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

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.