Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy

Wiedmann, Felix; Beyersdorf, Christoph; Zhou, Xiaobo; Kraft, Manuel; Paasche, A; Jávorszky, Natasa; Rinné, Susanne; Sutanto, Henry; Büscher, Antonius; Foerster, Kathrin I.; Blank, Antje; El‐Battrawy, Ibrahim; Li, Xin; Lang, Siegfried; Tochtermann, U.; Kremer, Jamila; Arif, Rawa; Kretzler, Matthias; Decher, Niels; Loon, Gunther van; Akın, İbrahim; Borggrefe, Martin; Kallenberger, Stefan M.; Heijman, Jordi; Haefeli, Walter E.; Katus, Hugo A.; Schmidt, Constanze

doi:10.1093/cvr/cvab177

Cited by 26 publications

(24 citation statements)

References 50 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Cardiac mRNA and protein expression mRNA abundance in sinoatrial and atrioventricular node [51] Pig mRNA (RT-qPCR, TaqMan) and protein (WB)…”

Section: Dogmentioning

confidence: 99%

“…Humans, however, show an almost atrial-specific K 2P 3.1 (TASK-1) expression within the heart with 14- to 16-fold lower expression levels in ventricular tissue (RT-PCR, Taq-Man qPCR, microarray, bulk RNAseq, Western blot) [ 10 , 12 , 14 , 39 , 40 , 49 , 54 , 56 , 57 ]. In guinea pigs and domestic swine, atrial-specific K 2P 3.1 (TASK-1) expression was also described [ 49 , 51 , 52 , 53 , 54 ].…”

Section: K 2p 31 (Task-1)mentioning

confidence: 99%

See 1 more Smart Citation

Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

Wiedmann

Frey

Schmidt

2021

Cells

Self Cite

View full text Add to dashboard Cite

Two-pore-domain potassium (K2P-) channels conduct outward K+ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K2P channel family are widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K2P-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K2P3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K2P3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K2P2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K2P channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K2P channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K2P channels.

show abstract

“…Cardiac mRNA and protein expression mRNA abundance in sinoatrial and atrioventricular node [51] Pig mRNA (RT-qPCR, TaqMan) and protein (WB)…”

Section: Dogmentioning

confidence: 99%

Section: K 2p 31 (Task-1)mentioning

confidence: 99%

Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

Wiedmann

Frey

Schmidt

2021

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…TASK-1 current inhibition through either siRNA (small interfering RNA) [135] or high-affinity antagonist A293 [136] represent a novel antiarrhythmic strategy. Furthermore, doxapram, a respiratory stimulant and TASK-1 inhibitor, was effective in reducing AF burden in a porcine model of persistent AF [137].…”

Section: Atrial Selective Ion Channel Inhibitors and Gene Therapymentioning

confidence: 97%

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

et al. 2021

View full text Add to dashboard Cite

The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

show abstract

“…Selective TASK-1 inhibitors have also been developed and have been used in preclinical investigations. Recent in vivo and ex vivo investigations in pigs, cellular recordings from isolated human atrial cardiomy-ocytes, and computational modeling suggests that in the atria, the respiratory stimulant doxapram [177,178] acts as a selective TASK-1 blocker with strong antiarrhythmic properties [123] (Table 1). Doxapram is currently being investigated in the DOxapram Conversion To Sinus rhythm (DOCTOS) trial for cardioversion of both paroxysmal and persistent non-valvular AF (EudraCT No: 2018-002979-18) (Table 2).…”

Section: Task-1 Channel Blockersmentioning

confidence: 99%

Emerging Antiarrhythmic Drugs for Atrial Fibrillation

Saljic

Heijman

Dobrev

2022

IJMS

Self Cite

View full text Add to dashboard Cite

Atrial fibrillation (AF), the most common cardiac arrhythmia worldwide, is driven by complex mechanisms that differ between subgroups of patients. This complexity is apparent from the different forms in which AF presents itself (post-operative, paroxysmal and persistent), each with heterogeneous patterns and variable progression. Our current understanding of the mechanisms responsible for initiation, maintenance and progression of the different forms of AF has increased significantly in recent years. Nevertheless, antiarrhythmic drugs for the management of AF have not been developed based on the underlying arrhythmia mechanisms and none of the currently used drugs were specifically developed to target AF. With the increased knowledge on the mechanisms underlying different forms of AF, new opportunities for developing more effective and safer AF therapies are emerging. In this review, we provide an overview of potential novel antiarrhythmic approaches based on the underlying mechanisms of AF, focusing both on the development of novel antiarrhythmic agents and on the possibility of repurposing already marketed drugs. In addition, we discuss the opportunity of targeting some of the key players involved in the underlying AF mechanisms, such as ryanodine receptor type-2 (RyR2) channels and atrial-selective K+-currents (IK2P and ISK) for antiarrhythmic therapy. In addition, we highlight the opportunities for targeting components of inflammatory signaling (e.g., the NLRP3-inflammasome) and upstream mechanisms targeting fibroblast function to prevent structural remodeling and progression of AF. Finally, we critically appraise emerging antiarrhythmic drug principles and future directions for antiarrhythmic drug development, as well as their potential for improving AF management.

show abstract

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy

Cited by 26 publications

References 50 publications

Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

Emerging Antiarrhythmic Drugs for Atrial Fibrillation

Contact Info

Product

Resources

About