The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation

Area of Science:

• Cardiology
• Pharmacology
• Computational Biology

Background:

• Persistent atrial fibrillation (AF) presents a significant clinical challenge for pharmacological management.
• Targeting specific ion channels, like inward rectifier potassium currents, may offer novel antiarrhythmic strategies.

Purpose of the Study:

• To investigate the antiarrhythmic potential of blocking background (I_K1) and acetylcholine-activated (I_KACh) potassium currents in persistent atrial fibrillation.
• To evaluate chloroquine as a therapeutic agent for reducing persistent AF burden by inhibiting I_K1 and I_KACh.

Main Methods:

• Utilized patch clamp electrophysiology to determine the IC₅₀ of chloroquine for I_K1 and I_KACh.
• Employed molecular modeling to simulate chloroquine's interaction with Kir2.1 and Kir3.1 channels.
• Conducted a proof-of-concept study involving oral chloroquine administration in a patient with persistent AF.
• Performed computational simulations using a 3D human atrial model to assess chloroquine's electrophysiological effects.

Main Results:

• Chloroquine demonstrated similar IC₅₀ values for blocking both I_K1 and I_KACh.
• A 14-day oral chloroquine regimen significantly reduced arrhythmia burden in a patient with persistent AF.
• Computational models indicated that chloroquine prolongs action potential duration, inhibiting reentrant excitation and terminating the arrhythmia.

Conclusions:

• Combined blockade of I_K1 and I_KACh presents a viable therapeutic strategy for persistent atrial fibrillation.
• Chloroquine's ability to inhibit these currents suggests its potential as a targeted antiarrhythmic drug for persistent AF.