FLT PET depicts heterogeneous proliferation pathology in IPAH patient lung: a potential biomarker for PAH

Background Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodelling in pulmonary arterial hypertension (PAH). A non-invasive 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 (PET). Methods and Results We performed dynamic FLT PET scanning in 8 idiopathic PAH patients (IPAH) and applied in-depth kinetic analysis with a reversible 2-compartment 4k model. Our results show significantly increased lung FLT phosphorylation (k3) in IPAH patients compared with nonPAH controls (0.086±0.034 min vs 0.054±0.009 min; P<0.05). There was heterogeneity in the lung FLT signal both between IPAH patients and within the lungs of each patient, compatible with histopathological reports of lungs from IPAH patients. Consistent with FLT PET data, thymidine kinase TK1 expression was evident in the remodelled vessels in IPAH patient lung. In addition, hyperproliferative pulmonary vascular fibroblasts isolated from IPAH patients exhibited upregulated expression of TK1 and the thymidine transporter, ENT1. In the monocrotaline and Sugen hypoxia rat PAH models, increased lung FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation marker, Ki-67 score, together with prominent thymidine kinase TK1 expression in remodelled vessels. Importantly, lung FLT uptake was attenuated by two antiproliferative treatments, dichloroacetate and the tyrosine kinase inhibitor, imatinib. Conclusion –Dynamic FLT PET imaging can be used to report hyperproliferation in pulmonary hypertension and merits further study to evaluate response to treatment in IPAH patients.