Статья
Позитронная эмиссионная томография в оценке метаболизма миокарда правого желудочка и ремоделирования сосудов малого круга кровообращения при легочной артериальной гипертензии
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.
1. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655–1665. doi:10.1056/NEJMra035488
2. Mielniczuk LM, Birnie D, Ziadi MC, deKemp RA, DaSilva JN, Burwash I et al. Relation between right ventricular function and increased right ventricularfluorodeoxyglucose accumulation in patients with heart failure. Circ Cardiovasc Imaging. 2011;4(1):59–66. doi:10.1161/CIRCIMAGING.109.905984
3. van 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/ehm567
4. Ruiter 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.2012.09.025
5. Lundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K et al. Fasting 2-deoxy-2-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.201206–029OC
6. Sutendra 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/s00109-013-1059-4
7. Graham 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.00169.2015
8. Izquierdo-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.2018.00110
9. Marsboom 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.201108-1562OC
10. Hagan 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:10.4103/20458932.93543
11. Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J et al. Increasedfluorodeoxyglucose 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.2005.02.065
12. Saygin 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--Fluoro-2-deoxy-Dglucose Positron Emission Tomography. Pulm Circ. 2017;7(2):428–438. doi:10.1177/2045893217701917
13. 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.
14. 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.0b013e3182177389
15. Bokhari 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.110.963207
16. Ohira 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/jev136
17. Oguz 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_19
18. Fang 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:10.4103/2045-8932.101651
19. Tatebe S, Fukumoto Y, Oikawa-Wakayama M, Sugimura K, Satoh K, Miura Y et al. Enhancedfluorodeoxyglucose 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/jet276
20. Li 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.0000000000000956
21. 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.
22. 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.111.962381
23. Higuchi 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/cvn033
24. 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.
25. 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.2014.08.012
26. Zhao 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.113.004136
27. Rehman 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_11
28. Ryan 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.114.006979
29. Kim 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.2006.02.002
30. Frille A, Steinhoff KG, Hesse S, Grachtrup S, Wald A, Wirtz H et al. Thoracicfluorodeoxyglucose uptake measured by positron emission tomography/computed tomography in pulmonary hypertension. Medicine (Baltimore). 2016;95(25): e3976. doi:10.1097/MD.0000000000003976
31. Ohira 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)61150-0
32. Farkas 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.2010-0365TR
33. Barbera JA. Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension. Pulmon Circ. 2013;3(1):160–164. doi:10.4103/2045-8932.109949
34. Dupuis 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/s40336-014-0076-9
35. Johnstrom P, Richards HK, Fryer TD, Clark JC, Weissberg PL, Rudd JH et al. Imaging endothelin ET(B) receptors using-BQ3020: in vitro characterization and positron emission tomography (microPET). Exp Biol Med (Maywood). 2006;231(6): 736–740.
36. 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.
37. Jakobsen S, Kodahl GM, Olsen AK, Cumming P. Synthesis, radiolabeling and in vivo evaluation ofRAL-01, a potential phosphodiesterase 5 radioligand. Nucl Med Biol. 2006;33(5): 593–597.
38. 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.108.057901
39. Ashek A, Spruijt OA, Harms HJ, Lammertsma AA, Cupitt J, Dubois O et al. 3’-Deoxy-3’-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.117.007402
40. Vesselle H, Grierson J, Muzi M, Pugsley JM, Schmidt RA, Rabinowitz P et al. In vivo validation of 3’deoxy-3’-fluorothymidine (FLT) as a proliferation imaging tracer in humans: correlation ofFLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors. Clin Cancer Res. 2002;8(11):3315–3323.
41. 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.