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.


CONCLUSIONS
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.
Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Aamir
A
Jeewa
Ashok Kumar
AK
Manickaraj
Luc
L
Mertens
Cedric
C
Manlhiot
Caroline
C
Kinnear
Tapas
T
Mondal
John
J
Smythe
Herschel
H
Rosenberg
Jane
J
Lougheed
Brian W
BW
McCrindle
Glen
G
van Arsdell
Andrew N
AN
Redington
Seema
S
Mital
D000222:Adaptation, Physiological; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D002675:Child, Preschool; D005355:Fibrosis; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000860:Hypoxia / Q000235:genetics / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D016015:Logistic Models; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012042:Registries; D012086:Reoperation; D013771:Tetralogy of Fallot / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016896:Treatment Outcome; D018497:Ventricular Dysfunction, Right / Q000235:genetics / Q000473:pathology / Q000601:surgery; D020257:Ventricular Remodeling / Q000235:genetics*
D042501:Angiogenic Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1