Chronic Rapid Atrial Pacing: Structural, Functional, and Electrophysiological Characteristics of a New Model of Sustained Atrial Fibrillation

Abstract

Background Despite the clinical importance of atrial fibrillation (AF), the development of chronic nonvalvular AF models has been difficult. Animal models of sustained AF have been developed primarily in the short-term setting. Recently, models of chronic ventricular myopathy and fibrillation have been developed after several weeks of continuous rapid ventricular pacing. We hypothesized that chronic rapid atrial pacing would lead to atrial myopathy, yielding a reproducible model of sustained AF. Methods and Results Twenty-two halothane-anesthetized mongrel dogs underwent insertion of a transvenous lead at the right atrial appendage that was continuously paced at 400 beats per minute for 6 weeks. Two-dimensional echocardiography was performed in 11 dogs to assess the effects of rapid atrial pacing on atrial size. Atrial vulnerability was defined as the ability to induce sustained repetitive atrial responses during programmed electrical stimulation and was assessed by extrastimulus and burst-pacing techniques. Effective refractory period (ERP) was measured at two endocardial sites in the right atrium. Sustained AF was defined as AF ≥15 minutes. In animals with sustained AF, 10 quadripolar epicardial electrodes were surgically attached to the right and left atria. The local atrial fibrillatory cycle length (AFCL) was measured in a 20-second window, and the mean AFCL was measured at each site. Marked biatrial enlargement was documented; after 6 weeks of continuous rapid atrial pacing, the left atrium was 7.8±1 cm 2 at baseline versus 11.3±1 cm 2 after pacing, and the right atrium was 4.3±0.7 cm 2 at baseline versus 7.2±1.3 cm 2 after pacing. An increase in atrial area of at least 40% was necessary to induce sustained AF and was strongly correlated with the inducibility of AF ( r =.87). Electron microscopy of atrial tissue demonstrated structural changes that were characterized by an increase in mitochondrial size and number and by disruption of the sarcoplasmic reticulum. After 6 weeks of continuous rapid atrial pacing, sustained AF was induced in 18 dogs (82%) and nonsustained AF was induced in 2 dogs (9%). AF occurred spontaneously in 4 dogs (18%). Right atrial ERP, measured at cycle lengths of 400 and 300 milliseconds at baseline, was significantly shortened after pacing, from 150±8 to 127±10 milliseconds and from 147±11 to 123±12 milliseconds, respectively ( P <.001). This finding was highly predictive of inducibility of AF (90%). Increased atrial area (40%) and ERP shortening were highly predictive for the induction of sustained AF (88%). Local epicardial ERP correlated well with local AFCL ( R 2 =.93). Mean AFCL was significantly shorter in the left atrium (81±8 milliseconds) compared with the right atrium 94±9 milliseconds ( P <.05). An area in the posterior left atrium was consistently found to have a shorter AFCL (74±5 milliseconds). Cryoablation of this area was attempted in 11 dogs. In 9 dogs (82%; mean, 9.0±4.0; range, 5 to 14), AF was terminated and no longer induced after serial cryoablation. Conclusions Sustained AF was readily inducible in most dogs (82%) after rapid atrial pacing. This model was consistently associated with biatrial myopathy and marked changes in atrial vulnerability. An area in the posterior left atrium was uniformly shown to have the shortest AFCL. The results of restoration of sinus rhythm and prevention of inducibility of AF after cryoablation of this area of the left atrium suggest that this area may be critical in the maintenance of AF in this model.