,,,,,, Cardioversion of atrial fibrillation and atrial flutter revisited: current evidence and practical guidance for a common procedure, 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, Environmental factors, serum biomarkers and risk of atrial fibrillation: an exposure-wide umbrella review of meta-analyses, Innovative tools for atrial fibrillation ablation. Following jugular vein preparation, diagnostic electrophysiology catheters were placed under fluoroscopic guidance in the upper right atrium and at the right ventricular apex position. J. Med. Res. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Many inherited arrhythmia syndromes, which are characterized by mutations in cardiac ion channels, cause AF in structurally normal hearts64,65. Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. J. Cardiol. Heart J. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. P.K. Currents were recorded using two‐electrode voltage clamp technique measurements after application of the depicted pulse protocol. The parameters of the TASK‐1 model were then adjusted to reconstruct the measured AERPs without A293 at the BCLs: the TASK‐1 conductivity for AF cells was set to 0.0035 nS/pF to simulate the state without drug bound to the channel. H, Micrographs of representative isolated human (left) and porcine (right) atrial cardiomyocytes. Global burden of atrial fibrillation in developed and developing nations. National Center Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC guidelines on atrial fibrillation: primary results of the PREvention oF thromboemolic events — European Registry in Atrial Fibrillation (PREFER in AF). 86‐23, revised 1985), with European Union Directive 2010/63/EU, and with the current version of the German Law on the Protection of Animals. The American Heart Association is qualified 501(c)(3) tax-exempt Rev. Two‐electrode voltage clamp recordings of macroscopic currents were performed, as reported earlier.18 In brief, measurements were performed 1 to 4 days after cRNA injection using a Warner OC‐725C amplifier (Warner Instruments, Hamden, CT) and pCLAMP9 (Axon Instruments, Foster City, CA) software for data acquisition. Correspondence to 29, 632–639 (2008). In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. A list of the major health modifiers causing AF, and of the corresponding clinical markers, would form a valid basis for stratified or personalized approaches to prevention and treatment (Box 2). While human atrial cardiomyocytes displayed slightly higher background potassium current densities at the baseline level, administration of A293 (200 nmol/L) resulted in comparable current inhibition (Figure 2E). The highest conductivity value at which persistent reentry could be stopped by A293 was at 1.2 S/m (equal to 90 cm/sec). (2020), European Journal of Epidemiology Spach, M. S., Heidlage, J. F., Dolber, P. C. & Barr, R. C. Mechanism of origin of conduction disturbances in aging human atrial bundles: experimental and model study. Electrodes were pulled from borosilicate glass (GB 100F‐10, Science Products, Hofheim, Germany) using a Flaming/Brown P‐87 micropipette puller (Sutter Instruments, Novato, CA). This experimental compound was later found to be a much more potent TASK‐1 inhibitor that is active in the 3‐digit nanomolar range.16, 17, 18. Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment. Drca, N., Wolk, A., Jensen-Urstad, M. & Larsson, S. C. Atrial fibrillation is associated with different levels of physical activity levels at different ages in men. In contrast, a cardioversion rate of 100% (n=5 pigs) was documented after intravenous application of A293 (Figure 5B). This preclinical study was designed as a proof‐of‐concept trial to assess the antiarrhythmic potential of the pharmacologic TASK‐1 K+ channel inhibitor A293 for acute cardioversion in a porcine model of AF as well as in a translational in silico model of human atrial electrophysiology. PubMed  Additional 5 seconds for each conductivity were calculated for both blocked and unblocked TASK‐1 channels. The prevalence and incidence of AF increase with age. Gudbjartsson, D. F. et al. Their finding that the effect of A293 on AERPs was even more pronounced in the Alessi goat model of tachypacing‐induced artificial AF is most likely explained by AF‐associated upregulation of TASK‐1, as KV1.5 was described to be downregulated in atrial remodeling.36. Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options. JACC Cardiovasc. *Correspondence to: Constanze Schmidt, MD, FESC, SOT, Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D‐69120 Heidelberg, Germany. While the transmembrane regions were found to be highly conserved between hTASK‐1 and pTASK‐1, minor differences were found for the N‐ and C‐termini of the channel protein. © American Heart Association, Inc. All rights reserved. Atrial Nox2 activity was significantly increased shortly after AF induction in goats, and in atrial samples from patients in sinus rhythm who developed AF after cardiac surgery20. The lower section of the flow chart illustrates some of the potential health benefits of a new classification of AF. Circulation 107, 2355–2360 (2003). Europace 16, 6–14 (2014). Data are presented as mean±SEM. Res. In particular, TASK‐1 currents were recently shown to modulate atrial action potential duration (APD) in AF and heart failure.10, 11 In the human heart, the expression of TASK‐1 subunits is restricted to the atria.10, 12, 13 Strikingly, the atrial TASK‐1 levels were upregulated in paroxysmal and chronic AF, which contributes to pathological shortening of the atrial APD.10 In vitro experiments demonstrated that pharmacologic blockade of TASK‐1 currents could revert the APD shortening observed in atrial cardiomyocytes isolated from patients with AF to levels observed among controls with sinus rhythm.10 Therefore, TASK‐1 inhibition may represent an atrial‐specific, mechanism‐based approach for AF therapy.14, 15, The aromatic carbonamide A293 was initially developed as an inhibitor of the KV1.5 channel by Sanofi‐Aventis (Frankfurt, Germany). Abed, H. S. et al. Increases in spontaneous electrical activity have been suggested to have a major role in abnormal intracellular Ca2+ handling in the genesis of AF59. Coll. B, Percentage of cardioversions to sinus rhythm (SR) during the 10‐minute observation interval in the solvent control (Control) and the A293 treatment group (A293). Nat. Larissa Fabritz. The pig therefore represents an adequate model to study the cardiac role of TASK‐1. *P<0.05; **P<0.01 for Student t tests. J.D. Eur. CMR-guided approach to localize and ablate gaps in repeat AF ablation procedure. Such personalized concepts will add to the existing practice of cardiovascular risk reduction. Heterologously expressed human and porcine TASK‐1 channels are blocked by A293 to a similar extent. 34, 2725–2730 (2013). Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial. Finally, our results confirmed the role of TASK‐1 as a promising drug target in AF and might therefore promote the translation of a novel, mechanism‐based antiarrhythmic paradigm into clinical practice. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. Larissa Fabritz and Eduard Guasch: *These authors are joint first authors. A simplified left atrial geometry consisting of a 2‐dimensional spherical surface with a diameter of 5 cm and 5 orifices representing the 4 pulmonary veins and the mitral valve (see Figure 6D, black spheres) was employed. contributed equally to this Consensus Statement. Therefore, epicardial adipose tissue could be an important health modifier for AF. The pharmacologic sensitivity of porcine and human TASK‐1 currents to A293 was similar. After drug exposure, no clinical adverse effects were observed over a period of 3 to 5 days. 4, 123–133 (2011). Pharmacologic cardioversion with A293 yielded cardioversion times of 177±63 seconds, differing significantly from that of the control group (P=0.0034, Kruskal–Wallis test) as visualized in Figure 5C. PubMed  Circulation 127, 1466–1475 (2013). has received consulting fees/honoraria from Daiichi Sankyo, Genzyme, and Shire, and has received research grants (to institution) from Amgen, AstraZeneca, Boehringer Ingelheim, the DFG, Heisenberg professorship, the Else Kröner-Fresenius-Foundation, the EU, Genzyme, the German Ministry of Education and Research (BMBF), the Kuratorium für Dialyse und Nierentransplantation (KfH)-Stiftung Präventivmedizin, Novartis, Sanofi Aventis, Shire, and the Société Française d'Hypertension Artérielle. We investigated in which range of tissue conductivities A293 was able to eliminate the rotor. Google Scholar. J. Local Info Article  Circ. Heart Rhythm 10, 1661–1668 (2013). 60, 539–545 (2012). Shear stress triggers insertion of voltage-gated potassium channels from intracellular compartments in atrial myocytes. Jackson, N. et al. Cardiol. If the hypothesis of equal means could be rejected at the 0.05 level, pairwise comparisons of groups were made and the probability values were adjusted for multiple comparisons using the Bonferroni correction. Cardiovasc. Patients with AF who have these mutations have been referred to as patients with 'monogenic AF' (Ref. Google Scholar. Kirchhof, P. et al. Nurse-led care versus usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care versus routine clinical care in ambulatory patients with atrial fibrillation. Nat. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. declares that he has received consulting fees/honoraria from Biosense, Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical, and that he has received research grants from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical. Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. Commun. In the human heart, TASK‐1 channels are specifically expressed in the atria, whereas ventricular TASK‐1 expression levels are virtually negligible.10, 12, 13 Real‐time quantitative real‐time polymerase chain reaction experiments showed that subcompartment‐specific patterns of KCNK3 mRNA levels in the porcine heart are similar to expression patterns in the human heart. AF has a strong familial component. However, neither vitamin K antagonist anticoagulant therapies, nor the non-vitamin-K antagonist oral anticoagulants, such as apixaban, dabigatran, edoxaban, or rivaroxaban, have been sufficiently tested in patients with severe chronic kidney disease to suggest safe use at present87,88. The proposed AF types were: monogenic AF, focally induced AF, postoperative AF, valvular AF, AF in the elderly, polygenic AF, and unclassified AF45,46. Am. It was predicted that the number of patients with AF will significantly rise in our aging population.2 Despite the epidemiologic and individual relevance of AF, current pharmacologic, interventional, or surgical therapeutic strategies show suboptimal effectiveness and frequently cause severe adverse events.3 Currently, safe and effective management of AF remains an unmet medical need. Glob. It remains speculative whether this slight elevation of the atrial TASK‐1 currents may be linked to the underlying atrial cardiomyopathy, as patients that underwent open heart surgery due to ischemic or valvular heart disease were compared with young and healthy pigs. , Institute for Experimental Cardiovascular Medicine, , University Heart Center Freiburg, , Bad Krozingen, , Germany. Comparison of the current approach to atrial fibrillation (AF) management, which is disconnected from the established insights into AF pathophysiology, and the proposed approach to AF management in which the major changes leading to AF will lead to a classification of patients with AF and provide a basis for personalized prevention and management. At present, a disconnect exists between the known mechanisms of atrial fibrillation (AF), and the current management of AF, which is based on a useful, but weak, estimation scheme of the risk of stroke and on AF duration and symptoms (see the figure). Marrouche, N. F. et al. T.R.B. 92, 1317–1358 (2012). During experiments, 1 mg/kg body weight of A293 was administered as short infusion (100 mL 0.9% NaCl) over 5 minutes. declares that he has received consulting fees and honoraria from Boehringer Ingelheim, Boston Scientific, Medtronic, and St. Jude Medical, and that he has received research grants from BMS and St. Jude Medical. For example, weight reduction can help to prevent AF recurrence in overweight patients with AF47,48, and physical activity reduction might contribute to the prevention of AF in athletes49. Tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K+ channel (TASK‐1; K2P3.1) is a member of the two‐pore–domain potassium (K2P‐) channel family. 89, 816–824 (2011). Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. 66, 1–11 (2015). Further, the efficacy of TASK‐1 current inhibition in rhythm control of persistent AF remains to be elucidated. de Vos, C. B. et al. Res. Mit dem Button "Anfrage senden" öffnet sich ein Fenster Ihres E-Mail-Programmes mit einer vorgefertigten E-Mail. D, Black spheres: geometrical model consisting of a spherical surface (diameter of 5 cm) with 5 orifices representing the left and right inferior and superior pulmonary veins (LIPV/RIPV/LSPV/RSPV) as well as the mitral valve annulus. We selected the major mechanisms of AF on the basis of a group discussion and a review of the literature. Cloning and functional characterization of the porcine TASK‐1 orthologs was described earlier.14 Amino acid sequence alignments of pTASK‐1 and hTASK‐1 showed 96.7% conservation at the protein level (Figure 1A). Eur. Quantification was performed at the end of the +20 mV pulse (n=3 cells). In addition, accumulating data support important contributions to the pathogenesis of AF of high levels of oxidative stress, infiltration of fat into the atria, as well as increases in the paracrine activity of atrial adipocytes and maladaptation owing to chronic kidney disease. Circ. Long-term effect of goal-directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). 62, 68–77 (2013). Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment. Heart J. All recordings were performed at room temperature (20–22°C) in a standard physiological extracellular solution, consisting of: 96 mmol/L NaCl, 4 mmol/L KCl, 1.1 mmol/L CaCl2, 1 mmol/L MgCl2, and 5 mmol/L HEPES (pH 7.4). Article  G.B.-S. is an employee of Roche Professional Diagnostics. 89, 825–833 (2011). To view a copy of this license, visit Coupling intervals of extrastimuli were decreased in 10‐ms decrements until refractoriness of the S2 stimulus was achieved. The context of health-care delivery is also important. This work was supported by research grants from the University of Heidelberg, Faculty of Medicine (Rahel Goitein‐Straus Scholarship and Olympia‐Morata Scholarship to Schmidt); from the German Center for Cardiovascular Research (DZHK) (Excellence Grant to Schmidt, Postdoc Startup Grant to Wiedmann); from the German Cardiac Society (DGK) (Research Scholarship DGK082018 to Wiedmann, Otto‐Hess Fellowship to Wiedmann); from the German Heart Foundation/German Foundation of Heart Research (F/15/18 to Wiedmann, F/41/15 to Schmidt, Kaltenbach Scholarship to Büscher and Wiedmann); from the Ministry of Science, Research and the Arts Baden‐Wuerttemberg (Sonderlinie Medizin to Thomas); from the Joachim‐Herz Foundation (Addon‐Fellowship for interdisciplinary life sciences to Wiedmann) and from the German Research Foundation (DFG) (LO 2093/1‐1 to Loewe, SCHM 3358/1‐1 to Schmidt, SE 1758/3‐3 to Seemann TH 1120/7‐1 to Thomas). Circulation 123, 2204–2212 (2011). Extracellular Tyrode's solution was composed of 137 mmol/L NaCl, 5.4 mmol/L KCl, 2 mmol/L CaCl2, 1 mmol/L MgSO4, 10 mmol/L glucose and 10 mmol/L HEPES, pH 7.3 with NaOH. CAS  Sci. C, Cloned human and porcine TASK‐1 ion channel subunits, heterologously expressed in Xenopus laevis oocytes, are inhibited by A293 (100 μmol/L) to a similar extent. Circulation 100, 376–380 (1999). Pigs that still remained in AF after this 5‐minute period were subjected to treatment with A293 or respective vehicle controls. Specific AF services, for example in the form of specialist AF clinics89 and integrated AF services50,90, will have an important role in the validation and clinical evaluation of the major health modifiers of AF91. Am. Similarly, the CHADS2 score predicts new-onset AF incidence44, but does not add information on the causes or the mechanisms involved. It was reported that members of the K2P family are susceptible to a wide range of narcotics. J. Cardiol. 35, 3250–3257 (2014). Plasmid constructs containing cDNA encoding human TASK‐1 (GenBank accession no. Chugh, S. S., Roth, G. A., Gillum, R. F. & Mensah, G. A. The initial rotor was simulated for 10 seconds with different tissue conductivities, resulting in differing conduction velocities. Of note, human tissue samples were taken from patients with sinus rhythm without documentation of AF in their prior medical history and without relevant left ventricular dysfunction. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Circ. Porcine hearts were extracted after intracardiac injection of KCl in deep anesthesia, rinsed in phosphate buffered saline and quickly dissected. Contact force threshold for permanent lesion formation in atrial fibrillation ablation: a cardiac magnetic resonance-based study to detect ablation gaps. Chao, T. F. et al. USA 110, E3955–E3964 (2013). Venteclef, N. et al. Subsequently, tissue pieces were subjected to digestion with collagenase type I, 288 U/mL (Worthington Biochemical Corporation, Lakewood, NJ) and protease type XXIV, 5 mg/mL (Sigma‐Aldrich) in Ca2+‐free Tyrode's solution for 15 minutes. Circ. All these mechanisms of AF (Box 1) have the potential to lead to atrial dysfunction (Fig. To assess the effects of TASK‐1 inhibition by A293 on cardiac electrophysiology, we recorded the surface ECGs from anesthetized pigs before and after application of A293. When a pig remained in AF >10 minutes, an electrical cardioversion was performed. L.F., E.G., E.B., G. Breithardt, B.C., L.M., U.S., and P.K. In addition, a deeper knowledge of a patient's disease would enable a better-informed joint patient–physician decision on which therapeutic strategies to employ. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials.

Try a few lessons a day and you'll start to notice your fingers naturally move to the right keys. Arrhythm. organization. and JavaScript. Scalebars are given as inserts. Early-onset AF is associated with common genetic variants (17 independent loci have been identified to date), with a hotspot for such variants on chromosome 4q25 (Refs 18,66). Sportliche Gründe hatte der Wechsel von Julian Büscher nicht, vielmehr verließ er die Halterner aus beruflichen Gründen. 97, 629–636 (2005). Am. Voigt, N. et al. Or, for best results, complete both sets! A, Left panel: Amino acid alignments of pTASK‐1 and hTASK‐1 show high similarity between human and porcine orthologs at the protein level. Now you have the ability to set typing goals for your typing lessons! Heart J. & Antzelevitch, C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity. Authors involved in this work have received funding from the European Union's Horizon 2020 research and innovation programme, under grant agreement No. In contrast, in rodents, TASK‐1 expression is not confined to the atria, and AF‐related TASK‐1 remodeling differed from the effects observed in the tissue samples of AF patients.21 Finally, patch clamp recordings performed on native isolated atrial cardiomyocytes confirmed comparable TASK‐1 current densities in humans and pigs with a nonsignificant trend toward higher TASK‐1 currents in patient samples. Autonomic trigger patterns and anti-arrhythmic treatment of paroxysmal atrial fibrillation: data from the Euro Heart Survey. E, Comparison of mean current density, quantified at +40 mV membrane potential. AERPs, measured at different BCLs, were significantly prolonged upon TASK‐1 inhibition by A293 (Figure 4A through 4H). Am. Additionally, microalbuminuria and macroalbuminuria were associated with increased risk of AF87,88.


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