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The endothelin-1 G5665T polymorphism impacts transplant-free survival for single ventricle patients
Paul M Kirshbom1, William T Mahle, Ronald W Joyner
1Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA. Paul.Kirshbom@emoryhealthcare.org
Insights
The endothelin-1 G5665T gene variant impacts transplant-free survival in children with single-ventricle congenital heart disease, especially those with hypoplastic left heart syndrome. This genetic factor, along with prematurity and surgical era, predicts poor outcomes.
Area of Science:
- Pediatric Cardiology
- Medical Genetics
- Congenital Heart Disease Research
Background:
- Improved early survival for single-ventricle congenital heart disease (SV-CHD) highlights the need to address late attrition.
- The endothelin-1 G5665T single nucleotide polymorphism (SNP) is associated with increased vascular reactivity and hypertension.
- Investigating the role of this SNP in long-term outcomes for pediatric SV-CHD patients is crucial.
Purpose of the Study:
- To determine if the endothelin-1 G5665T SNP influences transplant-free survival in children with SV-CHD.
- To identify genetic factors contributing to late mortality in this vulnerable pediatric population.
Main Methods:
- DNA analysis of 165 children with SV-CHD using real-time polymerase chain reaction to determine endothelin-1 G5665T SNP genotype.
- Kaplan-Meier survival analysis with death or transplantation as the combined endpoint.
- Cox proportional hazard modeling to assess independent predictors of outcome.
Main Results:
- The endothelin-1 G5665T genotype significantly correlated with transplant-free survival overall (P = .002) and particularly in hypoplastic left heart syndrome (HLHS) cases (P = .0002).
- Independent predictors of poor outcome included the endothelin G5665T (T/T) genotype, prematurity (gestational age <37 weeks), and surgical intervention during the 1990s.
- The T/T genotype showed a significant association with adverse outcomes (P = .001).
Conclusions:
- Long-term survival in single-ventricle patients is multifactorial.
- Genetic variations in vascular resistance modifiers like endothelin-1 may significantly impact outcomes, especially in HLHS.
- Future research should explore endothelin genotype-plasma levels and consider endothelin blocker trials for high-risk patients.
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.
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