Atrial fibrillation (AF) alters atrial-cardiomyocyte (ACM) Ca2+-handling, promoting ectopic-beat formation. Here, we examined the effects of AF-associated remodeling on Ca2+-related action-potential (AP) dynamics and consequences for AF-susceptibility. AF was maintained electrically (x1 week) 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 APD alternans versus controls. Similarly, 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 both ACMs and AF-dog RA, while suppressing AF-susceptibility; caffeine increased Ca2+-leak, 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 vs control, as was AF-vulnerability. Intravenous dantrolene restored repolarization alternans-threshold and reduced AF-vulnerability. Immunoblots showed significantly reduced expression of total and phosphorylated ryanodine-receptors and calsequestrin in AF, along with unchanged phospholamban/SERCA expression. Thus, in addition to promoting spontaneous ectopy, AF-induced Ca2+-handling abnormalities favor AF-occurrence by enhancing vulnerability to repolarization-alternans, thereby promoting the initiation and maintenance of reentrant activity; the clinically-available compound dantrolene provides a lead-molecule to target this mechanism.
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