汪道武 南京医科大学第一附属医院心脏科 江苏省人民医院 江苏省心肺疾病研究所 2012 年 9 月 15 日 中华医学会心电生理和起搏分会第十次年会 汪道武 南京医科大学第一附属医院心脏科 江苏省人民医院 江苏省心肺疾病研究所 2012 年 9 月 15 日 中华医学会心电生理和起搏分会第十次年会 SCN5A 相关的心律失常的 动物模型

一、 长 QT 综合征（ LQTS ） 二、 儿茶酚胺敏感性室速（ CPVT ） 三、 Brugada 综合征 (BrS) 四、 进行性心脏传导疾病（ CCD ） 五、 短 QT 综合征 (SQTS) 六、 心房颤动 七、 肥厚性心肌病（ HCM ） 八、 致心律失常型心肌病（ ACM ） / 致心律失常型右室心肌病（ ARVC ） 九、 扩张型心肌病（ DCM ） 十、 左室心肌致密化不全（ LVNC ） 十一、 限制性心肌病（ RCM ） 十二、 院外心脏骤停（ OHCA ）幸存者 十三、 尸检阴性猝死患者遗传学检测 遗传性心律失常和心肌病

Physiology Initial upstroke of cardiac action potentials Critical for rapid conduction Pharmacology Target for antiarrhythmics Genetics Encoded by SCN5A (3p21) Inherited arrhythmias and conduction disorders Physiology Initial upstroke of cardiac action potentials Critical for rapid conduction Pharmacology Target for antiarrhythmics Genetics Encoded by SCN5A (3p21) Inherited arrhythmias and conduction disorders Cardiac Voltage-Gated Sodium Channel 3 SCN5A 3p21

Congenital long QT syndrome SCN5A, KCNQ1, HERG, KCNE1, KCNE2 Brugada Syndrome SCN5A Isolated Cardiac Conduction Diseases SCN5A Congenital Sick Sinus Syndrome SCN5A Sudden Infant Death Syndrome SCN5A Atrial Fibrillation (Flutter, Standstill) SCN5A, … Dilated Cardiomyopathy SCN5A, … Catecholaminergic polymorphic ventricular tachycardia RYR2 Andersen Syndrome KCNJ2 Timothy Syndrome CACNA1C Congenital long QT syndrome SCN5A, KCNQ1, HERG, KCNE1, KCNE2 Brugada Syndrome SCN5A Isolated Cardiac Conduction Diseases SCN5A Congenital Sick Sinus Syndrome SCN5A Sudden Infant Death Syndrome SCN5A Atrial Fibrillation (Flutter, Standstill) SCN5A, … Dilated Cardiomyopathy SCN5A, … Catecholaminergic polymorphic ventricular tachycardia RYR2 Andersen Syndrome KCNJ2 Timothy Syndrome CACNA1C Cardiac Channelopathies

Current Mouse Models Reported

Previously reported: 1.Conduction disease 2.Dilated Cardiomyopathy 3.Ventricular tachyarrhythmias SCN5A-D1275N Mutation

SCN5A-D1275N Mutation — 2 In patient with: 1.Atrial flutter 2.Atrial standstill 3.Conduction disease 4.Sinus node dysfunction

Case Presentation 1.19 yrs. white man, with recurrent exertional syncope 2.PE and Echocardiography are normal 3.ECG: slow atrial flutter (1:1 to ventricles) 4.Hypotension during exertion After Catheter ablation (for atrial flutter): 1.Atrial standstill 2.Prolonged QRS 3.Sinus node dysfunction 4.High degree atrioventricular block 5.Normal QT interval 6.ICD Asymptomatic for 10+ years and Echocardiography is normal

SCN5A-D1275N Mutation Studied in Vitro SCN5A-D1275N Mutation Studied in Vitro There was no major difference in biophysical properties between wild-type and D1275N channels expressed in CHO or tsA201 cells

ECG Echocardiogram Histology mRNA Quantification Western Blotting Immunostaining / Confocal Microscopy Sodium Current Recording Action Potential Recordings Studies in Mouse

SCN5A-D1275N Mutation —— in Vivo In mouse: 1.Slow conduction 2.Atrial fibrillation 3.Ventricular tachycardia 4.Dilated cardiomyopathy

Previously reported: 1.Conduction disease 2.Dilated Cardiomyopathy 3.Ventricular tachyarrhythmia In patient with: 1.Atrial flutter 2.Atrial standstill 3.Conduction disease 4.Sinus node dysfunction In mouse: 1.Slow conduction 2.Atrial fibrillation 3.Ventricular tachycardia 4.Dilated cardiomyopathy Conclusion