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.

项目摘要 二尖瓣脱垂（MVP）是一种常见的瓣膜病，具有强大的遗传成分影响7 美国百万个人。每年，多达1.8％的MVP将出现突然心脏骤停 （SCA）或心脏猝死（SCD）。在先前的研究中，MVP中的SCD/SCA要么与严重有关 二尖瓣反流（MR）或具有轻度MR，二尖瓣环形分离（MAD）的恶性双性表型 和异常的瓣膜心肌力学，导致复杂的心室异位（Comve）和/或左 心室替代纤维化[晚期增强或通过心脏磁共振（CMR）LGE（CMR） 成像]。我们已经表明，在正在进行的R01的支持下，CMR/T1映射的分散纤维化与 心律不齐的风险增加，无论双叶表型，严重的MR或LGE的存在如何。因此， 心律不齐的MVP可能不是“纯”瓣膜病，而是主要亚临床肌病的组成部分。 除了纤毛相关基因的突变（DCHS1，TNS1，LMCD1，DZIP1）外 最近已经是“通用” MVP，心肌病或通道病基因（FLNC，LMNA，ALPK3，SCN5A） 在心律不齐的MVP中提出，尽管在情况报告中或具有异质性演示的GWAS研究。 通过正在进行的R01和我们机构不断扩大的MVP注册表，我们总共确定了14个 心律不齐的MVP问题和血统，以及50个零星心律失常的MVP病例。在此管理中 补充应用，我们试图完成整个外显子组测序，心律不齐和CMR 在少数尚未接受这些调查的家庭成员中。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起作或与纤毛结合起作用 相关变体以增加MVP中SCD/SCA的风险。检验我们的中心假设并完成我们的 总体目标，我们提出以下特定目的：目标1：确定临床特征和遗传 MVP SCD/SCA谱系中心律失常风险的决定因素，目标2：测试通用性的致病性 使用蛋白质表达数据和细胞模型测定法，变体和理解心律失常MVP的机制。 通过此行政补充获得的数据对于更好的MVP SCD/SCA风险分层至关重要 因此，在适当选择的MVP患者中，通过ICD放置可以预防SCD。使用细胞 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。 我们的建议是由NHLBI最近的MVP研究机会和《 Carol Act》的研究机会的动机 为了纪念一个美国国会议员的妻子，他突然死于MVP。

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

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

Left ventricular fibrosis in arrhythmic mitral valve prolapse: quantification and comparison of semi-automated techniques assessed by cardiac magnetic resonance.

心律失常二尖瓣脱垂中的左心室纤维化：通过心脏磁共振评估的半自动技术的量化和比较。

• DOI: 10.1007/s10554-023-03006-6
• 发表时间: 2024
• 期刊: The international journal of cardiovascular imaging
• 作者: Cecere,Annagrazia;Cipriani,Alberto;DeLazzari,Manuel;Graziano,Francesca;Brunetti,Giulia;DeConti,Giorgio;Motta,Raffaella;Ravagnin,Alberto;Lorenzoni,Giulia;Gregori,Dario;Basso,Cristina;Tona,Francesco;Lee,YooJin;Delling,Francesca
• 通讯作者: Delling,Francesca