Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca
            <sup>2+</sup>
            -Activated K
            <sup>+</sup>
            Channels in Pigs

Diness, Jonas Goldin; Skibsbye, Lasse; Simó-Vicens, Rafel; Santos, Joana Larupa; Lundegaard, Pia R.; Citerni, Carlotta; Sauter, Daniel; Bomholtz, Sofia Hammami; Svendsen, Jesper Hastrup; Olesen, Søren‐Peter; Sørensen, Ulrik; Jespersen, Thomas; Grunnet, Morten; Bentzen, Bo Hjorth

doi:10.1161/circep.117.005125

Cited by 63 publications

(90 citation statements)

References 44 publications

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“…Pharmacological inhibition of SK channels was shown to promote conversion of vernakalant-resistant AF in a porcine model. 2 Given atrial-selectivity of SK channels, this work positions SK blockade as a promising novel pharmacotherapeutic for AF. Cellular modeling provided important insight into the mechanisms underlying successful rotorguided ablation of AF.…”

Section: Atrial Arrhythmiasmentioning

confidence: 99%

Year in Review in Cardiac Electrophysiology

Tzou

Hussein

Madhavan

et al. 2018

Circ: Arrhythmia and Electrophysiology

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1 In the past year, there have been key advances in our understanding of arrhythmia mechanisms and diagnosis and important new therapies. We have seen advances in basic cardiac electrophysiology with demonstration of optogenetic targeting of atrial fibrillation (AF) rotors, induced pluripotent stem cell-based biological pacemakers, small-conductance Ca 2+ -activated K + (SK) channels as targets for AF treatment, and reductions in inward rectifier potassium current in promoting ventricular fibrillation. Hand-held ECG devices and implantable loop recorders have been shown to detect subclinical AF. Catheter ablation of AF in patients with left ventricular dysfunction improves outcomes compared with medical therapy. Both hybrid thoracoscopic surgical and catheter ablation procedures and off-pump surgery for AF have demonstrated efficacy. Anticoagulation with uninterrupted dabigatran had a lower major bleeding rate compared with uninterrupted warfarin after AF ablation. Studies have examined optimizing access to automatic external defibrillators by identifying optimal locations for placement and possibility of using a drone delivery network. In long-QT syndrome, there are advances in understanding of ECG predictors of arrhythmic events, the role of the role of gene variants in conferring arrhythmic risk, and effect of age and sex on QTc interval. There are numerous advances in the treatment of ventricular tachycardia, including noninvasive cardiac radiation. Catheter ablation and implantable devices continue to demonstrate effectiveness in patients with congenital heart disease.In the past year, there have been numerous ground-breaking discoveries and observations that illustrate the vibrancy and promise of our field. In this review, we have tried to capture articles published in the year 2017 of particular interest to cardiac electrophysiologists. Although we have focused on articles from our journal, we have captured many of the most impactful articles in numerous other journals. We apologize for omitting a large number of other important articles that cannot be included in this review because of space limitations. We have placed some of these in our Data Supplement. BASIC ELECTROPHYSIOLOGY BradyarrhythmiasThe search for new biological therapies for bradycardia met with recent progress as human keratinocytes genetically reprogrammed into electrically unstable cardiomyocytes were shown to persist and provide continued catecholaminergic-responsive pacing for 13 weeks after subepicardial injection into immunosuppressed dogs at the time of atrioventricular (AV) node ablation.1 Although only 40% to 80% of the beats matched the site of cell injection, this is first study to test a human induced pluripotent stem cell-based biological pacemaker in a large animal model of heart block and represents an important step forward in biological pacing.

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Section: Atrial Arrhythmiasmentioning

confidence: 99%

Year in Review in Cardiac Electrophysiology

Tzou

Hussein

Madhavan

et al. 2018

Circ: Arrhythmia and Electrophysiology

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“…In the present issue of Circulation Arrhythmia & Electrophysiology , Diness et al 13 describe the antiarrhythmic effects of a novel, reasonably selective SK-channel blocker (AP14145; with a 10-fold difference between the IC 50 for SK-channels and I K,ACh ) in pigs. AP14145 prolongs atrial ERP and reduces the duration of acutely induced AF in pigs subjected to one week of atrial tachycardia remodeling.…”

mentioning

confidence: 99%

“…These results were similar to those obtained with vernakalant, a multichannel blocker affecting, among others, I Kur and the fast Na + -current, which is approved for pharmacological cardioversion of recent-onset AF in patients without severe heart failure in Europe. 3 Moreover, using long-lasting rapid atrial pacing protocols that were continued until AF could no longer be terminated by vernakalant, Diness et al 13 show that SK-channel inhibition is able to terminate vernakalant-resistant AF. This important finding suggests that SK-channel inhibition may be effective in more persistent, drug-refractory forms of AF.…”

mentioning

confidence: 99%

“…At the mRNA level the KCNN2 gene encoding the SK2 isoform appears to be most abundantly expressed in the human heart, 10, 17 whereas dogs predominantly express SK1. 18 Although pigs appear to have an isoform expression pattern more similar to humans, 13 little is known about the functional regulation of SK-channels, e.g., due to species-specific differences in intracellular Ca 2+ -handling. Moreover, even between different studies in human atrial samples, there is disagreement about the direction of disease-related changes in SK-channel expression and function, with both up- and downregulation of SK-channel expression and SK current amplitude being reported in AF patients compared to sinus rhythm controls.…”

mentioning

confidence: 99%

“…Indeed, all conscious pigs in the study by Diness et al showed adverse effects requiring additional treatment. 13 …”

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confidence: 99%

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Inhibition of Small-Conductance Ca ²⁺ -Activated K ⁺ Channels

Heijman

Dobrev

2017

Circ: Arrhythmia and Electrophysiology

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Ablation alleviates atrial fibrillation by regulating the signaling pathways of endothelial nitric oxide synthase/nitric oxide via miR‐155‐5p and miR‐24‐3p

Wang

Sun

Ding³

et al. 2018

J of Cellular Biochemistry

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Background: This study aimed to identify the microRNAs implicated in atrial fibrillation (AF) to investigate the molecular mechanisms underlying the role of microRNAs in ablation-based AF treatment. Methods: Real-time polymerase chain reaction (PCR) and microRNA microarrays were utilized to measure the profiles of microRNA expression in AF to identify differentially expressed microRNAs. Enzyme-linked immunosorbent assay, real-time PCR, Western blot analysis, and immunohistochemistry assays were also performed to investigate the regulatory relationships among various factors implicated in AF. Finally, bioinformatic tools and luciferase assays were used to confirm the roles of miR-155-5p, miR-24-3p, endothelial nitric oxide synthase (eNOS), and nitric oxide (NO) in the pathogenesis of AF.Results: We demonstrated that the levels of miR-155-5p and miR-24-3p were greatly reduced in postablation AF patients compared with those AF patients not treated by ablation. Furthermore, the NO level in the AF+ group was much lower than that of the AF− group. Finally, in a swine model of AF, evident upregulation of miR-155-5p and miR-24-3p was found in AF pigs, whereas the ablation treatment reduced the levels of miR-155-5p and miR-24-3p in AF pigs.On contrary, as targets of miR-155-5p and miR-24-3p, the levels of eNOS and NO increased when the expression of miR-155-5p and miR-24-3p decreased.Conclusion: MiR-155-5p and miR-24-3p are involved in the pathogenesis of AF via regulating the expression of eNOS and the production of NO. In addition, ablation treatment helps the recovery from AF by reducing the expression of miR-155-5p and miR-24-3p. K E Y W O R D S ablation, atrial fibrillation, endothelial nitric oxide synthase, expression profiling, microarray, microRNA, nitric oxide 1 | INTRODUCTION As one of the most frequently diagnosed chronic arrhythmia, atrial fibrillation (AF) significantly affects the quality of life of its patients. Triggered by an irregular ventricular rate and the disorder in atrial contraction, AF is featured by a high rate (up to 600 beats/min) of asynchronous depolarization of atrial cells. 1 The prevalence of AF is about 2% in developed countries and the mean age of AF patients is about 80 years old. 2 Although J Cell Biochem. 2019;120:4451-4462.wileyonlinelibrary.com/journal/jcb

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Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca ²⁺ -Activated K ⁺ Channels in Pigs

Abstract: Supplemental Digital Content is available in the text.

Cited by 63 publications

References 44 publications

Year in Review in Cardiac Electrophysiology

Year in Review in Cardiac Electrophysiology

Inhibition of Small-Conductance Ca ²⁺ -Activated K ⁺ Channels

Ablation alleviates atrial fibrillation by regulating the signaling pathways of endothelial nitric oxide synthase/nitric oxide via miR‐155‐5p and miR‐24‐3p

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Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca 2+ -Activated K + Channels in Pigs

Abstract: Supplemental Digital Content is available in the text.

Cited by 63 publications

References 44 publications

Year in Review in Cardiac Electrophysiology

Year in Review in Cardiac Electrophysiology

Inhibition of Small-Conductance Ca 2+ -Activated K + Channels

Ablation alleviates atrial fibrillation by regulating the signaling pathways of endothelial nitric oxide synthase/nitric oxide via miR‐155‐5p and miR‐24‐3p

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Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca ²⁺ -Activated K ⁺ Channels in Pigs

Inhibition of Small-Conductance Ca ²⁺ -Activated K ⁺ Channels