Hypoxia inducible factor (HIF1A) is associated with increased right ventricular fibrosis by T1 mapping cardiac magnetic resonance in patients with repaired tetralogy of Fallot

Abstract

Abstract Background Right ventricular fibrotic remodeling has been identified pre- and postoperatively in patients with tetralogy of Fallot (ToF) and linked to adverse outcomes. Polymorphisms of hypoxia inducible factor-1-alpha (HIF1α) have been associated with fibrotic burden by cardiac magnetic resonance (CMR) late gadolinium enhancement imaging. Their association with diffuse fibrotic myocardial remodeling is unknown. Purpose We sought to determine whether polymorphisms in hypoxia inducible factor (HIF1α) are related to CMR markers of diffuse myocardial fibrosis in pediatric patients with repaired ToF. Methods Patients with repaired ToF who had undergone CMR with T1 mapping as well as whole genome sequencing were included. Myocardial native T1 was quantified using a modified Look-Locker inversion recovery sequence and measured in the left ventricular free wall, the interventricular septum, and the right ventricular free wall. Patients who had at least one functioning allele of HIF1α were compared to those who did not using Mann Whitney U test for continuous variables and chi-square or Fischer test for discrete variables. Data are displayed in Table 1 as median (IQR) for continuous variables and frequency (percentage) for discrete variables. Results 46 patients had both CMR and whole genome sequencing. Only one HIF1α variant was identified in the cohort and present in 13 patients. There were no significant differences in demographics, surgical variables, right or left ventricular volumes or function between the groups (Table 1). Despite a trend towards a lower age at the time of CMR (11.3 vs 13.7 years; p=0.07), patients with HIF1α had higher native T1 values (1094 vs. 1050; p=0.027; Table 1) in the right ventricular outflow tract myocardium, reflecting increased diffuse interstitial ventricular fibrosis in patients with the HIF1α variant. Conclusion Hypoxia-inducible factor is associated with imaging markers of increased diffuse right ventricular fibrosis late after repair of tetralogy of Fallot. Funding Acknowledgement Type of funding sources: None. Table 1