arthyperАртериальная гипертензия"Arterial’naya Gipertenziya" ("Arterial Hypertension")1607-419X2411-8524Antihypertensive League10.18705/1607-419X-2020-26-5-501-508arthyper-2037Research ArticleОБЗОРREVIEWПозитронная эмиссионная томография в оценке метаболизма миокарда правого желудочка и ремоделирования сосудов малого круга кровообращения при легочной артериальной гипертензииEvaluation of right ventricular myocardial metabolism and pulmonary vascular remodeling in pulmonary arterial hypertension by positron emission tomographyМолоковаЕ. Р.MolokovaE. R.

Молокова Евгения Руслановна — клинический ординатор кафедры ядерной медицины и радиационных технологий

ул. Аккуратова, д. 2, Санкт-Петербург, 197341

Evgeniia R. Molokova, MD, Resident (Radiology), Department of Nuclear Medicine and Radiation Technology

2 Akkuratov street, St Petersburg, 197341

jmolokov@mail.ruРыжковаД. В.RyzhkovaD. V.

Рыжкова Дарья Викторовна — доктор медицинских наук, профессор РАН, руководитель научно-клинического объединения ядерной медицины, заведующая кафедрой ядерной медицины и радиационных технологий, главный научный сотрудник научно-исследовательского отдела ядерной медицины и тераностики института онкологии и гематологии

Санкт-Петербург

Daria V. Ryzhkova, MD, PhD, DSc, Professor, Head, Clinical Research Department of Nuclear Medicine, Head, Department of Nuclear Medicine and Radiation Technology, Researcher, Department of the Nuclear Medicine and Theranostics

St Petersburg

ryzhkova_dv@almazovcentre.ruФедеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр имени B. A. Алмaзoвa» Министерства здравоохранения Российской ФедерацииРоссияAlmazov National Medical Research CentreRussian Federation202014122020265501508Copyright © Молокова Е.Р., Рыжкова Д.В., 20202020Молокова Е.Р., Рыжкова Д.В.Molokova E.R., Ryzhkova D.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://htn.almazovcentre.ru/jour/article/view/2037

Легочная артериальная гипертензия (ЛАГ) является редкой и клинически неблагоприятной формой легочной гипертензии, для которой характерны ремоделирование сосудов малого круга кровообращения, а также обменные и функциональные нарушения в миокарде правого желудочка. Доказанная смена путей метаболизма на анаэробный гликолиз в сердце и легких может быть количественно и качественно оценена с помощью метода молекулярной визуализации — позитронной эмиссионной томографии (ПЭТ) с 18F-фтордезоксиглюкозой (18F-ФДГ). В настоящей статье проведен анализ зарубежной литературы, представлены результаты исследований, подтверждающих диагностическую значимость выполнения процедуры ПЭТ, совмещенной с компьютерной томографией (КТ), с 18F-ФДГ и другими перспективными радиофармацевтическими препаратами у пациентов с ЛАГ. Данная методика позволяет оценить тяжесть заболевания, определить клинический прогноз и сделать вывод об эффективности проводимого лечения в каждом конкретном случае. Кроме того, методы молекулярной визуализации предоставляют возможность проанализировать патогенетическую основу ЛАГ и рассмотреть новые биологические мишени, такие как факторы развития эндотелиальной дисфункции и ремоделирования сосудов малого круга кровообращения.

Pulmonary arterial hypertension (PAH) is a rare and severe form of pulmonary hypertension, which is characterized by pulmonary vascular remodeling, as well as metabolic and functional alterations in the right ventricular myocardium. The proven metabolic shift towards anaerobic glycolysis in the heart and lungs can be quantitatively and qualitatively evaluated with a molecular imaging technique — 2-[18F] fluoro-2-deoxy-Dglucose (FDG) positron emission tomography (PET). This review is devoted to the analysis of foreign scientific publications. There are presented research results that prove the diagnostic value of fused PET/computer tomography (CT) (PET/CT) images with FDG and other promising radiopharmaceuticals in patients with PAH. This tool allows estimation of the severity of the disease, to determine the clinical prognosis and monitor the effectiveness of treatment in each case. Furthermore, the methods of molecular visualization allow the analysis of the PAH pathogenesis and description of the new biologic targets, such as development factors of endothelial dysfunction and remodeling of pulmonary vasculature.

позитронная эмиссионная томографиялегочная гипертензияремоделирование легочных сосудовкомпьютерная томографияфтордезоксиглюкоза18F-фтордезоксиглюкозаметаболизм правого желудочкаpositron emission tomographypulmonary hypertensionpulmonary vascular remodeling2-[18F] fluoro-2-deoxy-D-glucosecomputer tomographyright ventricular metabolismReferencesFarber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655–1665. doi:10.1056/NEJMra035488Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655–1665. doi:10.1056/NEJMra035488Mielniczuk LM, Birnie D, Ziadi MC, deKemp RA, DaSilva JN, Burwash I et al. Relation between right ventricular function and increased right ventricular [18F] fluorodeoxyglucose accumulation in patients with heart failure. Circ Cardiovasc Imaging. 2011;4(1):59–66. doi:10.1161/CIRCIMAGING.109.905984Mielniczuk LM, Birnie D, Ziadi MC, deKemp RA, DaSilva JN, Burwash I et al. Relation between right ventricular function and increased right ventricular [18F] fluorodeoxyglucose accumulation in patients with heart failure. Circ Cardiovasc Imaging. 2011;4(1):59–66. doi:10.1161/CIRCIMAGING.109.905984van Wolferen SA, Marcus JT, Westerhof N, Spreeuwenberg MD, Marques KM, Bronzwaer JG et al. Right coronary artery flow impairment in patients with pulmonary hypertension. Eur Heart J. 2008;29(1):120–127. doi:10.1093/eurheartj/ehm567van Wolferen SA, Marcus JT, Westerhof N, Spreeuwenberg MD, Marques KM, Bronzwaer JG et al. Right coronary artery flow impairment in patients with pulmonary hypertension. Eur Heart J. 2008;29(1):120–127. doi:10.1093/eurheartj/ehm567Ruiter G, Ying Wong Y, de Man FS, Louis Handoko M, Jaspers RT, Postmus PE et al. Right ventricular oxygen supply parameters are decreased in human and experimental pulmonary hypertension. J Heart Lung Transplant. 2013;32(2):231–240. doi:10.1016/j.healun.2012.09.025Ruiter G, Ying Wong Y, de Man FS, Louis Handoko M, Jaspers RT, Postmus PE et al. Right ventricular oxygen supply parameters are decreased in human and experimental pulmonary hypertension. J Heart Lung Transplant. 2013;32(2):231–240. doi:10.1016/j.healun.2012.09.025Lundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K et al. Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc. 2013;10(1):1–9. doi:10.1513/AnnalsATS.201206–029OCLundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K et al. Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc. 2013;10(1):1–9. doi:10.1513/AnnalsATS.201206–029OCSutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J et al. A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mod Med (Berl). 2013;91(11):13151327. doi:10.1007/s00109-013-1059-4Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J et al. A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mod Med (Berl). 2013;91(11):13151327. doi:10.1007/s00109-013-1059-4Graham BB, Kumar R, Mickael C, Sanders L, Gebreab L, Huber KM et al. Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake. Am J Physiol Lung Cell Mol Physiol. 2015;309(5):L435–L440. doi:10.1152/ajplung.00169.2015Graham BB, Kumar R, Mickael C, Sanders L, Gebreab L, Huber KM et al. Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake. Am J Physiol Lung Cell Mol Physiol. 2015;309(5):L435–L440. doi:10.1152/ajplung.00169.2015Izquierdo-Garcia JL, Arias T, Rojas Y, Garcia-Ruiz V, Santos A, Martin-Puig S et al. Metabolic reprogramming in the heart and lung in a murine model of pulmonary arterial hypertension. Front Cardiovasc Med. 2018;5:110. doi:10.3389/fcvm.2018.00110Izquierdo-Garcia JL, Arias T, Rojas Y, Garcia-Ruiz V, Santos A, Martin-Puig S et al. Metabolic reprogramming in the heart and lung in a murine model of pulmonary arterial hypertension. Front Cardiovasc Med. 2018;5:110. doi:10.3389/fcvm.2018.00110Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E et al. Lung (1)(8) F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185(6):670–679. doi:10.1164/rccm.201108-1562OCMarsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E et al. Lung (1)(8) F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185(6):670–679. doi:10.1164/rccm.201108-1562OCHagan G, Southwood M, Treacy C, Ross RM, Soon E, Coulson J et al. (18)FDG PET imaging can quantify increased cellular metabolism in pulmonary arterial hypertension: a proof-ofprinciple study. Pulm Circ. 2011;1(4):448–455. doi:10.4103/20458932.93543Hagan G, Southwood M, Treacy C, Ross RM, Soon E, Coulson J et al. (18)FDG PET imaging can quantify increased cellular metabolism in pulmonary arterial hypertension: a proof-ofprinciple study. Pulm Circ. 2011;1(4):448–455. doi:10.4103/20458932.93543Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J et al. Increased [18F] fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45(11):1849–1855. doi:10.1016/j.jacc.2005.02.065Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J et al. Increased [18F] fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45(11):1849–1855. doi:10.1016/j.jacc.2005.02.065Saygin D, Highland KB, Farha S, Park M, Sharp J, Roach EC et al. Metabolic and functional evaluation of the heart and lungs in pulmonary hypertension by gated 2-[18F]-Fluoro-2-deoxy-Dglucose Positron Emission Tomography. Pulm Circ. 2017;7(2):428–438. doi:10.1177/2045893217701917Saygin D, Highland KB, Farha S, Park M, Sharp J, Roach EC et al. Metabolic and functional evaluation of the heart and lungs in pulmonary hypertension by gated 2-[18F]-Fluoro-2-deoxy-Dglucose Positron Emission Tomography. Pulm Circ. 2017;7(2):428–438. doi:10.1177/2045893217701917Kluge R, Barthel H, Pankau H, Seese A, Schauer J, Wirtz H et al. Different mechanisms for changes in glucose uptake of the right and left ventricular myocardium in pulmonary hypertension. J Nucl Med. 2005;46(1):25–31.Kluge R, Barthel H, Pankau H, Seese A, Schauer J, Wirtz H et al. Different mechanisms for changes in glucose uptake of the right and left ventricular myocardium in pulmonary hypertension. J Nucl Med. 2005;46(1):25–31.Can MM, Kaymaz C, Tanboga IH, Tokgoz HC, Canpolat N, Turkyilmaz E et al. Increased right ventricular glucose metabolism in patients with pulmonary arterial hypertension. Clin Nucl Med. 2011;36(9):743–748. doi:10.1097/RLU.0b013e3182177389Can MM, Kaymaz C, Tanboga IH, Tokgoz HC, Canpolat N, Turkyilmaz E et al. Increased right ventricular glucose metabolism in patients with pulmonary arterial hypertension. Clin Nucl Med. 2011;36(9):743–748. doi:10.1097/RLU.0b013e3182177389Bokhari S, Raina A, Rosenweig EB, Schulze PC, Bokhari J, Einstein AJ et al. PET imaging may provide a novel biomarker and understanding ofright ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension. Circ Cardiovasc Imaging. 2011;4(6):641–647. doi:10.1161/CIRCIMAGING.110.963207Bokhari S, Raina A, Rosenweig EB, Schulze PC, Bokhari J, Einstein AJ et al. PET imaging may provide a novel biomarker and understanding ofright ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension. Circ Cardiovasc Imaging. 2011;4(6):641–647. doi:10.1161/CIRCIMAGING.110.963207Ohira H, deKemp R, Pena E, Davies RA, Stewart DJ, Chandy G et al. Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: a potential mechanism for a maladaptive right ventricular response. Eur Heart J Cardiovasc Imaging. 2016;17(12):1424–1431. doi:10.1093/ehjci/jev136Ohira H, deKemp R, Pena E, Davies RA, Stewart DJ, Chandy G et al. Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: a potential mechanism for a maladaptive right ventricular response. Eur Heart J Cardiovasc Imaging. 2016;17(12):1424–1431. doi:10.1093/ehjci/jev136Oguz M, Kivrak T, Sunbul M, Dede F, Yildizeli B, Mutlu B. Diagnostic modality for evaluation of right ventricle in chronic thromboembolic pulmonary hypertension patients. Int J Cardiovasc Acad. 2019;5:152–158. doi:10.4103/IJCA.IJCA_35_19Oguz M, Kivrak T, Sunbul M, Dede F, Yildizeli B, Mutlu B. Diagnostic modality for evaluation of right ventricle in chronic thromboembolic pulmonary hypertension patients. Int J Cardiovasc Acad. 2019;5:152–158. doi:10.4103/IJCA.IJCA_35_19Fang W, Zhao L, Xiong CM, Ni XH, He ZX, He JG et al. Comparison of 18F FDG uptake by right ventricular myocardium in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. Pulm Circ. 2012;2(3):365–372. doi:10.4103/2045-8932.101651Fang W, Zhao L, Xiong CM, Ni XH, He ZX, He JG et al. Comparison of 18F FDG uptake by right ventricular myocardium in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. Pulm Circ. 2012;2(3):365–372. doi:10.4103/2045-8932.101651Tatebe S, Fukumoto Y, Oikawa-Wakayama M, Sugimura K, Satoh K, Miura Y et al. Enhanced [18F] fluorodeoxyglucose accumulation in the right ventricular free wall predicts longterm prognosis of patients with pulmonary hypertension: a preliminary observational study. Eur Heart J Cardiovasc Imaging. 2014;15(6):666–672. doi:10.1093/ehjci/jet276Tatebe S, Fukumoto Y, Oikawa-Wakayama M, Sugimura K, Satoh K, Miura Y et al. Enhanced [18F] fluorodeoxyglucose accumulation in the right ventricular free wall predicts longterm prognosis of patients with pulmonary hypertension: a preliminary observational study. Eur Heart J Cardiovasc Imaging. 2014;15(6):666–672. doi:10.1093/ehjci/jet276Li W, Wang L, Xiong C–M, Yang T, Zhang Y, Gu Q et al. The prognostic value of 18F-FDG uptake ratio between the right and left ventricles in idiopathic pulmonary arterial hypertension. Clin Nucl Med. 2015;40(11):859–863. doi:10.1097/RLU.0000000000000956Li W, Wang L, Xiong C–M, Yang T, Zhang Y, Gu Q et al. The prognostic value of 18F-FDG uptake ratio between the right and left ventricles in idiopathic pulmonary arterial hypertension. Clin Nucl Med. 2015;40(11):859–863. doi:10.1097/RLU.0000000000000956Gomez A, Bialostozky D, Zajarias A, Santos E, Palomar A, Martinez ML et al. Right ventricular ischemia in patients with primary pulmonary hypertension. J Am Coll Cardiol. 2001;38(4): 1137–1142.Gomez A, Bialostozky D, Zajarias A, Santos E, Palomar A, Martinez ML et al. Right ventricular ischemia in patients with primary pulmonary hypertension. J Am Coll Cardiol. 2001;38(4): 1137–1142.Wong YY, Ruiter G, Lubberink M, Raijmakers PG, Knaapen P, Marcus JT et al. Right ventricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient myocardial oxygen utilization. Circ Heart Fail. 2011;4(6):700–706. doi:10.1161/CIRCHEARTFAILURE.111.962381Wong YY, Ruiter G, Lubberink M, Raijmakers PG, Knaapen P, Marcus JT et al. Right ventricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient myocardial oxygen utilization. Circ Heart Fail. 2011;4(6):700–706. doi:10.1161/CIRCHEARTFAILURE.111.962381Higuchi T, Bengel FM, Seidl S, Watzlowik P, Kessler H, Hegenloh R et al. Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography. Cardiovasc Res. 2008;78(2):395–403. doi:10.1093/cvr/cvn033Higuchi T, Bengel FM, Seidl S, Watzlowik P, Kessler H, Hegenloh R et al. Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography. Cardiovasc Res. 2008;78(2):395–403. doi:10.1093/cvr/cvn033Pietila M, Malminiemi K, Ukkonen H, Saraste M, Nagren K, Lehikoinen P et al. Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med. 2001;28(3):373–376.Pietila M, Malminiemi K, Ukkonen H, Saraste M, Nagren K, Lehikoinen P et al. Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med. 2001;28(3):373–376.Freund-Michel V, Khoyrattee N, Savineau JP, Muller B, Guibert C. Mitochondria: roles in pulmonary hypertension. Int J Biochem Cell Biol. 2014;55:93–97. doi:10.1016/j.biocel.2014.08.012Freund-Michel V, Khoyrattee N, Savineau JP, Muller B, Guibert C. Mitochondria: roles in pulmonary hypertension. Int J Biochem Cell Biol. 2014;55:93–97. doi:10.1016/j.biocel.2014.08.012Zhao L, Ashek A, Wang L, Fang W, Dabral S, Dubois O et al. Heterogeneity in lung (18) FDG uptake in pulmonary arterial hypertension: potential of dynamic (18) FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments. Circulation. 2013;128(11):1214–1224. doi:10.1161/CIRCULATIONAHA.113.004136Zhao L, Ashek A, Wang L, Fang W, Dabral S, Dubois O et al. Heterogeneity in lung (18) FDG uptake in pulmonary arterial hypertension: potential of dynamic (18) FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments. Circulation. 2013;128(11):1214–1224. doi:10.1161/CIRCULATIONAHA.113.004136Rehman J, Archer SL. A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the Warburg model of pulmonary arterial hypertension. Adv Exp Med Biol. 2010;661:171–185. doi:10.1007/978-1-60761-500-2_11Rehman J, Archer SL. A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the Warburg model of pulmonary arterial hypertension. Adv Exp Med Biol. 2010;661:171–185. doi:10.1007/978-1-60761-500-2_11Ryan JJ, Archer SL. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation. 2015;131(19):1691–1702. doi:10.1161/CIRCULATIONAHA.114.006979Ryan JJ, Archer SL. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation. 2015;131(19):1691–1702. doi:10.1161/CIRCULATIONAHA.114.006979Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177–185. doi:10.1016/j.cmet.2006.02.002Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177–185. doi:10.1016/j.cmet.2006.02.002Frille A, Steinhoff KG, Hesse S, Grachtrup S, Wald A, Wirtz H et al. Thoracic [18F] fluorodeoxyglucose uptake measured by positron emission tomography/computed tomography in pulmonary hypertension. Medicine (Baltimore). 2016;95(25): e3976. doi:10.1097/MD.0000000000003976Frille A, Steinhoff KG, Hesse S, Grachtrup S, Wald A, Wirtz H et al. Thoracic [18F] fluorodeoxyglucose uptake measured by positron emission tomography/computed tomography in pulmonary hypertension. Medicine (Baltimore). 2016;95(25): e3976. doi:10.1097/MD.0000000000003976Ohira H, Beanlands R, McArdle B, deKemp R, Renaud J, Klein R et al. Evaluation of lung glucose uptake with fluorine-18 fluorodeoxy glucose Positron Emission Tomography/CT in patients with pulmonary artery hypertension and pulmonary hypertension due to left heart disease. J Am Col Cardiol. 2015;65:10S. doi:10.1016/S0735-1097(15)61150-0Ohira H, Beanlands R, McArdle B, deKemp R, Renaud J, Klein R et al. Evaluation of lung glucose uptake with fluorine-18 fluorodeoxy glucose Positron Emission Tomography/CT in patients with pulmonary artery hypertension and pulmonary hypertension due to left heart disease. J Am Col Cardiol. 2015;65:10S. doi:10.1016/S0735-1097(15)61150-0Farkas L, Gauldie J, Voelkel NF, Kolb M. Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors. Am J Respir Cell Mol Biol. 2011;45(1):1–15. doi:10.1165/rcmb.2010-0365TRFarkas L, Gauldie J, Voelkel NF, Kolb M. Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors. Am J Respir Cell Mol Biol. 2011;45(1):1–15. doi:10.1165/rcmb.2010-0365TRBarbera JA. Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension. Pulmon Circ. 2013;3(1):160–164. doi:10.4103/2045-8932.109949Barbera JA. Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension. Pulmon Circ. 2013;3(1):160–164. doi:10.4103/2045-8932.109949Dupuis J, Harel F, Nguyen QT. Molecular imaging of the pulmonary circulation in health and disease. Clin Transl Imaging. 2014;2(5):415–426. doi:10.1007/s40336-014-0076-9Dupuis J, Harel F, Nguyen QT. Molecular imaging of the pulmonary circulation in health and disease. Clin Transl Imaging. 2014;2(5):415–426. doi:10.1007/s40336-014-0076-9Johnstrom P, Richards HK, Fryer TD, Clark JC, Weissberg PL, Rudd JH et al. Imaging endothelin ET(B) receptors using [18 F]-BQ3020: in vitro characterization and positron emission tomography (microPET). Exp Biol Med (Maywood). 2006;231(6): 736–740.Johnstrom P, Richards HK, Fryer TD, Clark JC, Weissberg PL, Rudd JH et al. Imaging endothelin ET(B) receptors using [18 F]-BQ3020: in vitro characterization and positron emission tomography (microPET). Exp Biol Med (Maywood). 2006;231(6): 736–740.Qing F, McCarthy TJ, Markham J, Schuster DP. Pulmonary angiotensin-converting enzyme (ACE) binding and inhibition in humans. A positron emission tomography study. Am J Respir Crit Care Med. 2000;161(6):2019–2025.Qing F, McCarthy TJ, Markham J, Schuster DP. Pulmonary angiotensin-converting enzyme (ACE) binding and inhibition in humans. A positron emission tomography study. Am J Respir Crit Care Med. 2000;161(6):2019–2025.Jakobsen S, Kodahl GM, Olsen AK, Cumming P. Synthesis, radiolabeling and in vivo evaluation of [11C]RAL-01, a potential phosphodiesterase 5 radioligand. Nucl Med Biol. 2006;33(5): 593–597.Jakobsen S, Kodahl GM, Olsen AK, Cumming P. Synthesis, radiolabeling and in vivo evaluation of [11C]RAL-01, a potential phosphodiesterase 5 radioligand. Nucl Med Biol. 2006;33(5): 593–597.Groves AM, Win T, Screaton NJ, Berovic M, Endozo R, Booth H et al. Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with 18 F-FDG PET/CT. J Nucl Med. 2009;50(4):538–545. doi:10.2967/jnumed.108.057901Groves AM, Win T, Screaton NJ, Berovic M, Endozo R, Booth H et al. Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with 18 F-FDG PET/CT. J Nucl Med. 2009;50(4):538–545. doi:10.2967/jnumed.108.057901Ashek A, Spruijt OA, Harms HJ, Lammertsma AA, Cupitt J, Dubois O et al. 3’-Deoxy-3’-[18F] Fluorothymidine Positron Emission Tomography depicts heterogeneous proliferation pathology in idiopathic pulmonary arterial hypertension patient lung. Circ Cardiovasc Imaging. 2018;11(8):e007402. doi:10.1161/CIRCIMAGING.117.007402Ashek A, Spruijt OA, Harms HJ, Lammertsma AA, Cupitt J, Dubois O et al. 3’-Deoxy-3’-[18F] Fluorothymidine Positron Emission Tomography depicts heterogeneous proliferation pathology in idiopathic pulmonary arterial hypertension patient lung. Circ Cardiovasc Imaging. 2018;11(8):e007402. doi:10.1161/CIRCIMAGING.117.007402Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P et al. In vivo validation of 3’deoxy-3’-[(18) F] fluorothymidine ([(18) F]FLT) as a proliferation imaging tracer in humans: correlation of [(18) F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res. 2002;8(11):3315–3323.Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P et al. In vivo validation of 3’deoxy-3’-[(18) F] fluorothymidine ([(18) F]FLT) as a proliferation imaging tracer in humans: correlation of [(18) F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res. 2002;8(11):3315–3323.van Waarde A, Cobben DC, Suurmeijer AJ, Maas B, Vaalburg W, de Vries EF et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med. 2004;45(4):695–700.van Waarde A, Cobben DC, Suurmeijer AJ, Maas B, Vaalburg W, de Vries EF et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med. 2004;45(4):695–700.

The authors declare that there are no conflicts of interest present.