scholarly journals Pharmacologic TWIK‐Related Acid‐Sensitive K+ Channel (TASK‐1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model

2020 ◽  
Vol 9 (10) ◽  
Author(s):  
Felix Wiedmann ◽  
Christoph Beyersdorf ◽  
Xiaobo Zhou ◽  
Antonius Büscher ◽  
Manuel Kraft ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Model ◽  
Potassium Channel ◽  
Paroxysmal Atrial Fibrillation ◽  
Large Animal Model ◽  
K Channel ◽  
Large Animal

scholarly journals The Experimental TASK-1 Potassium Channel Inhibitor A293 Can Be Employed for Rhythm Control of Persistent Atrial Fibrillation in a Translational Large Animal Model

2021 ◽  
Vol 11 ◽  
Author(s):  
Felix Wiedmann ◽  
Christoph Beyersdorf ◽  
Xiao-Bo Zhou ◽  
Manuel Kraft ◽  
Kathrin I. Foerster ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Model ◽  
Pulmonary Artery ◽  
Action Potential ◽  
Potassium Channel ◽  
Treatment Period ◽  
Rhythm Control ◽  
Large Animal Model ◽  
Large Animal ◽  
Antiarrhythmic Effects

BackgroundUpregulation of the two-pore-domain potassium channel TASK-1 (hK2P3.1) was recently described in patients suffering from atrial fibrillation (AF) and resulted in shortening of the atrial action potential. In the human heart, TASK-1 channels facilitate repolarization and are specifically expressed in the atria. In the present study, we tested the antiarrhythmic effects of the experimental ion channel inhibitor A293 that is highly affine for TASK-1 in a porcine large animal model of persistent AF.MethodsPersistent AF was induced in German landrace pigs by right atrial burst stimulation via implanted pacemakers using a biofeedback algorithm over 14 days. Electrophysiological and echocardiographic investigations were performed before and after the pharmacological treatment period. A293 was intravenously administered once per day. After a treatment period of 14 days, atrial cardiomyocytes were isolated for patch clamp measurements of currents and atrial action potentials. Hemodynamic consequences of TASK-1 inhibition were measured upon acute A293 treatment.ResultsIn animals with persistent AF, the A293 treatment significantly reduced the AF burden (6.5% vs. 95%; P < 0.001). Intracardiac electrophysiological investigations showed that the atrial effective refractory period was prolonged in A293 treated study animals, whereas, the QRS width, QT interval, and ventricular effective refractory periods remained unchanged. A293 treatment reduced the upregulation of the TASK-1 current as well as the shortening of the action potential duration caused by AF. No central nervous side effects were observed. A mild but significant increase in pulmonary artery pressure was observed upon acute TASK-1 inhibition.ConclusionPharmacological inhibition of atrial TASK-1 currents exerts in vivo antiarrhythmic effects that can be employed for rhythm control in a porcine model of persistent AF. Care has to be taken as TASK-1 inhibition may increase pulmonary artery pressure levels.

Abstract 297: Paroxysmal And Sustained Atrial Fibrillation In A New Large Animal Model Of Nonischemic Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Saad Sikanderkhel ◽  
Olawale Onibile ◽  
Gregory P Walcott ◽  
Steven M Pogwizd
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Animal Model ◽  
Holter Monitoring ◽  
Aortic Insufficiency ◽  
Large Animal Model ◽  
Large Animal ◽  
Aortic Constriction ◽  
Holter Monitor ◽  
Human Scale

Introduction: Atrial fibrillation is common in heart failure (HF). Understanding of the mechanisms of atrial fibrillation (AF) is limited by the paucity of large animal AF models, especially in the failing heart. We developed a large animal model of nonischemic heart failure (HF) in dogs by combined aortic insufficiency and aortic constriction and observed that a number of HF dogs developed paroxysmal AF on holter monitor. Here we characterize the spontaneously-occurring pAF in these HF dogs and perform electrophysiologic (EP) assessment of atrial refractoriness and AF inducibility along with echocardiographic imaging of left ventricle (LV) and left atrium (LA). Methods: HF was induced in dogs by aortic insufficiency and aortic constriction, and serial echocardiography (for LV fractional shortening (FS) and LA size) and Holter monitoring was performed. In control and HF dogs, EP study of atrial refractory period (AERP) and AF inducibility (duration and atrial cycle length (CL)) was performed. Results: By Holter monitoring, paroxysmal AF was noted in 5 dogs with episodes ranging from 15 to 94 beats long (mean of 49±27 beats, n=12). In EP studies, control dogs (N=3) exhibited AERP of 176±8 ms. Burst pacing resulted in AF of very brief duration (mean 32±24 sec) and a mean AF CL of 138±6 ms. LV FS averaged 37% and LA size averaged 4.3 cm2. HF dogs (N=5) exhibited RAERP of 150±8 (p=0.05 vs control). Two of these dogs had sustained AF with ventricular response up to 230 bpm on Holter monitor. In the other 3 HF dogs, burst pacing induced AF with a mean duration of 232±185 sec (at times with conversion to atrial flutter) and with a mean AF CL = 110±4 ms (p=0.002 vs control). Echo data showed LVFS averaged 30% and LA area of 14.9 cm2 (p=0.05 vs control). Conclusion: Thus we have developed a novel large animal model of HF that exhibits paroxysmal and sustained AF. This model will provide an opportunity for the study of underlying AF mechanisms, the progression of remodeling in HF hearts leading to AF, and the assessment of human-scale interventions to better treat and prevent this arrhythmia.

scholarly journals 197Inhibition of TASK-1 by gene therapy and pharmacological compounds suppresses atrial fibrillation in a large animal model

2018 ◽  
Vol 39 (suppl_1) ◽  
Author(s):  
C Schmidt ◽  
F Wiedmann ◽  
C Beyersdorf ◽  
Z Zhao ◽  
I El-Battrawy ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Gene Therapy ◽  
Animal Model ◽  
Large Animal Model ◽  
Large Animal

scholarly journals Transcriptome and proteome mapping in the sheep atria reveal molecular features of atrial fibrillation progression

2020 ◽  
Author(s):  
Alba Alvarez-Franco ◽  
Raquel Rouco ◽  
Rafael J Ramirez ◽  
Guadalupe Guerrero-Serna ◽  
Maria Tiana ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cell Proliferation ◽  
Animal Model ◽  
Large Animal Model ◽  
Neural Function ◽  
Large Animal ◽  
Late Time ◽  
Molecular Map ◽  
Atrial Remodelling ◽  
Gene And Protein Expression

Abstract Aims Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. In this study, we aimed to create a molecular map of AF and find the distinct molecular programs underlying cell type-specific atrial remodelling and AF progression. Methods and Results We used a sheep model of long-standing, tachypacing-induced AF, sampled right and left atrial tissue and isolated cardiomyocytes from control, intermediate (transition) and late time points during AF progression, and performed transcriptomic and proteome profiling. We have merged all these layers of information into a meaningful 3-component space in which we explored the genes and proteins detected and their common patterns of expression. Our data-driven analysis points at extracellular matrix remodelling, inflammation, ion channel, myofibril structure, mitochondrial complexes, chromatin remodelling, and genes related to neural function, as well as critical regulators of cell proliferation as hallmarks of AF progression. Most important, we prove that these changes occur at early transitional stages of the disease, but not at later stages, and that the left atrium undergoes significantly more profound changes than the right atrium in its expression program. The pattern of dynamic changes in gene and protein expression replicate the electrical and structural remodelling demonstrated previously in the sheep and in humans, and uncover novel mechanisms potentially relevant for disease treatment. Conclusions Transcriptomic and proteomic analysis of AF progression in a large animal model shows that significant changes occur at early stages, and that among others involve previously undescribed increase in mitochondria, changes to the chromatin of atrial cardiomyocytes, and genes related to neural function and cell proliferation. Translational Perspective We have generated a detailed molecular map of AF progression in a clinically relevant large-animal model. Such data would be very difficult if not impossible to obtain from patients. Our results provide a framework for a comprehensive molecular analysis of the disease, pointing to novel avenues of research toward identifying early events that can lead to therapeutically targets to prevent AF-induced atrial remodelling.

scholarly journals Mild hypothermia (33°C) increases the inducibility of atrial fibrillation: An in vivo large animal model study

2018 ◽  
Vol 41 (7) ◽  
pp. 720-726 ◽  
Author(s):  
Martin Manninger ◽  
Alessio Alogna ◽  
David Zweiker ◽  
Birgit Zirngast ◽  
Stefan Reiter ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Model ◽  
Mild Hypothermia ◽  
Large Animal Model ◽  
Large Animal ◽  
Model Study ◽  
Animal Model Study

scholarly journals Effect of flecainide on atrial fibrillatory rate in a large animal model with induced atrial fibrillation

2017 ◽  
Vol 17 (1) ◽  
Author(s):  
Eva Z. Hesselkilde ◽  
Helena Carstensen ◽  
Maria M. Haugaard ◽  
Jonas Carlson ◽  
Steen Pehrson ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Animal Model ◽  
Large Animal Model ◽  
Large Animal

scholarly journals Genomic Association of Chronic Idiopathic Anhidrosis to a Potassium Channel Subunit in a Large Animal Model

2021 ◽  
Author(s):  
Laura Patterson Rosa ◽  
Neely Walker ◽  
Martha Mallicote ◽  
Robert J. MacKay ◽  
Samantha A. Brooks
Keyword(s):  
Animal Model ◽  
Potassium Channel ◽  
Large Animal Model ◽  
Large Animal ◽  
Genomic Association
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