Background: Early survival for children with single-ventricle congenital heart disease has improved, but late attrition remains a serious problem. The endothelin-1 G5665T single nucleotide polymorphism has been linked to increased vascular reactivity and hypertension. The goal of this study was to determine whether this single nucleotide polymorphism alters transplant-free survival for children with single-ventricle congenital heart disease.
Methods: DNA was isolated from 165 children with single-ventricle congenital heart disease born between January 1980 and December 2006. The endothelin-1 G5665T single nucleotide polymorphism genotype was determined by using real-time polymerase chain reaction. Kaplan-Meier survival curves were generated with a combined end point of death or transplantation. The Cox proportional hazard method was used to evaluate potential covariates.
Results: The endothelin-1 G5665T genotype was significantly associated with transplant-free survival for the group as a whole (P = .002), with the greatest effect in children with hypoplastic left heart syndrome (n = 64, P = .0002) as opposed to patients with other types of single-ventricle anatomy (n = 101, P = .1). Cox proportional hazard modeling revealed 3 independent predictors of poor outcome: endothelin G5665T genotype (T/T genotype, P = .001), prematurity (gestational age <37 weeks, P = .02), and era of surgical intervention (1990s vs other decades, P = .02).
Conclusions: Long-term survival of single-ventricle patients is dependent on many factors. These data suggest that genetic variability involving vascular resistance modifiers, such as endothelin-1, might play an important role, particularly in patients with hypoplastic left heart syndrome. Future studies should include evaluation of the relationship between endothelin genotype and plasma endothelin levels and possibly therapeutic trials of endothelin blockers in high-risk patients.