Genetic Determinants of Early Heart Failure in Hypoplastic Left Heart Syndrome

BACKGROUND Survivors of hypoplastic left heart syndrome (HLHS), the most severe form of congenital heart disease, are at high risk for heart failure (HF). HF in early life is a major contributor to mortality in this vulnerable population. However, reliable approaches to identify infants at highest risk for early HF are currently lacking. OBJECTIVES The purpose of this study was to evaluate whether ultra-rare variants in cardiomyopathy-associated genes are associated with HF risk in HLHS. METHODS Neonates with HLHS were prospectively enrolled within the first 21 days of life at Duke University Health System. Children and adults with HLHS who were older than 21 days were enrolled from Duke University Health System and the University of North Carolina into an ambispective cohort. External HLHS cohorts from Nationwide Children's Hospital and Vanderbilt University Medical Center were evaluated to assess for reproducibility across institutions. Participants underwent genome sequencing, and ultra-rare variants in dilated cardiomyopathy-associated genes (minor allele frequency ≤0.01%) were evaluated. The primary outcome was HF, categorized as severe (ventricular assist device implantation, heart transplantation, or death) or medically managed (reduced systemic ventricular ejection fraction and/or HF diagnosis requiring initiation or escalation of HF therapy). Associations between variant status and HF risk were assessed using Cox regression. RESULTS Among 35 neonates in the prospective cohort, 7 (20.0%) developed severe HF, 10 (28.6%) developed medically managed HF, and 18 (51.4%) remained HF free. The presence of a likely pathogenic/pathogenic variant was associated with a marked 9-fold increased risk of severe HF compared with genotype-negative individuals (P = 0.02). Most severe HF events occurred within the first month of life (67%). Similar associations between likely pathogenic/pathogenic variants and severe HF were observed in the Nationwide Children's Hospital and Vanderbilt University Medical Center cohorts (11- and 3-fold increased risk, respectively; all P < 0.05). Associations were attenuated in the ambispective cohort (all P > 0.05), which consisted of individuals significantly older than the prospective cohort (P < 0.0001). CONCLUSIONS This study provides the first prospective evidence linking dilated cardiomyopathy-associated variants to early-onset HF in HLHS. These findings suggest that genetic variation may contribute to myocardial vulnerability in HLHS, highlighting the potential for genetic screening to enable early risk stratification and guide precision medicine approaches in this high-risk population.