BACKGROUND: 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 ((18)FLT) using positron emission tomography. METHODS AND RESULTS: We performed dynamic (18)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 (18)FLT phosphorylation (k3) in patients with IPAH compared with nonpulmonary arterial hypertension controls (0.086+/-0.034 versus 0.054+/-0.009 min(-1); P<0.05). There was heterogeneity in the lung (18)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 (18)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 (18)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 (18)FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib. CONCLUSIONS: Dynamic (18)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.
- Ashek, A.
- Spruijt, O. A.
- Harms, H. J.
- Lammertsma, A. A.
- Cupitt, J.
- Dubois, O.
- Wharton, J.
- Dabral, S.
- Pullamsetti, S. S.
- Huisman, M. C.
- Frings, V.
- Boellaard, R.
- de Man, F. S.
- Botros, L.
- Jansen, S.
- Vonk Noordegraaf, A.
- Wilkins, M. R.
- Bogaard, H. J.
- Zhao, L.
Keywords
- positron emission tomography
- pulmonary hypertension
- thymidine kinase 1
- vascular remodeling
