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@article{Ashek:2018:10.1161/CIRCIMAGING.117.007402,
author = {Ashek, A and Spruijt, OA and Harms, HJ and Lammertsma, AA and Cupitt, J and Dubois, O and Wharton, J and Dabral, S and Pullamsetti, SS and Huisman, MC and Frings, V and Boellaard, R and de, Man FS and Botros, L and Jansen, S and Noordegraaf, AV and Wilkins, MR and Bogaard, HJ and Zhao, L},
doi = {10.1161/CIRCIMAGING.117.007402},
journal = {Circulation: Cardiovascular Imaging},
title = {3 '-deoxy-3'-[18F]fluorothymidine positron emission tomography depicts heterogeneous proliferation pathology in idiopathic pulmonary arterial hypertension patient lung: a potential biomarker for pulmonary arterial hypertension},
url = {http://dx.doi.org/10.1161/CIRCIMAGING.117.007402},
volume = {11},
year = {2018}
}

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TY  - JOUR
AB  - 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 (18FLT) using positron emission tomography.Methods and Results:We performed dynamic 18FLT 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 18FLT 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 18FLT 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 18FLT 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 18FLT 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 18FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib.Conclusions:Dynamic 18FLT positron emission tomography imaging can be used to report hyperproliferation in pulmonary h
AU  - Ashek,A
AU  - Spruijt,OA
AU  - Harms,HJ
AU  - Lammertsma,AA
AU  - Cupitt,J
AU  - Dubois,O
AU  - Wharton,J
AU  - Dabral,S
AU  - Pullamsetti,SS
AU  - Huisman,MC
AU  - Frings,V
AU  - Boellaard,R
AU  - de,Man FS
AU  - Botros,L
AU  - Jansen,S
AU  - Noordegraaf,AV
AU  - Wilkins,MR
AU  - Bogaard,HJ
AU  - Zhao,L
DO  - 10.1161/CIRCIMAGING.117.007402
PY  - 2018///
SN  - 1941-9651
TI  - 3 '-deoxy-3'-[18F]fluorothymidine positron emission tomography depicts heterogeneous proliferation pathology in idiopathic pulmonary arterial hypertension patient lung: a potential biomarker for pulmonary arterial hypertension
T2  - Circulation: Cardiovascular Imaging
UR  - http://dx.doi.org/10.1161/CIRCIMAGING.117.007402
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000442406300004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/62735
VL  - 11
ER  -

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