Genetics of arrhythmic mitral valve prolapse: large pedigree collection within the UCSF MVP registry

心律失常二尖瓣脱垂的遗传学：UCSF MVP 登记处的大量谱系收集

• 批准号: 10850759
• 负责人: Francesca N Delling
• 金额: $ 77.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-26 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10850759
• 关键词: 18 year old; 3-Dimensional; ATAC-seq; Administrative Supplement; Adult; Affect; Ambulatory Monitoring; Arrhythmia; Biological Assay; Biological Models; Cardiac; Cardiac Electrophysiologic Techniques; Cardiomyopathies; Case Study; Cell Culture Techniques; Cell model; Characteristics; Cilia; Clinical; Collection; Complex; Computer Models; Data; Data Set; Detection; Development; Diffuse; Disease; Echocardiography; Educational workshop; Electrocardiogram; Embryo; FLNC gene; Family; Family member; Fibrosis; Foundations; Future; Gadolinium; General Population; Generations; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic study; Genotype; Genotype-Tissue Expression Project; Goals; Heart Arrest; Holter Electrocardiography; Image; Implantable Defibrillators; In Vitro; Individual; Inherited; Institution; Investigation; Knock-in; Left; Life; Link; Magnetic Resonance; Malignant - descriptor; Maps; Mechanics; Memory; Minority; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Mutation; Myocardial; Myopathy; National Heart, Lung, and Blood Institute; Neonatal; Outcome; Outcome Study; Participant; Pathogenicity; Pathology; Patients; Phenotype; Prevention; Primary Prevention; Proteins; Registries; Research; Risk; Testing; United States; Variant; Ventricular; Ventricular Arrhythmia; Wife; cardiac magnetic resonance imaging; cohort; coronary fibrosis; data modeling; demographics; exome sequencing; genetic pedigree; genetic variant; genome wide association study; heart imaging; imaging biomarker; in vivo; multimodality; novel; phenotypic biomarker; predictive marker; proband; prospective; protein expression; recruit; risk prediction model; risk stratification; screening; segregation; sudden cardiac death

PROJECT SUMMARY Mitral valve prolapse (MVP) is a common valvulopathy with a strong hereditary component affecting over 7 million individuals in the United States. Every year, up to 1.8% of MVPs will develop sudden cardiac arrest (SCA) or sudden cardiac death (SCD). In prior studies, SCD/SCA in MVP has either been linked to severe mitral regurgitation (MR) or to a malignant bileaflet phenotype with mild MR, mitral annular disjunction (MAD) and abnormal valvular-myocardial mechanics leading to complex ventricular ectopy (ComVE) and/or left ventricular replacement fibrosis [late gadolinium enhancement or LGE by cardiac magnetic resonance (CMR) imaging]. We have shown, supported by an ongoing R01, that diffuse fibrosis by CMR/T1 mapping is linked to increased arrhythmic risk, regardless of bileaflet phenotype, severe MR, or presence of LGE. Hence, arrhythmic MVP may not be a “pure” valvulopathy, but rather a component of a primary subclinical myopathy. In addition to mutations in cilia-related genes (DCHS1, TNS1, LMCD1, DZIP1) previously described in “general” MVP, cardiomyopathy or channelopathy genes (FLNC, LMNA, ALPK3, SCN5A) have been recently proposed in arrhythmic MVP, albeit in case reports, or GWAS studies with heterogeneous presentations. Through an ongoing R01 and an expanding MVP registry at our institution, we have identified a total of 14 arrhythmic MVP probands and pedigrees, and 50 sporadic arrhythmic MVP cases. In this administrative supplement application, we seek to complete whole exome sequencing, arrhythmic characterization, and CMR in a minority of family members that have yet to undergo these investigations. Our central hypothesis is that among MVP genetic variants, cardiomyopathy or channelopathy genes act alone or in combination with cilia- related variants to increase the risk of SCD/SCA in MVP. To test our central hypothesis and accomplish our overall objective, we propose the following Specific Aims: Aim 1: To identify clinical features and genetic determinants of arrhythmic risk in MVP SCD/SCA pedigrees, and Aim 2: To test pathogenicity of genetic variants and understand mechanisms of arrhythmic MVP using protein expression data and cell model assays. Data obtained through this administrative supplement is essential for better MVP SCD/SCA risk stratification, thus enabling future prevention of SCD via ICD placement in appropriately selected MVP patients. Use of cell model assays to validate our genetic findings is essential to understand arrhythmogenesis in MVP patients. Our proposal is motivated by a recent NHLBI workshop on research opportunities in MVP and the CAROL Act in memory of a US congressman’s wife who died suddenly from MVP.

项目概要 二尖瓣脱垂 (MVP) 是一种常见的瓣膜病，具有很强的遗传性，影响超过 7 名患者 美国有 100 万人。每年，高达 1.8% 的 MVP 会发生心脏骤停 （SCA）或心源性猝死（SCD）。在之前的研究中，MVP 中的 SCD/SCA 要么与严重的 二尖瓣反流 (MR) 或伴有轻度 MR 的恶性双叶表型、二尖瓣环分离 (MAD) 以及导致复杂心室异位 (ComVE) 和/或左心室异常的瓣膜心肌力学 心室置换纤维化 [晚期钆增强或心脏磁共振 (CMR) 的 LGE 成像]。我们已经证明，在正在进行的 R01 的支持下，CMR/T1 映射的弥漫性纤维化与 无论双叶表型、严重 MR 或是否存在 LGE，心律失常风险都会增加。因此， 心律失常 MVP 可能不是“纯粹的”瓣膜病，而是原发性亚临床肌病的一个组成部分。 除了之前描述的纤毛相关基因（DCHS1、TNS1、LMCD1、DZIP1）的突变外， “一般”MVP、心肌病或通道病基因（FLNC、LMNA、ALPK3、SCN5A）最近已被 在心律失常 MVP 中提出，尽管是在病例报告或具有异质性表现的 GWAS 研究中提出的。 通过我们机构正在进行的 R01 和不断扩大的 MVP 注册，我们总共确定了 14 心律失常 MVP 先证者和家系，以及 50 例散发性心律失常 MVP 病例。在本行政 补充申请，我们寻求完成全外显子组测序、心律失常特征和 CMR 少数尚未接受这些调查的家庭成员。我们的中心假设是 在 MVP 遗传变异中，心肌病或通道病基因单独作用或与纤毛联合作用 相关变异会增加 MVP 中 SCD/SCA 的风险。检验我们的中心假设并实现我们的 总体目标，我们提出以下具体目标： 目标 1：确定临床特征和遗传特征 MVP SCD/SCA 家系中心律失常风险的决定因素，以及目标 2：测试遗传致病性 使用蛋白质表达数据和细胞模型分析来了解心律失常 MVP 的变异和机制。 通过此行政补充获得的数据对于更好地进行 MVP SCD/SCA 风险分层至关重要， 从而能够通过在适当选择的 MVP 患者中放置 ICD 来预防 SCD。电池的使用 验证我们的遗传发现的模型测定对于了解 MVP 患者的心律失常发生至关重要。 我们的提议是受到最近 NHLBI 举办的关于 MVP 和 CAROL 法案研究机会研讨会的推动 纪念一位因 MVP 突然去世的美国国会议员的妻子。

项目成果

Cardiac Imaging for Risk Assessment of Malignant Ventricular Arrhythmias in Patients With Mitral Valve Prolapse.

• DOI: 10.3389/fcvm.2021.574446
• 发表时间: 2021
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Tayal B;Delling FN;Malahfji M;Shah DJ
• 通讯作者: Shah DJ

Interstitial Fibrosis and Arrhythmic Mitral Valve Prolapse: Unravelling Sex-Based Differences.

间质纤维化和心律失常二尖瓣脱垂：揭示性别差异。

• DOI: 10.1101/2024.01.12.24301217
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Tastet,Lionel;Dixit,Shalini;Nguyen,Thuy;Lim,LisaJ;Al-Akchar,Mohammad;Bibby,Dwight;Arya,Farzin;Cristin,Luca;Anwar,Shafkat;Higuchi,Satoshi;Hsia,Henry;Lee,YooJin;Delling,FrancescaN
• 通讯作者: Delling,FrancescaN

Mechanical Dispersion Discriminates Between Arrhythmic and Nonarrhythmic Sudden Death: From the POST SCD Study.

机械弥散区分心律失常性和非心律失常性猝死：来自 POST SCD 研究。

• DOI: 10.1016/j.jacep.2024.01.002
• 发表时间: 2024
• 期刊: JACC. Clinical electrophysiology
• 作者: Tastet,Lionel;Ramakrishna,Satvik;Lim,LisaJ;Bibby,Dwight;Olgin,JeffreyE;Connolly,AndrewJ;Moffatt,Ellen;Tseng,ZianH;Delling,FrancescaN
• 通讯作者: Delling,FrancescaN

Sex Differences and Similarities in Valvular Heart Disease.

瓣膜心脏病的性别差异和相似之处。

• DOI: 10.1161/circresaha.121.319914
• 发表时间: 2022-02-18
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: DesJardin JT;Chikwe J;Hahn RT;Hung JW;Delling FN
• 通讯作者: Delling FN

Antemortem and Post-Mortem Characteristics of Lethal Mitral Valve Prolapse Among All Countywide Sudden Deaths.

• DOI: 10.1016/j.jacep.2021.01.007
• 发表时间: 2021-08
• 期刊: JACC. Clinical electrophysiology
• 作者: Delling FN;Aung S;Vittinghoff E;Dave S;Lim LJ;Olgin JE;Connolly A;Moffatt E;Tseng ZH
• 通讯作者: Tseng ZH