Regions of Highly Recurrent Electrogram Morphology at Sites of Low Cycle Length Accurately Reflect Arrhythmogenic Substrate for Atrial Fibrillation – Implications For a New, Mechanism Guided Therapeutic Approach for Atrial Fibrillation

Background Although atrial electrograms (EGMs) are thought to reflect pathophysiological substrate for atrial fibrillation (AF), it is not known which electrograms are suitable targets during AF ablation. We hypothesized that electrogram morphology recurrence (EMR) better reflects arrhythmogenic AF substrate than traditional frequency and complexity measures of AF. In a canine rapid atrial pacing (RAP) model of AF, we assessed the relationship between EMR and traditional AF electrogram measures, rotational activity in the atria, fibrosis, myofiber orientation and parasympathetic innervation. Methods Persistent AF was induced in 13 dogs by RAP for 6-8 weeks. High-density epicardial mapping (117 electrodes) was performed in six atrial sub-regions. EMR measures Recurrence percentage (Rec%) and cycle length of the most frequent electrogram morphology (CLR), Fractionated Interval (FI), Organization Index (OI), Dominant Frequency (DF) and Shannon’s Entropy (ShEn) were analyzed before and after atropine administration. Myocyte fiber orientation, amount of fibrosis and spatial distribution of parasympathetic nerve fibers were quantified. Results Rec% was greatest in the appendages, and CLR was lowest in the posterior left atrium. Rec%/CLR correlated with FI, OI and the complexity measure ShEn, but not with DF. All electrogram measures were poorly correlated with fibrosis and myofiber anisotropy. Rec% correlated closely with stability of rotational activity. Unlike other measures, Rec% correlated closely with spatial heterogeneity of parasympathetic nerve fibers; this was reflected in CLR response to atropine. Conclusion EMR correlates closely with stability of rotational activity and with the pattern of atrial parasympathetic innervation. CLR may therefore be a viable therapeutic target in persistent AF. ### Competing Interest Statement RA: Ownership interest, Rhythm Therapeutics, Inc. * AF : Atrial fibrillation AI : Anisotropy index ANOVA : Analysis of variance CFAE : Complex fractionated atrial electrograms CLR : Cycle length of the most recurrent electrogram morphology DF : Dominant frequency EGM : Electrogram EMR : Electrogram morphology recurrence FI : Fractionation interval LAT : Local activation time LAA : Left atrial appendage LAFW : Left atrial free wall PLA : Posterior left atrium PRA : Posterior right atrium RAA : Right atrial appendage RAFW : Right atrial free wall Rec% : Recurrence percentage PV : Pulmonary vein SD : Standard deviation SEM : Standard error of the mean ShEn : Shannon’s entropy