TY - JOUR
T1 - Genetic variants of HIF1α are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients
T2 - A cardiovascular magnetic resonance study
AU - Hoang, Thanh T.
AU - Manso, Paulo Henrique
AU - Edman, Sharon
AU - Mercer-Rosa, Laura
AU - Mitchell, Laura E.
AU - Sewda, Anshuman
AU - Swartz, Michael D.
AU - Fogel, Mark A.
AU - Agopian, A. J.
AU - Goldmuntz, Elizabeth
N1 - Funding Information:
This work was supported by grants from the Congenital Heart Defect Coalition (CHD Coalition), the National Institutes of Health [P50-HL74731 (EG, LEM, MAF), 5T32HL007915 (LMR)], as well as Grant UL1TR000003 from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Center for Research Resources or the National Institutes of Health. This work was also supported by a grant from the American Heart Association Award [16GRNT29660001] and the Fundação de Amparo à Pesquisa do Estado de Sao Paulo (FAPESP) [2014/12006–6].
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/8/19
Y1 - 2019/8/19
N2 - 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.
AB - 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.
KW - Cardiovascular magnetic resonance imaging
KW - Fibrosis
KW - HIF1α
KW - Right ventricular ejection fraction
KW - Right ventricular end-diastolic volume
KW - Tetralogy of Fallot
UR - http://www.scopus.com/inward/record.url?scp=85071021692&partnerID=8YFLogxK
U2 - 10.1186/s12968-019-0555-2
DO - 10.1186/s12968-019-0555-2
M3 - Article
C2 - 31422771
AN - SCOPUS:85071021692
SN - 1097-6647
VL - 21
JO - Journal of Cardiovascular Magnetic Resonance
JF - Journal of Cardiovascular Magnetic Resonance
IS - 1
M1 - 51
ER -