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Genetic variants of HIF1? are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients: a cardiovascular magnetic resonance study.

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 (HIF1?) and promote transforming growth factor ?1 (TGF?1)-mediated fibrosis. We hypothesized that there would be associations between: (1) RV fibrosis and RV function, (2) HIF1? variants and RV fibrosis, and (3) HIF1? 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 HIF1? polymorphisms (representing two unique signals) were associated with fibrotic score. None of the HIF1? polymorphisms were associated with indexed fibrotic volume, RVEDVI, or RVEF. CONCLUSION:The association of some HIF1? polymorphisms and fibrotic score suggests that HIF1? may modulate the fibrotic response in TOF.

SUBMITTER: Hoang TT

PROVIDER: S-EPMC6699069 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Hoang Thanh T TT Manso Paulo Henrique PH Edman Sharon S Mercer-Rosa Laura L Mitchell Laura E LE Sewda Anshuman A Swartz Michael D MD Fogel Mark A MA Agopian A J AJ Goldmuntz Elizabeth E

Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance 20190819 1

<h4>Background</h4>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 amo ...[more]

PMID: 31422771

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Project description:BackgroundFour-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows quantification of biventricular blood flow by flow components and kinetic energy (KE) analyses. However, it remains unclear whether 4D flow parameters can predict cardiopulmonary exercise testing (CPET) as a clinical outcome in repaired tetralogy of Fallot (rTOF). Current study aimed to (1) compare 4D flow CMR parameters in rTOF with age- and gender-matched healthy controls, (2) investigate associations of 4D flow parameters with functional and volumetric right ventricular (RV) remodelling markers, and CPET outcome.MethodsSixty-three rTOF patients (14 paediatric, 49 adult; 30 ± 15 years; 29 M) and 63 age- and gender-matched healthy controls (14 paediatric, 49 adult; 31 ± 15 years) were prospectively recruited at four centers. All underwent cine and 4D flow CMR, and all adults performed standardized CPET same day or within one week of CMR. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes. Four flow components were analyzed: direct flow, retained inflow, delayed ejection flow and residual volume. Additionally, three phasic KE parameters normalized to end-diastolic volume (KEiEDV), were analyzed for both LV and RV: peak systolic, average systolic and peak E-wave.ResultsIn comparisons of rTOF vs. healthy controls, median LV retained inflow (18% vs. 16%, P = 0.005) and median peak E-wave KEiEDV (34.9 µJ/ml vs. 29.2 µJ/ml, P = 0.006) were higher in rTOF; median RV direct flow was lower in rTOF (25% vs. 35%, P < 0.001); median RV delayed ejection flow (21% vs. 17%, P < 0.001) and residual volume (39% vs. 31%, P < 0.001) were both greater in rTOF. RV KEiEDV parameters were all higher in rTOF than healthy controls (all P < 0.001). On multivariate analysis, RV direct flow was an independent predictor of RV function and CPET outcome. RV direct flow and RV peak E-wave KEiEDV were independent predictors of RV remodelling index.ConclusionsIn this multi-scanner multicenter 4D flow CMR study, reduced RV direct flow was independently associated with RV dysfunction, remodelling and, to a lesser extent, exercise intolerance in rTOF patients. This supports its utility as an imaging parameter for monitoring disease progression and therapeutic response in rTOF. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifier: NCT03217240.

Project description:Background and objectiveThe effect of chronic pulmonary regurgitation (PR) on right ventricular (RV) dysfunction in repaired Tetralogy of Fallot (RTOF) patients is well recognized by cardiac magnetic resonance (CMR). However, the link between RV wall motion, intracardiac flow and PR has not been established. Hemodynamic force (HDF) represents the global force exchanged between intracardiac blood volume and endocardium, measurable by 4D flow or by a novel mathematical model of wall motion. In our study, we used this novel methodology to derive HDF in a cohort of RTOF patients, exclusively using routine CMR imaging.MethodsRTOF patients and controls with CMR imaging were retrospectively included. Three-dimensional (3D) models of RV were segmented, including RV outflow tract (RVOT). Feature-tracking software (QStrain 2.0, Medis Medical Imaging Systems, Leiden, Netherlands) captured endocardial contours from long/short-axis cine and used to reconstruct RV wall motion. A global HDF vector was computed from the moving surface, then decomposed into amplitude/impulse of three directional components based on reference (Apical-to-Basal, Septal-to-Free Wall and Diaphragm-to-RVOT direction). HDF were compared and correlated against CMR and exercise stress test parameters. A subset of RTOF patients had 4D flow that was used to derive vorticity (for correlation) and HDF (for comparison against cine method).Results68 RTOF patients and 20 controls were included. RTOF patients had increased diastolic HDF amplitude in all three directions (p<0.05). PR% correlated with Diaphragm-RVOT HDF amplitude/impulse (r = 0.578, p<0.0001, r = 0.508, p < 0.0001, respectively). RV ejection fraction modestly correlated with global HDF amplitude (r = 0.2916, p = 0.031). VO2-max correlated with Septal-to-Free Wall HDF impulse (r = 0.536, p = 0.007). Diaphragm-to-RVOT HDF correlated with RVOT vorticity (r = 0.4997, p = 0.001). There was no significant measurement bias between Cine-derived HDF and 4D flow-derived HDF by Bland-Altman analysis.ConclusionRTOF patients have abnormal diastolic HDF that is correlated to PR, RV function, exercise capacity and vorticity. HDF can be derived from conventional cine, and is a potential link between RV wall motion and intracardiac flow from PR in RTOF patients.

Dataset Information

Genetic variants of HIF1? are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients: a cardiovascular magnetic resonance study.

Publications

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

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