Abstract 12665: Remodeling of Nuclear Ca2+ Disposition in Atrial Fibrillation Associated Remodeling
Introduction: Atrial fibrillation (AF) induces substantial self-promoting remodeling related to the rapid atrial rate. There is evidence that changes in nuclear Ca2+ content alter ion channel gene expression and thereby effect electrophysiological changes that increase AF vulnerability and maintenance. However, the ways in which AF affects atrial cardiomyocyte (ACM) nuclear Ca2+ disposition are unknown. Here, we studied the effects of AF-related remodeling on ACM nuclear structure and Ca2+ handling.
Methods and Results: ACMs were isolated from control (CTL) dogs and dogs subjected to 1 week of AF maintained by atrial tachypacing at 600 bpm (n=7, 6 respectively). We used nuclear imaging with Fluo-5N AM and nucleoplasmic and cytoplasmic calcium transient (CaT) recordings from intact ACMs loaded with Fluo-4 AM. AF significantly decreased the number of nuclear invaginations (NIV) normalized to nuclear envelope (NE) circumference, and increased nuclear length and perimeter in ACMs (Figure A). Diastolic [Ca2+]nuc and [Ca2+ ]cyto increased in AF vs CTL (Figure B, by 110%*, 89%* respectively, *P<0.05). Nucleoplasmic Ca2+ transient amplitude decreased significantly with AF, but simultaneously measured cytoplasmic transient amplitude did not change (Figure C). Relaxation time from peak of the Ca2+ transient to 50% decline (TD50) of nucleoplasmic and cytoplasmic CaTs were significantly prolonged in AF. The addition of a physiological nuclear Ca2+ transient enhancer, endothelin (200 nM), increased diastolic [Ca2+]nuc and [Ca2+ ]cyto in both CTL (by 25±6%, 21±6%) and AF (by 40±4%, 31±2 ) ACMs. The IP3 receptor blocker 2-aminoethoxydiphenyl borate (2-APB, 5 μM) abolished endothelin effects on [Ca2+]nuc.
Conclusions: AF-related remodeling alters atrial cardiomyocyte nuclear structure and nucleoplasmic [Ca2+] handling. These alterations may play an important role in associated gene-expression changes that produce the AF substrate.
Author Disclosures: X.Y. Qi: None. L. Villeneuve: None. F. Xiong: None. Y. Sun: None. D. Dobrev: None. S. Nattel: None.
- © 2015 by American Heart Association, Inc.