Kory Lavine, M.D. Ph.D.
Project Overview:
Pediatric dilated cardiomyopathy (DCM) is an important cause of mortality and is the most common indication for heart transplantation in children. Unfortunately, outcomes for patients with pediatric DCM remain poor and clinical trials have revealed that children with heart failure do not respond to medications used in adults. In fact, despite modern therapies, there has been no improvement in outcomes for children with heart failure since the implementation of medical regimens established in the 1970s. These observations support the concept that pediatric and adult heart failure represent distinct entities and highlight the clinically unmet need to identify underlying mechanisms that contribute to the progression of pediatric cardiomyopathy, strategies to predict outcomes, and new treatments.
Mechanistically, adult heart failure therapeutics target a process termed adverse remodeling, a common pathway by which the adult heart responds to injury. One potential explanation for why adult heart failure therapeutics do not improve outcomes in the pediatric population is that adverse remodeling does not govern disease progression in children. Intriguingly, no studies have rigorously determined whether or when adverse remodeling occurs in children and limited data is available comparing myocardial gene expression in pediatric and adult cardiomyopathy.
The primary goal of this proposal is to define disease mechanisms that contribute to the progression of pediatric cardiomyopathy and test the hypothesis that pediatric and adult heart failure represent distinct entities. Our research has three aims:
- Test the hypothesis that adverse remodeling does not drive disease progression in pediatric DCM.
- Define evolutionarily conserved pathways that distinguish pediatric from adult DCM using RNA sequencing.
- Define serum biomarkers predictive of outcomes for children with heart failure.
The proposed studies will provide novel insights into pediatric DCM pathogenesis and test whether adverse remodeling (the target of adult heart failure therapies) occurs in children. The RNA sequencing and biomarker discovery experiments will define gene expression signatures and serum biomarkers that distinguish pediatric from adult heart failure, predict outcomes, and identify putative disease mechanisms that contribute to the progression of pediatric DCM.
