2019, 20(24), 6331; https://doi.org/10.3390/ijms20246331 - 15 Dec 2019
Abstract
Melatonin is assumed to confer cardioprotective action via antioxidative properties. We evaluated the association between ventricular tachycardia and/or ventricular fibrillation (VT/VF) incidence, oxidative stress, and myocardial electrophysiological parameters in experimental ischemia/reperfusion under melatonin treatment. Melatonin was given to 28 rats (10 mg/kg/day, orally, [...] Read more.
Melatonin is assumed to confer cardioprotective action via antioxidative properties. We evaluated the association between ventricular tachycardia and/or ventricular fibrillation (VT/VF) incidence, oxidative stress, and myocardial electrophysiological parameters in experimental ischemia/reperfusion under melatonin treatment. Melatonin was given to 28 rats (10 mg/kg/day, orally, for 7 days) and 13 animals received placebo. In the anesthetized animals, coronary occlusion was induced for 5 min followed by reperfusion with recording of unipolar electrograms from ventricular epicardium with a 64-lead array. Effects of melatonin on transmembrane potentials were studied in ventricular preparations of 7 rats in normal and “ischemic” conditions. Melatonin treatment was associated with lower VT/VF incidence at reperfusion, shorter baseline activation times (ATs), and activation-repolarization intervals and more complete recovery of repolarization times (RTs) at reperfusion (less baseline-reperfusion difference, ΔRT) (p < 0.05). Superoxide dismutase (SOD) activity was higher in the treated animals and associated with ΔRT (p = 0.001), whereas VT/VF incidence was associated with baseline ATs (p = 0.020). In vitro, melatonin led to a more complete restoration of action potential durations and resting membrane potentials at reoxygenation (p < 0.05). Thus, the antioxidative properties of melatonin were associated with its influence on repolarization duration, whereas the melatonin-related antiarrhythmic effect was associated with its oxidative stress-independent action on ventricular activation. Full article
Show Figures

Figure 1

Open AccessArticle
Ischemic Postconditioning Reduces Reperfusion Arrhythmias by Adenosine Receptors and Protein Kinase C Activation but Is Independent of KATP Channels or Connexin 43
Int. J. Mol. Sci. 2019, 20(23), 5927; https://doi.org/10.3390/ijms20235927 - 25 Nov 2019
Abstract
Ischemic postconditioning (IPoC) reduces reperfusion arrhythmias but the antiarrhythmic mechanisms remain unknown. The aim of this study was to analyze IPoC electrophysiological effects and the role played by adenosine A1, A2A and A3 receptors, protein kinase C, ATP-dependent potassium [...] Read more.
Ischemic postconditioning (IPoC) reduces reperfusion arrhythmias but the antiarrhythmic mechanisms remain unknown. The aim of this study was to analyze IPoC electrophysiological effects and the role played by adenosine A1, A2A and A3 receptors, protein kinase C, ATP-dependent potassium (KATP) channels, and connexin 43. IPoC reduced reperfusion arrhythmias (mainly sustained ventricular fibrillation) in isolated rat hearts, an effect associated with a transient delay in epicardial electrical activation, and with action potential shortening. Electrical impedance measurements and Lucifer-Yellow diffusion assays agreed with such activation delay. However, this delay persisted during IPoC in isolated mouse hearts in which connexin 43 was replaced by connexin 32 and in mice with conditional deletion of connexin 43. Adenosine A1, A2A and A3 receptor blockade antagonized the antiarrhythmic effect of IPoC and the associated action potential shortening, whereas exogenous adenosine reduced reperfusion arrhythmias and shortened action potential duration. Protein kinase C inhibition by chelerythrine abolished the protective effect of IPoC but did not modify the effects on action potential duration. On the other hand, glibenclamide, a KATP inhibitor, antagonized the action potential shortening but did not interfere with the antiarrhythmic effect. The antiarrhythmic mechanisms of IPoC involve adenosine receptor activation and are associated with action potential shortening. However, this action potential shortening is not essential for protection, as it persisted during protein kinase C inhibition, a maneuver that abolished IPoC protection. Furthermore, glibenclamide induced the opposite effects. In addition, IPoC delays electrical activation and electrical impedance recovery during reperfusion, but these effects are independent of connexin 43. Full article
Show Figures

Figure 1

Open AccessArticle
Examination of the Changes in Calcium Homeostasis in the Delayed Antiarrhythmic Effect of Sodium Nitrite
Int. J. Mol. Sci. 2019, 20(22), 5687; https://doi.org/10.3390/ijms20225687 - 13 Nov 2019
Abstract
We have evidence that the intravenous infusion of sodium nitrite (NaNO2) results in an antiarrhythmic effect when given 24 h prior to an ischemia and reperfusion (I/R) insult in anaesthetized dogs. This protection was associated with the reduction of reactive oxygen [...] Read more.
We have evidence that the intravenous infusion of sodium nitrite (NaNO2) results in an antiarrhythmic effect when given 24 h prior to an ischemia and reperfusion (I/R) insult in anaesthetized dogs. This protection was associated with the reduction of reactive oxygen species resulting from I/R through the attenuation of mitochondrial respiration. Here, we examined whether the changes in calcium, which also contributes to arrhythmia generation, play a role in the NaNO2-induced effect. On the first day, 30 anaesthetized dogs were treated either with saline or NaNO2 (0.2 µmol/kg/min) for 20 min. Some animals were subjected to a 25 min LAD (anterior descending branch of the left coronary artery) occlusion and 2 min reperfusion (I/R = 4; NaNO2-I/R = 6), or the heart was removed 24 h later. We have shown that nitrite prevented the I/R-induced increase in cellular and mitochondrial calcium deposits. During simulated I/R, the amplitude of the calcium transient and the diastolic calcium level were significantly lower in the nitrite-treated hearts and the ERP (effective refractory period) fraction of the action potential was significantly increased. Furthermore, nitrite also enhanced the mitochondrial respiratory response and prevented the MPTPT opening during calcium overload. These results suggest that nitrite can reduce the harmful consequences of calcium overload, perhaps directly by modulating ion channels or indirectly by reducing the mitochondrial ROS (reactive oxygen species) production. Full article
Show Figures

Figure 1

Open AccessArticle
Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress
Int. J. Mol. Sci. 2019, 20(17), 4076; https://doi.org/10.3390/ijms20174076 - 21 Aug 2019
Cited by 1
Abstract
Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and [...] Read more.
Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca2+-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsufficiency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response. Full article
Show Figures

Graphical abstract

Review

Jump to: Research

Open AccessReview
Missing Link Between Molecular Aspects of Ventricular Arrhythmias and QRS Complex Morphology in Left Ventricular Hypertrophy
Int. J. Mol. Sci. 2020, 21(1), 48; https://doi.org/10.3390/ijms21010048 - 19 Dec 2019
Abstract
The aim of this opinion paper is to point out the knowledge gap between evidence on the molecular level and clinical diagnostic possibilities in left ventricular hypertrophy (LVH) regarding the prediction of ventricular arrhythmias and monitoring the effect of therapy. LVH is defined [...] Read more.
The aim of this opinion paper is to point out the knowledge gap between evidence on the molecular level and clinical diagnostic possibilities in left ventricular hypertrophy (LVH) regarding the prediction of ventricular arrhythmias and monitoring the effect of therapy. LVH is defined as an increase in left ventricular size and is associated with increased occurrence of ventricular arrhythmia. Hypertrophic rebuilding of myocardium comprises interrelated processes on molecular, subcellular, cellular, tissue, and organ levels affecting electrogenesis, creating a substrate for triggering and maintaining arrhythmias. The knowledge of these processes serves as a basis for developing targeted therapy to prevent and treat arrhythmias. In the clinical practice, the method for recording electrical phenomena of the heart is electrocardiography. The recognized clinical electrocardiogram (ECG) predictors of ventricular arrhythmias are related to alterations in electrical impulse propagation, such as QRS complex duration, QT interval, early repolarization, late potentials, and fragmented QRS, and they are not specific for LVH. However, the simulation studies have shown that the QRS complex patterns documented in patients with LVH are also conditioned remarkably by the alterations in impulse propagation. These QRS complex patterns in LVH could be potentially recognized for predicting ventricular arrhythmia and for monitoring the effect of therapy. Full article
Show Figures

Figure 1

Open AccessReview
New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure—Targeting the Sympathetic Nervous System
Int. J. Mol. Sci. 2019, 20(10), 2430; https://doi.org/10.3390/ijms20102430 - 16 May 2019
Abstract
Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the [...] Read more.
Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising results, CVDs are responsible for ~17 million deaths per year globally with ~25% of these attributable to sudden cardiac death (SCD). Pre-clinical data demonstrated that renal denervation (RDN) decreases sympathetic activation as evaluated by decreased renal catecholamine concentrations. RDN is successful in reducing ventricular arrhythmias (VAs) triggering and its outcome was not found inferior to metoprolol in rat myocardial infarction model. Registry clinical data also suggest an advantageous effect of RDN to prevent VAs in HF patients and electrical storm. An in-depth investigation of how RDN, a minimally invasive and safe method, reduces the burden of HF is urgently needed. Myocardial systolic dysfunction is correlated to neuro-hormonal overactivity as a compensatory mechanism to keep cardiac output in the face of declining cardiac function. Sympathetic nervous system (SNS) overactivity is supported by a rise in plasma noradrenaline (NA) and adrenaline levels, raised central sympathetic outflow, and increased organ-specific spillover of NA into plasma. Cardiac NA spillover in untreated HF individuals can reach ~50-fold higher levels compared to those of healthy individuals under maximal exercise conditions. Increased sympathetic outflow to the renal vascular bed can contribute to the anomalies of renal function commonly associated with HF and feed into a vicious cycle of elevated BP, the progression of renal disease and worsening HF. Increased sympathetic activity, amongst other factors, contribute to the progress of cardiac arrhythmias, which can lead to SCD due to sustained ventricular tachycardia. Targeted therapies to avoid these detrimental consequences comprise antiarrhythmic drugs, surgical resection, endocardial catheter ablation and use of the implantable electronic cardiac devices. Analogous NA agents have been reported for single photon-emission-computed-tomography (SPECT) scans usage, specially the 123I-metaiodobenzylguanidine (123I-MIBG). Currently, HF prognosis assessment has been improved by this tool. Nevertheless, this radiotracer is costly, which makes the use of this diagnostic method limited. Comparatively, positron-emission-tomography (PET) overshadows SPECT imaging, because of its increased spatial definition and broader reckonable methodologies. Numerous ANS radiotracers have been created for cardiac PET imaging. However, so far, [11C]-meta-hydroxyephedrine (HED) has been the most significant PET radiotracer used in the clinical scenario. Growing data has shown the usefulness of [11C]-HED in important clinical situations, such as predicting lethal arrhythmias, SCD, and all-cause of mortality in reduced ejection fraction HF patients. In this article, we discussed the role and relevance of novel tools targeting the SNS, such as the [11C]-HED PET cardiac imaging and RDN to manage patients under of SCD risk. Full article
Show Figures

Graphical abstract

Back to TopTop