Determining the genetic and social determinants of heart failure and mortality in patients with congenital heart disease

项目摘要/摘要 在美国，先天性心脏病(CHDS)影响了近1%的活产婴儿。CHDS与高血压症有关 发病率高，是与出生缺陷有关的最常见的死亡原因。在早期诊断、医学方面的快速发展 CHD的管理和治疗极大地提高了存活率；然而，心力衰竭(HF)是主要的 成人冠心病死亡原因分析。这使得确定整个生命周期内心力衰竭的风险因素至关重要 处于最高风险的个人可以被识别和管理。我们已经组建了一支多学科团队， 在基于人群的冠心病结局、健康的社会决定因素和心血管遗传学方面的重要经验需要填补 这些关键的知识差距。自2008年以来，我们的团队一直领导着北卡罗来纳州的先天性心脏病监测 网络(NC-CHD)，它将北卡罗来纳州的5个主要学术中心连接起来，形成一个监控网络， 大多数冠心病患者在该州。NC-CHD将临床记录链接到各种可靠的、州和国家的数据库 对冠心病幸存者进行以结果为基础的终生研究。这使我们的团队处于一个独特的位置 建立一个具有丰富临床表型的冠心病幸存者前瞻性队列，以进行全面的基因和 以结果为基础的研究，以确定该人群中发生心力衰竭的原因。我们研究的目标是开发一种大型的，良好的- 北卡罗来纳州(NC-DEFINE)有计划的、基于人群的冠心病患者队列，以识别社会 影响CHD结局的健康决定因素和遗传因素，特别是心力衰竭。我们假设社会 健康的决定因素和定位于肉瘤基因的罕见遗传变异与以下人群的心力衰竭发生有关 先心病的幸存者。为了验证这一假设，我们提出了三个具体目标：1)确定健康的社会决定因素 与600例CHD患者队列中心力衰竭的发展相关，这将包括NC-DEFINE。2)至 在NC-DEFINE中确定与CHD患者心力衰竭发生相关的编码基因变异。 3)使用患者来源的心脏来确定CHD中心衰相关的候选变异对功能的影响 肌细胞。如果我们成功，这个项目将允许识别出心力衰竭风险较高的冠心病患者 社会或遗传风险，允许在手术修复时进行知情咨询和早期干预以控制 与心衰相关的可逆危险因素。进一步，NC-DEFINE将为以基因组医学为基础的 预测冠心病预后和结局的方法。

PROJECT SUMMARY/ABSTRACT Congenital heart defects (CHDs) affect nearly 1% of live births in the United States. CHDs are associated with high morbidity and are the most common birth defect-related cause of death. Rapid advancement in the early diagnosis, medical management, and treatment of CHD have led to tremendous gains in survival; however, heart failure (HF) is the leading cause of death in adults with CHD. This makes identifying the risk factors of HF across the lifespan critical so that individuals at the highest risk can be identified and managed. We have brought together a multi-disciplinary team with significant experience in population-based CHD outcomes, social determinants of health, and cardiovascular genetics to fill these critical knowledge gaps. Since 2008, our team has led the North Carolina Congenital Heart Disease Surveillance Network (NC-CHD) which links the 5 major academic centers in North Carolina in a surveillance network for the vast majority of patients with CHD in the state. NC-CHD links clinical records to a variety of robust, state, and national databases to conduct outcomes-based research on survivors of CHD across the lifespan. This puts our team in a unique position to establish a prospectively enrolled cohort of CHD survivors with rich clinical phenotyping for comprehensive genetic and outcomes-based research to determine the causes of HF in this population. The goal of our study is to develop a large, well- curated, population-based cohort of individuals with CHD in the state of North Carolina (NC-DEFINE) to identify social determinants of health and genetic factors which influence CHD outcomes, specifically HF. We hypothesize that social determinants of health and rare genetic variants localizing to sarcomeric genes are associated with HF development among survivors of CHD. To test this hypothesis, we propose 3 specific aims: 1) To identify the social determinants of health associated with the development of HF in cohort of 600 patients with CHD which will comprise NC-DEFINE. 2) To determine the coding genetic variants associated with the development of HF among patients with CHD in NC-DEFINE. 3) To determine the functional impact of candidate variants associated with HF in CHD using patient-derived cardiac myocytes. If we are successful, this project will allow for identification of CHD patients at heightened risk of HF based on either social or genetic risk, allowing for informed counseling at the time of surgical repair and early intervention to control reversible risk factors associated with HF. Further, NC-DEFINE will lay the foundation for a genomic medicine-based approach to predicting CHD prognosis and outcomes.