Po-455617-1 exploring the interplay of functional and structural remodeling progression in atrial fibrillation in a rapid atrial pacing canine model

In sustained atrial fibrillation (AF) it is still unclear to what extent, at which time points functional and structural remodeling processes develop over time, and which parameters can measure the progression state. We hypothesized that persistent AF progression state induced by rapid atrial pacing (RAP) can be uncovered by measuring electrogram characteristics, OS levels, nerve activity, and the degree of fibrosis with MRI imaging. AF was induced in 15 dogs (25-35 kg, ≥1 year) by RAP (3-17 weeks RAP, 600 beats/min), and 8 controls were used. We performed high-resolution epicardial mapping (6 regions, 130 electrodes, distance 2.5mm) (Figure 1) and analyzed bipolar peak-to-peak voltage, cycle length (CL), and organization index (OI). We quantified OS levels as damaged nuclei against total number in 8-OHdG staining (N=36 samples, 6 animals) and degree of fibrosis (Masson’s trichrome) (N=24, 4 dogs). We also quantified in implantable telemetry recordings (DSI) parasympathetic nerve activity (PNA) (2 hours) assessed as the time between PNA spikes (3 AF dogs, 3 controls). MRI native T1, post-contrast T1, and T2 mapping, and late gadolinium enhancement (LGE) were assessed (1.5T clinical scanner, Siemens Aera) in the posterior left atrium (PLA) (7 AF, 8 at baselines). Voltage, CL, and OI decreased (R=0.9, P<0.05), (R=0.6, P<0.05), (R=0.5, P<0.05) over time of RAP (Figure 1). After 80 RAP days voltage changed, but no more changes in other EGM measures were observed. OS levels in AF were highest in the left atrial free wall and lowest in the appendages (Figure 2). The electrogram measures OI and CL decreased with increased oxidative stress levels (Figure 2). Fibrosis (R=0.6, P<0.05) increased with OS (R=0.6, P<0.05) in all atrial regions (Figure 2). Parasympathetic nerve activity increased by factor 5 after 120 RAP days, (Figure 3). Native T1, T2 times increased with RAP days (R=0.6, P<0.05), (R=0.4, P<0.05) in PLA (<120 pacing days) (Fig. 4). Functional and structural remodeling in persistent AF is the result of an interplay among the development of increased OS, fibrosis, and nerve activity in a RAP canine model and can moderately be uncovered using the electrogram measures CL and OI until the saturation point after 80 RAP days. Voltage also uncovers the AF progression state post 80- RAP days with a strong correlation coefficient. Additional parasympathetic nerve recordings and MRI imaging including T1 mapping may be complementary to detect AF remodeling states.