PDF(Pubmed)
Abstract：
Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca2+ signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified mechanisms that contribute to the higher risk of atrial arrhythmias in HF. Ca2+ transient (CaT) alternans-beat-to-beat alternations in CaT amplitude-served as indicator of increased arrhythmogenicity. We demonstrate that HF atrial myocytes were more prone to alternans despite no change in action potentials duration and only moderate decrease of L-type Ca2+ current. Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition suppressed CaT alternans. Activation of IP3 signaling by endothelin-1 (ET-1) and angiotensin II (Ang II) resulted in acute, but transient reduction of CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ load, and lowered the alternans risk. However, prolonged exposure to ET-1 and Ang II enhanced SR Ca2+ release and increased the degree of alternans. Inhibition of IP3 receptors prevented the transient ET-1 and Ang II effects and by itself increased the degree of CaT alternans. Our data suggest that activation of CaMKII and IP3 signaling contribute to atrial arrhythmogenesis in HF.
摘要：
心力衰竭（HF）增加心律失常的可能性，包括心房颤动(AF),但对HF与AF的连接机制了解甚少。我们研究了来自正常心脏和衰竭心脏的兔心房肌细胞的Ca2信号传导和电生理紊乱，并确定了导致HF中房性心律失常风险较高的机制。CaT振幅中的Ca2瞬时（CaT）交替-搏动-搏动交替作为心律失常性增加的指标。我们证明，尽管动作电位持续时间没有变化，L型Ca2电流仅适度降低，但HF心房肌细胞更容易发生交替变化。Ca2/钙调蛋白依赖性激酶II（CaMKII）抑制抑制了CaT交替。内皮素-1（ET-1）和血管紧张素II（AngII）激活IP3信号导致急性，但CaT振幅和肌浆网（SR）Ca2+负荷的瞬时降低，降低了交替糖的风险。然而,长时间暴露于ET-1和AngII可增强SRCa2释放并增加交替糖的程度。抑制IP3受体可防止短暂的ET-1和AngII作用，并本身增加了CaT交替的程度。我们的数据表明，CaMKII和IP3信号的激活有助于HF的房性心律失常发生。
