Congenital heart disease (CHD) is the most common human congenital malformation, and represents a leading cause of infant mortality. Roughly half of children with CHD will require surgical repairs/palliations, and are at risk for postoperative complications. Arrhythmias are common after CHD surgery, contribute substantially to morbidity and mortality, and are important long-term concerns for the more than 1 million US adults living with CHD. An individual patient's risk for arrhythmias is variable and not predicted by clinical factors alone, thus we hypothesize that genetic variants predispose patients to these serious complications. Dexmedetomidine is a widely used sedative after CHD surgery but is associated with marked inter-patient variability in efficacy, and potential adverse effects including bradyarrhythmias. Previous studies in adults have demonstrated genetic variants that alter dexmedetomidine pharmacodynamics, but studies in children have not been performed. The long term goal of this research program is to identify genetic variants that affect adverse outcomes after CHD surgery, along with actionable pharmacogenetic (drug-gene) interactions, in order to perform pre-operative genotyping and incorporation of genetic and clinical risk factors into individualized treatment plans, ultimately improving the care and reducing mortality and morbidity for patients with CHD. In order to achieve these goals, we established an ongoing cohort of over 1,600 children undergoing more than 2,200 CHD surgical procedures with detailed phenotypic information, coupled with DNA samples. Further, we have developed methods using mass spectrometry to accurately determine drug concentrations using small sample volumes (100L plasma) enabling the use of leftover plasma from blood samples obtained for clinical purposes to probe disposition of drugs such as dexmedetomidine.
In Specific Aim 1, we will test the hypothesis that genetic variants are associated with atrial arrhythmias after CHD surgery in children under 1 year of age.
In Specific Aim 2 we will test the hypothesis that genetic variants alter pharmacokinetics and pharmacodynamics of dexmedetomidine after CHD surgery in children. Accomplishing these aims will ultimately lead to a personalized approach to care and improve clinical outcomes for patients with CHD.
Congenital heart disease, which often requires surgery in childhood, is a leading killer of children in the United States. The proposed research will study how genes affect heart surgery outcomes, and how genes and medicines interact. With this information, we can use a child's genes to decide the best way to treat them, ultimately improving public health by reducing deaths from congenital heart disease.
