Frequent Premature Atrial Contractions Lead to Adverse Atrial Remodeling and Atrial Fibrillation in a Swine Model

Abstract

Background: Frequent premature atrial complexes (PACs) are associated with future incident atrial fibrillation (AF), but whether PACs contribute to development of AF through adverse atrial remodeling has not been studied. This study aimed to explore the effect of frequent PACs from different sites on atrial remodeling in a swine model.

Methods: Forty swine underwent baseline electrophysiologic studies and echocardiography followed by pacemaker implantations and paced PACs (50% burden) at 250-ms coupling intervals for 16 weeks in 4 groups: (1) lateral left atrium (LA) PACs by the coronary sinus (Lat-PAC; n=10), (2) interatrial septal PACs (Sep-PAC; n=10), (3) regular LA pacing at 130 beats/min (Reg-130; n=10), and (4) controls without PACs (n=10). At the final study, repeat studies were performed, followed by tissue histology and molecular analyses focusing on fibrotic pathways.

Results: Lat-PACs were associated with a longer P-wave duration (93.0±9.0 versus 74.2±8.2 and 58.8±7.6 ms; P<0.001) and greater echocardiographic mechanical dyssynchrony (57.5±11.6 versus 35.7±13.0 and 24.4±11.1 ms; P<0.001) compared with Sep-PACs and controls, respectively. After 16 weeks, Lat-PACs led to slower LA conduction velocity (1.1±0.2 versus 1.3±0.2 [Sep-PAC] versus 1.3±0.1 [Reg-130] versus 1.5±0.2 [controls] m/s; P<0.001) without significant change in atrial ERP. The Lat-PAC group had a significantly increased percentage of LA fibrosis and upregulated levels of extracellular matrix proteins (lysyl oxidase and collagen 1 and 8), as well as TGF-β1 (transforming growth factor-β1) signaling proteins (latent and monomer TGF-β1 and phosphorylation/total ratio of SMAD2/3; P<0.05). The Lat-PAC group had the longest inducible AF duration (terminal to baseline: 131 [interquartile range 30, 192] seconds versus 16 [6, 26] seconds [Sep-PAC] versus 22 [11, 64] seconds [Reg-130] versus -1 [-16, 7] seconds [controls]; P<0.001).

Conclusions: In this swine model, frequent PACs resulted in adverse atrial structural remodeling with a heightened propensity to AF. PACs originating from the lateral LA produced greater atrial remodeling and longer induced AF duration than the septal-origin PACs. These data provide evidence that frequent PACs can cause adverse atrial remodeling as well as AF, and that the location of ectopic PACs may be clinically meaningful.

Keywords: atrial fibrillation; atrial premature contractions; atrial remodeling.

Figure 1:. Study protocol

(A) Baseline and terminal study flowchart describing the protocol for the four groups of swine in the study (see Methods). Location of the pacing lead on anteroposterior fluoroscopy and gross pathology (yellow arrows) after sacrifice is shown for representative animals in the (B) lateral LA PAC and (C) septal PAC groups. PAC=premature atrial complex; LA = left atrial; LAA = left atrial appendage; LV = left ventricle; RAA = right atrial appendage; ERP = effective refractory period; EP=electrophysiologiy; PPM = pacemaker; TV = tricuspid valve.

Figure 2:. Measurements of LA dyssynchrony

(A) Electrical dyssynchrony was assessed by measuring the max P-wave duration (total atrial conduction time) per pacing site. The max P-wave duration is measured from the earliest onset to the latest offset in all ECG leads using digital callipers on a polygraph system. (B) Mechanical dyssynchrony was assessed by measuring the regional coordination among 6 LA segments according to the pacing site. The difference in the time-to-peak of the earliest and latest activated segments among the 6 LA segments was measured during regular constant pacing (120ppm) from each pacing lead. Note that during septal pacing, the atrial segments on the septal side have the earliest time-to-peak activation, while during lateral pacing, those on the lateral side show the earliest time-to-peak activation.

Figure 3:. Electrical and mechanical atrial dyssynchrony

(A) Electrical atrial dyssynchrony as assessed by the max P-wave duration according to the pacing site. (B) Mechanical dyssynchrony as assessed by 2D speckle tracking strain analysis.

Figure 4:. LA size and function after frequent PACs

Change in the (A) LA area and (B) LA peak reservoir strain between the baseline and 16-week terminal studies in each group.

Figure 5:. LA electrophysiology after frequent PACs

(A) Change in the atrial effective refractory period (ERP) between the baseline and 16-week terminal studies in each group. The atrial ERPs are obtained by the average of the ERPs on the right atrial free wall, right atrial mid-septum and coronary sinus. (B) LA posterior wall conduction velocity during the terminal study in each group. LA= left atrial

Figure 6:. AF maintenance after frequent PACs

(A) AF sustainability: change in duration of induced AF between baseline and 16-week terminal studies in each group. AF sustainability was defined as the average of maximum AF duration obtained on the right atrial free wall, right atrial mid-septum and coronary sinus. Cardioversion was performed after 7 minutes (420 secs) of sustained AF. (B) AF inducibility: change in the percentage of an inducible AF duration of ≧5 seconds among the 9 total AF induction attempts between the baseline and 16-week terminal studies in each group. AF = atrial fibrillation.

Figure 7:. Histopathology analysis

Representative histological slides for the (A) Control, (B) Regular 130, (C) Septal PAC and (D) Lateral left atrial (LA) PAC groups. Differences in the histological %fibrosis in the (E) LA anterior wall, (F) LA posterior wall, and (G) RA appendages by group.

Figure 8:. Molecular analysis

Left panel: Western Blot of extra cellular matrix proteins (pink) and TGFβ1 signaling proteins (yellow) in the control, Septal PAC, and Lateral LA PAC groups. Right panel: Comparison of the specific extra cellular proteins (above) and TGFβ1 signaling proteins (below) by the group.