Predictive Factors to Effectively Terminate Paroxysmal Atrial Fibrillation by Blocking Atrial Selective Ionic Currents

Summary

* The main objective of this project is to study the efficacy and the mechanistic value of blocking both atrial specific and atria-preferential dynamics of ionic currents to terminate paroxysmal atrial fibrillation (AF). * The hypothesis is that a drug blocking atrial specific and atria-preferential dynamics of ionic currents (IK,ACh - acetylcholine sensitive K+ current - and INa - inward sodium current - , respectively) will be more effective to terminate paroxysmal AF episodes with fast atrial activation rates, than a classical INa blocker, which will be more effective to terminate AF episodes with slower activation rates. * The investigators will include patients without structural heart disease and short-lasting AF episodes (\<48 h.). Double blind and single center study, in which patients will be randomly assigned to a cardioversion group using intravenous flecainide or to an atria-preferential and atrial-specific blockade group using intravenous vernakalant. Patients will be routinely monitored in the electrophysiology room to acquire both 12-lead digitized ECG signals and non-invasive body surface potential mapping. Atrial signals will be extracted from both the multisite body surface and ECG recordings to obtain temporal and spectral parameters, and measure organization and atrial rate in both groups. The results obtained in the clinical setting will be studied in mathematical models to understand their capability to terminate paroxysmal AF. The project expects to provide consistent, reliable and reproducible parameters that will assist clinicians to know what type of paroxysmal AF episodes will be more suitable to effectively terminate, upon administration of drugs with an atrial specific and atria-preferential profile.

Timeline

Start

2017-01

Primary completion

2023-06

Completion

2023-08

Publications

• Background Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998 Oct 16;82(8A):2N-9N. doi: 10.1016/s0002-9149(98)00583-9.
• Background Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991 Aug;22(8):983-8. doi: 10.1161/01.str.22.8.983.
• Background Mandapati R, Skanes A, Chen J, Berenfeld O, Jalife J. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation. 2000 Jan 18;101(2):194-9. doi: 10.1161/01.cir.101.2.194.
• Background Gray RA, Jalife J, Panfilov AV, Baxter WT, Cabo C, Davidenko JM, Pertsov AM. Mechanisms of cardiac fibrillation. Science. 1995 Nov 17;270(5239):1222-3; author reply 1224-5. No abstract available.
• Background Berenfeld O, Mandapati R, Dixit S, Skanes AC, Chen J, Mansour M, Jalife J. Spatially distributed dominant excitation frequencies reveal hidden organization in atrial fibrillation in the Langendorff-perfused sheep heart. J Cardiovasc Electrophysiol. 2000 Aug;11(8):869-79. doi: 10.1111/j.1540-8167.2000.tb00066.x.
• Background Sanders P, Berenfeld O, Hocini M, Jais P, Vaidyanathan R, Hsu LF, Garrigue S, Takahashi Y, Rotter M, Sacher F, Scavee C, Ploutz-Snyder R, Jalife J, Haissaguerre M. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation. 2005 Aug 9;112(6):789-97. doi: 10.1161/CIRCULATIONAHA.104.517011. Epub 2005 Aug 1.
• Background Atienza F, Almendral J, Moreno J, Vaidyanathan R, Talkachou A, Kalifa J, Arenal A, Villacastin JP, Torrecilla EG, Sanchez A, Ploutz-Snyder R, Jalife J, Berenfeld O. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism. Circulation. 2006 Dec 5;114(23):2434-42. doi: 10.1161/CIRCULATIONAHA.106.633735. Epub 2006 Nov 13.
• Background Castells F, Mora C, Rieta JJ, Moratal-Perez D, Millet J. Estimation of atrial fibrillatory wave from single-lead atrial fibrillation electrocardiograms using principal component analysis concepts. Med Biol Eng Comput. 2005 Sep;43(5):557-60. doi: 10.1007/BF02351028.
• Background Bollmann A, Sonne K, Esperer HD, Toepffer I, Klein HU. Patients with persistent atrial fibrillation taking oral verapamil exhibit a lower atrial frequency on the ECG. Ann Noninvasive Electrocardiol. 2002 Apr;7(2):92-7. doi: 10.1111/j.1542-474x.2002.tb00148.x.
• Background Bollmann A, Binias KH, Toepffer I, Molling J, Geller C, Klein HU. Importance of left atrial diameter and atrial fibrillatory frequency for conversion of persistent atrial fibrillation with oral flecainide. Am J Cardiol. 2002 Nov 1;90(9):1011-4. doi: 10.1016/s0002-9149(02)02690-5. No abstract available.
• Background Bollmann A, Kanuru NK, McTeague KK, Walter PF, DeLurgio DB, Langberg JJ. Frequency analysis of human atrial fibrillation using the surface electrocardiogram and its response to ibutilide. Am J Cardiol. 1998 Jun 15;81(12):1439-45. doi: 10.1016/s0002-9149(98)00210-0.
• Background Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C. Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation. 2007 Sep 25;116(13):1449-57. doi: 10.1161/CIRCULATIONAHA.107.704890. Epub 2007 Sep 4.
• Background Fedida D, Orth PM, Chen JY, Lin S, Plouvier B, Jung G, Ezrin AM, Beatch GN. The mechanism of atrial antiarrhythmic action of RSD1235. J Cardiovasc Electrophysiol. 2005 Nov;16(11):1227-38. doi: 10.1111/j.1540-8167.2005.50028.x.
• Background Duggan ST, Scott LJ. Intravenous vernakalant: a review of its use in the management of recent-onset atrial fibrillation. Drugs. 2011 Jan 22;71(2):237-52. doi: 10.2165/10489050-000000000-00000.
• Background Feng J, Xu D, Wang Z, Nattel S. Ultrarapid delayed rectifier current inactivation in human atrial myocytes: properties and consequences. Am J Physiol. 1998 Nov;275(5):H1717-25. doi: 10.1152/ajpheart.1998.275.5.H1717.
• Background Kneller J, Kalifa J, Zou R, Zaitsev AV, Warren M, Berenfeld O, Vigmond EJ, Leon LJ, Nattel S, Jalife J. Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model. Circ Res. 2005 Mar 18;96(5):e35-47. doi: 10.1161/01.RES.0000160709.49633.2b.
• Background Stiell IG, Roos JS, Kavanagh KM, Dickinson G. A multicenter, open-label study of vernakalant for the conversion of atrial fibrillation to sinus rhythm. Am Heart J. 2010 Jun;159(6):1095-101. doi: 10.1016/j.ahj.2010.02.035.
• Background Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997 Oct;81(4):512-25. doi: 10.1161/01.res.81.4.512.
• Background Castells F, Cervigon R, Millet J. On the preprocessing of atrial electrograms in atrial fibrillation: understanding Botteron's approach. Pacing Clin Electrophysiol. 2014 Feb;37(2):133-43. doi: 10.1111/pace.12288. Epub 2013 Nov 12.
• Background Castells F, Cebrian A, Millet J. The role of independent component analysis in the signal processing of ECG recordings. Biomed Tech (Berl). 2007 Feb;52(1):18-24. doi: 10.1515/BMT.2007.005.
• Background Quintanilla JG, Moreno J, Archondo T, Chin A, Perez-Castellano N, Usandizaga E, Garcia-Torrent MJ, Molina-Morua R, Gonzalez P, Rodriguez-Bobada C, Macaya C, Perez-Villacastin J. KATP channel opening accelerates and stabilizes rotors in a swine heart model of ventricular fibrillation. Cardiovasc Res. 2013 Aug 1;99(3):576-85. doi: 10.1093/cvr/cvt093. Epub 2013 Apr 23.
• Background Perez-Castellano N, Villacastin J, Salinas J, Vega M, Moreno J, Doblado M, Ruiz E, Macaya C. Epicardial connections between the pulmonary veins and left atrium: relevance for atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2011 Feb;22(2):149-59. doi: 10.1111/j.1540-8167.2010.01873.x. Epub 2010 Aug 30.
• Background Perez-Castellano N, Villacastin J, Aragoncillo P, Fantidis P, Sabate M, Garcia-Torrent MJ, Prieto C, Corral JM, Moreno J, Fernandez-Ortiz A, Vano E, Macaya C. Pathological effects of pulmonary vein beta-radiation in a swine model. J Cardiovasc Electrophysiol. 2006 Jun;17(6):662-9. doi: 10.1111/j.1540-8167.2006.00462.x.

Drugs

Indications