Brugada综合征的临床电生理及分子遗传机制研究

The Brugada syndrome is increasingly being recognized in clinical medicine characterized by an ST-segment elevation in the right pericardial electrocardiogram (ECG) leads and a high incidence of sudden death in patients with structurally normal hearts. This syndrome generally manifests during adulthood, especially in males as they enter their third and fourth decades of life. Several dozen mutations have been linked to the syndrome in SCN5A, the gene encoding for the subunit of the sodium channel. In the early years, the concepts of all-or-none repolarization of the ventricular epicardial action potential and of phase 2 reentry were developed as the cellular mechanisms. Study also suggested that among asymptomatic patients, inducibility of VT during electrophysiologic study may be prognostic of risk.. In our study, we enroll patients referred to our center for evaluation and treatment after the detection of ECG abnormalities consistent with Brugada syndrome, who would undergo an electrophysiologic study and catheter ablation for symptomatic arrhythmias. We would examine the electrocardiogram and electrophysiologic characteristics in relation to programmed ventricular stimulation - induced ventricular tachycardia in patients with Brugada syndrome. Genomic DNA was extracted from peripheral blood leucocytes of patients and their families. Genetic analysis of SCN5A would be done. Cellular and ionic mechanisms underlying the development of the Brugada would be investigated in order to find the relationship between the genotype and the phenotype. We aim at the identification of patients at risk of sudden death and further on the diagnostic and the prognostic schemes on the basis of the available clinical and basic science data.

Brugada综合征是一种遗传性心脏离子通道病，病人心脏结构正常，有特征性心电图表现，因致命性室性快速性心律失常发作引起反复晕厥和猝死，国内散发和家族性病例逐年增多，大多数患者以猝死为首发症状，来不及防范和救冶。. 既往一系列单从临床或基础角度出发的研究使我们对该病有了初步认识，本项目拟对Brugada综合征进行临床电生理与分子遗传机制研究，从临床与基础两个层面出发，针对收集的每一例病例，建立完整的临床与遗传资料库，总结发病特点、心电图及心内电生理特征、筛查基因及离子通道改变、以及随访预后转归，阐明基因信息、心脏电生理、和临床表现之间的内在联系，建立从临床征象推测基因突变的诊断方法，从基因型评估危险，全面探讨该病的发病机制，寻找早期发现、早期预防和有效的治疗策略。

Brugada综合征是一种遗传性心脏离子通道病，患者心脏结构正常，有特征性心电图表现，因致命性室性心律失常发作引起反复晕厥和猝死，目前发现相关致病基因已有12个。本研究入选Brugada综合征病例，筛查致病相关基因，对新发突变进行细胞电生理研究，同时探讨患者心律失常事件的临床电生理特点。. 分析40例Brugada心电图表现患者的动态心电图，发现夜间发作室性心律失常事件和猝死的风险高，主要集中在午夜至凌晨，分析P波时限>120ms、I度房室传导阻滞、束支阻滞及T波电交替情况，初步显示AV间期及T波电交替与室性心律失常的发生密切相关。这可能与自主神经活动有关，而呼吸睡眠障碍患者夜间反复发作的低氧血症和高碳酸血症会引起自主神经功能紊乱，进一步分析呼吸睡眠障碍对Brugada患者的影响，发现合并呼吸睡眠障碍组总的心律变异性（HRV）减低，发生心律失常情况更严重。. 对50例Brugada心电图表现病例进行了主要致病基因SCN5A的多态性研究，发现各位点的等位基因和基因型关联分析结果均无统计学意义，单体型分析无统计学意义。. 3例Brugada综合征确诊患者高通量测序捕获到新发基因突变CACNA1C（R1950K）、SCN1B（T189M）、HCN4（E237R），临床意义未明，采用全细胞膜片钳进行细胞电生理功能研究显示，CACNA1C（R1950K）突变导致Lca电流密度显著减小，SCN1B野生型引起INa电流的增大，而SCN1B（T189M）突变引起INa电流显著减小。. 本研究针对Brugada心电图表现患者进行的心律失常事件分析有利于患者危险因素的评估，指导临床诊疗，对3例新发突变进行的细胞电生理功能研究有助于疾病的基因诊断。