The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation

Figures

• 

  Figure 1. IK1 block with chloroquine. (A) Docking of chloroquine in the intracellular domain of Kir2.1. The lowest energy pose is shown. Chloroquine makes hydrogen bonds with residue E224 from subunit B and with E224 from subunit D (black circles). Bottom panel: Extracellular bird’s eye views of the van der Waals representation of the channel (gray) in complex with chloroquine (cyan). Chloroquine blocks the ion permeation pathway. (B) Barium sensitive IK1 traces in response to −140mV step pulses from a holding potential of 0 mV in the presence of 1 μM chloroquine (CQ). Concentration–response curves. IC50 for chloroquine block of IK1: 1.3 μM, Hill Slope = −0.42, R2=0.9. (C) Top panel: Longitudinal view of chloroquine bound to Kir2.1. Orange box denotes the voxelated part of the channel shown below. Bottom panel: Voxelation of Kir2.1 ion permeation pathway (grey) in complex with chloroquine (cyan). A probe (magenta) of radius 2.1 Å or larger, is blocked by chloroquine.

• 

  Figure 2. IKACh block with chloroquine. (A) Docking of chloroquine in the intracellular domain of Kir3.1. The lowest energy pose is shown. The D260 and F255 residues from each of the four Kir3.1 subunits are shown in green and orange sticks respectively. The tertiary amine nitrogen of chloroquine (cyan sticks) forms a hydrogen bond (black circle) with the side chain of D260 in the B subunit, while the aminoquinoline ring of chloroquine is in close proximity to the phenylalanine ring of F255 in the A subunit. Van der Waals representations of the channel bound to the drugs (cyan) viewed from the extracellular side is shown in the bottom panel. (B) Barium sensitive IKACh traces in response to −140mV step pulses from a holding potential of −20 mV in the presence of 1 μM chloroquine (CQ). (B) Concentration–response curves. IC50 for chloroquine block of IKACh: 1.2 μM, Hill Slope = −0.48, R2=0.74. (C) Top panel: Longitudinal view of chloroquine bound to Kir3.1. Orange box denotes the voxelated part of the channel shown below. Bottom panel: Voxelation of Kir3.1 ion permeation pathway (grey) in complex with chloroquine (cyan). A probe (magenta) of radius 2.2 Å or larger, is blocked by chloroquine.

• 

  Figure 3. Chloroquine effects on persistent AF. (A) Daily AF burden for 14 days in Holter monitoring at baseline, and for 14 days upon initiation of oral chloroquine (amebiasis treatment regimen). (B) 12 lead ECG on the day of chloroquine initiation, confirming the presence of AF. (C) Holter ECG strips from baseline (top), right before treatment initiation (middle), and on the 3rd day of treatment when AF converted to sinus rhythm (bottom).

• 

  Figure 4. Computational simulations of persistent AF in a 3D model of the human atria. (A) Snapshots of membrane voltage during persistent AF maintained by 2 rotors (curved arrows indicate rotation direction) in the posterior left atrium and the superior vena cava (SVC). Numbered dots indicate the locations of EGM recordings. (B) EGM traces displaying single (trace 2), double (traces 1 and 4) and fractionated (trace 3) potentials with low amplitude and high frequency of activation (DF of 11 Hz). (C) Single cell left atrial action potentials, at baseline AF (red trace), when IKr (blue dotted line), IK1 (blue solid line), IKACh (blue dashed line), IK1 and IKACh together (black dashed line), or the three currents together (black solid line) were blocked by 1 μM of chloroquine. LIPV, and LSPV: left inferior and superior pulmonary vein. RIPV, and RSPV: right inferior and superior pulmonary vein. SVC, and IVC: superior and inferior vena cava.

• 

  Figure 5. Simulations of IK1, IKACh, or IKr block on persistent AF. (A) Snapshot of the single re-entry maintaining atrial tachycardia when IKACh was blocked by 70%, with the EGMs showing a DF of 8 Hz. (B) Snaphots of the single re-entry maintaining atrial tachycardia when IK1 was blocked by 90%, with the EGMs showing a DF of 9 Hz. (C) Snaphots of the 2 rotors maintaining AF when IKr was blocked by 90%, with the EGMs showing a DF of 11 Hz.

• 

  Figure 6. Simulations of 1 μM chloroquine terminating AF by dual block of IK1 and IKACh by 50% (A), or by block of IKr by 30% and block of IK1 and IKACh by 50% (B). Voltage maps are snapshots of the last rotation of the re-entrant wave, where AF terminates after the wavefront interacts with the wavetail (white parallel lines). Curved white arrows: rotation direction. EGMs show arrhythmia termination.