Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy

癫痫猝死的心脏机制

• 批准号: 10661021
• 负责人: Lori L. Isom
• 金额: $ 69.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661021
• 关键词: Action Potentials; Apnea; Arrhythmia; Autonomic Dysfunction; Autopsy; Biological Markers; Biological Models; Brain; Calcium; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cause of Death; Cells; Complex; Complication; DNA-Binding Proteins; Development; Dissection; Early Infantile Epileptic Encephalopathy; Epilepsy; Exhibits; FRAP1 gene; Future; Gene Mutation; Genes; Genetic; Goals; Heart; Heart Abnormalities; Heart Atrium; Human; Impaired cognition; Incidence; Ion Channel; Link; Maps; Modeling; Mus; Outcome; Partial Epilepsies; Pathogenicity; Pathway interactions; Patients; Phenotype; Population; Reporting; Research; Risk; Role; SCN1A protein; SCN8A gene; Sleep; Sodium; Sodium Channel; Testing; Transgenic Mice; Variant; Ventricular; Work; behavioral impairment; childhood epilepsy; clinical diagnosis; cohort; comparison control; density; diagnostic biomarker; dravet syndrome; early onset; effective therapy; epileptic encephalopathies; experimental study; gain of function; helicase; indium arsenide; induced pluripotent stem cell; loss of function; member; mouse model; novel; personalized intervention; prevent; programs; risk variant; sudden unexpected death in epilepsy; translational model; virulence gene; voltage

Sudden Unexpected Death in EPilepsy, or SUDEP, is a leading cause of death in patients with epilepsy. SUDEP mechanisms are not understood, although there is evidence to implicate apnea, autonomic dysfunction, and cardiac arrhythmias. We will take advantage of recent progress in the understanding of SUDEP risk in the genetic epilepsies to investigate the role of cardiac arrhythmias. SUDEP risk varies in a gene-specific manner. Loss-of- function variants in the voltage-gated sodium channel (VGSC) genes, SCN1A or SCN1B, are identified in patients with Dravet syndrome (DS) and gain-of-function variants in the VGSC SCN8A are found in patients with Early Infantile Epileptic Encephalopathy 13 (EIEE13). DS and EIEE13 patients have the highest SUDEP risk, up to 20%. In contrast, variants in chromodomain helicase DNA binding protein 2 (CHD2) are also associated with early onset EE, but SUDEP has not been reported in this population. SCN1A-, SCN1B-, SCN8A-, and CHD2- linked epilepsies are developmental and epileptic encephalopathies (DEEs), severe childhood epilepsies associated with cognitive and behavioral impairments. The familial focal epilepsies, are attributed to pathogenic variants in DEPDC5, encoding a member of the GATOR complex in the mTOR pathway. SUDEP is reported in 10% of these patients. Because VGSC genes are expressed in both heart and brain, we have proposed that cardiac arrhythmias contribute to the mechanism of SUDEP in channelopathy-linked genetic epilepsies. Our overall goal is to understand the mechanisms of SUDEP in the genetic epilepsies. Our objectives are to use patient-derived or transgenic mouse cardiac myocytes (CMs) to understand how epileptic VGSC gene mutations alter CM function and arrhythmogenic potential, and to determine whether similar changes are found in non-ion channel epilepsy genes that are expressed in the heart. Our central hypothesis is that both ion channel and non- ion channel genetic epilepsies with high, but not low, SUDEP risk exhibit pro-arrhythmogenic changes in patient- derived CMs and mouse models. To ask whether abnormal CM excitability also occurs in a non-ion channel genetic epilepsy with high SUDEP risk, we will investigate DEPDC5 variant iPSC-CMs and Depdc5-/- mice. Finally, we will examine Chd2-/- mice and human iPSC-CMs with variants in CHD2, a non-ion channel gene with a low SUDEP risk, to test whether altered CM excitability is specific to genetic epilepsies with high SUDEP rates. Like the VGSCs, DEPDC5 and CHD2 are expressed in brain and heart. Our Specific Aims are: 1. To determine the effects of SCN1A, SCN1B, and SCN8A epilepsy variants on CM excitability using patient-derived iPSC-CMs. 2. To ascertain whether CMs from DEPDC5 patients or Depdc5+/- mice display abnormal excitability and whether Depdc5+/- mice have arrhythmia. 3. To determine whether CMs from CHD2 patients or Chd2+/- mice display abnormal excitability and whether Chd2+/- mice have arrhythmia. There are no effective therapies for any of the genetic epilepsies and no reliable biomarkers for SUDEP risk. This work may lead to the discovery of diagnostic biomarkers for SUDEP risk in the future.

癫痫猝死（SUDEP）是癫痫患者死亡的主要原因。南苏丹发展计划 尽管有证据表明呼吸暂停、自主神经功能障碍和 心律失常。我们将利用对遗传性 SUDEP 风险了解的最新进展 癫痫研究心律失常的作用。 SUDEP 风险因基因而异。丢失- 电压门控钠通道 (VGSC) 基因 SCN1A 或 SCN1B 的功能变异在 患有 Dravet 综合征 (DS) 且 VGSC SCN8A 功能获得性变异的患者存在于以下患者中： 早期婴儿癫痫性脑病 13 (EIEE13)。 DS 和 EIEE13 患者的 SUDEP 风险最高， 至 20%。相反，染色质结构域解旋酶 DNA 结合蛋白 2 (CHD2) 的变异也与 早发性 EE，但 SUDEP 尚未在该人群中报道。 SCN1A-、SCN1B-、SCN8A- 和 CHD2- 相关的癫痫包括发育性脑病和癫痫性脑病 (DEE)、严重儿童癫痫 与认知和行为障碍有关。家族性局灶性癫痫是由致病因素引起的 DEPDC5 的变体，编码 mTOR 通路中 GATOR 复合体的成员。 SUDEP 报告于 这些患者中有10%。由于 VGSC 基因在心脏和大脑中都有表达，因此我们提出： 心律失常有助于 SUDEP 在通道病相关遗传性癫痫中的作用机制。我们的 总体目标是了解 SUDEP 在遗传性癫痫中的机制。我们的目标是使用 患者来源的或转基因小鼠心肌细胞 (CM) 以了解癫痫 VGSC 基因突变如何发生 改变 CM 功能和致心律失常电位，并确定非离子中是否发现类似的变化 通道在心脏中表达的癫痫基因。我们的中心假设是离子通道和非 具有高（但不低）SUDEP 风险的离子通道遗传性癫痫在患者中表现出促心律失常的变化。 衍生的 CM 和小鼠模型。询问非离子通道是否也出现异常的CM兴奋性 对于具有高 SUDEP 风险的遗传性癫痫，我们将研究 DEPDC5 变异 iPSC-CM 和 Depdc5-/- 小鼠。 最后，我们将检查具有 CHD2 变异的 Chd2-/- 小鼠和人类 iPSC-CM，CHD2 是一种非离子通道基因，具有 低 SUDEP 风险，以测试 CM 兴奋性改变是否特定于具有高 SUDEP 发生率的遗传性癫痫。 与 VGSC 一样，DEPDC5 和 CHD2 在大脑和心脏中表达。我们的具体目标是： 1. 确定 使用源自患者的 iPSC-CM，研究 SCN1A、SCN1B 和 SCN8A 癫痫变异对 CM 兴奋性的影响。 2. 确定DEPDC5患者或Depdc5+/-小鼠的CM是否表现出异常兴奋性以及是否 Depdc5+/- 小鼠有心律失常。 3. 确定来自 CHD2 患者或 Chd2+/- 小鼠的 CM 是否显示 兴奋性异常以及Chd2+/-小鼠是否有心律失常。对于任何一种病症都没有有效的治疗方法 遗传性癫痫，并且没有可靠的 SUDEP 风险生物标志物。这项工作可能会导致诊断方法的发现 未来 SUDEP 风险的生物标志物。

项目成果

NADPH Oxidases and Oxidative Stress in the Pathogenesis of Atrial Fibrillation.

NADPH 氧化酶和氧化应激在心房颤动发病机制中的作用。

• 发表时间: 2023-10-06
• 作者: Ramos;Lozhkin, Andrey;Vendrov, Aleksandr E;Runge, Marschall S;Isom, Lori L;Madamanchi, Nageswara R
• 通讯作者: Madamanchi, Nageswara R

Physiologic biomechanics enhance reproducible contractile development in a stem cell derived cardiac muscle platform.

生理生物力学增强干细胞衍生的心肌平台的可重复收缩发育。

• 发表时间: 2021
• 影响因子: 16.6
• 作者: Tsan, Yao;DePalma, Samuel J;Zhao, Yan;Capilnasiu, Adela;Wu, Yu;Elder, Brynn;Panse, Isabella;Ufford, Kathryn;Matera, Daniel L;Friedline, Sabrina;O'Leary, Thomas S;Wubshet, Nadab;Ho, Kenneth K Y;Previs, Michael J;Nordsletten, Da
• 通讯作者: Nordsletten, Da