Early Protein Signals May Help Predict Language Delays in Children with Single Ventricle Heart Disease

Research study background

In single ventricle heart disease (SVHD), neurodevelopmental (ND) impairment is the most common long-term complication, with more than 75% of children showing delays early in life. The drivers of ND challenges in SVHD remain largely unknown. Acute brain injury biomarkers guide risk assessment in premature neonates, but in SVHD these injuries occur within the broader context of abnormal neural development beginning in the fetal period.

Experts in the Cardiac Neurodevelopmental Program at Children’s Hospital Colorado sought to determine if combining biomarkers of abnormal neural development and neural injury with other risk factors could help predict the risk of ND challenges in SVHD. In earlier work, the team examined biomarkers of pulmonary vascular development in infants with SVHD and found widespread proteomic abnormalities, including 62 proteins enriched for neural development including neuron growth, maintenance, and repair. In this JAMA Pediatrics report, researchers evaluated these proteins for associations with ND challenges in a cohort of 44 children between their first and second corrective SVHD surgeries.

When researchers reviewed how participants performed on standardized assessments of early childhood development delay, language scores were a standard deviation below population norms. An analysis of participant blood samples revealed that 27 of the 62 proteins were linked to language scores.

“Our findings suggest a potential shift in how we understand neurodevelopment in SVHD,” says Kelly Wolfe, PhD, a neuropsychologist in the Neuroscience Institute at Children’s Colorado and primary study author. “These children may experience persistent dysregulation of proteins vital for neuronal development and repair — proteins linked to language outcomes and detectable through routine blood testing.”

“The results of this study are exciting on several levels,” says Dr. Wolfe. “From a research perspective, these findings informed the development of the CAN-DO study, which is a prospective observational study including biomarkers of neural development and neural injury before and after neonatal catheterization versus surgery for children born with certain types of critical CHD, including some with SVHD. From an advocacy perspective, SVHD is currently NOT an automatic qualifying condition to receive early intervention services in the state of Colorado.”

Clinical implications

While previous research has uncovered biomarker evidence of neural injury after cardiac surgery in SVHD, this study is the first to examine biomarkers of neural development and demonstrate protein abnormalities present before stage II repair. Future research should assess whether these abnormalities appear at birth, stem from genetic or epigenetic changes, and are influenced by postnatal factors such as medications, duration of hospitalization or social determinants of health.