Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue.

Area of Science:

• Cardiology
• Stem Cell Biology
• Pharmacology

Background:

• Current experimental models for Atrial Fibrillation (AF) exhibit significant limitations.
• Human embryonic stem cells (hESCs) offer a promising source for developing patient-specific disease models.

Purpose of the Study:

• To develop a human atrial-specific tissue model using hESC-derived cardiomyocytes for pharmacologic testing in Atrial Fibrillation.
• To investigate the effects of anti-arrhythmic drugs on AF-related rotor dynamics within this novel model.

Main Methods:

• Generation of atrial-like cardiomyocytes (CMs) from hESCs, confirmed by atrial-specific gene expression and shorter action potential (AP) durations.
• Creation of confluent atrial-like CM sheets for interrogation using optical mapping techniques.
• Pharmacologic testing of flecainide and dofetilide on isolated CMs and cell sheets to assess their impact on APs, conduction velocity (CV), and rotor dynamics.

Main Results:

• hESC-derived atrial CM sheets exhibited uniform AP propagation and could be induced to form rapid re-entrant rotor patterns characteristic of AF.
• Flecainide slowed upstroke velocity, reduced CV, and rotor cycle lengths, promoting rotor organization.
• Dofetilide prolonged APs, reduced rotor cycle lengths, and blocked rapid delayed rectifier K+ currents (Ikr) without affecting CV.

Conclusions:

• hESC-derived atrial CM preparations provide a valuable experimental platform for studying AF.
• Flecainide and dofetilide modulate reentrant rotor activation patterns in AF, offering mechanistic insights into their therapeutic effects.