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.

中文翻译：

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HIF1α的遗传变异与法洛患者四联症修复后的右心室纤维化负荷有关：一项心血管磁共振研究。

背景研究表明，在患有法洛四联症（TOF）的患者中，右心室（RV）纤维化与RV重塑和长期预后相关。术前缺氧可能增加缺氧诱导因子-1-α（HIF1α）的表达并促进转化生长因子β1（TGFβ1）介导的纤维化。我们假设在以下情况之间存在关联：（1）术后TOF病例中RV纤维化与RV功能，（2）HIF1α变异体与RV纤维化以及（3）HIF1α变异体与RV功能之间存在关联。方法我们回顾性分析了237例TOF患者的手术后纤维化负荷（指数量和纤维化评分），这些患者已经使用晚期g增强（LGE）进行了心血管磁共振成像，并显示了RV重塑的指标（即射血分数[RVEF]和终点） -舒张期容积索引为[RVEDVI]）。有125例病例的遗传数据。使用具有随机截距的多变量线性混合效应回归和具有随机截距的多变量广义泊松回归进行分析。结果指数化纤维化量和纤维化评分分别使RVEF分别降低了1.6％（p = 0.04）和0.9％（p = 0.03）。索引的纤维化体积和评分与RVEDVI不相关。在调整了多个比较之后，将48个HIF1α多态性中的6个（代表两个独特信号）与纤维化评分相关联。没有HIF1α多态性与索引纤维化体积，RVEDVI或RVEF相关。结论某些HIF1α基因多态性与纤维化评分有关，提示HIF1α可能调节TOF中的纤维化反应。使用具有随机截距的多变量线性混合效应回归和具有随机截距的多变量广义泊松回归进行分析。结果指数化纤维化体积和纤维化评分分别使RVEF分别降低了1.6％（p = 0.04）和0.9％（p = 0.03）。索引的纤维化体积和评分与RVEDVI不相关。在调整了多个比较之后，将48个HIF1α多态性中的6个（代表两个独特信号）与纤维化评分相关联。没有HIF1α多态性与索引纤维化体积，RVEDVI或RVEF相关。结论某些HIF1α基因多态性与纤维化评分有关，提示HIF1α可能调节TOF中的纤维化反应。使用具有随机截距的多变量线性混合效应回归和具有随机截距的多变量广义泊松回归进行分析。结果指数化纤维化体积和纤维化评分分别使RVEF分别降低了1.6％（p = 0.04）和0.9％（p = 0.03）。索引的纤维化体积和评分与RVEDVI不相关。在调整了多个比较之后，将48个HIF1α多态性中的6个（代表两个独特信号）与纤维化评分相关联。没有HIF1α多态性与索引纤维化体积，RVEDVI或RVEF相关。结论某些HIF1α基因多态性与纤维化评分有关，提示HIF1α可能调节TOF中的纤维化反应。