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

扩张型心肌病的精准医学——通过斑点追踪超声心动图对心脏力学进行新的评估以识别早期表型

• 批准号: 10436899
• 负责人: RAY E. HERSHBERGER
• 金额: $ 39.3万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436899
• 关键词: Affect; Ancillary Study; Blinded; Cardiac; Case Report Form; Clinical; Clinical Management; Clinical Research; Collection; Data; Data Analyses; Development; Diagnosis; Dilated Cardiomyopathy; Disease; Echocardiography; Enrollment; Exercise; Family; Family member; Fibrinogen; First Degree Relative; Functional disorder; Future; Genes; Genetic; Genetic Risk; Genetic study; Heart Abnormalities; Heart failure; Image; Impairment; Individual; Knowledge; Left; Masks; Measurement; Measures; Mechanics; Mediating; Methods; Mutation; Myocardial dysfunction; National Heart, Lung, and Blood Institute; Parents; Participant; Pathogenicity; Pathway interactions; Patients; Persons; Phenotype; Physiological; Physiology; Population Control; Primary idiopathic dilated cardiomyopathy; Public Health; Race; Reporting; Research; Resources; Rest; Risk; Sarcomeres; Severities; Site; Stress; Sudden Death; Techniques; Test Result; Testing; Variant; Ventricular; Work; adjudication; advanced disease; base; cost effective; digital; disorder risk; genetic analysis; genetic architecture; genetic information; genetic risk assessment; genetic testing; heart function; improved; mutation carrier; novel; physiologic stressor; population based; precision medicine; prevent; proband; recruit; screening; sex; variant of unknown significance

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.

项目摘要 未知原因（DCM）的扩张心肌病，这是一个主要的公共卫生问题，影响了超过一百万 在美国的人们通常会因明显的心力衰竭或猝死而被诊断出来。最近的 初步证据表明，大多数DCM具有基本的遗传基础。该假设正在检验 在DCM Precision Medicine研究中，该辅助应用的父母研究正在指导家庭 在26个中心的1300名DCM患者及其2600名亲戚的招生。在父母研究中， 当前在病例报告表上收集的超声心动图（ECHO）数据只是确认的必要条件 或检测左心室肿大或收缩功能障碍。遗传分析也在概率中进行 在与DCM相关的基因中确定相关变体（致病性，可能的致病性或不确定意义），但 亲戚的级联测试仅限于致病性和可能改变临床的致病变异 管理。尽管这些超声心动图和遗传数据足以达到父母的目标 研究，收集超出父母研究范围的其他数据对于测试中心是必不可少的 这项辅助研究的假设：心脏力学中与DCM相关的异常存在（1） 在发展左心室收缩功能障碍和扩张之前，遗传上有DCM的风险 （2）反映遗传风险的水平。特别是，我们建议目前集中收集数字回声数据 存储在站点上并使用Speckle Tracking超声心动图（Ste），在Echo Core Lab上分析这些数据， 能够检测心脏力学的微妙异常。我们还建议其他级联 测试一级亲戚（FDR）中具有不确定意义（vus）的变体；在 到目前为止，有46％的检验有完成的裁决，但它们对FDR的遗传风险的影响是 目前不确定。使用这些数据，我们将（1）检查SteDer的应变测量如何随着 使用两倍方法的遗传风险水平。首先，我们将（a）比较这些测量 具有不同水平的遗传风险水平的遗传风险FDR（即严重程度和突变数量 通过测试和正常种群对照鉴定的DCM相关基因。其次，我们将（b）举办一个家庭 - 基于分析以确定这些测得的和其他未衡量的遗传因素的相对贡献 这些测量值的变化。我们还将（2）确定生理压力（运动）对 有200名不确定遗传风险的未受影响的FDR中的心脏力学 与匹配对照相比，具有负基因检测的概率。如果成功的话，这项研究将导致 对遗传风险的不同程度，尤其是范围的新颖理解与异常相关 心脏力学，从而提高了我们对DCM遗传结构和生理学的理解。经过 收集和汇总了所有回声数据，这项辅助研究也将大大增加机会 在父母研究的预期之后，重复基于回声的分析。