Acute regional left atrial ischemia causes acceleration of atrial drivers during atrial fibrillation.

BACKGROUND: The mechanisms by which acute left atrial ischemia (LAI) leads to atrial fibrillation (AF) initiation and perpetuation remain unclear. OBJECTIVE: To investigate the electrophysiological mechanisms of AF perpetuation in the presence of regional atrial ischemia. METHODS: LAI (90-minute ischemia) was obtained in isolated sheep hearts by selectively perfusing microspheres into the left anterior atrial artery. Two charge-coupled device cameras and several bipolar electrodes enabled recording from multiple atrial locations: with a dual-camera setup (protocol 1, n = 10, and protocol 1', n = 4, for biatrial or atrioventricular camera setups, respectively), in the presence of propranolol/atropine (1 µM) added to the perfusate after LAI (protocol 2, n = 3) and after a pretreatment with glibenclamide (10 µM; protocol 3, n = 4). RESULTS: Spontaneous AF occurred in 41.2% (7 of 17) of the hearts that were in sinus rhythm before LAI. LAI caused action potential duration shortening in both the ischemic (IZ) and nonischemic (NIZ) zones by 21% ± 8% and 34% ± 13%, respectively (pacing, 5 Hz; P<.05 compared to baseline). Apparent impulse velocity was significantly reduced in the IZ but not in the NIZ (-65% ± 19% and 9% ± 18%; P = .001 and NS, respectively). During LAI-related AF, a significant NIZ maximal dominant frequency increase from 7.4 ± 2.5 to 14.0 ± 5.5 Hz (P<.05) was observed. Glibenclamide, an ATP-sensitive potassium current (IKATP) channel blocker, averted LAI-related maximal dominant frequency increase (NIZ: LAI vs glibenclamide 14.0 ± 5.5 Hz vs 5.9 ± 1.3 Hz; P<.05). An interplay between spontaneous focal discharges and rotors, locating at the IZ-NIZ border zone, maintained LAI-related AF. CONCLUSIONS: LAI leads to an IKATP conductance-dependent action potential duration shortening and spontaneous AF maintained by both spontaneous focal discharges and reentrant circuits locating at the IZ border zone.

Heterogeneous atrial wall thickness and stretch promote scroll waves anchoring during atrial fibrillation.

AIMS: Atrial dilatation and myocardial stretch are strongly associated with atrial fibrillation (AF). However, the mechanisms by which the three-dimensional (3D) atrial architecture and heterogeneous stretch contribute to AF perpetuation are incompletely understood. We compared AF dynamics during stretch-related AF (pressure: 12 cmH(2)O) in normal sheep hearts (n = 5) and in persistent AF (PtAF, n = 8)-remodelled hearts subjected to prolonged atrial tachypacing. We hypothesized that, in the presence of stretch, meandering 3D atrial scroll waves (ASWs) anchor in regions of large spatial gradients in wall thickness. METHODS AND RESULTS: We implemented a high-resolution optical mapping set-up that enabled simultaneous epicardial- and endoscopy-guided endocardial recordings of the intact atria in Langendorff-perfused normal and PtAF (AF duration: 21.3 ± 11.9 days) hearts. The numbers and lifespan of long-lasting ASWs (>3 rotations) were greater in PtAF than normal (lifespan 0.9 ± 0.5 vs. 0.4 ± 0.2 s/(3 s of AF), P< 0.05). Than normal hearts, focal breakthroughs interacted with ASWs at the posterior left atrium and left atrial appendage to maintain AF. In PtAF hearts, ASW filaments seemed to span the atrial wall from endocardium to epicardium. Numerical simulations using 3D atrial geometries (Courtemanche-Ramirez-Nattel human atrial model) predicted that, similar to experiments, filaments of meandering ASWs stabilized at locations with large gradients in myocardial thickness. Moreover, simulations predicted that ionic remodelling and heterogeneous distribution of stretch-activated channel conductances contributed to filament stabilization. CONCLUSION: The heterogeneous atrial wall thickness and atrial stretch, together with ionic and anatomic remodelling caused by AF, are the main factors allowing ASW and AF maintenance.

Chloroquine terminates stretch-induced atrial fibrillation more effectively than flecainide in the sheep heart.

BACKGROUND: Blockade of inward-rectifier K+ channels by chloroquine terminates reentry in cholinergic atrial fibrillation (AF). However, it is unknown whether inward-rectifier K+ channels and reentry are also important in maintaining stretch-induced AF (SAF). We surmised that reentry underlies SAF, and that abolishing reentry with chloroquine terminates SAF more effectively than traditional Na+-channel blockade by flecainide. METHODS AND RESULTS: Thirty Langendorff-perfused sheep hearts were exposed to acute and continuous atrial stretch, and mapped optically and electrically. AF dynamics were studied under control and during perfusion of either chloroquine (4 µmol/L, n=7) or flecainide (2-4 µmol/L, n=5). Chloroquine increased rotor core size and decreased reentry frequency from 10.6±0.7 Hz in control to 6.3±0.7 Hz (P<0.005) just before restoring sinus rhythm (7/7). Flecainide had lesser effects on core size and reentry frequency than chloroquine and did not restore sinus rhythm (0/5). Specific IKr blockade by E-4031 (n=7) did not terminate AF when frequency values were >8 Hz. During pacing (n=11), flecainide reversibly reduced conduction velocity (≈30% at cycle length 300, 250, and 200 ms; P<0.05) to a larger extent than chloroquine (11% to 19%; cycle length, 300, 250, and 200 ms; P<0.05). Significant action potential duration prolongation was demonstrable only for chloroquine at cycle length 300 (12%) and cycle length 250 ms (9%) (P<0.05). CONCLUSIONS: Chloroquine is more effective than flecainide in terminating SAF in isolated sheep hearts by significantly increasing core size and decreasing reentry frequency. Chloroquine's effectiveness may be explained by its inward-rectifier K+ channel blockade profile and suggest that reentry is important to maintain acute SAF.