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

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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
Authors: Ashek, A
Spruijt, OA
Harms, HJ
Lammertsma, AA
Cupitt, J
Dubois, O
Wharton, J
Dabral, S
Pullamsetti, SS
Huisman, MC
Frings, V
Boellaard, R
De Man, FS
Botros, L
Jansen, S
Noordegraaf, AV
Wilkins, MR
Bogaard, HJ
Zhao, L
Item Type: Journal Article
Abstract: 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 hypertension and merits further study to evaluate response to treatment in patients with IPAH.
Issue Date: 20-Aug-2018
Date of Acceptance: 19-Jun-2018
URI: http://hdl.handle.net/10044/1/62735
DOI: https://dx.doi.org/10.1161/CIRCIMAGING.117.007402
ISSN: 1941-9651
Publisher: American Heart Association
Journal / Book Title: Circulation: Cardiovascular Imaging
Volume: 11
Issue: 8
Copyright Statement: © 2018 American Heart Association, Inc.
Sponsor/Funder: Pfizer Limited
British Heart Foundation
Funder's Grant Number: WS729114
PG/14/88/31183
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Radiology, Nuclear Medicine & Medical Imaging
Cardiovascular System & Cardiology
positron emission tomography
pulmonary hypertension
vascular remodeling
thymidine kinase 1
TUMOR-CELL-PROLIFERATION
IN-VIVO
KI-67 IMMUNOHISTOCHEMISTRY
IMAGING PROLIFERATION
PET
F-18-FLT
CANCER
QUANTIFICATION
INFLAMMATION
THYMIDINE
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Radiology, Nuclear Medicine & Medical Imaging
Cardiovascular System & Cardiology
positron emission tomography
pulmonary hypertension
vascular remodeling
thymidine kinase 1
TUMOR-CELL-PROLIFERATION
IN-VIVO
KI-67 IMMUNOHISTOCHEMISTRY
IMAGING PROLIFERATION
PET
F-18-FLT
CANCER
QUANTIFICATION
INFLAMMATION
THYMIDINE
1103 Clinical Sciences
Cardiovascular System & Hematology
Publication Status: Published
Article Number: ARTN e007402
Online Publication Date: 2018-08-20
Appears in Collections:Department of Medicine
Faculty of Medicine



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