Redox State in Atrial Fibrillation Pathogenesis and Relevant Therapeutic Approaches

Background: Myocardial redox state is a critical determinant of atrial biology, regulating cardiomyocyte apoptosis, ion channel function, and cardiac hypertrophy/fibrosis and function. Nevertheless, it remains unclear whether the targeting of atrial redox state is a rational therapeutic strategy for atrial fibrillation prevention. Objective: To review the role of atrial redox state and anti-oxidant therapies in atrial fibrillation. Method: Published literature in Medline was searched for experimental and clinical evidence linking myocardial redox state with atrial fibrillation pathogenesis as well as studies looking into the role of redoxtargeting therapies in the prevention of atrial fibrillation. Results: Data from animal models have shown that altered myocardial nitroso-redox balance and NADPH oxidases activity are causally involved in the pathogenesis of atrial fibrillation. Similarly experimental animal data supports that increased reactive oxygen / nitrogen species formation in the atrial tissue is associated with altered electrophysiological properties of atrial myocytes and electrical remodeling, favoring atrial fibrillation development. In humans, randomized clinical studies using redox-related therapeutic approaches (e.g. statins or antioxidant agents) have not documented any benefits in the prevention of atrial fibrillation development (mainly post-operative atrial fibrillation risk). Conclusion: Despite strong experimental and translational data supporting the role of atrial redox state in atrial fibrillation pathogenesis, such mechanistic evidence has not been translated to clinical benefits in atrial fibrillation risk in randomized clinical studies using redox-related therapies.

Download Full-text

Role of Glutathione in Cancer: From Mechanisms to Therapies

Biomolecules ◽

10.3390/biom10101429 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1429

Author(s):

Luke Kennedy ◽

Jagdeep K. Sandhu ◽

Mary-Ellen Harper ◽

Miroslava Cuperlovic-Culf

Keyword(s):

Antioxidant System ◽

Redox State ◽

Lipid Peroxides ◽

Chemotherapeutic Drugs ◽

Therapeutic Approaches ◽

Protein Thiol ◽

Cellular Redox ◽

Comprehensive Review ◽

Mammalian Tissues

Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.

Download Full-text

Oxidative Stress in Graves Disease and Graves Orbitopathy

European Thyroid Journal ◽

10.1159/000509615 ◽

2020 ◽

Vol 9 (Suppl. 1) ◽

pp. 40-50

Author(s):

Giulia Lanzolla ◽

Claudio Marcocci ◽

Michele Marinò

Keyword(s):

Oxidative Stress ◽

Clinical Studies ◽

Therapeutic Option ◽

Protective Role ◽

Beneficial Effects ◽

Antioxidant Agents ◽

Graves Orbitopathy

Oxidative stress is involved in the pathogenesis of Graves hyperthyroidism (GH) and Graves orbitopathy (GO) and an antioxidant approach has been proposed for both. In GH, a disbalance of the cell redox state is associated with thyroid hyperfunction and antithyroid medications may reduce oxidative stress. Tissue hypoxia participates in the pathogenesis of GO, and oxygen free radicals are involved in the typical changes of orbital tissues as reported by in vitro and clinical studies. Antioxidant agents, especially selenium, have been proposed as a therapeutic option for GH and GO. A clinical study regarding the use of selenium in mild GO has provided evidence for a beneficial effect in the short term, even though its beneficial effects in the long term are still to be investigated. In addition to selenium, a protective role of other antioxidant agents, i.e., quercetin, enalapril, vitamin C, <i>N</i>-acetyl-L-cysteine and melatonin has been suggested by in vitro studies, although clinical studies are lacking. Here, we review the role of oxidative stress and antioxidant agents in GH and GO.

Download Full-text

In-silico study of the ionic current gradients determining left-to-right atrial frequencies during paroxysmal atrial fibrillation

SIMULATION ◽

10.1177/0037549719837346 ◽

2019 ◽

Vol 95 (12) ◽

pp. 1129-1139

Author(s):

Laura C Palacio ◽

Juan P Ugarte ◽

Catalina Tobón

Keyword(s):

Atrial Fibrillation ◽

Paroxysmal Atrial Fibrillation ◽

Potassium Current ◽

Ionic Current ◽

Dominant Frequency ◽

Right Atrial ◽

Therapeutic Approaches ◽

In Silico Study ◽

Frequency Gradient

Atrial fibrillation is the most prevalent cardiac arrhythmia. Paroxysmal atrial fibrillation (pAF) may occur in episodes lasting from minutes to days. Recent studies suggest that some pAF episodes present a left-to-right dominant frequency gradient caused by ionic current gradients. However, how each ionic current gradient affects the left-to-right dominant frequency gradient during pAF has not been studied. In this work, we use a 3D model of human atria to study how the ionic current gradients affect the dominant frequency gradient during pAF induced by continuous ectopic activity. The role of the specific gradients of acetylcholine-activated potassium current ( IKACh) and inward-rectifier potassium current ( IK1) on determining the left-to-right dominant frequency gradient was assessed. The main outcome of this study is that either or both of the IKACh or IK1 gradients are necessary to induce a left-to-right dominant frequency gradient during pAF. However, both gradients are necessary to the left atrium maintaining, by itself, the pAF episode. These findings have potentially important implications for the development of atrial-selective therapeutic approaches.

Download Full-text

Antioxidant Vitamins in the Prevention of Atrial Fibrillation: What Is the Evidence?

Cardiology Research and Practice ◽

10.4061/2011/164078 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

Sonia Rasoli ◽

Nicholaos Kakouros ◽

Leanne Harling ◽

Philemon Gukop ◽

Manish Soni ◽

...

Keyword(s):

Oxidative Stress ◽

Atrial Fibrillation ◽

Clinical Studies ◽

Symptom Control ◽

Antioxidant Vitamins ◽

Oxygen Species ◽

Significant Morbidity ◽

Ros Scavenging ◽

Scavenging Effect

Atrial fibrillation (AF) is the most common sustained arrhythmia that is associated with significant morbidity and mortality. Current available therapies remain inadequate in symptom control and secondary prevention and are often associated with significant side effects. The mechanisms underlying the pathogenesis of AF are poorly understood, although electrophysiological remodeling has been described as an important initiating step. Recently, increasing evidence implicates oxidative stress and inflammation in the pathogenesis of AF. We searched the literature for evidence to support the use of antioxidant vitamins C and E in the prevention of AF. These vitamins, through their reactive-oxygen-species- (ROS-) scavenging effect, have shown a role in AF prevention in both animal and small clinical studies. The available evidence, however, is currently insufficient to support recommendations for their use in the wider patient population. Larger-scale clinical studies are required to confirm these preliminary results. Research is also required to further the understanding of the processes involved in the pathogenesis of AF and the role of antioxidant therapies to prevent the arrhythmia.

Download Full-text

Telocytes and Atrial Fibrillation: From Basic Research to Clinical Practice

Rational Pharmacotherapy in Cardiology ◽

10.20996/1819-6446-2020-08-18 ◽

2020 ◽

Vol 16 (4) ◽

pp. 590-594

Author(s):

V. I. Podzolkov ◽

A. I. Tarzimanova ◽

A. S. Frolova

Keyword(s):

Atrial Fibrillation ◽

Basic Research ◽

Ventricular Myocardium ◽

Heart Tissue ◽

Interstitial Cells ◽

Pacemaker Activity ◽

Negative Effects ◽

Integrated Network ◽

Electrophysiological Properties

The emergence of new research methods makes it possible to study the tissue, structural, cellular, and molecular causes of atrial fibrillation (AF). Recently, the role of interstitial telocyte cells in the pathogenesis of AF has been actively discussed. Telocytes are a special type of interstitial cells identified in many organs and tissues, including the heart. The roles of telocytes in the myocardium are diverse: they have pacemaker activity, and carry out structural and coordination communication between cells. The ability of these cells to change the speed of the electrical pulse in the atrial and ventricular myocardium has been proven. Telocytes form "atypical" connections with almost all types of cells in the human heart, which collects them in an integrated network. Using electron microscopy, it was found that interstitial cells have different types of connections in the network and can integrate "information" from the vascular and nervous systems, interstitial, immune system, stem cells, progenitor cells, and contractile cardiomyocytes. Currently, the results of studies have been obtained that prove both positive and negative effects of telocytes on the occurrence of various diseases of the cardiovascular system. The role of telocytes in AF arrhythmogenesis remains a subject of discussion. The unique properties of telocytes in providing intercellular contacts, transmitting genetic information, and their ability to regenerate heart tissue are undoubtedly the most promising areas of modern cardiology. There is evidence of both direct and indirect effects of telocytes on the electrophysiological properties of the myocardium. There is no doubt that the development of this area opens up new therapeutic targets for the prevention and treatment of AF.

Download Full-text

FIBROSIS AND ATRIAL FIBRILLATION — МECHANISMS AND TREATMENT

Arterial’naya Gipertenziya (Arterial Hypertension) ◽

10.18705/1607-419x-2013-19-6-487-494 ◽

2013 ◽

Vol 19 (6) ◽

pp. 487-494 ◽

Cited By ~ 3

Author(s):

O. M. Drapkina ◽

I. M. Emelyanov

Keyword(s):

Atrial Fibrillation ◽

Molecular Mechanisms ◽

Atrial Fibrosis ◽

Therapeutic Approaches

The molecular mechanisms of atrial fibrosis, including the role of serotonin, in atrial fibrillation as well as possible therapeutic approaches are discussed.

Download Full-text