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

Tao Liu,Jiening Xiao,Congxin Huang,Xiao-Yan Qi,Louis Villeneuve,Stanley Nattel,Feng Xiong,Issam Abu-Taha,Dobromir Dobrev

doi:10.1172/jci.insight.133754

Abstract

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.

Highlights

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia in clinical practice, is associated with significant morbidity and mortality [1]
It has long been recognized that changes in [Ca2+]i are central to the development of repolarization alternans [12]
We evaluated for the first time to our knowledge the relationships among Ca2+ mishandling induced by AF, the susceptibility to different forms of atrial alternans behavior in atrial tissues and intact hearts, and AF susceptibility

Summary

Introduction

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia in clinical practice, is associated with significant morbidity and mortality [1]. AF-associated remodeling has long been known to alter atrial Ca2+ handling [3]. The rapid atrial rates associated with AF produce early cellular Ca2+ loading [4], followed by changes in cell Ca2+ handling that reduce the systolic Ca2+ transient while causing marked hypocontractility [3]. One curious finding in such remodeled cardiomyocytes is that the steady-state Ca2+ transient during sustained activity is very small, the initial transient after a period of inactivity is nearly normal [3]. One possible explanation would be an alteration in refractoriness of the Ca2+ transient. Prolonged Ca2+ transient refractoriness (CTR) decreases Ca2+ transients with repeated activation, especially at rapid rates, and increases susceptibility to alternans behavior [5]

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Results

Conclusion