3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Depicts Heterogeneous Proliferation Pathology in Idiopathic Pulmonary Arterial Hypertension Patient Lung.

Autor:	Ashek A; 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.)., Spruijt OA; Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.)., Harms HJ; Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.)., Lammertsma AA; Department of Radiology and Nuclear Medicine (A.A.L., M.C.H., V.F., R.B., F.S.d.M.), VU University Medical Center, Amsterdam, the Netherlands., Cupitt J; 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.)., Dubois O; 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.)., Wharton J; 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.)., Dabral S; Max-Planck Institute for Heart and Lung Research, University of Giessen and Marburg Lung Center, German Center for Lung Research, Bad Nauheim (S.D., S.S.P.)., Pullamsetti SS; Max-Planck Institute for Heart and Lung Research, University of Giessen and Marburg Lung Center, German Center for Lung Research, Bad Nauheim (S.D., S.S.P.)., Huisman MC; Department of Radiology and Nuclear Medicine (A.A.L., M.C.H., V.F., R.B., F.S.d.M.), VU University Medical Center, Amsterdam, the Netherlands., Frings V; Department of Radiology and Nuclear Medicine (A.A.L., M.C.H., V.F., R.B., F.S.d.M.), VU University Medical Center, Amsterdam, the Netherlands., Boellaard R; Department of Radiology and Nuclear Medicine (A.A.L., M.C.H., V.F., R.B., F.S.d.M.), VU University Medical Center, Amsterdam, the Netherlands., de Man FS; Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.).; Department of Radiology and Nuclear Medicine (A.A.L., M.C.H., V.F., R.B., F.S.d.M.), VU University Medical Center, Amsterdam, the Netherlands., Botros L; Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.)., Jansen S; Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.)., Vonk Noordegraaf A; Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.)., Wilkins MR; 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.)., Bogaard HJ; Department of Pulmonary Medicine (O.A.S., H.J.H., F.S.d.M., L.B., S.J., A.V.N., H.J.B.)., Zhao L; 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.).
Jazyk:	angličtina
Zdroj:	Circulation. Cardiovascular imaging [Circ Cardiovasc Imaging] 2018 Aug; Vol. 11 (8), pp. e007402.
DOI:	10.1161/CIRCIMAGING.117.007402
Abstrakt:	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 (k 3 ) 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.
Databáze:	MEDLINE
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