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      Electrophysiological Mechanisms of Bayés Syndrome: Insights from Clinical and Mouse Studies

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          Abstract

          Bayés syndrome is an under-recognized clinical condition characterized by inter-atrial block (IAB). This is defined electrocardiographically as P-wave duration > 120 ms and can be categorized into first, second and third degree IAB. It can be caused by inflammatory conditions such as systemic sclerosis and rheumatoid arthritis, abnormal protein deposition in cardiac amyloidosis, or neoplastic processes invading the inter-atrial conduction system, such as primary cardiac lymphoma. It may arise transiently during volume overload, autonomic dysfunction or electrolyte disturbances from vomiting. In other patients without an obvious cause, the predisposing factors are diabetes mellitus, hypertensive heart disease, and hypercholesterolemia. IAB has a strong association with atrial arrhythmogenesis, left atrial enlargement (LAE), and electro-mechanical discordance, increasing the risk of cerebrovascular accidents as well as myocardial and mesenteric ischemia. The aim of this review article is to synthesize experimental evidence on the pathogenesis of IAB and its underlying molecular mechanisms. Current medical therapies include anti-fibrotic, anti-arrhythmic and anti-coagulation agents, whereas interventional options include atrial resynchronization therapy by single or multisite pacing. Future studies will be needed to elucidate the significance of the link between IAB and atrial tachyarrhythmias in patients with different underlying etiologies and optimize the management options in these populations.

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          Most cited references122

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          NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart.

          NAD(P)H oxidases (Noxs) produce O(2)(-) and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4(-/-) (c-Nox4(-/-)) mice. Nox4 expression was inhibited in c-Nox4(-/-) mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O(2)(-) in the heart, indicating that Nox4 is a significant source of O(2)(-) in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4(-/-) mice. In response to pressure overload (PO), however, increases in Nox4 expression and O(2)(-) production in mitochondria were abolished in c-Nox4(-/-) mice, and c-Nox4(-/-) mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4(-/-) mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.
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            Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor.

            The cardiac ryanodine receptor (RyR2)/calcium release channel on the sarcoplasmic reticulum is required for muscle excitation-contraction coupling. Using site-directed mutagenesis, we identified the specific Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation site on recombinant RyR2, distinct from the site for protein kinase A (PKA) that mediates the "fight-or-flight" stress response. CaMKII phosphorylation increased RyR2 Ca2+ sensitivity and open probability. CaMKII was activated at increased heart rates, which may contribute to enhanced Ca2+-induced Ca2+ release. Moreover, rate-dependent CaMKII phosphorylation of RyR2 was defective in heart failure. CaMKII-mediated phosphorylation of RyR2 may contribute to the enhanced contractility observed at higher heart rates. The full text of this article is available online at http://circres.ahajournals.org.
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              Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation.

              Several ion channels are reportedly redox responsive, but the molecular basis for the changes in activity is not known. The mechanism of nitric oxide action on the cardiac calcium release channel (ryanodine receptor) (CRC) in canines was explored. This tetrameric channel contains approximately 84 free thiols and is S-nitrosylated in vivo. S-Nitrosylation of up to 12 sites (3 per CRC subunit) led to progressive channel activation that was reversed by denitrosylation. In contrast, oxidation of 20 to 24 thiols per CRC (5 or 6 per subunit) had no effect on channel function. Oxidation of additional thiols (or of another class of thiols) produced irreversible activation. The CRC thus appears to be regulated by poly-S-nitrosylation (multiple covalent attachments), whereas oxidation can lead to loss of control. These results reveal that ion channels can differentiate nitrosative from oxidative signals and indicate that the CRC is regulated by posttranslational chemical modification(s) of sulfurs.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                31 May 2016
                2016
                : 7
                : 188
                Affiliations
                [1] 1Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, University of Hong Kong Hong Kong, China
                [2] 2School of Medicine, Imperial College London London, UK
                [3] 3Department of Medicine and Therapeutics, The Chinese University of Hong Kong Hong Kong, China
                [4] 4Department of Epidemiology and Preventive Medicine, Monash University Melbourne, VIC, Australia
                Author notes

                Edited by: Mark Potse, Inria Bordeaux Sud-Ouest, France

                Reviewed by: Jan Pavel Kucera, University of Bern, Switzerland; Adrian Marco Baranchuk, Queen's University, Canada

                *Correspondence: Gary Tse gary.tse@ 123456doctors.org.uk ;

                This article was submitted to Cardiac Electrophysiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2016.00188
                4886053
                27303306
                81e2cd71-7084-43c7-84cc-8a930acce25c
                Copyright © 2016 Tse, Lai, Yeo and Yan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 31 March 2016
                : 10 May 2016
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 147, Pages: 10, Words: 8005
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council 10.13039/501100000268
                Award ID: Doctoral Training Award
                Categories
                Physiology
                Review

                Anatomy & Physiology
                bayés syndrome,inter-atrial block,intra-atrial block,conduction,electrophysiological remodeling,structural remodeling

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