Cardiovascular Research Institute, Department of Molecular Physiology&Biophysics, Baylor College of Medicine, Houston, TX.
TBMM program, Baylor College of Medicine, Houston, TX.
Circulation. 2014 Mar 25;129(12):1276-1285. doi: 10.1161/CIRCULATIONAHA.113.006611. Epub 2014 Jan 7.
The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca(2+) leak via the ryanodine receptor type 2 (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 was designed to test the hypothesis that enhanced RyR2-mediated Ca(2+) release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms.
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 Ca(2+) release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca(2+)/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca(2+) 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 Ca(2+)-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice.
RyR2-mediated SR Ca(2+) 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 Ca(2+) 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.
心房颤动（AF）从阵发性向持续性进展仍然是一个主要的临床挑战。在各种 AF 模型中，观察到通过兰尼碱受体 2（RyR2）的肌质网（SR）Ca2+异常渗漏是异位活动的来源。然而，其在向持续性自发性 AF（sAF）进展中的潜在作用从未被检验过。本研究旨在检验增强的 RyR2 介导的 Ca2+释放是导致 sAF 基质形成的假说，并阐明其潜在机制。
CREM-IbΔC-X 转基因（CREM）小鼠出现自发性心房异位搏动、阵发性、最终为持续性 AF 的年龄依赖性进展。在 CREM 小鼠中，sAF 的发展先于舒张期 Ca2+释放增加、心房扩大和明显的传导异常。在 CREM 小鼠中，抑制 Ca2+/钙调蛋白依赖性蛋白激酶 II 介导的 RyR2-S2814 磷酸化可使 RyR2 通道和 SR Ca2+释放的开放概率正常化，延迟自发性心房异位搏动的发生，完全预防 sAF，抑制心房扩张，并阻止心房传导异常。活性过高的 RyR2 通道直接刺激 Ca2+依赖性肥大途径活化 T 细胞核因子/ Rcan1-4，表明活化 T 细胞核因子/ Rcan1-4 系统在 CREM 小鼠的 sAF 基质形成中发挥作用。
RyR2 介导的 SR Ca2+渗漏直接导致 CREM 小鼠 sAF 基质的形成，这是在实验模型中首次证明 AF 进展和 sAF 基质形成的分子机制。我们的工作表明，异常舒张期 Ca2+释放在 AF 中的作用可能不仅限于产生心房异位搏动，而且扩展到 AF 基质下的心房重构的发展。
