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

摘要 外科修复和心脏干预方面的巨大进步甚至提高了大多数患者的存活率 复杂形式的先天性心脏病(CHD)。随着这一显著的成功，出现了从 围术期到慢性心脏病发病率和加速死亡率。右室(RV)功能障碍是一种 多种形式的CHD儿童和成人的长期预后的重要决定因素。结果如下 由于RV功能障碍和相关的合并症目前主要从血流动力学或 生理因素。然而，常规的临床和影像变量只能解释一小部分。 冠心病患者右室功能和临床结局的变异性，提示迄今- 未被认可的贡献者。我们假设有多种遗传因素导致了无法解释的 房车性能和患者预后的差异。探讨基因组因素与遗传易感性的关系 临床结果：我们将研究两个右室(RV)功能不全的CHD样本 尤其影响预后：法洛四联症(TOF)和左心发育不全综合征(HLHS)。 我们建议的研究群体将利用PCGC开发的独特的临床和基因数据库， 以及各个PCGC中心和其他财团内的队列。在目标1中，我们将研究 在TOF和HLHS患者中发现的罕见破坏性变异对RV功能、临床结果、 以及影响预后的解剖亚型。我们的主要结果将是RV射血分数 心脏MRI(CMR)。次要结果将包括收缩和舒张期功能的其他CMR测量， 以及临床结果，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 TOF和HLHS患者中发现的常见变异对RV功能、临床结果和 影响预后的解剖亚型。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对 心肌细胞功能、代谢、基因表达和染色质可及性 诱导多能干细胞向心肌细胞和CHD组织分化。我们会 使用生物信息学和功能分析定义与结果相关的常见变量，并推导出IPSC-CMS 对于CHD变异，单独或除了罕见和常见的结果相关变异。我们将评估 IPSC-CMS的收缩松弛、能量参数和转录活性。我们将互为补充 这些研究用单核细胞测序(NucSeq)和ATACseq分析CHD组织来探索 结果相关变异如何影响活体心肌细胞生物学。通过识别影响基因 结果，我们的提案将推进机械性见解，改进风险分层，并提供 为整个生命周期的冠心病患者提供更精确的个性化治疗的资源。

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.