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 journalArticle

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.

Original languageEnglish (US)
Pages (from-to)407-413
Number of pages7
JournalPediatric research
Volume72
Issue number4
DOIs
StatePublished - Oct 1 2012
Externally publishedYes

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Ventricular Remodeling
Tetralogy of Fallot
Dilatation
Alleles
Fibrosis
Right Ventricular Dysfunction
Pulmonary Valve
Right Ventricular Function
Transforming Growth Factors
Single Nucleotide Polymorphism
Hemodynamics
Genotype
Phenotype
Lung
Hypoxia
Proteins

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Jeewa, A., Manickaraj, A. K., Mertens, L., Manlhiot, C., Kinnear, C., Mondal, T., ... Mital, S. (2012). Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair. Pediatric research, 72(4), 407-413. https://doi.org/10.1038/pr.2012.95

Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair. / Jeewa, Aamir; Manickaraj, Ashok Kumar; Mertens, Luc; Manlhiot, Cedric; Kinnear, Caroline; Mondal, Tapas; Smythe, John; Rosenberg, Herschel; Lougheed, Jane; McCrindle, Brian W.; Van Arsdell, Glen; Redington, Andrew N.; Mital, Seema.

In: Pediatric research, Vol. 72, No. 4, 01.10.2012, p. 407-413.

Research output: Contribution to journalArticle

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 2012, 'Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair', Pediatric research, vol. 72, no. 4, pp. 407-413. https://doi.org/10.1038/pr.2012.95
Jeewa, Aamir ; Manickaraj, Ashok Kumar ; Mertens, Luc ; Manlhiot, Cedric ; Kinnear, Caroline ; Mondal, Tapas ; Smythe, John ; Rosenberg, Herschel ; Lougheed, Jane ; McCrindle, Brian W. ; Van Arsdell, Glen ; Redington, Andrew N. ; Mital, Seema. / Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair. In: Pediatric research. 2012 ; Vol. 72, No. 4. pp. 407-413.
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AU - Manickaraj, Ashok Kumar

AU - Mertens, Luc

AU - Manlhiot, Cedric

AU - Kinnear, Caroline

AU - Mondal, Tapas

AU - Smythe, John

AU - Rosenberg, Herschel

AU - Lougheed, Jane

AU - McCrindle, Brian W.

AU - Van Arsdell, Glen

AU - Redington, Andrew N.

AU - Mital, Seema

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