Longitudinal RNA-seq of LVAD platelets

Patients with heart failure (HF) and left ventricular assist devices (LVAD) have dysregulated thrombo-inflammatory responses, mediated in part by platelets. While studies of platelet activation have been undertaken in HF, changes in the platelet transcriptome in HF patients following mechanical unloading with an LVAD have not been investigated. We prospectively enrolled and longitudinally followed advanced HF patients (n=32) for a mean of 57 months post-LVAD implantation. For comparison, healthy donors were also enrolled (n=20). Platelets were hyperactive in HF, as evidenced by significantly increased formation of circulating platelet-monocyte aggregate formation. Platelet transcriptome interrogation by next-generation RNA-sequencing identified that the expression of numerous genes (n=588) was significantly (FDR<0.05) altered in HF patients prior to LVAD implantation. Differentially expressed genes were predicted to have roles in angiogenesis, immune and inflammatory responses, apoptosis, and cardiac muscle contraction. 90 days following LVAD implantation, the majority (80%) of differentially expressed genes in HF patients normalized, as compared to the platelet transcriptomes of healthy donors. In conclusion, advanced HF is associated with marked alterations in the platelet transcriptome. While LVAD implantation to off load the failing heart results in resolution in the majority of differentially expressed genes, a subset of the platelet transcriptome remains persistently altered.

心力衰竭（heart failure, HF）患者及左心室辅助装置（left ventricular assist devices, LVAD）使用者存在失调的血栓炎症反应，该反应部分由血小板介导。既往虽已有针对心力衰竭患者血小板活化的相关研究，但尚未有探究左心室辅助装置机械卸载术后心力衰竭患者血小板转录组变化的相关工作。本研究前瞻性纳入32例晚期心力衰竭患者，并在其左心室辅助装置植入后进行了平均57个月的纵向随访；同时纳入20名健康志愿者作为对照。研究发现，心力衰竭患者的血小板处于高活化状态，循环血小板-单核细胞聚集体的形成显著增加即可佐证这一点。通过下一代RNA测序（next-generation RNA-sequencing）对血小板转录组进行分析后发现，左心室辅助装置植入前的心力衰竭患者体内，共有588个基因的表达发生显著变化（错误发现率False Discovery Rate, FDR<0.05）。经生物信息学预测，这些差异表达基因参与血管生成、免疫与炎症反应、细胞凋亡及心肌收缩等生物学过程。左心室辅助装置植入90天后，与健康志愿者的血小板转录组相比，心力衰竭患者体内80%的差异表达基因已恢复至正常水平。综上，晚期心力衰竭与血小板转录组的显著改变密切相关。尽管通过左心室辅助装置植入以减轻衰竭心脏的负荷，可使多数差异表达基因的表达恢复正常，但仍有部分血小板转录组相关基因持续处于异常表达状态。