Abstract 14534: Sarcoplasmic Reticulum Ca2+ Release via Ryanodine Receptor Type-2 Promotes Maintenance to Chronic Atrial Fibrillation
Introduction: Cellular mechanisms underlying the maintenance of chronic atrial fibrillation (cAF) are not completely understood. Although, Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of ryanodine receptor type-2 (RyR2) is enhanced in patients with cAF, it is unclear whether CaMKII-phosphorylation of RyR2 promotes maintenance of cAF. Separately, we have demonstrated that sarcoplasmic reticulum (SR) Ca2+ release is increased in CREM-IbΔC-X transgenic mice (CREM), a mouse model of spontaneous cAF.
Hypothesis: Enhanced SR Ca2+ release due to CaMKII-phosphorylation of RyR2 promotes maintenance of cAF in CREM mice.
Methods and Results: CREM mice were intercrossed with RyR2-S2814A mice, in which CaMKII phosphorylation of RyR2 is inactivated. At the age of 5 months, all CREM mice showed atrial ectopy on 24 hour ECG telemetry, and 40% developed spontaneously cAF (6/15). At the age of 7 months, 71% of CREM mice (15/21) had cAF, whereas cAF was not observed in any of the WT and CREM:S2814A mice (0/10, P<0.01 vs CREM).Ca2+ spark frequency in atrial myocytes was higher in CREM (4.0±0.8 sparks/100μ m/s), compared with both WT (2.0±0.3 sparks/100μ m/s, P<0.05) and CREM:S2814A cardiomyocytes (2.1±0.4 sparks/100μ m/s, P<0.05). The ratio of atrial weight to tibia length was higher in CREM (1.10±0.29 mg/mm) than in WT (0.42±0.10 mg/mm, P<0.05) and CREM:S2814A mice (0.43±0.04 mg/mm, P<0.05), suggesting that only CREM mice had atrial hypertrophy. Atrial fibrosis was more prominent in CREM (5.3±0.6%) and CREM:S2814A (5.4±1.0%) mice, compared with WT mice (1.4±0.4%; n=3-4 in each group, P<0.05). Prior to the onset of spontaneous AF (at the age of 3-months), T286-autophosphorylation of CaMKII was increased by 73% in CREM mice (P<0.05 vs WT) and 62% in CREM:S2814A mice (P<0.05 vs WT), whereas CaMKII-phosphorylated RyR2 at S2814 was strongly increased in CREM mice only.
Conclusion: Our data suggest that enhanced CaMKII-phosphorylation of RyR2 and subsequent diastolic SR Ca2+ releases promote maintenance of cAF in CREM mice. Inhibition of CaMKII phosphorylation of RyR2 in CREM:S2814A mice prevents development of cAF by normalizing SR Ca2+ release and atrial structure. Inhibition of CaMKII phosphorylation of RyR2 might be useful in preventing cAF.
- © 2012 by American Heart Association, Inc.