Abstract

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.

Links

Publisher Full Text

Authors

Jeewa A, Manickaraj AK, Mertens L, Manlhiot C, Kinnear C, Mondal T, Smythe J, Rosenberg H, Lougheed J, McCrindle BW, van Arsdell G, Redington AN, Mital S

Institution

Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

Source

Pediatric research 72:4 2012 Oct pg 407-13

MeSH

Adaptation, Physiological
Angiogenic Proteins
Anoxia
Cardiac Surgical Procedures
Child, Preschool
Fibrosis
Follow-Up Studies
Gene Frequency
Genotype
Heart Ventricles
Humans
Hypertrophy, Right Ventricular
Hypoxia-Inducible Factor 1, alpha Subunit
Infant
Kaplan-Meier Estimate
Linear Models
Logistic Models
Phenotype
Polymorphism, Single Nucleotide
Prospective Studies
Registries
Reoperation
Tetralogy of Fallot
Time Factors
Transforming Growth Factor beta1
Treatment Outcome
Ventricular Dysfunction, Right
Ventricular Remodeling

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22797143