Precision Medicine for Dilated Cardiomyopathy-Cardiac Magnetic Resonance to Identify Early Family Phenotypes

扩张型心肌病精准医疗——心脏磁共振识别早期家族表型

• 批准号: 10441299
• 负责人: RAY E. HERSHBERGER
• 金额: $ 77.91万
• 依托单位: OHIO STATE UNIVERSITY
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441299
• 关键词: Affect; African; Angiotensin-Converting Enzyme Inhibitors; Biological; Biology; Budgets; Cardiac; Characteristics; Classification; Clinical; Clinical Research; Data; Diffuse; Dilatation - action; Dilated Cardiomyopathy; Disease; Early identification; Echocardiography; Enrollment; European; Family; Family member; Fibrosis; First Degree Relative; Foundations; Functional disorder; Future; Gadolinium; Genes; Genetic; Genetic Risk; Genetic study; Guidelines; Heart failure; Individual; Infrastructure; Intervention; Knowledge; Left; Left Ventricular Dysfunction; Magnetic Resonance; Maps; Measures; Myocardial; Myocardial tissue; Myocardium; Pathogenicity; Pathway interactions; Patients; Persons; Phenotype; Practice Guidelines; Primary idiopathic dilated cardiomyopathy; Public Health; Race; Recommendation; Recording of previous events; Relative Risks; Risk; Risk Management; Scanning; Site; Specific qualifier value; Structure; Symptoms; Testing; Tissues; Uncertain Risk; Variant; Ventricular; Work; advanced disease; age group; cardiac magnetic resonance imaging; diagnostic value; exome sequencing; high risk; inhibitor therapy; innovation; interstitial; precision medicine; prevent; proband; prognostic value; rare variant; screening; serial imaging; sex; variant of unknown significance

Project Description Dilated cardiomyopathy of unknown cause (DCM) is a major public health problem affecting more than a million people in the U.S. Most DCM is now known to have an underlying genetic basis. First-degree relatives (FDRs) of an individual with DCM are considered to be genetically at risk, particularly if they carry variants classified as pathogenic (P), likely pathogenic (LP) or uncertain significance (VUS) in DCM genes. Practice guidelines recommend that these FDRs undergo serial imaging because prompt intervention may avert advanced disease. While tissue damage is already well underway when DCM is manifest, myocardial tissue changes, termed “pre- DCM” herein, are known to precede adverse changes in myocardial structure and function. Our central hypothesis states that cardiac magnetic resonance (CMR) imaging may detect pre-DCM in individuals with increased genetic risk by identifying myocardial tissue changes prior to myocardial structural and functional changes. CMR measures of myocardial tissue characteristics, including late gadolinium enhancement and myocardial T1 mapping, have been histopathologically validated and have established diagnostic and prognostic value in DCM. Thus, our specific hypotheses state that adverse CMR-based myocardial tissue characteristics will be associated with (1) A higher burden (number) of relevant variants (P, LP, VUS) in established DCM genes; and (2) Subsequent adverse changes in measures of cardiac structure and function. We propose to leverage the DCM Precision Medicine Study, a multisite DCM Consortium study now completing the enrollment of 1300 DCM patients (probands), balanced for race and sex, and their FDRs, most with no history of DCM. FDRs are cascade tested for relevant variants (P, LP, VUS) in DCM genes identified in probands. We aim to (1) Estimate the associations between CMR-based myocardial tissue characteristics and the number (burden) of the proband's variants in DCM genes in at-risk FDRs. In 650 FDRs of probands with LP/P variants and/or VUSs, CMR scans will be completed at 9 participating DCM Consortium sites. The association between CMR-based myocardial tissue characteristics and the number of the proband's variants of each class (LP/P, VUS) carried by an at-risk FDR in a particular age group will be evaluated, adjusting for biologically relevant covariates. We will also (2) Estimate the association between CMR-based myocardial tissue characteristics and subsequent changes in measures of cardiac structure and function in FDRs with normal baseline left-ventricular size and function. FDRs examined in Aim 1 with normal left ventricular size and systolic function will receive a second CMR exam 2.5 years after their baseline exam. We will estimate the covariate-adjusted associations between baseline myocardial tissue characteristics and subsequent changes in CMR-derived measures of cardiac structure and function in groups defined by the most deleterious of the proband's variants carried (none, VUS, or LP/P). This study will validate a CMR-derived “pre-DCM” phenotype for FDRs who carry P or LP variants (established risk), and also provide preliminary evidence that some VUSs are biologically relevant.

项目描述 未知原因（DCM）扩张的心肌病是影响超过一百万的主要公共卫生问题 现在，美国大多数DCM的人都具有基本的遗传基础。一级亲戚（FDR） DCM的个人的普遍危险，尤其是当他们携带被归类为 DCM基因中的致病性（P），可能的致病性（LP）或不确定的显着性（VU）。练习指南 建议这些FDR进行串行成像，因为迅速干预可能避免晚期疾病。 尽管DCM体现出来，但组织损伤已经很好 DCM”此处已知在心肌结构和功能的不利变化之前。我们的中央 假设指出，心脏磁共振（CMR）成像可能检测 通过在心肌结构和功能之前鉴定心肌组织变化来增加遗传风险 更改。心肌组织特征的CMR测量，包括晚期增强和 心肌T1映射，已在组织病理学上得到验证，并建立了诊断和预后 DCM中的价值。这是我们的特定假设表明，不良CMR基于CMR的心肌组织特征 将与已建立的DCM基因中相关变体（P，LP，VU）的（1）相关变体（数量）相关； （2）随后的心脏结构和功能测量结果的不利变化。我们建议利用 DCM Precision Medicine研究，一项多站点DCM联盟研究，目前完成1300 DCM患者（Probands），用于种族和性别及其FDR，大多数没有DCM史。 FDR是 在探针中鉴定的DCM基因中测试了相关变体（P，LP，VUS）的级联反应。我们的目标是（1）估计 基于CMR的心肌组织特征与数量（负担）之间的关联 Proband在高危FDR中的DCM基因中的变体。在具有LP/P变体和/或vuss的650个FDR中， CMR扫描将在9个参与的DCM财团站点完成。基于CMR的关联 心肌组织特征和每个类别的概率变体的数量（LP/P，VUS）由 将评估特定年龄段的高危FDR，以调整与生物学相关的协变量。我们将 （2）估计基于CMR的心肌组织特征与随后的关联 基线正常左心室大小的FDR中心脏结构和功能的测量变化 功能。在AIM 1中检查的FDR具有正常的左心室大小和收缩功能 CMR考试距离基线考试2。5年。我们将估算协变量调整的关联 基线心肌组织特征和随后的CMR衍生措施的变化 结构和函数的组中由携带的概率变体中最多删除的组定义（无，vus，，vus， 或LP/P）。这项研究将验证携带P或LP变体的FDR的CMR衍生的“二级联”表型 （已建立的风险），还提供了一些范围在生物学上相关的初步证据。

项目成果

T2 mapping in myocardial disease: a comprehensive review.

• DOI: 10.1186/s12968-022-00866-0
• 发表时间: 2022-06-06
• 期刊: JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE
• 影响因子: 6.4
• 作者: O'Brien, Aaron T.;Gil, Katarzyna E.;Varghese, Juliet;Simonetti, Orlando P.;Zareba, Karolina M.
• 通讯作者: Zareba, Karolina M.

The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy.

• DOI: 10.1161/circresaha.121.318157
• 发表时间: 2021-05-14
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Hershberger RE;Cowan J;Jordan E;Kinnamon DD
• 通讯作者: Kinnamon DD

The Evolving Science of Dilated Cardiomyopathy.

扩张型心肌病的不断发展的科学。

• DOI: 10.1016/j.jacc.2021.08.038
• 发表时间: 2021
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Hershberger,RayE

Validating an Idiopathic Dilated Cardiomyopathy Diagnosis Using Cardiovascular Magnetic Resonance: The Dilated Cardiomyopathy Precision Medicine Study.

• DOI: 10.1161/circheartfailure.121.008877
• 发表时间: 2022-05
• 期刊: CIRCULATION-HEART FAILURE
• 影响因子: 9.7
• 作者: Haas, Garrie J.;Zareba, Karolina M.;Ni, Hanyu;Bello-Pardo, Erika;Huggins, Gordon S.;Hershberger, Ray E.
• 通讯作者: Hershberger, Ray E.