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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: None.

Figures

Figure 1

A, left, single pixel AP from the LAA (red) and RAA (black). Right, APD70 at varying pacing CLs is shorter in LAA than RAA. APD70 significantly shortens in both appendages from 300 to 200 ms CL. B, left column, DF maps of the PLA and LAA, and electrode location on the RAA. Center column; single pixel activations (PLA, LAA) and bipolar electrograms (RAA). Right Column, power spectra showing DFmax at each location. C, top, LAA, RAA and PLA/PVs DFmax during 15 min of control AF. Bottom, bar graph of mean±SEM DFmax during control AF shows significant DF gradient between PLA and LAA/RAA.

Figure 2

Chloroquine terminates AF. A, top: DF maps of PLA during control AF and before termination; middle and bottom: single pixel recordings and electrograms from LSPV. B, top: time course of DFmax, before and during chloroquine; bottom: electrograms from LSPV at the moment of termination.

Figure 3

A, time-course of DFmax before and during flecainide. B, flecainide is significantly inferior to chloroquine in resuming SR. C, DF maps of the PLA and bipolar electrograms from the left inferior PV (LIPV) show control AF and conversion to AT during flecainide.

Figure 4

A, left, sustained AF/AT is re-inducible during flecainide but not during chloroquine perfusion. Right, after washout sustained AF/AT is re-inducible in both groups. B, representative traces; rapid pacing at 12 Hz did not capture or re-induce non-sustained AF during chloroquine (top); at the same pacing frequency, sustained AF was readily induced during flecainide (bottom). C, time-course of DFmax, SR is restored when chloroquine was perfused after flecainide washout.

Figure 5

Chloroquine effects on reentry and breakthroughs (5-sec movies). A, number of rotations/cm2 in the PLA/LAA in control and just before chloroquine-induced AF termination. B, average core width significantly increases in size during chloroquine. C, phase maps show a wavebreak and the initiation of a rotor that cannot complete an entire rotation during chloroquine. D, number of breakthroughs/cm2 in control and during chloroquine.

Figure 6

Comparing chloroquine to flecainide. A and B, although flecainide reduces the number of rotations/cm2 at the PLA and LAA (5-sec movies), only chloroquine significantly decrease the number of rotations/cm2 at the PLA. C, the core size does not significantly increase during flecainide. D, Similarly, only chloroquine significantly decreases the number breakthroughs/cm2 at the PLA.

Figure 7

A, left, mean APD70 for control, chloroquine and washout at 300, 250, and 250 ms CL; right, mean CV for control, chloroquine and washout; 300, 250, and 250 ms CL. B, left: flecainide does not significantly affect the APD70 at any CL; right, flecainide strongly reduces velocity in a reversible manner.

Figure 8

A, time-course of DFmax after E-4031 0.5–1 μM. B, E-4031 restored SR in those cases with DFmax<8 Hz. C, chloroquine was more effective than E-4031 to terminate SAF with DFmax>8 Hz.