Ryanodine-Receptor Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model
Background—The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca2+-leak via the ryanodine receptor (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study tested the hypothesis that enhanced RyR2-mediated Ca2+-release underlies the development of a substrate for sAF and to understand the underlying mechanisms.
Methods and Results—CREM-IbΔC-X transgenic (CREM)-mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM-mice was preceded by enhanced diastolic Ca2+-release, atrial enlargement and marked conduction abnormalities. Genetic inhibition of CaMKII-mediated RyR2-S2814 phosphorylation in CREM-mice normalized open probability of RyR2-channels and SR Ca2+-release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation and forestalled atrial conduction-abnormalities. Hyperactive RyR2-channels directly stimulated the Ca2+-dependent hypertrophic pathway NFAT/Rcan1-4, suggesting a role for the NFAT/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice.
Conclusions—RyR2-mediated SR Ca2+-leak directly underlies the development of a substrate for sAF in CREM-mice, the first demonstration of a molecular mechanism underlying AF-progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca2+ release in AF may not be restricted to the generation of atrial ectopy, but extends to the development of atrial remodeling underlying the AF substrate.
- Received October 3, 2013.
- Revision received December 3, 2013.
- Accepted December 26, 2013.