抗M2乙酰胆碱能受体自身抗体在心房颤动发病机制的研究

Atrial fibrillation (AF) is the most common and complex arrhythmia, with high incidence and serious complications. At present, catheter ablation is the effective measure in treatment of AF, but there is a certain recurrence rate after ablation. Atrial electrical remodeling and abnormal intracellular calcium regulation plays an important role in the occurrence and maintainance of AF. Previous studies indicated that serum autoantibodies against M2 acetylcholine receptor (M2-AAB) were related with AF. The main purpose of this research is to explore the pathogenesis of M2-AAB in AF and the predictive value of M2-AAB for recurrence after radiofrequency catheter ablation. We will take M2-AAB as the center using immunology, electric physiology, molecular biology, laser scanning confocal microscopy and real-time monitoring of intracellular calcium technique to find the differences of M2-AAB in AF patients and healthy controls, the functional role of M2-AAB on L-type calcium current,muscarinic acetylcholine receptor-operated K+ current and ultrarapid delayed rectifier K+ current in the rats atrial myocyte, incubating sinus node cells and atrial myocytes with M2-AAB,carbachol, M2-AAB and atropin or negative serum of M2-AAB for one week, detecting the differences of downstream signaling molecules with Western blotting and ELISA and the currents changes of the three chanel. This study may provide theoretical foundation and experimental basis for further study the pathogenesis of AF and predictive index for recurrence after radiofrequency ablation.

心房颤动（房颤）是临床最为常见而又复杂的心律失常，其发病率高，并发症严重，但发病机制不明。目前导管射频消融术是治疗房颤的有效措施，但消融术后存在一定的复发率。心房电重塑和细胞内钙调控异常在房颤的发生和维持中起重要作用。既往研究提示血清抗M2受体自身抗体与房颤发生相关，本研究的主要目的是研究抗M2受体自身抗体在房颤发病中的机制及其对射频消融术后房颤复发的预测价值。我们将以抗M2受体自身抗体为中心，运用电生理学、分子生物学、免疫学、激光共聚焦显微成像技术以及胞内 Ca2＋实时监测技术研究抗M2受体自身抗体在房颤和正常人血清中的差异，抗M2受体自身抗体对大鼠心房肌细胞L型钙通道、乙酰胆碱依赖钾通道和超快速延迟整流钾通道的影响，以抗M2受体自身抗体分别孵育大鼠窦房结和心房肌细胞，检测下游信号分子和离子通道改变，为进一步探讨房颤的发病机制和寻找房颤射频消融术后复发的预测指标提供理论基础和实验依据。

前期研究结果发现： M2-乙酰胆碱能受体（M2-受体）自身抗体通过与心肌M2-受体相结合，起“激动剂样”作用，在心血管疾病及其相关疾病的发生、发展和治疗中起着非常重要的作用。研究显示M2-受体自身抗体与心房颤动的发生与维持相关。本课题深入探讨M2-受体自身抗体在心房颤动患者中的作用。有三个重要发现：.1、发现证实：房颤患者血清M2-受体自身抗体阳性率及抗体滴度明显高于窦性心律者。在房颤组中，持续性房颤患者血清M2-受体自身抗体阳性率及抗体滴度均明显高于阵发性房颤患者。.2、随访发现：房颤患者射频消融术后随访1年，76例患者中有25例房颤复发，多因素Logistic回归分析提示房颤患者射频消融术前血清M2受体自身抗体阳性是术后短期房颤复发的预测因素之一，即M2受体自身抗体在房颤发病中的机制及其对射频消融术后房颤复发的预测价值。.3、实验证实：通过全细胞钳制技术，M2-受体激动剂碳酰胆碱能使由异丙肾上腺素预先增大的ICa-L峰值电流强度和标准电流密度下降，阿托品可以阻断这一作用。M2-受体自身抗体具有M2-受体激动剂样作用，其阳性血清可以使ICa-L的峰值电流强度和标准电流密度降低，同样可以被阿托品所阻断。

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