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

项目说明 原因不明的扩张型心肌病(DCM)是影响100多万人的重大公共卫生问题 美国人。现在已知大多数DCM都有潜在的遗传基础。一级亲属(FDR) DCM患者的遗传风险被认为是有遗传风险的，特别是如果他们携带被归类为 DCM基因的致病(P)、可能致病(LP)或意义不明(VUS)。实践指南 建议这些FDR接受序列成像，因为及时干预可能会避免晚期疾病。 当DCM明显时，组织损伤已经很好地进行了，而心肌组织发生了变化，被称为“预激综合征” 在此，DCM是已知的先于心肌结构和功能的不利变化。我们的中央 假说认为，心脏磁共振(CMR)成像可以在患有 在心肌结构和功能发生变化之前确定心肌组织变化会增加遗传风险 改变。心肌组织特征的CMR测量，包括晚期Gd增强和 心肌T1图已被组织病理学证实，并已建立诊断和预后 以DCM表示的价值。因此，我们的特定假设表明，基于CMR的不利心肌组织特征 将与(1)在已建立的DCM基因中相关变异(P、LP、VUS)的更高负担(数量)相关； 以及(2)随后心脏结构和功能指标的不良变化。我们建议利用 DCM精密医学研究，一项多站点DCM联盟研究，现已完成1300人的登记 DCM患者(先证者)，种族和性别平衡，以及他们的FDR，大多数没有DCM病史。FDR是 对先证者中发现的DCM基因的相关变异(P、LP、VUS)进行CASCADE测试。我们的目标是(1)估计 基于CMR的心肌组织特征与心肌梗死数量(负荷)的关系 高危FDR中DCM基因的先证者变异。在具有LP/P变体和/或VUS的先证者的650个FDR中， CMR扫描将在9个参与DCM联盟的地点完成。基于CMR的关联 心肌组织特征和先证者各类型(Lp/P，VUS)变异的数量 将对特定年龄段的高危FDR进行评估，调整与生物学相关的协变量。我们会 另外(2)估计基于CMR的心肌组织特征与随后的 基线左心室大小和心功能正常的FDR患者心脏结构和功能的变化 功能。在AIM 1中检查的左心室大小和收缩功能正常的FDR将获得第二次 CMR考试是在基线考试后2.5年进行的。我们将估计协变量调整后的相关性 心脏CMR测量的基础心肌组织特征和随后的变化 结构和功能由携带的最有害的先证者变体(NONE，VUS， 或LP/P)。这项研究将验证携带P或LP变异体的FDR的CMR衍生的DCM前表型 (已确定的风险)，还提供了一些VUS具有生物学相关性的初步证据。

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.