Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair

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.