Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation-remodeled hearts.

Atrial fibrillation (AF) alters atrial cardiomyocyte (ACM) Ca2+ handling, promoting ectopic beat formation. We examined the effects of AF-associated remodeling on Ca2+-related action potential dynamics and consequences for AF susceptibility. AF was maintained electrically in dogs by right atrial (RA) tachypacing. ACMs isolated from AF dogs showed increased Ca2+ release refractoriness, spontaneous Ca2+ spark frequency, and cycle length (CL) threshold for Ca2+ and action potential duration (APD) alternans versus controls. AF increased the in situ CL threshold for Ca2+/APD alternans and spatial dispersion in Ca2+ release recovery kinetics, leading to spatially discordant alternans associated with reentrant rotor formation and susceptibility to AF induction/maintenance. The clinically available agent dantrolene reduced Ca2+ leak and CL threshold for Ca2+/APD alternans in ACMs and AF dog right atrium, while suppressing AF susceptibility; caffeine increased Ca2+ leak and CL threshold for Ca2+/APD alternans in control dog ACMs and RA tissues. In vivo, the atrial repolarization alternans CL threshold was increased in AF versus control, as was AF vulnerability. Intravenous dantrolene restored repolarization alternans threshold and reduced AF vulnerability. Immunoblots showed reduced expression of total and phosphorylated ryanodine receptors and calsequestrin in AF and unchanged phospholamban/SERCA expression. Thus, along with promoting spontaneous ectopy, AF-induced Ca2+ handling abnormalities favor AF by enhancing vulnerability to repolarization alternans, promoting initiation and maintenance of reentrant activity; dantrolene provides a lead molecule to target this mechanism.