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

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          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.

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            Haemodynamic definitions and updated clinical classification of pulmonary hypertension

            Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management. Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup “pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers”, due to the specific prognostic and management of these patients, and a subgroup “PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement”, due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH.
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              Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.

              The global burden of atrial fibrillation (AF) is unknown. We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5-22.2 million] and 12.6 million women [95% UI, 12.0-13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8-19.3) in men and 18.9% (95% UI, 15.8-23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8-612.7) and 359.9 in women (95% UI, 334.7-392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2-78.5) and 43.8 in women (95% UI, 35.9-55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4-636.7) in men and 373.1 (95% UI, 347.9-402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2-95.4) in men and 59.5 (95% UI, 49.9-74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0-2.2) and 1.9-fold (95% UI, 1.8-2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                04 March 2021
                2021
                : 12
                : 638445
                Affiliations
                [ 1 ]Department of Cardiology, University of Heidelberg, Heidelberg, Germany
                [ 2 ]DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany
                [ 3 ]HCR, Heidelberg Center for Heart Rhythm Disorders, University of Heidelberg, Heidelberg, Germany
                [ 4 ]Clinic for Cardiology II: Electrophysiology, University Hospital Münster, Münster, Germany
                [ 5 ]Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
                Author notes

                Edited by: Michael Curtis, King’s College London, United Kingdom

                Reviewed by: Bin-Nan Wu, Kaohsiung Medical University, Taiwan

                Oscar Casis, Universidad del País Vasco UPV/EHU, Spain

                *Correspondence: Constanze Schmidt, Constanze.Schmidt@ 123456med.uni-heidelberg.de

                This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                638445
                10.3389/fphar.2021.638445
                8058608
                33897427
                7fc7f520-27fb-490e-9d2e-7d7b8b436f84
                Copyright © 2021 Kraft, Büscher, Wiedmann, L’hoste, Haefeli, Frey, Katus and Schmidt.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 December 2020
                : 21 January 2021
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                atrial fibrillation,anti-arrhythmic drugs,task-1,cardioversion,kcnk3

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