Center for Pharmacology and Therapeutics, Experimental Medicine, Hammersmith Hospital, Imperial College London, United Kingdom (A.A., J.C., O.D., J.W., M.R.W., L.Z.).
Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.).
Circ Cardiovasc Imaging. 2018 Aug;11(8):e007402. doi: 10.1161/CIRCIMAGING.117.007402.
Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodeling in pulmonary arterial hypertension. A noninvasive imaging biomarker is needed to track the pathology and assess the response to novel treatments targeted at resolving the structural changes. Here, we evaluated the application of radioligand 3'-deoxy-3'-[18F]-fluorothymidine (FLT) using positron emission tomography.
We performed dynamic FLT positron emission tomography in 8 patients with idiopathic pulmonary arterial hypertension (IPAH) and applied in-depth kinetic analysis with a reversible 2-compartment 4k model. Our results show significantly increased lung FLT phosphorylation (k) in patients with IPAH compared with nonpulmonary arterial hypertension controls (0.086±0.034 versus 0.054±0.009 min; P<0.05). There was heterogeneity in the lung FLT signal both between patients with IPAH and within the lungs of each patient, compatible with histopathologic reports of lungs from patients with IPAH. Consistent with FLT positron emission tomographic data, TK1 (thymidine kinase 1) expression was evident in the remodeled vessels in IPAH patient lung. In addition, hyperproliferative pulmonary vascular fibroblasts isolated from patients with IPAH exhibited upregulated expression of TK1 and the thymidine transporter, ENT1 (equilibrative nucleoside transporter 1). In the monocrotaline and SuHx (Sugen hypoxia) rat pulmonary arterial hypertension models, increased lung FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation marker, Ki-67 score, together with prominent TK1 expression in remodeled vessels. Importantly, lung FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib.
Dynamic FLT positron emission tomography imaging can be used to report hyperproliferation in pulmonary hypertension and merits further study to evaluate response to treatment in patients with IPAH.
肺血管细胞的过度增殖是肺动脉高压中肺血管重构的特征。需要一种非侵入性的成像生物标志物来跟踪病理学并评估针对解决结构变化的新型治疗方法的反应。在这里，我们评估了使用正电子发射断层扫描的放射性配体 3'-脱氧-3'-[18F]-氟胸苷（FLT）的应用。
我们对 8 例特发性肺动脉高压（IPAH）患者进行了动态 FLT 正电子发射断层扫描，并应用了具有可逆 2 隔室 4k 模型的深入动力学分析。我们的结果显示，与非肺动脉高压对照组相比，IPAH 患者的肺 FLT 磷酸化（k）显着增加（0.086±0.034 与 0.054±0.009 min；P<0.05）。IPAH 患者之间以及每个患者的肺部之间的肺 FLT 信号存在异质性，与 IPAH 患者肺部的组织病理学报告一致。与 FLT 正电子发射断层扫描数据一致，TK1（胸苷激酶 1）在 IPAH 患者肺中的重构血管中表达明显。此外，从 IPAH 患者中分离出的增殖性肺血管成纤维细胞表现出 TK1 和胸苷转运蛋白 ENT1（平衡核苷转运蛋白 1）的上调表达。在单克隆鼠和 SuHx（苏根缺氧）大鼠肺动脉高压模型中，肺 FLT 摄取的增加与外周肺血管肌化和增殖标志物 Ki-67 评分强烈相关，同时在重构血管中表达明显的 TK1。重要的是，两种增殖抑制剂：二氯乙酸和酪氨酸激酶抑制剂伊马替尼可减轻肺 FLT 摄取。
动态 FLT 正电子发射断层扫描成像可用于报告肺动脉高压中的过度增殖，并值得进一步研究以评估 IPAH 患者的治疗反应。
