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Genetic Determinants of Right Ventricular Remodeling after Tetralogy of Fallot Repair.
MedLine Citation:
PMID:  22797143     Owner:  NLM     Status:  Publisher    
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 3 single nucleotide polymorphisms (SNPs) 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 (FAC), and freedom from pulmonary valve/conduit replacement on follow-up.Results:In 180 TOF patients, mean age at repair was 1.0±0.8 yrs with follow-up at 9.0±3.5 yrs; 82% had moderate-severe pulmonary insufficiency. Freedom from RV re-interventions at 5, 10 and 15 years was 92%, 84% and 67% respectively. Patients with more HIF1A-functioning alleles had higher transforming-growth factor, TGFβ1 expression and more fibrosis at initial repair compared to controls (p<0.05). During follow-up, patients with more HIF1A -functioning alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV re-interventions (p<0.05). This was confirmed in a replication cohort of 69 patients.Conclusions:In children after TOF repair, lower number of HIF1A-functioning alleles were associated with RV dilation and dysfunction suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.
Aamir Jeewa; Ashok Kumar Manickaraj; Luc Mertens; Cedric Manlhiot; Caroline Kinnear; Tapas Mondal; John Smythe; Herschel Rosenberg; Jane Lougheed; Brian W McCrindle; Glen van Arsdell; Andrew N Redington; Seema Mital
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-13
Journal Detail:
Title:  Pediatric research     Volume:  -     ISSN:  1530-0447     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0100714     Medline TA:  Pediatr Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada, M5G1X8.
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