Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing

Abstract

Background: The mechanism(s) for acute changes in electrophysiological properties of the atria during rapid pacing induced atrial fibrillation (AF) is not completely understood. We sought to evaluate the contribution of the intrinsic cardiac autonomic nervous system in acute atrial electrical remodeling and AF induced by 6-hour rapid atrial pacing.

Methods and results: Continuous rapid pacing (1200 bpm, 2x threshold [TH]) was performed at the left atrial appendage. Group 1 (n=7) underwent 6-hour pacing immediately followed by ganglionated plexi (GP) ablation; group 2 (n=7) underwent GP ablation immediately followed by 6-hour pacing; and group 3 (n=4) underwent administration of autonomic blockers, atropine (1 mg/kg), and propranolol (0.6 mg/kg) immediately followed by 6-hour pacing. The effective refractory period (ERP) and window of vulnerability (WOV, in milliseconds), ie, the difference between the longest and the shortest coupling interval of the premature stimulus that induced AF, were measured at 2xTH and 10xTH at the left atrium, right atrium, and pulmonary veins every hour before and after GP ablation or autonomic blockade. In group 1, ERP was markedly shortened in the first 2 hours and then stabilized both at 2xTH and 10xTH; however, WOV was progressively widened throughout the 6-hour period. After GP ablation, ERP was significantly longer than before ablation and AF could not be induced (WOV=0) at either 2xTH or 10xTH. In groups 2 and 3, rapid atrial pacing failed to shorten the ERP. AF could not be induced in 6 of 7 dogs in group 2 and all 4 dogs in group 3 during the 6-hour pacing period.

Conclusions: The intrinsic cardiac autonomic nervous system plays a crucial role in the acute stages of atrial electrical remodeling induced by rapid atrial pacing.

Figure 1

Schematic representation and catheter position in the atrium. (A) Left thoracotomy approach. SLGP: superior left ganglionated plexi (GP), located adjacent to the junction of left superior pulmonary vein (LSPV) and left atrium (LA); ILGP: inferior left GP located near the junction of left inferior pulmonary vein (LIPV) and LA. Multi-electrode catheters were sutured to the LSPV, LIPV, LA and left atrial appendage (LAA). Continuous rapid pacing (1200 bpm) was performed at the LAA. LV: left ventricle; RV: right ventricle; LOM: ligament of Marshall. (B) Right thoracotomy approach. ARGP: anterior right GP, located adjacent to the right superior pulmonary vein (RSPV) - atrial junction; IRGP: inferior right GP, located at the junction of the inferior vena cava (IVC) and both atria. SVC: superior vena cava. Similarly, multi-electrode catheters were sutured to RSPV, right inferior pulmonary vein (RIPV), right atrium (RA) and right atrial appendage (RAA).

Figure 2

Changes of effective refractory period (ERP) and window of vulnerability (WOV) during 6-hour pacing and after GP (ARGP+IRGP+SLGP+ILGP+LOM) ablation in Group 1 (N=7). (A-G) The mean ERP of the 7 dogs (filled squares and triangles) was progressively shortened in the first two hours at 2×thresholds (TH) or 10×TH at all sites; however, longer period of pacing failed to further shorten the ERP. After GP (ARGP+IRGP+SLGP+ILGP+LOM) ablation, ERP were significantly longer than that prior to GP ablation and AF could no longer be induced (WOV=0) at any site at either 2×TH or 10×TH; (H) ΣWOV, serving as a quantitative measure of atrial fibrillation (AF) inducibility in the whole heart, was counted as the sum of WOV acquired at 2×TH and 10×TH at all sites. *: p<0.05 for comparisons of the ERP at the end of each hour of pacing vs. ERP in the baseline state (BS) at 2×TH or 10×TH; ^†: p<0.05 for comparisons of the ERP after GP ablation vs. ERP immediately prior to GP ablation at 2×TH or 10×TH. No significance was observed between the ERP in the baseline state and the ERP after GP ablation; ^‡: p<0.01 for comparisons of the ΣWOV after GP ablation vs. ΣWOV immediately prior to GP ablation, respectively. The time for determining the ERP and WOV after hour of pacing was less than 15 minutes in most cases.

Figure 3

Changes of ERP and WOV after GP (ARGP+IRGP+SLGP+ILGP+LOM) ablation followed by 6-hour atrial pacing in Group 2 (N=7). No shortening of ERP was observed during the pacing period. AF could not be induced (WOV=0) in 6/7 dogs during the 6-hour pacing, and was inducible in 1/7 with WOV of only 10 ms at 10×TH. Abbreviations as Figure 2.

Figure 4

Changes of ERP and WOV after administration of autonomic blockers followed by 6-hour atrial pacing in Group 3 (N=4). Atropine sulfate was infused intravenously in cumulative doses of 0.1, 0.3, 0.6, and 1.0 mg/kg in steps of 10 minutes. Propranolol HCl was given in a similar way in cumulative dosages of 0.1, 0.3, and 0.6 mg/kg. Six-hour rapid atrial pacing failed to shorten the ERP or induce AF at any site.

Figure 5

Example of histologic examination of the fat pad containing ARGP with or without ablation. (A) Panoramic view demonstrates the range of the ablation. Note the purple color of the collagen in the ablated area at the center in comparison to the non-ablated area at the periphery. Arrow: ablated area; Arrow head: ablated ganglion. (B) Collagen fibers under the epicardium in the ablated area turned deep purple and lost histologic details. (C) Non-ablated epicardium for comparison. (D)The blood vessels in the ablated area also turned dark purple and lost histologic details. (E) Non-ablated blood vessels for comparison. (F) In the ablated ganglion indicated by the arrow head in (A), the ganglioinic cells have contracted morphology with large vacuoles around the cells. (G) Non-ablated ganglion for comparison. (H) The myocardial cells are structurally intact although the collagen adjacent to them has purple changes. (I) Non-ablated myocardial muscle for comparison. Original magnification is X1 in (A), X20 in (B) and (C), x40 in (D) to (I). Panel A is generated by reconstruction from multiple images with Adobe Photoshop. Panel (C), (E), (G), (I) are taken from a control animal without ablation.

Figure 6

Changes of mean ERP and Cumulative WOV (ΣWOV) before and after stopping pacing without GP ablation in one dog. (A) After a 30-min blanking period, the mean ERP of the 7 sites (LSPV, LIPV, LA, RAA, RA, RSPV, RIPV) showed a slight but not significant increase in comparison with the value at the end of 6-hour pacing. The mean ERP did not return to the baseline value even after a one-hour blanking period. (B) The ΣWOV (i.e. the overall WOV from the above 7 sites) decreased to 165 ms after a 30-min blanking period; importantly, it remained 116 ms longer than the baseline state after one hour blanking period. This observation indicates that, compared with GP ablation (Fig. 2, after GP ablation), the reverse remodeling occurred during locating and ablating the GP (<15 minutes) was a minor factor contributing to the change of ERP and WOV after GP ablation.