Table_1_Pulmonary Arterial Hypertension and Consecutive Right Heart Failure Lead to Liver Fibrosis.DOCX

Hepatic congestion occurs in patients with right heart failure and can ultimately lead to liver fibrosis or cardiac cirrhosis. Elevated pulmonary arterial pressure is found in patients with hepatic congestion. However, whether pulmonary arterial hypertension (PAH) can be a cause of liver fibrosis is unknown. The aim of this study was to investigate whether rats in the SuHx model with severe PAH develop liver fibrosis and to explore the mechanisms of congestive hepatic fibrosis both in rats and humans. To achieve this, PAH was induced in six to eight-week old male Sprague Dawley rats by a single subcutaneous injection of the VEGFR 2 inhibitor SU5416 and subsequent hypoxia for 3 weeks, followed by a 6-week period in room air. SuHx-exposed rats developed severe PAH, right ventricular hypertrophy (RVH), and consecutive right ventricular failure. Cardiac magnetic resonance imaging (MRI) and histological analysis revealed that PAH rats developed both hepatic congestion and liver fibrosis. Gene set enrichment analysis (GSEA) of whole liver RNA sequencing data identified a hepatic stellate cell specific gene signature in PAH rats. Consistently, tissue microarray from liver of patients with histological evidence of hepatic congestion and underlying heart disease revealed similar fibrogenic gene expression patterns and signaling pathways. In conclusion, severe PAH with concomitant right heart failure leads to hepatic congestion and liver fibrosis in the SU5416/hypoxia rat PAH model. Patients with PAH should therefore be screened for unrecognized liver fibrosis.

右心衰竭患者可出现肝淤血，最终可进展为肝纤维化或心源性肝硬化。肝淤血患者常伴有肺动脉压升高。然而，肺动脉高压（pulmonary arterial hypertension, PAH）是否可作为肝纤维化的病因，目前尚不明确。本研究旨在探究患有重度肺动脉高压的SuHx模型大鼠是否会发生肝纤维化，并探讨大鼠及人类充血性肝纤维化的发病机制。为此，本研究对6~8周龄的雄性斯普拉格-道利（Sprague Dawley，SD）大鼠进行单次皮下注射血管内皮生长因子受体2（vascular endothelial growth factor receptor 2, VEGFR2）抑制剂SU5416，随后置于低氧环境中饲养3周，之后转移至常氧环境中饲养6周，以此诱导肺动脉高压模型。经SuHx造模的大鼠可出现重度肺动脉高压、右心室肥厚（right ventricular hypertrophy, RVH）以及继发性右心衰竭。心脏磁共振成像（cardiac magnetic resonance imaging, MRI）及组织学分析结果显示，肺动脉高压模型大鼠同时出现了肝淤血与肝纤维化。对全肝RNA测序数据进行基因集富集分析（gene set enrichment analysis, GSEA）后发现，肺动脉高压模型大鼠体内存在肝星状细胞特异性基因特征。与之相符的是，对伴有肝淤血组织学证据及基础心脏病的患者肝组织微阵列进行分析，结果显示其纤维化相关基因表达模式与信号通路均与大鼠模型一致。综上，在SU5416/缺氧大鼠肺动脉高压模型中，伴有右心衰竭的重度肺动脉高压可引发肝淤血与肝纤维化。因此，肺动脉高压患者应接受筛查，以发现未被识别的肝纤维化。