Inhibitory Effects of Dronedarone on Small Conductance Calcium Activated Potassium Channels in Patients with Chronic Atrial Fibrillation: Comparison to Amiodarone

Yu, Yiyan; Luo, Dan; Li, Zhiyi; Zhang, Juan; Li, Fang; Qiao, Jie; Yu, Fangming; Li, Miaoling

doi:10.12659/msm.924215

Cited by 6 publications

(4 citation statements)

References 44 publications

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“…For instance, in the study by Yu et al, 26 there was no significant difference in LA diameter between Ctl patients and patients with cAF. By contrast, in our study (Table S3) and others reporting larger I SK in RA of cAF versus Ctl, 20,56 LA diameter was significantly larger in patients with cAF versus Ctl patients. Our 2-way ANOVA analyses also suggest that LA diameter might influence protein levels of different SK-channel subunits, but rather point toward lower SK-channel protein levels with larger LA diameter (Table S13; Figures S28 through S30).…”

Section: Discussioncontrasting

confidence: 99%

“…However, other previous studies with similarly aged patient populations showed a comparably increased I SK in cAF. 20,56 In agreement, we did not find a significant age-dependent modulation of SK-channel mRNA or protein levels, or I SK in our 2-way ANOVA analyses (Table S13). To define I SK Skibsbye et al, 17 applied the nonselective SK-channel blockers NS9385 and ICAGEN instead of apamin.…”

Section: Discussionsupporting

confidence: 84%

“…In contrast, our data demonstrate an upregulation of I SK in patients with cAF versus Ctl patients, in line with the majority of functional studies (Table S2). 20,24,25,56 Our sensitivity analyses based on a population of in silico models also suggest that I SK is an important determinant of human atrial APD 90 , to a level potentially greater than the slow, rapid or ultrarapid delayed-rectifier K + currents (Figure 3). In general, the varying results between studies suggest heterogeneous SK-channel remodeling in patients with AF.…”

Section: Controversies Regarding the Role Of Sk-channels In Afmentioning

confidence: 75%

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Enhanced Ca ²⁺ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Heijman

Zhou

Morotti

et al. 2023

Circulation Research

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Background: Small-conductance Ca 2+ -activated K + (SK)–channel inhibitors have antiarrhythmic effects in animal models of atrial fibrillation (AF), presenting a potential novel antiarrhythmic option. However, the regulation of SK-channels in human atrial cardiomyocytes and its modification in patients with AF are poorly understood and were the object of this study. Methods and Results: Apamin-sensitive SK-channel current (I SK ) and action potentials were recorded in human right-atrial cardiomyocytes from sinus rhythm control (Ctl) patients or patients with (long-term persistent) chronic AF (cAF). I SK was significantly higher, and apamin caused larger action potential prolongation in cAF- versus Ctl- cardiomyocytes. Sensitivity analyses in an in silico human atrial cardiomyocyte model identified I K1 and I SK as major regulators of repolarization. Increased I SK in cAF was not associated with increases in mRNA/protein levels of SK-channel subunits in either right- or left-atrial tissue homogenates or right-atrial cardiomyocytes, but the abundance of SK2 at the sarcolemma was larger in cAF versus Ctl in both tissue-slices and cardiomyocytes. Latrunculin-A and primaquine (anterograde and retrograde protein-trafficking inhibitors) eliminated the differences in SK2 membrane levels and I SK between Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced I SK amplitude and abolished the difference between Ctl- and cAF-cardiomyocytes, indicating that reduced calmodulin-Thr80 phosphorylation due to increased protein phosphatase-2A levels in the SK-channel complex likely contribute to the greater I SK in cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased I SK and reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced I SK -upregulation. Conclusions: I SK is upregulated in patients with cAF due to enhanced channel function, mediated by phosphatase-2A-dependent calmodulin-Thr80 dephosphorylation and tachycardia-dependent enhanced trafficking and targeting of SK-channel subunits to the sarcolemma. The observed AF-associated increases in I SK , which promote reentry-stabilizing action potential duration shortening, suggest an important role for SK-channels in AF auto-promotion and provide a rationale for pursuing the antiarrhythmic effects of SK-channel inhibition in humans.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 84%

Section: Controversies Regarding the Role Of Sk-channels In Afmentioning

confidence: 75%

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Enhanced Ca ²⁺ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Heijman

Zhou

Morotti

et al. 2023

Circulation Research

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“…The degree of AF-induced remodeling has also been shown to impact ISK function, whereby studies in dog and human have shown that SK channel expression is reduced in cAF (23,(63)(64)(65), and ISK block does not affect the APD. Other studies have instead reported increased ISK in cAF (29,47,66). In our recent investigation, we did not find changes in SK channel expression at mRNA or protein level, but we demonstrated that ISK is significantly increased in human cAF vs. nSR, due to enhanced Ca 2+ -dependent SK channel gating and membrane trafficking and targeting (29).…”

Section: Sk Contribution To Af Remodeling and Arrhythmogenesiscontrasting

confidence: 56%

Dual effects of the small-conductance Ca²⁺-activated K⁺current on human atrial electrophysiology and Ca²⁺-driven arrhythmogenesis: anin silicostudy

Herrera

Zhang

et al. 2023

Preprint

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By sensing changes in intracellular Ca2+, small-conductance Ca2+-activated K+ (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria vs. ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF), the most common cardiac arrhythmia. However, the precise contribution of SK current (ISK) to atrial arrhythmogenesis is poorly understood, and may potentially involve different mechanisms that depend on species, heart rates, and degree of AF-induced atrial remodeling. Both reduced and enhanced ISK have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) vs. normal sinus rhythm (nSR) patient samples. Here, we use our multi-scale modeling framework to obtain mechanistic insights into the contribution of ISK in human atrial myocyte electrophysiology. We simulate several protocols to quantify how ISK modulation affects the regulation of AP duration (APD), Ca2+ transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that ISK activation shortens the APD and atrial effective refractory period, limits Ca2+ cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing ISK counteracts DAD development by reducing the coupling between transmembrane potential and intracellular Ca2+. Taken together, our results suggest that increasing ISK in human atrial myocytes could promote reentry, while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, ISK inhibition may thus be a beneficial or detrimental anti-AF strategy.

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The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome

Fei

Chen

et al. 2021

Pflugers Arch - Eur J Physiol

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Inhibitory Effects of Dronedarone on Small Conductance Calcium Activated Potassium Channels in Patients with Chronic Atrial Fibrillation: Comparison to Amiodarone

Cited by 6 publications

References 44 publications

Enhanced Ca ²⁺ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Enhanced Ca ²⁺ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Dual effects of the small-conductance Ca²⁺-activated K⁺current on human atrial electrophysiology and Ca²⁺-driven arrhythmogenesis: anin silicostudy

The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome

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Inhibitory Effects of Dronedarone on Small Conductance Calcium Activated Potassium Channels in Patients with Chronic Atrial Fibrillation: Comparison to Amiodarone

Cited by 6 publications

References 44 publications

Enhanced Ca 2+ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Enhanced Ca 2+ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Dual effects of the small-conductance Ca2+-activated K+current on human atrial electrophysiology and Ca2+-driven arrhythmogenesis: anin silicostudy

The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome

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Resources

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Enhanced Ca ²⁺ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Enhanced Ca ²⁺ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

Dual effects of the small-conductance Ca²⁺-activated K⁺current on human atrial electrophysiology and Ca²⁺-driven arrhythmogenesis: anin silicostudy