Genomic Effects on Right Ventricular Function, Clinical Features and Outcomes in CHD

基因组对冠心病右心室功能、临床特征和结果的影响

• 批准号: 10471255
• 负责人: Jane W. Newburger
• 金额: $ 48.95万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471255
• 关键词: ATAC-seq; Accounting; Adult; Affect; Anatomy; Atrial Flutter; Atrial Tachycardia; Autopsy; Bioinformatics; Biological Assay; Biological Models; Biology; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cells; Child; Chromatin; Chronic; Clinical; Complement; Complex; Congenital atresia of pulmonary valve; Data; Development; Disease model; EFRAC; Electric Countershock; Event; Future; Gene Expression; Genes; Genetic; Genetic Databases; Genetic Transcription; Genomics; Genotype; Heart; Heart Abnormalities; Heart Atrium; Heart Transplantation; Heart failure; Human; Hypoplastic Left Heart Syndrome; Image; Individual; Intervention; Lead; Longevity; Measures; Metabolism; Molecular Analysis; Morbidity - disease rate; Myocardial; New York; Nuclear; Operative Surgical Procedures; Outcome; Parents; Participant; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Penetrance; Performance; Perioperative; Physiological; Play; Recurrence; Regulation; Relaxation; Research; Resources; Right Ventricular Dysfunction; Right Ventricular Function; Risk; Risk Factors; Role; Signal Transduction; Tachyarrhythmias; Testing; Tetralogy of Fallot; Tissues; Transplantation; Variant; Ventricular; Ventricular Ejection Fractions; Ventricular End-Systolic Volumes; Ventricular Function; Ventricular Remodeling; Ventricular Tachycardia; base; cardiac magnetic resonance imaging; clinical database; clinical risk; cohort; comorbidity; congenital heart disorder; de novo mutation; drug testing; functional outcomes; genetic information; genetic variant; heart function; hemodynamics; improved; in vivo; indexing; induced pluripotent stem cell; insight; malformation; mortality; mouse model; personalized medicine; primary outcome; proband; prospective; rare variant; repaired; respiratory; response; risk stratification; risk variant; secondary outcome; small molecule; stem cell differentiation; stem cells; study population; success; translational therapeutics

ABSTRACT Dramatic advances in surgical repair and cardiac intervention have improved survival in even the most complex forms of congenital heart disease (CHD). With this notable success, there has been a shift from perioperative to chronic cardiac morbidity and accelerated mortality. Right ventricular (RV) dysfunction is an important determinant of long-term outcomes in children and adults with many forms of CHD. Outcomes such as RV dysfunction and associated comorbidities are currently thought of primarily in terms of hemodynamic or physiological factors. However, routine clinical and imaging variables have explained only a small percentage of the variability in RV function and clinical outcomes in CHD patients, suggesting an important role for as-yet- unrecognized contributors. We hypothesize that multiple genetic factors contribute to the unexplained variation in RV performance and patient outcomes. To investigate the relationship of genomic factors and clinical outcomes, we will study two exemplars of CHD for which right ventricular (RV) dysfunction especially impacts outcomes: tetralogy of Fallot (TOF) and hypoplastic left heart syndrome (HLHS). Our proposed study population will leverage a unique clinical and genetic database developed by the PCGC, as well cohorts within individual PCGC centers and other consortia. In Aim 1, we will study the effects of rare damaging variants identified in patients with TOF and HLHS on RV function, clinical outcomes, and anatomical subtypes influencing outcomes. Our primary outcome will be RV ejection fraction by cardiac MRI (CMR). Secondary outcomes will include other CMR measures of systolic and diastolic function, as well as clinical outcomes such as transplant-free survival, sustained ventricular and atrial tachycardias, and heart failure defined as New York Heart Association Class III or IV. In Aim 2, we will study the effects of common variants identified in patients with TOF and HLHS on RV function, clinical outcomes, and anatomical subtypes influencing outcomes. Primary and secondary outcomes will be identical to those in Aim 1. Aim 3 will assess the effects of rare and common variants associated with outcomes on cardiomyocyte function, metabolism, gene expression, and chromatin accessibility in isogenic induced pluripotent stem cells differentiated into cardiomyocytes (iPSC-CMs) and CHD tissues. We will define outcome-associated common variants using bioinformatic and functional assays, and derive iPSC-CMs with CHD variants, alone or in addition to rare and common outcome-associated variants. We will assess contraction relaxation, energetic parameters, and transcriptional activities in iPSC-CMs. We will complement these studies with single cell nuclear sequencing (NucSeq) and ATACseq analyses of CHD tissues to explore how outcome-associated variants influence in vivo cardiomyocyte biology. By identifying genes affecting outcomes, our proposal will advance mechanistic insights, improve risk-stratification and provide resources for more precise personalized therapies for CHD patients across the lifespan.

抽象的 外科修复和心脏介入方面的巨大进步甚至提高了大多数患者的生存率 复杂形式的先天性心脏病 (CHD)。随着这一显着的成功，已经发生了转变 围手术期慢性心脏病发病率和加速死亡率。右心室（RV）功能障碍是 是患有多种形式先心病的儿童和成人长期结局的重要决定因素。结果如 因为目前认为右心室功能障碍和相关合并症主要是在血流动力学或 生理因素。然而，常规临床和影像学变量只能解释一小部分。 CHD 患者 RV 功能和临床结果的变异性，表明迄今为止的重要作用 未被认可的贡献者。我们假设多种遗传因素导致了无法解释的现象 RV 性能和患者结果的变化。研究基因组因素与 为了临床结果，我们将研究两个导致右心室 (RV) 功能障碍的 CHD 范例 尤其影响结果：法洛四联症 (TOF) 和左心发育不全综合征 (HLHS)。 我们提议的研究人群将利用 PCGC 开发的独特临床和遗传数据库， 以及各个 PCGC 中心和其他联盟内的群体。在目标 1 中，我们将研究以下因素的影响： 在 TOF 和 HLHS 患者中发现的对 RV 功能、临床结果、 和影响结果的解剖亚型。我们的主要结果是 RV 射血分数 心脏 MRI (CMR)。次要结果将包括收缩和舒张功能的其他 CMR 测量， 以及临床结果，例如无移植生存、持续性室性和房性心动过速，以及 心力衰竭定义为纽约心脏协会 III 级或 IV 级。在目标 2 中，我们将研究以下因素的影响： TOF 和 HLHS 患者中发现的 RV 功能、临床结果和症状的常见变异 影响结果的解剖亚型。主要和次要结果将与 目标 1。目标 3 将评估与结果相关的罕见和常见变异的影响 等基因心肌细胞功能、代谢、基因表达和染色质可及性 诱导多能干细胞分化为心肌细胞（iPSC-CM）和CHD组织。我们将 使用生物信息学和功能测定定义与结果相关的常见变异，并衍生 iPSC-CM 单独或与罕见和常见的结果相关变异一起使用 CHD 变异。我们将评估 iPSC-CM 中的收缩弛豫、能量参数和转录活性。我们将补充 这些研究通过单细胞核测序 (NucSeq) 和 ATACseq 分析 CHD 组织来探索 结果相关变异如何影响体内心肌细胞生物学。通过识别影响基因 结果，我们的建议将推进机制见解，改善风险分层并提供 为冠心病患者的整个生命周期提供更精确的个性化治疗资源。