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. 2019 Aug 19;21(1):51.
doi: 10.1186/s12968-019-0555-2.

Genetic variants of HIF1α are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients: a cardiovascular magnetic resonance study

Thanh T Hoang  1 , Paulo Henrique Manso  2 , Sharon Edman  3 , Laura Mercer-Rosa  3   4 , Laura E Mitchell  1 , Anshuman Sewda  5 , Michael D Swartz  6 , Mark A Fogel  3   4 , A J Agopian  1 , Elizabeth Goldmuntz  7   8
Affiliations

Genetic variants of HIF1α are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients: a cardiovascular magnetic resonance study

Thanh T Hoang et al. J Cardiovasc Magn Reson. .

Abstract

Background: Studies 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.

Methods: We 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.

Results: Indexed 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.

Conclusion: The association of some HIF1α polymorphisms and fibrotic score suggests that HIF1α may modulate the fibrotic response in TOF.

Keywords: Cardiovascular magnetic resonance imaging; Fibrosis; HIF1α; Right ventricular ejection fraction; Right ventricular end-diastolic volume; Tetralogy of Fallot.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Proposed pathway and associations of interest between HIF1a, right ventricular fibrotic load, and right ventricular dysfunction. HIF1α, hypoxia inducible factor-1-alpha; RV, right ventricular; RVEDVI, indexed right ventricular end-diastolic volume; RVEF, right ventricular ejection fraction; SNP, single nucleotide polymorphism
Fig. 2
Fig. 2
Diagram of study population
Fig. 3
Fig. 3
Regional association plot constructed from LocusZoom for the 48 HIF1α variants, based on the 1000 Genomes European population (Nov 2014). Each point represents one of the 48 HIF1α variants. The r2 represents the linkage disequilibrium (i.e., correlation) between each variant and rs11549465. For example, the linkage disequilibrium between the two variants shaded in red and rs11549465 ranges from 0.80 to 1.0. These three variants reflect a unique signal. The linkage disequilibrium between variants shaded in yellow and rs11549465 ranges from 0.60 to 0.80. The variants shaded in yellow reflect another unique signal. Square: variants that were in Jeewa et al.’s study and significant in our study (purple square = rs11549465, yellow square = rs2057482); Triangle: variant analyzed in Jeewa et al.’s study but not significant in our study (green triangle = rs10873142); Diamond: variants significant in this study (left red diamond = rs76308410, yellow diamond = rs7161527, right red diamond = rs74481028, yellow diamond (underneath rs74481028): rs10147275; Circles: variants analyzed in our study but were not significant
See this image and copyright information in PMC

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