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

Ali Ashek, Onno A. Spruijt, Hendrik J. Harms, Adriaan A. Lammertsma, John Cupitt, Olivier Dubois, John Wharton, Swati Dabral, Soni Savai Pullamsetti, Marc C. Huisman, Virginie Frings, Ronald Boellaard, Frances S. de Man, Lisa Botros, Samara Jansen, Anton Vonk Noordegraaf, Martin R. Wilkins, Harm J. Bogaard, Lan Zhao

Research output: Contribution to journalArticleAcademicpeer-review

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.

LanguageEnglish
Pagese007402
JournalCirculation. Cardiovascular imaging
Volume11
Issue number8
DOIs
StatePublished - 2018

Cite this

Ashek, Ali ; Spruijt, Onno A. ; Harms, Hendrik J. ; Lammertsma, Adriaan A. ; Cupitt, John ; Dubois, Olivier ; Wharton, John ; Dabral, Swati ; Pullamsetti, Soni Savai ; Huisman, Marc C. ; Frings, Virginie ; Boellaard, Ronald ; de Man, Frances S. ; Botros, Lisa ; Jansen, Samara ; Vonk Noordegraaf, Anton ; Wilkins, Martin R. ; Bogaard, Harm J. ; Zhao, Lan. / 3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Depicts Heterogeneous Proliferation Pathology in Idiopathic Pulmonary Arterial Hypertension Patient Lung. In: Circulation. Cardiovascular imaging. 2018 ; Vol. 11, No. 8. pp. e007402
@article{d65d2aa5ea714ed092e8d74c899f91d8,
title = "3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Depicts Heterogeneous Proliferation Pathology in Idiopathic Pulmonary Arterial Hypertension Patient Lung",
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.",
author = "Ali Ashek and Spruijt, {Onno A.} and Harms, {Hendrik J.} and Lammertsma, {Adriaan A.} and John Cupitt and Olivier Dubois and John Wharton and Swati Dabral and Pullamsetti, {Soni Savai} and Huisman, {Marc C.} and Virginie Frings and Ronald Boellaard and {de Man}, {Frances S.} and Lisa Botros and Samara Jansen and {Vonk Noordegraaf}, Anton and Wilkins, {Martin R.} and Bogaard, {Harm J.} and Lan Zhao",
year = "2018",
doi = "10.1161/CIRCIMAGING.117.007402",
language = "English",
volume = "11",
pages = "e007402",
journal = "Circulation. Cardiovascular imaging",
issn = "1942-0080",
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}

3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Depicts Heterogeneous Proliferation Pathology in Idiopathic Pulmonary Arterial Hypertension Patient Lung. / Ashek, Ali; Spruijt, Onno A.; Harms, Hendrik J.; Lammertsma, Adriaan A.; Cupitt, John; Dubois, Olivier; Wharton, John; Dabral, Swati; Pullamsetti, Soni Savai; Huisman, Marc C.; Frings, Virginie; Boellaard, Ronald; de Man, Frances S.; Botros, Lisa; Jansen, Samara; Vonk Noordegraaf, Anton; Wilkins, Martin R.; Bogaard, Harm J.; Zhao, Lan.

In: Circulation. Cardiovascular imaging, Vol. 11, No. 8, 2018, p. e007402.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - 3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Depicts Heterogeneous Proliferation Pathology in Idiopathic Pulmonary Arterial Hypertension Patient Lung

AU - Ashek,Ali

AU - Spruijt,Onno A.

AU - Harms,Hendrik J.

AU - Lammertsma,Adriaan A.

AU - Cupitt,John

AU - Dubois,Olivier

AU - Wharton,John

AU - Dabral,Swati

AU - Pullamsetti,Soni Savai

AU - Huisman,Marc C.

AU - Frings,Virginie

AU - Boellaard,Ronald

AU - de Man,Frances S.

AU - Botros,Lisa

AU - Jansen,Samara

AU - Vonk Noordegraaf,Anton

AU - Wilkins,Martin R.

AU - Bogaard,Harm J.

AU - Zhao,Lan

PY - 2018

Y1 - 2018

N2 - 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.

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 hypertension and merits further study to evaluate response to treatment in patients with IPAH.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85055611806&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30354494

U2 - 10.1161/CIRCIMAGING.117.007402

DO - 10.1161/CIRCIMAGING.117.007402

M3 - Article

VL - 11

SP - e007402

JO - Circulation. Cardiovascular imaging

T2 - Circulation. Cardiovascular imaging

JF - Circulation. Cardiovascular imaging

SN - 1942-0080

IS - 8

ER -