Identification of Dominant Excitation Patterns and Sources of Atrial Fibrillation by Causality Analysis

Burden of atrial fibrillation (AF) can be reduced by ablation of sources of electrical impulses driving AF but driver identification is still challenging. This study presents a new methodology based on causality analysis that allows identifying the hierarchically dominant areas driving AF. Identification of dominant propagation patterns was achieved by computing causal relations between intracardiac multi-electrode catheter recordings of four paroxysmal AF patients during sinus rhythm, pacing and AF. In addition, realistic mathematical models of the atria during AF were used to validate the methodology both in the presence and absence of dominant frequency (DF) gradients. During electrical pacing, sources of propagation patterns detected by causality analysis were consistent with the location of the stimulating catheter. During AF, propagation patterns presented temporal variability, but a dominant direction accounted for significantly more propagations than other directions (49 +/- 15% vs. 14 +/- 13% or less, p < 0.01). Both in patients with a DF gradient and in mathematical models, causal maps allowed the identification of sites responsible for maintenance of AF. Causal maps allowed the identification of atrial dominant sites. In particular, causality analysis resulted in stable dominant cause-effect propagation directions during AF and could serve as a guide for performing ablation procedures in AF patients.FA served on the advisory board of Medtronic and has received research funding from St. Jude Medical Spain. OB received research support from Medtronic and St. Jude Medical. He is a Scientific Officer of Rhythm Solutions, Inc. and a consultant to Acutus Medical, inc. The other authors have no conflict of interest. None of the companies disclosed financed the research described in this manuscript.Rodrigo Bort, M.; Climent, A.; Liberos Mascarell, A.; Calvo, D.; Fernandez-Aviles, F.; Berenfeld, O.; Atienza, F.... (2016). Identification of Dominant Excitation Patterns and Sources of Atrial Fibrillation by Causality Analysis. Annals of Biomedical Engineering. 44(8):2364-2376. https://doi.org/10.1007/s10439-015-1534-x23642376448Atienza, F., J. Almendral, J. Jalife, S. Zlochiver, R. Ploutz-Snyder, E. G. Torrecilla, A. Arenal, J. Kalifa, F. Fernández-Avilés, and O. Berenfeld. Real-time dominant frequency mapping and ablation of dominant frequency sites in atrial fibrillation with left-to-right frequency gradients predicts long-term maintenance of sinus rhythm. Heart Rhythm. 6:33–40, 2009.Atienza, F., J. Almendral, J. Moreno, R. Vaidyanathan, A. Talkachou, J. Kalifa, A. Arenal, J. P. Villacastín, E. G. Torrecilla, A. Sánchez, R. Ploutz-Snyder, J. Jalife, and O. Berenfeld. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans evidence for a reentrant mechanism. Circulation 114:2434–2442, 2006.Atienza, F., J. Almendral, J. M. Ormaetxe, A. Moya, J. D. Martínez-Alday, A. Hernández-Madrid, E. Castellanos, F. Arribas, M. Á. Arias, L. Tercedor, R. Peinado, M. F. Arcocha, M. Ortiz, N. Martínez-Alzamora, A. Arenal, F. Fernández-Avilés, and J. Jalife. Comparison of radiofrequency catheter ablation of drivers and circumferential pulmonary vein isolation in atrial fibrillation. A noninferiority randomized multicenter RADAR-AF Trial. J. Am. Coll. Cardiol. 64:2455–2467, 2014.Atienza, F., D. Calvo, J. Almendral, S. Zlochiver, K. R. Grzeda, N. Martínez-Alzamora, E. González-Torrecilla, A. Arenal, F. Fernández-Avilés, and O. Berenfeld. Mechanisms of fractionated electrograms formation in the posterior left atrium during paroxysmal atrial fibrillation in humans. J. Am. Coll. Cardiol. 57:1081–1092, 2011.Benharash, P., E. Buch, P. Frank, M. Share, R. Tung, K. Shivkumar, and R. Mandapati. Quantitative analysis of localized sources identified by focal impulse and rotor modulation mapping in atrial fibrillation. Circ. Arrhythm. Electrophysiol. 8:554–561, 2015.Chao, T. F., H. M. Tsao, Y. J. Lin, C. F. Tsai, W. S. Lin, S. L. Chang, L. W. Lo, Y. F. Hu, T. C. Tuan, K. Suenari, C. H. Li, B. Hartono, H. Y. Chang, K. Ambrose, T. J. Wu, and S. A. Chen. Clinical outcome of catheter ablation in patients with nonparoxysmal atrial fibrillation: Results of 3-year follow-up. Circ. Arrhythm. Electrophysiol. 5:514–520, 2012.Cuculich, P. S., Y. Wang, B. D. Lindsay, M. N. Faddis, R. B. Schuessler, R. J. Damiano, L. Li, and Y. Rudy. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation. 5(122):1364–1372, 2010.Dössel, O., M. W. Krueger, F. M. Weber, M. Wilhelms, and G. Seemann. Computational modeling of the human atrial anatomy and electrophysiology. Med. Biol. Eng. Comput. 50:773–799, 2012.Freiwald, W. A., P. Valdes, J. Bosch, R. Biscay, J. C. Jimenez, L. M. Rodriguez, V. Rodriguez, A. K. Kreiter, and W. Singer. Testing non-linearity and directedness of interactions between neural groups in the macaque inferotemporal cortex. J. Neurosci. Methods 94:105–119, 1999.Gerstenfeld, E. P., A. V. Sahakian, and S. Swiryn. Evidence for transient linking of atrial excitation during atrial fibrillation in humans. Circulation. 86:375–382, 1992.Granger, C. W. J. Investigating causal relations by econometric models and cross-spectral methods. Econometrica 3:424–438, 1969.Guillem, M. S., A. M. Climent, J. Millet, A. Arenal, F. Fernández-Avilés, J. Jalife, F. Atienza, and O. Berenfeld. Noninvasive localization of maximal frequency sites of atrial fibrillation by body surface potential mapping. Circ. Arrhythm. Electrophysiol. 6:294–301, 2013.Haïssaguerre, M., P. Jaïs, D. C. Shah, A. Takahashi, M. Hocini, G. Quiniou, S. Garrigue, A. Le Mouroux, P. Le Métayer, and J. Clémenty. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N. Engl. J. Med. 339:659–666, 1998.Hsu, L. F., P. Jaïs, D. Keane, J. M. Wharton, I. Deisenhofer, M. Hocini, D. C. Shah, P. Sanders, C. Scavée, R. Weerasooriya, J. Clémenty, and M. Haïssaguerre. Atrial fibrillation originating from persistent left superior vena cava. Circulation. 109:828–832, 2004.Ideker, R. E., and J. M. Rogers. Human ventricular fibrillation: wandering wavelets, mother rotors, or both? Circulation. 114:530–532, 2006.Jalife, J. Déjà vu in the theories of atrial fibrillation dynamics. Cardiovasc. Res. 89:766–775, 2011.Jalife, J., D. Filgueiras Rama, and O. Berenfeld. Letter by Jalife et al. Regarding Article, “Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Modulation Mapping in Atrial Fibrillation. Circ. Arrhythm. Electrophysiol. 8:1296–1298, 2015.Kalifa, J., K. Tanaka, A. V. Zaitsev, M. Warren, R. Vaidyanathan, D. Auerbach, S. Pandit, K. L. Vikstrom, R. Ploutz-Snyder, A. Talkachou, F. Atienza, G. Guiraudon, J. Jalife, and O. Berenfeld. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation. 113:626–633, 2006.Nademanee, K., J. McKenzie, E. Kosar, M. Schwab, B. Sunsaneewitayakul, T. Vasavakul, C. Khunnawat, and T. Ngarmukos. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J. Am. Coll. Cardiol. 43:2044–2053, 2004.Narayan, S. M., D. E. Krummen, P. Clopton, K. Shivkumar, and J. M. Miller. Direct Or Coincidental Elimination of Stable Rotors or Focal Sources May Explain Successful Atrial Fibrillation Ablation: On-Treatment Analysis of the CONFIRM (CONventional ablation for AF with or without Focal Impulse and Rotor Modulation) Trial. J. Am. Coll. Cardiol. 62:137–147, 2013.Ng, J., D. Gordon, R. S. Passman, B. P. Knight, R. Arora, and J. J. Goldberger. Electrogram morphology recurrence patterns during atrial fibrillation. Heart Rhythm. 11:2027–2034, 2014.Providência, R., P. D. Lambiase, N. Srinivasan, G. Ganesha Babu, K. Bronis, S. Ahsan, F. Z. Khan, A. W. Chow, E. Rowland, M. Lowe, and O. R. Segal. Is there still a role for CFAE ablation in addition to pulmonary vein isolation in patients with paroxysmal and persistent atrial fibrillation? A meta-analysis of 1415 patients. Circ. Arrhythm. Electrophysiol. 8:1017–1029, 2015.Richter, U., L. Faes, A. Cristoforetti, M. Masè, F. Ravelli, M. Stridh, and L. Sörnmo. A novel approach to propagation pattern analysis in intracardiac atrial fibrillation signals. Ann. Biomed. Eng. 39:310–323, 2011.Rodrigo, M., M. S. Guillem, A. M. Climent, J. Pedrón-Torrecilla, A. Liberos, J. Millet, F. Fernández-Avilés, F. Atienza, and O. Berenfeld. Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: a clinical-computational study. Heart Rhythm. 11:1584–1591, 2014.Sanders, P., O. Berenfeld, M. Hocini, P. Jaïs, R. Vaidyanathan, L. F. Hsu, S. Garrigue, Y. Takahashi, M. Rotter, F. Sacher, C. Scavée, R. Ploutz-Snyder, J. Jalife, and M. Haïssaguerre. Spectral analysis identifies sites of high frequency activity maintaining atrial fibrillation in humans. Circulation. 112:789–797, 2005.Zlochiver, S., M. Yamazaki, J. Kalifa, and O. Berenfeld. Rotor meandering contributes to irregularity in electrograms during atrial fibrillation. Heart Rhythm. 5:846–854, 2008