Current Drug Treatment Strategies for Atrial Fibrillation and TASK-1 Inhibition as an Emerging Novel Therapy Option

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an increase in mortality and stroke incidences. While stroke risk can be significantly reduced through anticoagulant therapy, adequate treatment of other AF related symptoms remains an unmet medical need in many cases. Two main treatment strategies are available: rate control that modulates ventricular heart rate and prevents tachymyopathy as well as rhythm control that aims to restore and sustain sinus rhythm. Rate control can be achieved through drugs or ablation of the atrioventricular node, rendering the patient pacemaker-dependent. For rhythm control electrical cardioversion and pharmacological cardioversion can be used. While electrical cardioversion requires fasting and sedation of the patient, antiarrhythmic drugs have other limitations. Most antiarrhythmic drugs carry a risk for pro-arrhythmic effects and are contraindicated in patients with structural heart diseases. Furthermore, catheter ablation of pulmonary veins can be performed with its risk of intraprocedural complications and varying success. In recent years TASK-1 has been introduced as a new target for AF therapy. Upregulation of TASK-1 in AF patients contributes to prolongation of the action potential duration. In a porcine model of AF, TASK-1 inhibition by gene therapy or pharmacological compounds induced cardioversion to sinus rhythm. The DOxapram Conversion TO Sinus rhythm (DOCTOS)-Trial will reveal whether doxapram, a potent TASK-1 inhibitor, can be used for acute cardioversion of persistent and paroxysmal AF in patients, potentially leading to a new treatment option for AF.

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

“…Among the entire K 2P family, K 2P 3.1 (TASK-1) is the channel with the best characterized cardiac significance. K 2P 3.1 (TASK-1) channels are expressed in neuronal tissue, cardiomyocytes, vascular smooth muscle cells, the carotid body glomus, the adrenal gland, brown adipose tissue and immunocytes, where they control important physiological processes [ 2 , 115 ]. K 2P 3.1 (TASK-1) channels are regulated by a number of different stimuli, such as pH level, hypoxia, PKA, PKC, or PLC activity, and several drugs like volatile anesthetics [ 2 ].…”

“…These antiarrhythmic effects could further be employed for rhythm control in a porcine model of burst pacing induced “persistent” AF, induced via implanted pacemakers using a biofeedback algorithm [ 53 , 164 ] and reproduced with an AAV-mediated anti-K 2P 3.1 (TASK-1) gene therapy approach [ 52 ]. Based on these encouraging results, the currently ongoing DOCTOS trial (doxapram conversion to sinus rhythm; EudraCT No: 2018-002979-17) was started, which investigates whether the FDA and EMA approved K 2P 3.1 (TASK-1) inhibitor doxapram can cardiovert AF in patients [ 2 , 179 ].…”

“…Two-pore-domain potassium (K 2P ) channels are expressed throughout the human body and contribute to background potassium conductance in many different cell types [ 1 , 2 ]. In the human genome 15 K 2P channels have been described which differ from classical potassium channels by the fact that each subunit carries two pore-forming domains, and the channels thus assemble as dimers instead of tetramers ( Figure 1 ).…”

Lixarit — clinical and pharmaceutical aspects of efficacy and safety of flecainide acetate generic drug

“…Флекаїнід був синтезований у 1972 р., а в 1984 р. був схвалений FDA для клінічного засто-сування. Останнім часом частота використання флекаїніду в розвинених країнах підвищується [8][9][10], що пов'язано з інтенсивним вивченням його фармакологічних властивостей, доказами високої ефективності й безпеки. Так, за останні п'ять років флекаїніду було присвячено майже 2000 публікацій у рецензованих виданнях, з них 99 метааналізів і систематичних оглядів тільки за минулий рік.…”

“…Результати останніх досліджень підтверджують високу ефективність і безпеку застосування флекаїніду при лікуванні аритмій плода [19]. З плином часу з'являються нові показання до застосування цього ААП [10,11].…”