Precision Medicine for Dilated Cardiomyopathy—Novel Assessment of Cardiac Mechanics via Speckle Tracking Echocardiography to Identify Early Phenotypes

项目总结 原因不明的扩张型心肌病(DCM)，这是一个影响100多万人的重大公共卫生问题 在美国，患者通常在病程晚期被诊断为明显的心力衰竭或猝死。近期 初步证据表明，大多数DCM都有潜在的遗传基础；这一假设正在接受检验 在DCM精密医学研究中，家长研究这一辅助应用，这是进行家庭 基于26个中心的1300名DCM患者(先证者)及其2600名亲属的登记。在家长研究中， 目前在病例报告表上收集的超声心动图(ECHO)数据仅用于确认 或检测到左心室增大或收缩功能障碍。遗传分析也在先证者中进行，以 确定DCM相关基因中的相关变异(致病的、可能的致病的或不确定的意义)，但是 亲属中的级联检测仅限于可能改变临床的致病和可能致病的变异 管理层。虽然这些超声心动图和遗传数据足以实现父母的目标 研究，收集超出母研究范围的额外数据对于测试中央 这项辅助研究的假设：心脏力学中与DCM相关的异常(1)存在于 在发生左心室收缩功能障碍和扩张之前存在扩张性心肌梗死的遗传风险的个体 以及(2)反映遗传风险水平。特别是，我们建议目前集中收集数字回波数据 存储在现场并在回声核心实验室使用斑点跟踪超声心动图(STE)分析这些数据， 它能够检测心脏力学中的细微异常。我们还提出了额外的级联 在一级亲属(FDR)中检测不确定意义的变异(VUs)；VUs已在 到目前为止，46%的先证者已经完成了判决，但他们对FDR遗传风险的影响是 目前还不确定。使用这些数据，我们将(1)检查STE导出的应变测量如何随 使用两种方法来评估遗传风险水平。首先，我们将(A)将这些测量结果与 具有不同水平测量的遗传风险的遗传风险FDR(即 通过检测确定的DCM相关基因)和正常人群对照。第二，我们将(B)建立一个家庭-- 基于分析，以确定这些已测量和其他未测量的遗传因素的相对贡献 对这些测量结果的变化。我们还将(2)确定生理压力(锻炼)对 200名具有不确定遗传风险的未受影响的FDR(家族性VUS或FDR携带者)的心脏力学 基因测试阴性的先证者)与匹配的对照组进行比较。这项研究如果成功，将导致 对不同水平的遗传风险，特别是VUS如何与 心脏力学，从而提高了我们对扩张型心肌病遗传结构和生理学的理解。通过 收集和汇总所有ECHO数据，这项辅助研究也将极大地增加 在预期的后续父母研究中重复基于回声的分析。

PROJECT SUMMARY Dilated cardiomyopathy of unknown cause (DCM), a major public health problem affecting more than a million people in the U.S., is usually diagnosed late in its course with overt heart failure or sudden death. Recent preliminary evidence indicates that most DCM has an underlying genetic basis; this hypothesis is being tested in the DCM Precision Medicine Study, the parent study of this ancillary application, which is conducting family based enrollment of 1300 DCM patients (probands) and 2600 of their relatives at 26 centers. In the parent study, the echocardiographic (echo) data currently collected on case report forms are only those necessary to confirm or detect left ventricular enlargement or systolic dysfunction. Genetic analysis is also conducted in probands to identify relevant variants (pathogenic, likely pathogenic, or uncertain significance) in DCM-related genes, but cascade testing in relatives is limited to pathogenic and likely pathogenic variants that would change clinical management. While these echocardiographic and genetic data are sufficient to achieve the aims of the parent study, collection of additional data exceeding the scope of the parent study is essential to test the central hypothesis of this ancillary study: that DCM-related abnormalities in cardiac mechanics are (1) present in individuals genetically at risk for DCM prior to development of left ventricular systolic dysfunction and dilation and (2) reflect the level of genetic risk. In particular, we propose centrally collecting digital echo data currently stored at sites and analyzing these data at an echo core lab using speckle-tracking echocardiography (STE), which is capable of detecting subtle abnormalities in cardiac mechanics. We also propose additional cascade testing for variants of uncertain significance (VUSs) in first-degree relatives (FDRs); VUSs have been found in 46% of probands with completed adjudications thus far, but their implications for genetic risk in FDRs are currently uncertain. Using these data, we will (1) examine how STE-derived strain measurements vary with the level of genetic risk using a two-fold approach. First, we will (a) compare these measurements between genetically at-risk FDRs with varying levels of measured genetic risk (i.e., severity and number of mutations in DCM-related genes identified via testing) and normal population controls. Second, we will (b) conduct a family- based analysis to determine the relative contributions of these measured and other unmeasured genetic factors to variation in these measurements. We will also (2) determine the effect of physiologic stress (exercise) on cardiac mechanics in 200 unaffected FDRs who have uncertain genetic risk (carriers of familial VUSs or FDRs of probands with negative genetic testing) compared to matched controls. This study, if successful, will lead to novel understanding of how varying levels of genetic risk, and especially VUSs, associate with abnormalities of cardiac mechanics, thereby improving our understanding of the genetic architecture and physiology of DCM. By gathering and aggregating all echo data, this ancillary study would also greatly enhance the opportunities for repeated echo-based analysis in the anticipated follow on parent study.