TY - JOUR
T1 - Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair
AU - Jeewa, Aamir
AU - Manickaraj, Ashok Kumar
AU - Mertens, Luc
AU - Manlhiot, Cedric
AU - Kinnear, Caroline
AU - Mondal, Tapas
AU - Smythe, John
AU - Rosenberg, Herschel
AU - Lougheed, Jane
AU - McCrindle, Brian W.
AU - Van Arsdell, Glen
AU - Redington, Andrew N.
AU - Mital, Seema
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012/10
Y1 - 2012/10
N2 - Background: Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair. Methods: Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A. Genotypes were analyzed for association with RV myocardial protein expression and fibrosis at complete repair (n = 42) and RV dilation, fractional area change, and freedom from pulmonary valve/conduit replacement on follow-up. Results: In 180 TOF patients, mean age at repair was 1.0 ± 0.8 y with follow-up at 9.0 ± 3.5 y; 82% had moderate to severe pulmonary insufficiency. Freedom from RV reinterventions at 5, 10, and 15 y was 92, 84, and 67%, respectively. Patients with more functioning HIF1A alleles had higher transforming growth factor β1 expression and more fibrosis at initial repair as compared with controls (P 0.05). During follow-up, patients with more functioning HIF1A alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV reinterventions (P 0.05). This was confirmed in a replication cohort of 69 patients. Conclusion: In children who have had TOF repair, a lower number of functioning HIF1A alleles was associated with RV dilation and dysfunction, suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.
AB - Background: Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair. Methods: Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A. Genotypes were analyzed for association with RV myocardial protein expression and fibrosis at complete repair (n = 42) and RV dilation, fractional area change, and freedom from pulmonary valve/conduit replacement on follow-up. Results: In 180 TOF patients, mean age at repair was 1.0 ± 0.8 y with follow-up at 9.0 ± 3.5 y; 82% had moderate to severe pulmonary insufficiency. Freedom from RV reinterventions at 5, 10, and 15 y was 92, 84, and 67%, respectively. Patients with more functioning HIF1A alleles had higher transforming growth factor β1 expression and more fibrosis at initial repair as compared with controls (P 0.05). During follow-up, patients with more functioning HIF1A alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV reinterventions (P 0.05). This was confirmed in a replication cohort of 69 patients. Conclusion: In children who have had TOF repair, a lower number of functioning HIF1A alleles was associated with RV dilation and dysfunction, suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.
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U2 - 10.1038/pr.2012.95
DO - 10.1038/pr.2012.95
M3 - Article
C2 - 22797143
AN - SCOPUS:84867048696
SN - 0031-3998
VL - 72
SP - 407
EP - 413
JO - Pediatric research
JF - Pediatric research
IS - 4
ER -