Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely.

[1]  G. Moe,et al.  On the multiple wavelet hypothesis o f atrial fibrillation. , 1962 .

[2]  A. Harada,et al.  Atrial activation during chronic atrial fibrillation in patients with isolated mitral valve disease. , 1996, The Annals of thoracic surgery.

[3]  M. Courtemanche,et al.  Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. , 1998, The American journal of physiology.

[4]  N. Trayanova,et al.  Electrotonic coupling between human atrial myocytes and fibroblasts alters myocyte excitability and repolarization. , 2009, Biophysical journal.

[5]  Henggui Zhang,et al.  Simulation of clinical electrophysiology in 3D human atria: a high‐performance computing and high‐performance visualization application , 2008, Concurr. Comput. Pract. Exp..

[6]  S. Nattel,et al.  Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis. , 2008, Cardiovascular research.

[7]  Stanley Nattel,et al.  Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications , 2008, Circulation. Arrhythmia and electrophysiology.

[8]  A Garfinkel,et al.  Cardiac electrical restitution properties and stability of reentrant spiral waves: a simulation study. , 1999, The American journal of physiology.

[9]  B. Mensour,et al.  Influence of Propafenone on Resetting and Termination of Canine Atrial Flutter , 2000, Pacing and clinical electrophysiology : PACE.

[10]  B. Gersh,et al.  Epidemiological profile of atrial fibrillation: a contemporary perspective. , 2005, Progress in cardiovascular diseases.

[11]  Sanjiv M Narayan,et al.  Centrifugal Gradients of Rate and Organization in Human Atrial Fibrillation , 2009, Pacing and clinical electrophysiology : PACE.

[12]  P. Graux,et al.  Wavelength and Atrial Vulnerability: an Endocavitary Approach in Humans , 1998, Pacing and clinical electrophysiology : PACE.

[13]  Daniel Steven,et al.  Atrial fibrillation begets atrial fibrillation in the pulmonary veins on the impact of atrial fibrillation on the electrophysiological properties of the pulmonary veins in humans. , 2008, Journal of the American College of Cardiology.

[14]  A. Garfinkel,et al.  An advanced algorithm for solving partial differential equation in cardiac conduction , 1999, IEEE Transactions on Biomedical Engineering.

[15]  S Nattel,et al.  Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model. , 1999, Cardiovascular research.

[16]  Nathalie Virag,et al.  Wavelength and vulnerability to atrial fibrillation: Insights from a computer model of human atria. , 2005, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[17]  Javier Moreno,et al.  Activation of Inward Rectifier Potassium Channels Accelerates Atrial Fibrillation in Humans: Evidence for a Reentrant Mechanism , 2006, Circulation.

[18]  Alexander V Panfilov,et al.  Influence of diffuse fibrosis on wave propagation in human ventricular tissue. , 2007, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[19]  Elizabeth M Cherry,et al.  Properties of two human atrial cell models in tissue: restitution, memory, propagation, and reentry. , 2008, Journal of theoretical biology.

[20]  Henggui Zhang,et al.  Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans. , 2005, Cardiovascular research.

[21]  F. Fernández‐Avilés,et al.  In humans, chronic atrial fibrillation decreases the transient outward current and ultrarapid component of the delayed rectifier current differentially on each atria and increases the slow component of the delayed rectifier current in both. , 2010, Journal of the American College of Cardiology.

[22]  A. Holden,et al.  Heterogeneous three-dimensional anatomical and electrophysiological model of human atria , 2006, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[23]  Wouter-Jan Rappel,et al.  Repolarization and Activation Restitution near Human Pulmonary Veins and Atrial Fibrillation Initiation a Mechanism for the Initiation of Atrial Fibrillation by Premature Beats , 2022 .

[24]  Michel Haïssaguerre,et al.  Impact of Varying Ablation Patterns in a Simulation Model of Persistent Atrial Fibrillation , 2007, Pacing and clinical electrophysiology : PACE.

[25]  Leora Peltz,et al.  Epicardial Mapping of Chronic Atrial Fibrillation in Patients: Preliminary Observations , 2004, Circulation.

[26]  Peter A. J. Hilbers,et al.  The Role of the Hyperpolarization-Activated Inward Current$I_rm f$in Arrhythmogenesis: A Computer Model Study , 2006, IEEE Transactions on Biomedical Engineering.

[27]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .

[28]  D. Singer,et al.  Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. , 2001, JAMA.

[29]  Elizabeth M Cherry,et al.  Dynamics of human atrial cell models: restitution, memory, and intracellular calcium dynamics in single cells. , 2008, Progress in biophysics and molecular biology.

[30]  F. Marchlinski,et al.  Presence of Left-to-Right Atrial Frequency Gradient in Paroxysmal but Not Persistent Atrial Fibrillation in Humans , 2004, Circulation.

[31]  J Jalife,et al.  Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. , 2000, Circulation.

[32]  B. Lindsay,et al.  Noninvasive Characterization of Epicardial Activation in Humans With Diverse Atrial Fibrillation Patterns , 2010, Circulation.

[33]  Sanjiv M. Narayan,et al.  Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation , 2011, Circulation.

[34]  Ulrich Schotten,et al.  Electropathological Substrate of Long-Standing Persistent Atrial Fibrillation in Patients With Structural Heart Disease: Longitudinal Dissociation , 2010, Circulation. Arrhythmia and electrophysiology.

[35]  S. Nattel Pathophysiology of atrial fibrillation , 2011 .

[36]  L. Widman,et al.  Role of the tricuspid annulus and the eustachian valve/ridge on atrial flutter. Relevance to catheter ablation of the septal isthmus and a new technique for rapid identification of ablation success. , 1996, Circulation.

[37]  D. Levy,et al.  Prevention of Atrial Fibrillation: Report From a National Heart, Lung, and Blood Institute Workshop , 2009, Circulation.

[38]  Ulrich Schotten,et al.  Electropathological Substrate of Longstanding Persistent Atrial Fibrillation in Patients With Structural Heart Disease: Epicardial Breakthrough , 2010, Circulation.

[39]  Natalia A Trayanova,et al.  Action potential morphology heterogeneity in the atrium and its effect on atrial reentry: a two-dimensional and quasi-three-dimensional study , 2006, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[40]  Henggui Zhang,et al.  Atrial proarrhythmia due to increased inward rectifier current (I(K1)) arising from KCNJ2 mutation--a simulation study. , 2008, Progress in biophysics and molecular biology.

[41]  J Clémenty,et al.  Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. , 1998, The New England journal of medicine.

[42]  V. Jacquemet,et al.  Modeling Atrial Arrhythmias: Impact on Clinical Diagnosis and Therapies , 2008, IEEE Reviews in Biomedical Engineering.

[43]  J. M. Smith,et al.  Quantitative assessment of the spatial organization of atrial fibrillation in the intact human heart. , 1996, Circulation.

[44]  Topi Korhonen,et al.  Impact of Sarcoplasmic Reticulum Calcium Release on Calcium Dynamics and Action Potential Morphology in Human Atrial Myocytes: A Computational Study , 2011, PLoS Comput. Biol..

[45]  J. Olgin,et al.  Structural atrial remodeling alters the substrate and spatiotemporal organization of atrial fibrillation: a comparison in canine models of structural and electrical atrial remodeling. , 2006, American journal of physiology. Heart and circulatory physiology.

[46]  C. Henriquez,et al.  A computer model of normal conduction in the human atria. , 2000, Circulation research.

[47]  P. Kirchhof,et al.  Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. , 2011, Physiological reviews.

[48]  Alan Garfinkel,et al.  Mechanism Underlying Initiation of Paroxysmal Atrial Flutter/Atrial Fibrillation by Ectopic Foci: A Simulation Study , 2007, Circulation.

[49]  S. Nattel,et al.  Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. , 1998, Circulation.

[50]  C. Henriquez,et al.  Study of Unipolar Electrogram Morphology in a Computer Model of Atrial Fibrillation , 2003, Journal of cardiovascular electrophysiology.

[51]  José Jalife,et al.  Déjà vu in the theories of atrial fibrillation dynamics. , 2011, Cardiovascular research.

[52]  L. J. Leon,et al.  Cholinergic Atrial Fibrillation in a Computer Model of a Two-Dimensional Sheet of Canine Atrial Cells With Realistic Ionic Properties , 2002, Circulation research.

[53]  M. Mansour,et al.  Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. , 2002, Cardiovascular research.

[54]  M. Scheinman,et al.  Right atrial flutter due to lower loop reentry: mechanism and anatomic substrates. , 1999, Circulation.

[55]  Nathalie Virag,et al.  Atrial fibrillatory cycle length: computer simulation and potential clinical importance. , 2007, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[56]  C. Henriquez,et al.  Study of atrial arrhythmias in a computer model based on magnetic resonance images of human atria. , 2002, Chaos.

[57]  M. Allessie,et al.  Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. , 1995, Circulation.

[58]  H. Inoue,et al.  Entrainment Mapping of Dual‐Loop Macroreentry in Common Atrial Flutter: , 2004, Journal of cardiovascular electrophysiology.

[59]  Niels Voigt,et al.  Left-to-Right Atrial Inward Rectifier Potassium Current Gradients in Patients With Paroxysmal Versus Chronic Atrial Fibrillation , 2010, Circulation. Arrhythmia and electrophysiology.

[60]  Mathias Wilhelms,et al.  Atrial fibrillation-based electrical remodeling in a computer model of the human atrium , 2010, 2010 Computing in Cardiology.

[61]  T. Arts,et al.  Mechanoelectric feedback leads to conduction slowing and block in acutely dilated atria: a modeling study of cardiac electromechanics. , 2007, American journal of physiology. Heart and circulatory physiology.

[62]  Joseph L Greenstein,et al.  K+ current changes account for the rate dependence of the action potential in the human atrial myocyte. , 2009, American journal of physiology. Heart and circulatory physiology.

[63]  Charles Peskin,et al.  Arrhythmogenic consequences of action potential duration gradients in the atria. , 2011, The Canadian journal of cardiology.

[64]  Sanjay Dixit,et al.  Effect of pulmonary vein isolation on the left-to-right atrial dominant frequency gradient in human atrial fibrillation. , 2006, Heart rhythm.

[65]  F. Hornero,et al.  Influence of atrial dilatation in the generation of re-entries caused by ectopic activity in the left atrium , 2009, 2009 36th Annual Computers in Cardiology Conference (CinC).

[66]  R. Ruffy The Pathophysiology of Atrial Fibrillation , 1997 .

[67]  Sander Verheule,et al.  Arrhythmogenic Substrate of the Pulmonary Veins Assessed by High-Resolution Optical Mapping , 2003, Circulation.

[68]  José Jalife,et al.  Ionic determinants of functional reentry in a 2-D model of human atrial cells during simulated chronic atrial fibrillation. , 2005, Biophysical journal.

[69]  Frank Bogun,et al.  Effects of two different catheter ablation techniques on spectral characteristics of atrial fibrillation. , 2006, Journal of the American College of Cardiology.

[70]  N. Varma,et al.  Electroanatomic mapping of postpacing intervals clarifies the complete active circuit and variants in atrial flutter. , 2009, Heart rhythm.

[71]  J. Clark,et al.  Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. , 1998, Circulation research.

[72]  A. Skanes,et al.  Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. , 1998, Circulation.

[73]  Henggui Zhang,et al.  Simulating the effects of atrial fibrillation induced electrical remodeling: A comprehensive simulation study , 2008, 2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.