电压门控钠通道β2亚基缺失小鼠模拟的病态窦房结综合征机制

Cardiac sodium channelopathies are important reasons responsible for lethal cardiac arrhythmia. It is composed of one α subunit and two β subunits. Mutations in gene SCN2B, which encodes sodium channel β2 subunit, has been found associated with human Brugada syndrome and atrial fibrillation. To understand the physiological role of β2 in the heart, we studied cardiac phenotype in the Scn2b null mice. Scn2b null mice developed bradycardia comparing to wild-type mice, which could further deteriorate to asystole leading to death, mimicking human sick-sinus syndrome. Decreased sodium current were revealed in the cardiomyocytes isolated from Scn2b null mice, implicating that loss of β2 is sodium channel loss-of-function mutation. To investigate the mechanism of bradycardia, we planned to measure the sodium current from pacemaker cells in the sinus node. By which we may be able to understand the contribution of sodium current in regulating the automaticity of the sinus node. In addition, we will study the modulation of autonomic control to the bradycardia by blocking the autonomic nerve. Finally, we will quantify the fibrosis in the atrium. Thus, we will elucidate the underlying mechanism of bradycardia from multiple aspects including autologous, autonomic and functional contribution. This study will not only promote our understanding of electrophysiological role of β2 in the heart, but also be a critical step in the development of risk stratification and therapeutic strategies to the cardiac sodium channelopathy.

心脏电压门控钠离子通道突变是导致致死性恶性心律失常的重要原因。钠通道由一个α及两个β亚基构成。编码β2亚基的基因SCN2B发生的突变已被发现与Brugada综合征及房颤相关，提示该亚基在心脏电生理中的重要作用。在β2心脏生理作用的研究中，我们观测到β2缺失小鼠心脏表型时发现该小鼠发生心动过缓并可恶化为心脏停搏并最终导致死亡，类同人病态窦房结综合征。此外，我们还发现该小鼠分离的心肌细胞钠电流减小，提示缺失β2导致钠通道失活。为进一步研究心动过缓机制，我们将分离窦房结起搏细胞探究其钠电流变化在自律性中的作用。通过阻断自主神经控制了解神经系统对表型的贡献。据此，我们将从心脏自体，神经控制及功能多个方面探讨β2缺失导致的心动过缓的机制，以期阐明β2亚基的心脏电生理功能，及其突变所致的心律失常机制，为将来预后评估及治疗心脏钠离子通道病提供依据。

在本研究中，我们探索了Scn2b敲除小鼠的心房电生理表型。我们发现在体小鼠中Scn2b敲除可导致心率轻度下降，而离体心脏却无差异。窦房结恢复时间两组无差异，提示窦房结功能无改变。然而，Scn2b敲除小鼠更易诱发心房颤动。Scn2b敲除小鼠心房纤维化更显著，动作电位时程延长且复极离散度增加，并通过复杂的功能性折返----转子来维持Scn2b敲除小鼠的房颤。该研究为今后理解离子通道突变所致心律失常机制提供了重要线索。