Abstract
BackgroundStudies suggest that right ventricular (RV) fibrosis is associated with RV remodeling and long-term outcomes in patients with tetralogy of Fallot (TOF). Pre-operative hypoxia may increase expression of hypoxia inducible factor-1-alpha (HIF1α) and promote transforming growth factor β1 (TGFβ1)-mediated fibrosis. We hypothesized that there would be associations between: (1) RV fibrosis and RV function, (2) HIF1α variants and RV fibrosis, and (3) HIF1α variants and RV function among post-surgical TOF cases.MethodsWe retrospectively measured post-surgical fibrotic load (indexed volume and fibrotic score) from 237 TOF cases who had existing cardiovascular magnetic resonance imaging using late gadolinium enhancement (LGE), and indicators of RV remodeling (i.e., ejection fraction [RVEF] and end-diastolic volume indexed [RVEDVI]). Genetic data were available in 125 cases. Analyses were conducted using multivariable linear mixed-effects regression with a random intercept and multivariable generalized Poisson regression with a random intercept.ResultsIndexed fibrotic volume and fibrotic score significantly decreased RVEF by 1.6% (p = 0.04) and 0.9% (p = 0.03), respectively. Indexed fibrotic volume and score were not associated with RVEDVI. After adjusting for multiple comparisons, 6 of the 48 HIF1α polymorphisms (representing two unique signals) were associated with fibrotic score. None of the HIF1α polymorphisms were associated with indexed fibrotic volume, RVEDVI, or RVEF.ConclusionThe association of some HIF1α polymorphisms and fibrotic score suggests that HIF1α may modulate the fibrotic response in TOF.
Highlights
Tetralogy of Fallot (TOF) is one of the most common types of severe congenital heart defects [1]
Jeewa et al hypothesized that variants of hypoxia-inducible factor 1α (HIF1α) modulate the extent of fibrosis in patients with tetralogy of Fallot (TOF) [16] and reported that three HIF1α variants were associated with right ventricular (RV) fibrosis at the time of surgical repair, as well as RV function and RV dilation at follow-up [16]. These findings suggest that variants of HIF1α may modulate the extent of RV fibrosis and subsequent function in patients with TOF
While our study suggests an association between HIF1α variants and fibrosis while controlling for age of surgery and length of exposure to hypoxia, it cannot address the complex equation whether earlier versus later intervention with longer or shorter exposure to hypoxia is preferred based on genotype
Summary
Tetralogy of Fallot (TOF) is one of the most common types of severe congenital heart defects [1]. The majority of infants with repaired TOF reach adulthood [2, 3]. Despite similar cardiac anatomy and surgical intervention, patients with TOF experience disparate outcomes that may be partially explained by individual responses to physiologic stresses (e.g., pre-operative hypoxia). Postoperative scarring (i.e., fibrosis) is a well-recognized consequence of TOF repair, at the site of a ventriculotomy [5, 6]. Studies suggest that right ventricular (RV) fibrosis is associated with RV remodeling and long-term outcomes in patients with tetralogy of Fallot (TOF). We hypothesized that there would be associations between: (1) RV fibrosis and RV function, (2) HIF1α variants and RV fibrosis, and (3) HIF1α variants and RV function among post-surgical TOF cases
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