Congenital heart defects (CHD) are among the most common of all birth defects, with an incidence of about one per 100 live births. Approximately 40,000 children in the United States are born with CHD annually, and 50 percent require medical and/or surgical therapy. Despite dramatic improvements in surgical, anesthetic and intensive care techniques, morbidity and mortality remain significant. Exposure to increased pulmonary blood flow (PBF) and pressure result in early and progressive abnormalities in pulmonary endothelial structure and function. These functional abnormalities, which include decreased bioavailable nitic oxide (NO) and increased oxidative stress, occur prior to the development of vascular remodeling, and result in impaired pulmonary vascular relaxation and increased constriction, particularly in the post-operative period. Our understanding of the molecular mechanisms that mediate this process is incomplete and we have an active National Institutes of Health-funded program that is unraveling the complex mechanisms that underlie the loss of endothelial function in these children. Our major focus at the moment is how the disruption of β-oxidation and mitochondrial bioenergetics impacts NO signaling in the lung endothelium. Our long-term goal is to utilize our increased mechanistic understanding that will lead to development of improved therapies for these children. Further, regardless of the underlying etiology of advanced pulmonary vascular disease (flow, hypoxia, hypoplasia, toxin, infection, vasculitis, thrombus, etc.), once vascular remodeling begins, abnormal flow patterns result in increased shear stress. Thus, the early initiating mechanisms we are investigating in the endothelium exposed to increased PBF, likely participate in the progression of more advanced forms of pulmonary hypertension.
Related lines of research include: