Calcium Handling Abnormalities as a Target for Atrial Fibrillation Therapeutics

Heijman, Jordi; Voigt, Niels; Ghezelbash, Shokoufeh; Schirmer, Ilona; Dobrev, Dobromir

doi:10.1097/fjc.0000000000000253

Cited by 16 publications

(23 citation statements)

References 66 publications

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“…The persistence of abnormal Ca 2+ signaling and enhanced diastolic SR Ca 2+ leak can activate ion channels and trigger Ca 2+ -dependent signaling pathways, thereby promoting the evolution of atrial remodeling and the progression of AF to more persistent forms. 257 For example, small-conductance Ca 2+ -dependent K + -channels (SK channels) govern the risk of human AF likely by decreasing APD and promoting reentry, 258 and the association between SK channels and RyR2 as the potential internal source of SK channel activation, position SK channels as an important Ca 2+ -dependent link between triggered activity with reentry. 259, 260 Furthermore, reduced I Ca,L in AF causes APD shortening and promotes reentry.…”

Section: Calcium-dependent Acquired Arrhythmiasmentioning

confidence: 99%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

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385

313

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There has been significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function - in particular, excitation-contraction coupling and normal electrical rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

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Section: Calcium-dependent Acquired Arrhythmiasmentioning

confidence: 99%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

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385

313

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“…Aberrant Ca 2+ cycling is thought to contribute to AF substrate formation (29). We recently described a unique form of aberrant sarcoplasmic reticulum (SR) Ca 2+ release in atrial myocytes, wherein atrial myocytes demonstrate the presence of Ca 2+ waves that occur during rapid atrial stimulation, not during diastole (17).…”

Section: Increased Incidence Of Tcws In Hf Pla Myocytes and Attenuatimentioning

confidence: 99%

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

Yoo¹,

Aistrup²,

Shiferaw³

et al. 2018

JCI Insight

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The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII-induced (Ox-CaMKII-induced) RyR2 and Na v 1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca 2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Na v 1.5 (CaMKII-p-Na v 1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Na v 1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Na v 1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis. insight.jci.org https://doi.org/10.1172/jci.insight.120728 R E S E A R C H A R T I C L Epropensity for spontaneous calcium (Ca 2+ ) release (in the form of Ca 2+ waves) in atrial myocytes of patients with chronic AF (16). Our work indicates that atrial myocytes in the setting of HF have increased susceptibility to the development of Ca 2+ waves during rapid atrial pacing (i.e., triggered Ca 2+ waves; TCWs) (17). Ca 2+ waves are known to create conditions in both the ventricle and atrium for the genesis of afterdepolarizations, which can lead to triggered activity and/or dispersion of repolarization (18,19). Another major mechanism thought to underlie the development of a vulnerable AF substrate in HF is slow and inhomogeneous conduction in the intact atrium, which creates conditions for reentry (20)(21)(22). While several studies suggest that increased fibrosis in the HF atrium is a major cause of this inhomogeneous conduction (21,23), it is also known that the HF atrium undergoes significant electrical remodeling (24), with alterations in the I Na having been implicated in some studies in creation of the AF disease state (25). Our specific hypotheses for this study were, therefore, as follows: (a) OS generation -and downstream oxidation of key signaling proteins -is preferentially increased in the PLA/PVs in the HF atrium; (b) the increased vulnerability of HF atrial myocytes to TCW generation is at least partially mediated by OS, with OS creating substrate for TCWs by increasing CaMKII-p-RyR2 (S2814) in the HF PLA; and (c) OS, via Ox-CaMKII, increases the level of C...

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“…Given the central role for Ca 2+ -handling abnormalities in animal models of AF and atrial samples from AF patients, targeting the phosphorylation of Ca 2+ -handling proteins could be a promising antiarrhythmic strategy [2,113]. Although the functional relevance of RyR2 hyperphosphorylation remains a topic of debate [88], the proarrhythmic nature of RyR2 mutations and the antiarrhythmic efficacy of some drugs modulating RyR2 activity, suggest it could be an interesting target [99,113].…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

“…Although the functional relevance of RyR2 hyperphosphorylation remains a topic of debate [88], the proarrhythmic nature of RyR2 mutations and the antiarrhythmic efficacy of some drugs modulating RyR2 activity, suggest it could be an interesting target [99,113]. Furthermore, although our knowledge is far from complete, the RyR2 macromolecular complex is perhaps the best characterized, with multiple potential targets to modulate RyR2 function and some information about how to selectively modulate individual phosphorylation sites via alterations in phosphatase holoenzymes.…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

Serine/Threonine Phosphatases in Atrial Fibrillation

Heijman

Ghezelbash

Wehrens

et al. 2017

Journal of Molecular and Cellular Cardiology

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Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Accordingly, dysfunction of this regulation can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. Here, we review AF-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in AF-pathophysiology. We highlight the mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively). Finally, we discuss the challenges for phosphatase research, potential therapeutic significance of altered phosphatase-mediated protein dephosphorylation in AF, as well as future directions.

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Calcium Handling Abnormalities as a Target for Atrial Fibrillation Therapeutics

Cited by 16 publications

References 66 publications

Calcium Signaling and Cardiac Arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

Serine/Threonine Phosphatases in Atrial Fibrillation

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