This proposal describes a five-year training program for development of a career in clinical research focusing on outcomes in tetralogy of Fallot (TOF), the most common form of cyanotic congenital heart defect. The candidate is an under-represented minority with training in pediatric cardiology and epidemiology. The goals of this award are to rigorously conduct this research proposal, to use the training obtained to develop into a mentor to other under-represented minority and, ultimately, to use this award as a vehicle to become a federally funded independent investigator. To achieve these goals, the applicant has set up a training plan that will include mentoring, course work, hands-on conduct of research and didactic educational activities. This project will be carried out under the mentorship of Steven Kawut, MD, MSCE, a leader in pulmonary hypertension and in the study of the right ventricle. Dr. Kawut is a tenured Associate Professor of Medicine and Epidemiology. He has successfully mentored fellows and junior faculty and holds a K24 to support his mentoring endeavors. An advisory committee has been assembled to help guide the candidate's career development. This application focuses on two main questions related to TOF. First, surgical repair (mandatory in TOF) is electively performed in the first few months of life to avoid cardiac surgery in the neonatal period. However, the severely cyanotic patient that requires intervention in the neonatal period (first month of life) can undergo either a complete surgical repair or a staged repair. The staged repair consists of a neonatal palliative procedure followed by complete repair in subsequent months. Each approach has advantages and disadvantages, and the choice is center-dependent and highly debated. We propose to address this debate by conducting a retrospective cohort study using data from 42 children's hospitals to examine the outcome associated with the two approaches. This comparative effectiveness study will provide generalizable results in a real life population using a highly feasible design that will inform a future trial and will ultimately benefit patients. Second, the right ventricle (RV) in TOF remodel (changes in size, geometry and function) after surgery in response to surgery itself and from residual lesions resulting from the repair. The clinical response to the RV remodeling is quite variable and the determining mechanisms are poorly understood. We hypothesize that early perioperative RV remodeling represents a critical time period that has a significant impact on the phenotypical variability in TOF. We propose a prospective cohort study of TOF patients to detect adverse RV remodeling in the post-operative period with sensitive imaging markers and circulating biomarkers. We will establish the impact of surgical procedure and early pathophysiologic mechanisms of RV remodeling on clinical outcomes and set up future studies that will eventually lead to improved outcomes in children with TOF.
Tetralogy of Fallot is one of the most common forms of congenital heart defects and requires surgical repair. The early events associated with the surgical repair might determine short and long-term outcomes. The mechanisms underlying such evens have not been completely established and constitute the focus of this proposal.
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