Does Endothelin-1 Impact Single Ventricle Heart Disease Surgical Outcomes?

Research study background

Children with single ventricle heart disease (SVHD), a rare and serious congenital defect, typically require three surgeries early in life: the Norwood procedure within the first week after birth, the Glenn procedure at 4 to 6 months old, and the Fontan procedure between ages 2 and 4. Despite thorough presurgical evaluations of a patient’s tolerance and readiness for each stage of treatment, these tests are limited in predicting post-surgical recovery and long-term health outcomes.

Researchers at the Children’s Hospital Colorado Heart Institute have spent several years building a robust longitudinal dataset to help understand the molecular-level changes that occur in these patients with SVHD throughout childhood and multiple surgeries. Several published studies report their initial research findings on metabolomic fingerprinting and detail ongoing work using big data and multi-omics to better understand poor outcomes often seen in children with congenital heart disease.

The team’s recent work exploring endothelin-1 (ET1) as a potential biomarker fingerprint for SVHD outcomes uncovered that infants with elevated perioperative circulating ET1 levels experienced worse outcomes after the Glenn procedure (or stage 2 palliation). In this study, investigators examined the impact of elevated ET1 in the context of the Fontan procedure (or stage 3 palliation). The primary objective was to determine whether failure to suppress ET1 levels in infants at stage 3 would predict worse postoperative outcomes. Researchers also evaluated whether earlier exposure to elevated ET1 around stage 2 was associated with persistently high ET1 at stage 3.

This study’s preoperative cohort included 84 participants aged 31 days to 2 years with SVHD undergoing evaluation for stage 3 palliation between 2018 and 2021, 52 of whom participated in the stage 2 cohort. The team’s stage 3 postoperative outcome analysis included 72 patients. Researchers evaluated participants for specific variables and compared them with clinical predictors of stage 3 readiness, stage 3 perioperative ET1 levels and clinical outcomes.

They found that children with SVHD at stage 2 being evaluated for stage 3 palliation had overall lower ET1 levels than controls. Additionally, in the early period after stage 3 palliation, ET1 levels spiked and quickly dropped, but remained above baseline for at least 48 hours. After adjusting for demographic and other clinical variables, children who had higher ET1 concentrations leading up to and after stage 3 palliation experienced worse outcomes after the Fontan procedure.

Clinical implications

These results confirm earlier findings that support ET1 as a potential clinically relevant biomarker of pulmonary vascular risk in staged SVHD palliation and raises the possibility that endothelin receptor antagonists could improve vascular tolerance as patients progress through SVHD surgical stages.

While the team anticipates they can soon begin exploring how ET1 can be used in targeted therapeutic interventions, they must first conduct additional research to better understand the impact of fluctuating ET1 levels on short- and long-term pulmonary vascular outcomes at each stage.