atrial refractoriness
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2020 ◽  
Vol 9 (23) ◽  
Author(s):  
Lianne N. van Staveren ◽  
Natasja M. S. de Groot

Abstract Patients diagnosed with the same subtype of atrial fibrillation according to our current classification system may differ in symptom severity, severity of the arrhythmogenic substrate, and response to antiarrhythmic therapy. Hence, there is a need for an electrical biomarker as an indicator of the arrhythmogenic substrate underlying atrial fibrillation enabling patient‐tailored therapy. The aim of this review is to investigate whether atrial refractoriness, a well‐known electrophysiological parameter that is affected by electrical remodeling, can be used as an electrical biomarker of the arrhythmogenic substrate underlying atrial fibrillation. We discuss methodologies of atrial effective refractory period assessment, identify which changes in refractoriness‐related parameters reflect different degrees of electrical remodeling, and explore whether these parameters can be used to predict clinical outcomes.


Author(s):  
Brian J. Hansen ◽  
Jichao Zhao ◽  
Katelynn M. Helfrich ◽  
Ning Li ◽  
Alexander Iancau ◽  
...  

Background Atrial fibrillation (AF) driver mechanisms are obscured to clinical multielectrode mapping approaches that provide partial, surface‐only visualization of unstable 3‐dimensional atrial conduction. We hypothesized that transient modulation of refractoriness by pharmacologic challenge during multielectrode mapping improves visualization of hidden paths of reentrant AF drivers for targeted ablation. Methods and Results Pharmacologic challenge with adenosine was tested in ex vivo human hearts with a history of AF and cardiac diseases by multielectrode and high‐resolution subsurface near‐infrared optical mapping, integrated with 3‐dimensional structural imaging and heart‐specific computational simulations. Adenosine challenge was also studied on acutely terminated AF drivers in 10 patients with persistent AF. Ex vivo, adenosine stabilized reentrant driver paths within arrhythmogenic fibrotic hubs and improved visualization of reentrant paths, previously seen as focal or unstable breakthrough activation pattern, for targeted AF ablation. Computational simulations suggested that shortening of atrial refractoriness by adenosine may (1) improve driver stability by annihilating spatially unstable functional blocks and tightening reentrant circuits around fibrotic substrates, thus unmasking the common reentrant path; and (2) destabilize already stable reentrant drivers along fibrotic substrates by accelerating competing fibrillatory wavelets or secondary drivers. In patients with persistent AF, adenosine challenge unmasked hidden common reentry paths (9/15 AF drivers, 41±26% to 68±25% visualization), but worsened visualization of previously visible reentry paths (6/15, 74±14% to 34±12%). AF driver ablation led to acute termination of AF. Conclusions Our ex vivo to in vivo human translational study suggests that transiently altering atrial refractoriness can stabilize reentrant paths and unmask arrhythmogenic hubs to guide targeted AF driver ablation treatment.


2020 ◽  
Vol 11 ◽  
Author(s):  
Jonas Goldin Diness ◽  
Jeppe Egedal Kirchhoff ◽  
Tobias Speerschneider ◽  
Lea Abildgaard ◽  
Nils Edvardsson ◽  
...  

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S H Bomholtz ◽  
R Simo-Vicens ◽  
L Abildgaard ◽  
N G Edvardsson ◽  
U S Soerensen ◽  
...  

Abstract Background Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of SK-channels that is effective in converting vernakalant-resistant AF in tachy-paced pigs. Detailed understanding of the molecular mechanism of AP30663 is important for the development of SK channel inhibition for use in man. Purpose To establish the electrophysiological profile, mechanism of action and efficacy in prolonging atrial refractoriness ex vivo of AP30663. Methods AP30663 potency and mechanism of action were established by whole cell and inside-out patch clamp recordings of expressed SK channels. The ion channel selectivity profile of AP30663 was investigated on heterologous expressed channels. Effects of AP30663 or vehicle (DMSO) on atrial refractoriness (AERP) and ventricular repolarization (QTcB) were investigated on isolated perfused guinea pig hearts. Results AP30663 was found to be a selective negative allosteric modulator of SK channels (IC50=0.77±x0.13 μM) with no or minor effects on a panel of other cardiac ion channels, including hERG/KV11.1, (IKr), KV7.1/KCNE1 (IKs), KV4.3/KChiP2 (Ito), Kir2.1 (IK1), Kir3.1/Kir3.4 (IKACh), KV1.5 (IKur), NaV1.5 (INa) and CaV1.2 (ICa). AP30663 inhibited the SK-channel by right-shifting the calcium activation curve of the SK-channel (the EC50 of Ca2+ increased from 0.43±0.02 μM (control, n=6) to 1.37±0.05 μM (in the presence of 7μM AP30663, n=6). In isolated guinea pig hearts, administration of vehicle had no effect on AERP or QTcB. AP30663 significantly prolonged the AERP in 3 μM (to 131±6% of baseline) and 10 μM (to 165±3% of baseline) without any effects on the QTcB. Conclusion AP30663 is a selective negative allosteric modulator of SK channels, acting by means of shifting the calcium dependence of SK-channel activation. AP30663 prolonged atrial refractoriness without affecting the QT-interval in isolated perfused heart preparations. These properties support continued development of AP30663 for treatment of AF in man. Acknowledgement/Funding Innovation Fund Denmark, Wellcome Trust


2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Marieke W. Veldkamp ◽  
Guillaume S. C. Geuzebroek ◽  
Antonius Baartscheer ◽  
Arie O. Verkerk ◽  
Cees A. Schumacher ◽  
...  

2018 ◽  
Vol 114 (suppl_1) ◽  
pp. S80-S80
Author(s):  
O J Arias-Mutis ◽  
C J Calvo ◽  
A Bizy ◽  
L Such-Miquel ◽  
C Soler ◽  
...  

2016 ◽  
Vol 39 (12) ◽  
pp. 1366-1372 ◽  
Author(s):  
KAYLIN T. NGUYEN ◽  
RACHEL A. GLADSTONE ◽  
JONATHAN W. DUKES ◽  
BABAK NAZER ◽  
ERIC VITTINGHOFF ◽  
...  

Heart Rhythm ◽  
2016 ◽  
Vol 13 (8) ◽  
pp. 1575-1580 ◽  
Author(s):  
Jung Myung Lee ◽  
Hancheol Lee ◽  
Ajit H. Janardhan ◽  
Junbeom Park ◽  
Boyoung Joung ◽  
...  

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