Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA.
Sci Rep. 2019 Dec 20;9(1):19572. doi: 10.1038/s41598-019-55700-y.
Heart failure with preserved ejection fraction (HFpEF) patients who develop pulmonary hypertension (PH) have an increased risk of death, with combined pre- and post-capillary PH (CpcPH) having the highest risk. However, the mechanism behind PH development in HFpEF is poorly understood. We aimed to identify transcriptomic associations with PH development in HFpEF. Blood was collected from 30 HFpEF patients: 10 without PH, 10 with isolated post-capillary PH, and 10 with CpcPH. Gene expression measurements were completed using transcriptome-wide RNA sequencing. Gene expression differences were compared using a quasi-likelihood method adjusting for age, sex, race, and smoking-status. Biological pathways were compared using global gene expression differences. A replication in 34 additional heart failure patients and a validation in lung tissue from a representative mouse model were completed using quantitative PCR. Six differentially expressed genes were identified when comparing transcriptomics between subjects with CpcPH and those without PH. When tested in additional subjects, only the association with ID2 replicated. Consistent with clinical findings, Id2 expression was also upregulated in mice with HFpEF and PH. Pathway analysis identified proliferative and mitochondrial pathways associated with CpcPH. Thus, these patients may possess systemic pathophysiological differences similar to those observed in pulmonary arterial hypertension patients.
射血分数保留的心力衰竭（HFpEF）患者发生肺动脉高压（PH）时死亡风险增加，其中合并毛细血管前和毛细血管后 PH（CpcPH）的风险最高。然而，HFpEF 中 PH 发展的机制仍不清楚。我们旨在确定与 HFpEF 中 PH 发展相关的转录组关联。从 30 名 HFpEF 患者中采集血液：10 名无 PH，10 名孤立性毛细血管后 PH，10 名 CpcPH。使用全转录组 RNA 测序完成基因表达测量。使用调整年龄、性别、种族和吸烟状况的拟似似然方法比较基因表达差异。使用全局基因表达差异比较生物途径。使用定量 PCR 在另外 34 名心力衰竭患者中进行了复制，并在代表性小鼠模型的肺组织中进行了验证。当比较 CpcPH 患者和无 PH 患者之间的转录组时，确定了 6 个差异表达基因。在其他受试者中进行测试时，只有与 ID2 的关联得到复制。与临床发现一致，HFpEF 和 PH 小鼠的 Id2 表达也上调。通路分析确定了与 CpcPH 相关的增殖和线粒体通路。因此，这些患者可能具有与肺动脉高压患者相似的全身病理生理差异。
