This study provides the first prospective evidence linking dilated cardiomyopathy-associated variants to early-onset heart failure in hypoplastic left heart syndrome, with likely pathogenic/pathogenic variants associated with a 9-fold increased risk of severe heart failure.
Key Findings
Results
In the prospective cohort of HLHS neonates, 20% developed severe heart failure, 28.6% developed medically managed heart failure, and 51.4% remained heart failure free.
The prospective cohort consisted of 35 neonates with HLHS enrolled within the first 21 days of life at Duke University Health System.
Severe HF was defined as ventricular assist device implantation, heart transplantation, or death.
Medically managed HF was defined as reduced systemic ventricular ejection fraction and/or HF diagnosis requiring initiation or escalation of HF therapy.
7 of 35 neonates (20.0%) developed severe HF, 10 (28.6%) developed medically managed HF, and 18 (51.4%) remained HF free.
Results
The presence of a likely pathogenic/pathogenic variant in dilated cardiomyopathy-associated genes was associated with a 9-fold increased risk of severe heart failure in the prospective cohort.
Association was assessed using Cox regression.
The 9-fold increased risk of severe HF compared with genotype-negative individuals was statistically significant (P = 0.02).
Ultra-rare variants were defined as those with minor allele frequency ≤0.01%.
Variants evaluated were in dilated cardiomyopathy-associated genes identified through genome sequencing.
Results
The majority of severe heart failure events in HLHS neonates occurred within the first month of life.
67% of severe HF events occurred within the first month of life.
This finding was from the prospective cohort of 35 neonates enrolled within the first 21 days of life.
This temporal clustering underscores the vulnerability of HLHS patients in the earliest period of life.
Results
Similar associations between likely pathogenic/pathogenic variants and severe heart failure were observed in external validation cohorts at Nationwide Children's Hospital and Vanderbilt University Medical Center.
Nationwide Children's Hospital cohort showed an 11-fold increased risk of severe HF associated with likely pathogenic/pathogenic variants (P < 0.05).
Vanderbilt University Medical Center cohort showed a 3-fold increased risk of severe HF (P < 0.05).
Both external cohorts were evaluated to assess for reproducibility across institutions.
All associations in both external cohorts reached statistical significance (all P < 0.05).
Results
Associations between likely pathogenic/pathogenic variants and severe heart failure were attenuated in the ambispective cohort, which consisted of significantly older individuals.
The ambispective cohort enrolled children and adults with HLHS older than 21 days from Duke University Health System and the University of North Carolina.
All associations in the ambispective cohort were non-significant (all P > 0.05).
Individuals in the ambispective cohort were significantly older than those in the prospective cohort (P < 0.0001).
The attenuation of associations in the older cohort suggests the genetic effect may be most pronounced in early life.
Conclusions
This study is described as providing the first prospective evidence linking dilated cardiomyopathy-associated variants to early-onset heart failure in HLHS.
Prior to this study, reliable approaches to identify infants at highest risk for early HF were described as currently lacking.
The study used genome sequencing to evaluate ultra-rare variants (minor allele frequency ≤0.01%) in dilated cardiomyopathy-associated genes.
Neonates were prospectively enrolled within the first 21 days of life.
The findings highlight the potential for genetic screening to enable early risk stratification and guide precision medicine approaches.
What This Means
Hypoplastic left heart syndrome (HLHS) is the most severe form of congenital heart disease, in which the left side of the heart is severely underdeveloped. Babies born with HLHS face a high risk of heart failure, especially early in life, which is a major cause of death in this group. This research suggests that specific rare genetic variants — the kind associated with a condition called dilated cardiomyopathy — can dramatically increase the risk of severe heart failure in newborns with HLHS. In the main study group of 35 newborns, those who carried these genetic variants had about a 9-fold higher risk of developing severe heart failure compared to those without the variants, and two-thirds of severe heart failure events happened within the first month of life. These findings were confirmed in two separate groups of patients at other major children's hospitals, where the increased risks were 11-fold and 3-fold respectively.
Interestingly, when the researchers looked at older children and adults with HLHS (rather than just newborns), the link between these genetic variants and heart failure was much weaker. This suggests that the genetic contribution to heart failure risk may be especially important in the earliest and most vulnerable period of life, and that survivors who make it past infancy may be a selected group less affected by these variants.
This research suggests that genetic screening at birth could potentially help identify which HLHS babies are at the highest risk of early heart failure, allowing doctors to tailor monitoring and treatment more precisely. This represents an important step toward personalized medicine for one of the most complex and life-threatening forms of congenital heart disease.
Balint B, Sunthankar S, Monaco G, Bair C, Wolfe-Miller R, Gonzalez C, et al.. (2026). Genetic Determinants of Early Heart Failure in Hypoplastic Left Heart Syndrome: A Prospective NC-DEFINE Study.. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2026.06.031