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Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets

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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 November 2019) | Viewed by 52658

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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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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 “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

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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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Advances in Understanding of Cardiac Arrhythmias for Innovative Treatment in International Journal of Molecular Sciences (12 articles)

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Editorial

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2 pages, 191 KiB

Open AccessEditorial

Editorial for the IJMS Special Issue “Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets”

by Narcis Tribulova

Int. J. Mol. Sci. 2023, 24(11), 9134; https://doi.org/10.3390/ijms24119134 - 23 May 2023

Viewed by 942

Abstract

Cardiac rhythm disorders, in particular life-threatening ventricular fibrillation and stroke-provoking fibrillation of the atria, are a permanent focus of both clinical and experimental cardiologists [...] Full article

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

Research

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16 pages, 3713 KiB

Open AccessArticle

Suppression of β1-Adrenoceptor Autoantibodies is Involved in the Antiarrhythmic Effects of Omega-3 Fatty Acids in Male and Female Hypertensive Rats

by Barbara Szeiffova Bacova, Jana Radosinska, Gerd Wallukat, Miroslav Barancik, Anne Wallukat, Vladimir Knezl, Matus Sykora, Ludovit Paulis and Narcis Tribulova

Int. J. Mol. Sci. 2020, 21(2), 526; https://doi.org/10.3390/ijms21020526 - 14 Jan 2020

Cited by 16 | Viewed by 3024

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) 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-ε signaling; thus, abolish arrhythmia substrate and protect rats with an advanced stage of hypertension from malignant arrhythmias. Full article

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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15 pages, 2130 KiB

Open AccessArticle

Association Between Antiarrhythmic, Electrophysiological, and Antioxidative Effects of Melatonin in Ischemia/Reperfusion

by Ksenia A. Sedova, Olesya G. Bernikova, Julia I. Cuprova, Alexandra D. Ivanova, Galina A. Kutaeva, Michael G. Pliss, Ekaterina V. Lopatina, Marina A. Vaykshnorayte, Emiliano R. Diez and Jan E. Azarov

Int. J. Mol. Sci. 2019, 20(24), 6331; https://doi.org/10.3390/ijms20246331 - 15 Dec 2019

Cited by 29 | Viewed by 3514

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, 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

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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16 pages, 4363 KiB

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Ischemic Postconditioning Reduces Reperfusion Arrhythmias by Adenosine Receptors and Protein Kinase C Activation but Is Independent of K_ATP Channels or Connexin 43

by Emiliano Raúl Diez, Jose Antonio Sánchez, Natalia Jorgelina Prado, Amira Zulma Ponce Zumino, David García-Dorado, Roberto Miguel Miatello and Antonio Rodríguez-Sinovas

Int. J. Mol. Sci. 2019, 20(23), 5927; https://doi.org/10.3390/ijms20235927 - 25 Nov 2019

Cited by 11 | Viewed by 3188

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, A_2A and A₃ receptors, protein kinase C, ATP-dependent potassium (K_ATP) 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, A_2A 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 K_ATP 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

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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16 pages, 2612 KiB

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Examination of the Changes in Calcium Homeostasis in the Delayed Antiarrhythmic Effect of Sodium Nitrite

by Vivien Demeter-Haludka, Mária Kovács, János Prorok, Norbert Nagy, András Varró and Ágnes Végh

Int. J. Mol. Sci. 2019, 20(22), 5687; https://doi.org/10.3390/ijms20225687 - 13 Nov 2019

Cited by 4 | Viewed by 2630

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 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

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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21 pages, 4453 KiB

Open AccessArticle

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

by Chantal J.M. van Opbergen, Maartje Noorman, Anna Pfenniger, Jaël S. Copier, Sarah H. Vermij, Zhen Li, Roel van der Nagel, Mingliang Zhang, Jacques M.T. de Bakker, Aaron M. Glass, Peter J. Mohler, Steven M. Taffet, Marc A. Vos, Harold V.M. van Rijen, Mario Delmar and Toon A.B. van Veen

Int. J. Mol. Sci. 2019, 20(17), 4076; https://doi.org/10.3390/ijms20174076 - 21 Aug 2019

Cited by 35 | Viewed by 5860

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 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

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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Review

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16 pages, 904 KiB

Open AccessReview

Role of Oxidative Stress in the Genesis of Ventricular Arrhythmias

by Adriana Adameova, Anureet K. Shah and Naranjan S. Dhalla

Int. J. Mol. Sci. 2020, 21(12), 4200; https://doi.org/10.3390/ijms21124200 - 12 Jun 2020

Cited by 46 | Viewed by 4388

Abstract

Ventricular arrhythmias, mainly lethal arrhythmias, such as ventricular tachycardia and fibrillation, may lead to sudden cardiac death. These are triggered as a result of cardiac injury due to chronic ischemia, acute myocardial infarction and various stressful conditions associated with increased levels of circulating catecholamines and angiotensin II. Several mechanisms have been proposed to underlie electrical instability of the heart promoting ventricular arrhythmias; however, oxidative stress which adversely affects ion homeostasis due to changes in the ion channel structure and function, seems to play a critical role in eliciting different types of ventricular arrhythmias. Prevention or mitigation of the severity of ventricular arrhythmias due to antioxidants has been indicated as the fundamental contribution in the field of preventive cardiology; however, novel interventions have to be developed for greater effectiveness and specificity in attenuating the adverse effects of oxidative stress. In this review, we have attempted to discuss proarrhythmic effects of oxidative stress differing in time and concentration dependence and highlight a molecular and cellular concept how it alters cardiac cell automaticity and conduction velocity sensitizing the probability of ventricular arrhythmias with resultant sudden cardiac death due to ischemic heart disease and other stressful situations. It is concluded that pharmacological approaches targeting multiple mechanisms besides oxidative stress might be more effective in the treatment of ventricular arrhythmias than current antiarrhythmic therapy. Full article

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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19 pages, 1154 KiB

Open AccessReview

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

by Narcis Tribulova, Lin Hai Kurahara, Peter Hlivak, Katsuya Hirano and Barbara Szeiffova Bacova

Int. J. Mol. Sci. 2020, 21(8), 2844; https://doi.org/10.3390/ijms21082844 - 19 Apr 2020

Cited by 22 | Viewed by 4939

Abstract

A perennial task is to prevent the occurrence and/or recurrence of most frequent or life-threatening cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF). VF may be lethal in cases without an implantable cardioverter defibrillator or with failure of this device. Incidences of AF, even the asymptomatic ones, jeopardize the patient’s life due to its complication, notably the high risk of embolic stroke. Therefore, there has been a growing interest in subclinical AF screening and searching for novel electrophysiological and molecular markers. Considering the worldwide increase in cases of thyroid dysfunction and diseases, including thyroid carcinoma, we aimed to explore the implication of thyroid hormones in pro-arrhythmic signaling in the pathophysiological setting. The present review provides updated information about the impact of altered thyroid status on both the occurrence and recurrence of cardiac arrhythmias, predominantly AF. Moreover, it emphasizes the importance of both thyroid status monitoring and AF screening in the general population, as well as in patients with thyroid dysfunction and malignancies. Real-world data on early AF identification in relation to thyroid function are scarce. Even though symptomatic AF is rare in patients with thyroid malignancies, who are under thyroid suppressive therapy, clinicians should be aware of potential interaction with asymptomatic AF. It may prevent adverse consequences and improve the quality of life. This issue may be challenging for an updated registry of AF in clinical practice. Thyroid hormones should be considered a biomarker for cardiac arrhythmias screening and their tailored management because of their multifaceted cellular actions. Full article

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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15 pages, 608 KiB

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Molecular Mechanisms, Diagnostic Aspects and Therapeutic Opportunities of Micro Ribonucleic Acids in Atrial Fibrillation

by Allan Böhm, Marianna Vachalcova, Peter Snopek, Ljuba Bacharova, Dominika Komarova and Robert Hatala

Int. J. Mol. Sci. 2020, 21(8), 2742; https://doi.org/10.3390/ijms21082742 - 15 Apr 2020

Cited by 13 | Viewed by 4291

Abstract

Micro ribonucleic acids (miRNAs) are short non-coding RNA molecules responsible for regulation of gene expression. They are involved in many pathophysiological processes of a wide spectrum of diseases. Recent studies showed their involvement in atrial fibrillation. They seem to become potential screening biomarkers for atrial fibrillation and even treatment targets for this arrhythmia. The aim of this review article was to summarize the latest knowledge about miRNA and their molecular relation to the pathophysiology, diagnosis and treatment of atrial fibrillation. Full article

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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14 pages, 1351 KiB

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The Pathogenic Role of Very Low Density Lipoprotein on Atrial Remodeling in the Metabolic Syndrome

by Hsiang-Chun Lee and Yi-Hsiung Lin

Int. J. Mol. Sci. 2020, 21(3), 891; https://doi.org/10.3390/ijms21030891 - 30 Jan 2020

Cited by 15 | Viewed by 4045

Abstract

Atrial fibrillation (AF) is the most common persistent arrhythmia, and can lead to systemic thromboembolism and heart failure. Aging and metabolic syndrome (MetS) are major risks for AF. One of the most important manifestations of MetS is dyslipidemia, but its correlation with AF is ambiguous in clinical observational studies. Although there is a paradoxical relationship between fasting cholesterol and AF incidence, the beneficial benefit from lipid lowering therapy in reduction of AF is significant. Here, we reviewed the health burden from AF and MetS, the association between two disease entities, and the metabolism of triglyceride, which is elevated in MetS. We also reviewed scientific evidence for the mechanistic links between very low density lipoproteins (VLDL), which primarily carry circulatory triglyceride, to atrial cardiomyopathy and development of AF. The effects of VLDL to atria suggesting pathogenic to atrial cardiomyopathy and AF include excess lipid accumulation, direct cytotoxicity, abbreviated action potentials, disturbed calcium regulation, delayed conduction velocities, modulated gap junctions, and sarcomere protein derangements. The electrical remodeling and structural changes in concert promote development of atrial cardiomyopathy in MetS and ultimately lead to vulnerability to AF. As VLDL plays a major role in lipid metabolism after meals (rather than fasting state), further human studies that focus on the effects/correlation of postprandial lipids to atrial remodeling are required to determine whether VLDL-targeted therapy can reduce MetS-related AF. On the basis of our scientific evidence, we propose a pivotal role of VLDL in MetS-related atrial cardiomyopathy and vulnerability to AF. Full article

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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17 pages, 2396 KiB

Open AccessReview

Missing Link Between Molecular Aspects of Ventricular Arrhythmias and QRS Complex Morphology in Left Ventricular Hypertrophy

by Ljuba Bacharova

Int. J. Mol. Sci. 2020, 21(1), 48; https://doi.org/10.3390/ijms21010048 - 19 Dec 2019

Cited by 18 | Viewed by 4183

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 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

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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27 pages, 4294 KiB

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New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure—Targeting the Sympathetic Nervous System

by Márcio Galindo Kiuchi, Janis Marc Nolde, Humberto Villacorta, Revathy Carnagarin, Justine Joy Su-Yin Chan, Leslie Marisol Lugo-Gavidia, Jan K. Ho, Vance B. Matthews, Girish Dwivedi and Markus P. Schlaich

Int. J. Mol. Sci. 2019, 20(10), 2430; https://doi.org/10.3390/ijms20102430 - 16 May 2019

Cited by 25 | Viewed by 10689

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 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

(This article belongs to the Special Issue Progress in Understanding of Cardiac Arrhythmia Mechanisms and Antiarrhythmic Targets)

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