Genetic determinants of right-ventricular remodeling after tetralogy of Fallot 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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)407-413
Number of pages7
JournalPediatric research
Issue number4
StatePublished - Oct 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


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