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.

癫痫病（SUDEP）突然意外死亡是癫痫患者死亡的主要原因。 Sudep 尽管有证据表明呼吸暂停，自主神经功能障碍和 心律不齐。我们将利用遗传中对SUDEP风险的最新进展 癫痫病研究心律不齐的作用。 SUDEP风险以基因特异性方式变化。丧失 在电压门控钠通道（VGSC）基因SCN1A或SCN1B中的功能变异在 在VGSC SCN8A中，Dravet综合征（DS）和功能障碍的患者在患者中发现 早期婴儿癫痫性脑病13（EIEE13）。 DS和EIEE13患者的SUDEP风险最高，UP 至20％。相比之下，染色体构酶DNA结合蛋白2（CHD2）中的变体也与 EE的早期发作，但尚未在该人群中报道SUDEP。 SCN1A-，SCN1B-，SCN8A-和CHD2-- 连接的癫痫是发育和癫痫性脑病（DEES），严重的儿童癫痫 与认知和行为障碍有关。家族性局灶性癫痫归因于致病性 DEPDC5中的变体，编码MTOR途径中Gator复合物的成员。据报道Sudep 这些患者中有10％。由于VGSC基因在心脏和大脑中均表达，所以我们提出 心律不齐有助于与通道疾病相关的遗传性癫痫中SUDEP的机制。我们的 总体目标是了解遗传性癫痫中SUDEP的机制。我们的目标是使用 患者衍生或转基因小鼠心脏肌细胞（CMS）了解癫痫VGSC基因突变如何 改变CM功能和心律失常潜力，并确定在非离子中是否发现类似的变化 在心脏中表达的通道癫痫基因。我们的中心假设是离子通道和非 - 离子通道遗传性癫痫病的遗传性癫痫病在患者的患者中表现出促心律失常的变化 派生的CMS和鼠标模型。询问非离子通道中是否也发生异常CM兴奋性 遗传性癫痫患有高SUDEP风险，我们将研究DEPDC5变体IPSC-CMS和DEPDC5 - / - 小鼠。 最后，我们将检查具有CHD2变体的CHD2 - / - 小鼠和人IPSC-CM，它是一种非离子通道基因，具有具有 低SUDEP风险，以测试CM兴奋性是否适用于SUDEP率高的遗传性癫痫。 像VGSC一样，DEPDC5和CHD2在大脑和心脏中也表达。我们的具体目的是：1。确定 使用患者衍生的IPSC-CMS，SCN1A，SCN1B和SCN8A癫痫变量对CM兴奋性的影响。 2。确定来自DEPDC5患者或DEPDC5 +/-小鼠的CMS是否表现出异常兴奋性以及是否显示 DEPDC5 +/-小鼠具有心律不齐。 3。确定CHD2患者或CHD2 +/-鼠标的CMS显示 异常兴奋性以及CHD2 +/-小鼠是否具有心律不齐。没有任何有效的疗法 遗传性癫痫病，没有可靠的生物标志物来实现SUDEP风险。这项工作可能导致发现诊断 未来SUDEP风险的生物标志物。

项目成果

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

• DOI: 10.1038/s41467-021-26496-1
• 发表时间: 2021-10-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Tsan YC;DePalma SJ;Zhao YT;Capilnasiu A;Wu YW;Elder B;Panse I;Ufford K;Matera DL;Friedline S;O'Leary TS;Wubshet N;Ho KKY;Previs MJ;Nordsletten D;Isom LL;Baker BM;Liu AP;Helms AS
• 通讯作者: Helms AS

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

• DOI: 10.3390/antiox12101833
• 发表时间: 2023-10-06
• 期刊: Antioxidants (Basel, Switzerland)