LAUSR

AIMS No studies have assessed the specific contributions of atrial fibrillation (AF)-related atrial versus associated ventricular arrhythmia to remodeling. This study assessed the roles of atrial arrhythmia versus high ventricular rate in AF-associated remodeling. METHODS AND RESULTS Four primary dog-groups (12/group) were subjected to 3-week pacing: 600-bpm atrial-tachypacing maintaining AF (AF w/o-AVB); atrial-tachypacing with atrioventricular-node ablation (AF+AVB) and ventricular-demand pacing (80-bpm); 160-bpm ventricular-tachypacing (V160) reproducing the response-rate during AF; and sinus rhythm with AVB/ventricular-pacing at 80-bpm (CTL). At terminal study, left-atrial (LA) effective refractory period (ERP) was reduced equally in both AF-groups (w/o-AVB and AF+AVB). AF-inducibility was increased strongly in AF-groups (w/o-AVB and AF+AVB) and modestly in V160. AF-duration was significantly increased in AF w/o-AVB but not in AF+AVB or V160. Conduction velocity was decreased in AF w/o-AVB, to a greater extent than in AF+AVB and V160. Atrial fibrous-tissue content was increased in AF w/o-AVB, AF+AVB and V160, with collagen-gene upregulation only in AF w/o-AVB. Connexin43 gene-expression was reduced only in AF w/o-AVB. An additional group of 240-bpm ventricular tachypacing dogs (VTP240; to induce heart failure) was studied: versus other tachypaced groups, VTP240 caused greater fibrosis, but no change in LA-ERP or AF-inducibility. VTP240 also increased AF-duration, strongly decreased left-ventricular ejection fraction, and was the only group with LA natriuretic-peptide activation. CONCLUSIONS The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodeling and novel considerations for ventricular rate-control. TRANSLATIONAL PERSPECTIVE AF often produces a rapid and irregular arrhythmia in both the atria and ventricles. This study evaluates the contributions of AF-induced atrial versus ventricular arrhythmia to atrial remodeling. Each component produced discrete features: AF-induced atrial arrhythmia caused accelerated repolarization and abbreviated refractoriness, strongly increased vulnerability to AF-induction by premature ectopic beats, conduction slowing and moderate atrial fibrosis; whereas ventricular arrhythmia slightly increased vulnerability, slowed conduction and induced moderate fibrosis without affecting repolarization/refractoriness,. Combined atrial and ventricular arrhythmia abbreviated refractoriness, strongly increased vulnerability and fibrosis and greatly increased AF stability/duration. This work suggests that in the absence of ventricular rate control, the rapid ventricular response can cause AF-promoting atrial remodeling without overt heart failure; further research is needed to clarify the clinical relevance of these findings.