Decreased expression of small-conductance Ca2+-activated K+ channels SK1 and SK2 in human chronic atrial fibrillation

Tang, Yu; Deng, Chunyu; Wu, Ruo-bin; Guo, Huiming; Zheng, Shaoyi; Yu, Xiang; Shan, Zhi‐Xin; Kuang, Su‐Juan; Lin, Qiaoli

doi:10.1016/j.lfs.2011.11.008

Cited by 67 publications

(52 citation statements)

References 37 publications

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“…(B & C) cAF-remodeling shortens the AP and hyperpolarizes the membrane. Simulation results are compared to in vitro findings of Yu et al [42] and Dobrev et al [43]. (D & E) cAF-remodeling decreases the amplitude of CaT, diastolic Ca 2+ concentration and SR Ca 2+ content, corresponding to in vitro results of Voigt et al [21] (cyan bar), Voigt et al [14] (red bar), Wakili et al [10] (diastolic Ca 2+ ) and Grandi et al [11] (CaT amp and SR Ca 2+ content).…”

Section: Resultsmentioning

confidence: 99%

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

et al. 2014

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Chronic atrial fibrillation (AF) is a complex disease with underlying changes in electrophysiology, calcium signaling and the structure of atrial myocytes. How these individual remodeling targets and their emergent interactions contribute to cell physiology in chronic AF is not well understood. To approach this problem, we performed in silico experiments in a computational model of the human atrial myocyte. The remodeled function of cellular components was based on a broad literature review of in vitro findings in chronic AF, and these were integrated into the model to define a cohort of virtual cells. Simulation results indicate that while the altered function of calcium and potassium ion channels alone causes a pronounced decrease in action potential duration, remodeling of intracellular calcium handling also has a substantial impact on the chronic AF phenotype. We additionally found that the reduction in amplitude of the calcium transient in chronic AF as compared to normal sinus rhythm is primarily due to the remodeling of calcium channel function, calcium handling and cellular geometry. Finally, we found that decreased electrical resistance of the membrane together with remodeled calcium handling synergistically decreased cellular excitability and the subsequent inducibility of repolarization abnormalities in the human atrial myocyte in chronic AF. We conclude that the presented results highlight the complexity of both intrinsic cellular interactions and emergent properties of human atrial myocytes in chronic AF. Therefore, reversing remodeling for a single remodeled component does little to restore the normal sinus rhythm phenotype. These findings may have important implications for developing novel therapeutic approaches for chronic AF.

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Section: Resultsmentioning

confidence: 99%

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

et al. 2014

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“…139 The increase in SK current was prevented by the inhibition of retrograde channel trafficking, suggesting a rate-dependent influence on membrane channel availability. 139 However, another study reported reduced SK channel expression in cAF atrial cardiomyocytes, 140 possibly because of increased microRNA-499, downregulating the SK3 subunit. 141 Despite reduced APD at full repolarization, APD at 20% repolarization is generally prolonged.…”

Section: Apd Shorteningmentioning

confidence: 99%

Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

Heijman

Voigt

Nattel

et al. 2014

Circulation Research

545

603

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Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca 2+ -handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management.

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“…21 Reduced expression levels of SKCa channels were demonstrated in human patients with chronic AF, suggestive of the important role of SK channels in maintaining normal atrial function. 26, 57 Furthermore, in mice, ablation of SK2 resulted in prolongation of the atrial action potential duration (APD) and enhanced inducibility of AF. Optical mapping experiments in the atria from healthy canine hearts also showed that inhibition of SKCa channels prolongs and enhances heterogeneity of the APD, thereby promoting arrhythmia by inducing alternans and wavebrakes (for review 21 ).…”

Section: Skca and Cardiac Pathologymentioning

confidence: 99%

Ca<sup>2+</sup>-Activated K<sup>+</sup> Channels as Therapeutic Targets for Myocardial and Vascular Protection

Clements

Terentyev

Sellke

2015

Circ J

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Decreased expression of small-conductance Ca2+-activated K+ channels SK1 and SK2 in human chronic atrial fibrillation

Cited by 67 publications

References 37 publications

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance, and Progression

Ca<sup>2+</sup>-Activated K<sup>+</sup> Channels as Therapeutic Targets for Myocardial and Vascular Protection

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