russjcardiolРоссийский кардиологический журналRussian Journal of Cardiology1560-40712618-7620«SILICEA-POLIGRAF» LLC10.15829/1560-4071-2022-4840russjcardiol-4840Research ArticleОБЗОРЫREVIEWСистема нейротрофинов в патогенезе легочной артериальной гипертензии и дисфункции правогоNeurotrophins in the pathogenesis of pulmonary hypertension and right ventricular dysfunctionhttps://orcid.org/0000-0001-6081-1559АндрееваЕ. М.AndreevaE. M.

Елизавета Михайловна Андреева — лаборант-исследователь НИО микроциркулияции и метаболизма миокарда.

Санкт-Петербург

St. Petersburg

elizaa.andreeva@gmail.comhttps://orcid.org/0000-0001-6954-7096ГончароваН. С.GoncharovaN. S.

Наталья Сергеевна Гончарова — старший научный сотрудник НИЛ кардиомиопатии.

Санкт-Петербург

St. Petersburg

ns.goncharova@gmail.comhttps://orcid.org/0000-0002-6553-9141МихайловЕ. Н.MikhailovE. N.

Евгений Николаевич Михайлов — доктор медицинских наук, профессор, зам. директора института сердца и сосудов по научной части, руководитель и главный научный сотрудник НИЛ нейромодуляции.

Санкт-Петербург

St. Petersburg

evgenymikhaylov@gmail.comhttps://orcid.org/0000-0002-7817-3847МоисееваО. М.MoiseevaO. M.

Ольга Михайловна Моисеева — доктор медицинских наук, директор института сердца и сосудов, руководитель и главный научный сотрудник НИО некоронарогенных заболеваний сердца.

Санкт-Петербург

St. Petersburg

moiseeva.cardio@gmail.comФГБУ Национальный медицинский исследовательский центр им. В.А. Алмазова Минздрава РоссииРоссияAlmazov National Medical Research CenterRussian Federation20221203202227248404840Copyright © Андреева Е.М., Гончарова Н.С., Михайлов Е.Н., Моисеева О.М., 20222022Андреева Е.М., Гончарова Н.С., Михайлов Е.Н., Моисеева О.М.Andreeva E.M., Goncharova N.S., Mikhailov E.N., Moiseeva O.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://russjcardiol.elpub.ru/jour/article/view/4840

Легочная гипертензия (ЛГ) — патофизиологическое и гемодинамическое состояние, которое осложняет течение разнообразных заболеваний, крайне неблагоприятно влияет на показатели заболеваемости и выживаемости в целом. Поиск новых патофизиологических механизмов развития и прогрессирования ЛГ, маркеров прогнозирования течения ЛГ и возможных мишеней для создания таргетной терапии остается актуальным. Настоящий обзор посвящен роли системы нейротрофинов (НТ) в патогенезе ЛГ, возможному использованию НТ и рецепторов к ним в качестве лабораторного маркера тяжести ЛГ, а также в качестве потенциальной мишени для воздействия на процессы ремоделирования легочной артерии при ЛГ. Кроме того, охарактеризовано участие системы НТ в неоангиогенезе и восстановлении нервной и мышечной тканей.

Pulmonary hypertension (PH) is a pathophysiological and hemodynamic condition that complicates the course of various diseases and negatively affects morbidity and mortality. The search for the new pathophysiological mechanisms for PH development and progression, the markers for predicting the PH course, and the possible targets for therapy remains relevant. This review is devoted to the role of neurotrophin (NT) system in PH pathogenesis, the possible use of NT and their receptors as a laboratory marker of its severity, and also as a potential target for influencing the pulmonary artery remodeling in PH. In addition, the participation of NTs in neoangiogenesis and restoration of nervous and muscle tissues was described.

нейротрофинылегочная гипертензияремоделированиеneurotrophinspulmonary hypertensionremodelingРабота поддержана грантом Минобрнауки, соглашение № 075-15-2020-800ReferencesHumbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;130(24):2189-208. doi:10.1161/CIRCULATIONAHA.114.006974.Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;130(24):2189-208. doi:10.1161/CIRCULATIONAHA.114.006974.Авдеев С. Н., Барбараш О. Л., Баутин А.Е. и др. Легочная гипертензия, в том числе хроническая тромбоэмболическая легочная гипертензия. Клинические рекомендации 2020. Российский кардиологический журнал. 2021;26(12):4683. doi:10.15829/1560-4071-2021-4683.Avdeev SN, Barbarash OL, Bautin AE, et al. 2020 Clinical practice guidelines for Pulmonary hypertension, including chronic thromboembolic pulmonary hypertension. Russian Journal of Cardiology. 2021;26(12):4683. (In Russ.) doi:10.15829/1560-4071-2021-4683.Boucly A, Savale L, Jaïs X, et al. Association between Initial Treatment Strategy and Long-Term Survival in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2021;204(7):842-54. doi:10.1164/rccm.202009-3698OC.Boucly A, Savale L, Jaïs X, et al. Association between Initial Treatment Strategy and Long-Term Survival in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2021;204(7):842-54. doi:10.1164/rccm.202009-3698OC.Freund-Michel V, Cardoso Dos Santos M, Guignabert C, et al. Role of Nerve Growth Factor in Development and Persistence of Experimental Pulmonary Hypertension. Am J Respir Crit Care Med. 2015;192(3):342-55. doi:10.1164/rccm.201410-1851OC.Freund-Michel V, Cardoso Dos Santos M, Guignabert C, et al. Role of Nerve Growth Factor in Development and Persistence of Experimental Pulmonary Hypertension. Am J Respir Crit Care Med. 2015;192(3):342-55. doi:10.1164/rccm.201410-1851OC.Pius-Sadowska E, Machaliński B. Pleiotropic activity of nerve growth factor in regulating cardiac functions and counteracting pathogenesis. ESC Heart Fail. 2021;8(2):974-87. doi:10.1002/ehf2.13138.Pius-Sadowska E, Machaliński B. Pleiotropic activity of nerve growth factor in regulating cardiac functions and counteracting pathogenesis. ESC Heart Fail. 2021;8(2):974-87. doi:10.1002/ehf2.13138.Dechant G, Neumann H. Neurotrophins. Adv Exp Med Biol. 2002;513:303-34. doi:10. 1007/978-1-4615-0123-7_11.Dechant G, Neumann H. Neurotrophins. Adv Exp Med Biol. 2002;513:303-34. doi:10. 1007/978-1-4615-0123-7_11.Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006;110(2):167-73. doi:10.1042/CS20050163.Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond). 2006;110(2):167-73. doi:10.1042/CS20050163.Meuchel LW, Thompson MA, Cassivi SD, et al. Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells. Cardiovasc Res. 2011;91(4):668-76. doi:10.1093/cvr/cvr107.Meuchel LW, Thompson MA, Cassivi SD, et al. Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells. Cardiovasc Res. 2011;91(4):668-76. doi:10.1093/cvr/cvr107.Liu P, Li S, Tang L. Nerve Growth Factor: A Potential Therapeutic Target for Lung Diseases. Int J Mol Sci. 2021;22(17):9112. doi:10.3390/ijms22179112.Liu P, Li S, Tang L. Nerve Growth Factor: A Potential Therapeutic Target for Lung Diseases. Int J Mol Sci. 2021;22(17):9112. doi:10.3390/ijms22179112.Ricci A, Felici L, Mariotta S, et al. Neurotrophin and neurotrophin receptor protein expression in the human lung. Am J Respir Cell Mol Biol. 2004(1):12-9. doi:10.1165/rcmb.2002-0110OC.Ricci A, Felici L, Mariotta S, et al. Neurotrophin and neurotrophin receptor protein expression in the human lung. Am J Respir Cell Mol Biol. 2004(1):12-9. doi:10.1165/rcmb.2002-0110OC.Caporali A, Emanueli C. Cardiovascular actions of neurotrophins. Physiol Rev. 2009;89(1):279-308. doi:10.1152/physrev.00007.2008.Caporali A, Emanueli C. Cardiovascular actions of neurotrophins. Physiol Rev. 2009;89(1):279-308. doi:10.1152/physrev.00007.2008.Ricci A, Greco S, Amenta F, et al. Neurotrophins and neurotrophin receptors in human pulmonary arteries. J Vasc Res. 2000;37(5):355-63. doi:10.1159/000025751.Ricci A, Greco S, Amenta F, et al. Neurotrophins and neurotrophin receptors in human pulmonary arteries. J Vasc Res. 2000;37(5):355-63. doi:10.1159/000025751.Rush RA, Mayo R, Zettler C. The regulation of nerve growth factor synthesis and delivery to peripheral neurons. Pharmacol Ther. 1995;65(1):93-123. doi:10.1016/01637258(94)00059-c.Rush RA, Mayo R, Zettler C. The regulation of nerve growth factor synthesis and delivery to peripheral neurons. Pharmacol Ther. 1995;65(1):93-123. doi:10.1016/01637258(94)00059-c.Cardouat G, Guibert C, Freund-Michel V. Expression et rôle du facteur de croissance des nerfs NGF dans l’hypertension pulmonaire [The expression and role of nerve growth factor (NGF) in pulmonary hypertension]. Rev Mal Respir. 2020;37(3):205-9. French. doi:10.1016/j.rmr.2020.02.002.Cardouat G, Guibert C, Freund-Michel V. Expression et rôle du facteur de croissance des nerfs NGF dans l’hypertension pulmonaire [The expression and role of nerve growth factor (NGF) in pulmonary hypertension]. Rev Mal Respir. 2020;37(3):205-9. French. doi:10.1016/j.rmr.2020.02.002.Ziegenhorn AA, Schulte-Herbrüggen O, Danker-Hopfe H, et al. Serum neurotrophins–a study on the time course and influencing factors in a large old age sample. Neurobiol Aging. 2007;28(9):1436-45. doi:10.1016/j.neurobiolaging.2006.06.011.Ziegenhorn AA, Schulte-Herbrüggen O, Danker-Hopfe H, et al. Serum neurotrophins–a study on the time course and influencing factors in a large old age sample. Neurobiol Aging. 2007;28(9):1436-45. doi:10.1016/j.neurobiolaging.2006.06.011.Xing J, Lu J, Li J. Nerve growth factor decreases in sympathetic and sensory nerves of rats with chronic heart failure. Neurochem Res. 2014;39(8):1564-70. doi:10.1007/s11064-014-1348-5.Xing J, Lu J, Li J. Nerve growth factor decreases in sympathetic and sensory nerves of rats with chronic heart failure. Neurochem Res. 2014;39(8):1564-70. doi:10.1007/s11064-014-1348-5.Kiriazis H, Du XJ, Feng X, et al. Preserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation. Am J Physiol Heart Circ Physiol. 2005;289(4):H1359-65. doi:10.1152/ajpheart.01010.2004.Kiriazis H, Du XJ, Feng X, et al. Preserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation. Am J Physiol Heart Circ Physiol. 2005;289(4):H1359-65. doi:10.1152/ajpheart.01010.2004.Hoyle GW, Mercer EH, Palmiter RD, et al. Expression of NGF in sympathetic neurons leads to excessive axon outgrowth from ganglia but decreased terminal innervation within tissues. Neuron. 1993;10(6):1019-34. doi:10.1016/0896-6273(93)90051-r.Hoyle GW, Mercer EH, Palmiter RD, et al. Expression of NGF in sympathetic neurons leads to excessive axon outgrowth from ganglia but decreased terminal innervation within tissues. Neuron. 1993;10(6):1019-34. doi:10.1016/0896-6273(93)90051-r.Shelton DL, Reichardt LF. Expression of the beta-nerve growth factor gene correlates with the density of sympathetic innervation in effector organs. Proc Natl Acad Sci USA. 1984;81(24):7951-5. doi:10.1073/pnas.81.24.7951.Shelton DL, Reichardt LF. Expression of the beta-nerve growth factor gene correlates with the density of sympathetic innervation in effector organs. Proc Natl Acad Sci USA. 1984;81(24):7951-5. doi:10.1073/pnas.81.24.7951.DeCouto SA, Jones EE, Kudwa AE, et al. The effects of deafferentation and exogenous NGF on neurotrophins and neurotrophin receptor mRNA expression in the adult superior cervical ganglion. Brain Res Mol Brain Res. 2003;119(1):73-82. doi:10.1016/j.molbrainres.2003.08.015.DeCouto SA, Jones EE, Kudwa AE, et al. The effects of deafferentation and exogenous NGF on neurotrophins and neurotrophin receptor mRNA expression in the adult superior cervical ganglion. Brain Res Mol Brain Res. 2003;119(1):73-82. doi:10.1016/j.molbrainres.2003.08.015.Emanueli C, Salis MB, Pinna A, et al. Nerve Growth Factor Promotes Angiogenesis and Arteriogenesis in Ischemic Hindlimbs. Circulation. 2002;106(17):2257-62. doi:10.1161/01.cir.0000033971.56802.c5.Emanueli C, Salis MB, Pinna A, et al. Nerve Growth Factor Promotes Angiogenesis and Arteriogenesis in Ischemic Hindlimbs. Circulation. 2002;106(17):2257-62. doi:10.1161/01.cir.0000033971.56802.c5.Bristow MR, Quaife RA. The adrenergic system in pulmonary arterial hypertension: bench to bedside (2013 Grover Conference series). Pulm Circ. 2015;5(3):415-23. doi:10.1086/682223.Bristow MR, Quaife RA. The adrenergic system in pulmonary arterial hypertension: bench to bedside (2013 Grover Conference series). Pulm Circ. 2015;5(3):415-23. doi:10.1086/682223.Stenmark KR, Nozik-Grayck E, Gerasimovskaya E, et al. The adventitia: Essential role in pulmonary vascular remodeling. Compr Physiol. 2011;1(1):141-61. doi:10.1002/cphy.c090017.Stenmark KR, Nozik-Grayck E, Gerasimovskaya E, et al. The adventitia: Essential role in pulmonary vascular remodeling. Compr Physiol. 2011;1(1):141-61. doi:10.1002/cphy.c090017.Митрофанова Л.Б., Перминова А.А., Гончарова НАУЧНЫЙ СОТРУДНИК, Михайлов Е.Н. Гистологическое и иммуногистохимическое исследование нервных волокон и ганглиев в периартериальной жировой ткани бифуркации легочной артерии у пациентов с легочной гипертензией и без нее. Артериальная гипертензия. 2019;25(5):498509. doi:10.18705/1607-419X-2019-25-5-498-509.Mitrofanova LB, Perminova AA, Goncharova NS, Mikhailov EN. Histological and immunohistochemical study of nerve fibers and ganglia in the periarterial adipose tissue of the pulmonary artery bifurcation in patients with and without pulmonary hypertension. “Arterial’naya Gipertenziya” (“Arterial Hypertension”). 2019;25(5):498509. (In Russ.) doi:10.18705/1607-419X-2019-25-5-498-509.Kwapiszewska G, Chwalek K, Marsh LM, et al. BDNF/TrkB signaling augments smooth muscle cell proliferation in pulmonary hypertension. Am J Pathol. 2012;181(6):2018-29. doi:10.1016/j.ajpath.2012.08.028. 26. Minnone G, De Benedetti F, Bracci-Laudiero L. NGF and Its Receptors in the RegulationKwapiszewska G, Chwalek K, Marsh LM, et al. BDNF/TrkB signaling augments smooth muscle cell proliferation in pulmonary hypertension. Am J Pathol. 2012;181(6):2018-29. doi:10.1016/j.ajpath.2012.08.028. 26. Minnone G, De Benedetti F, Bracci-Laudiero L. NGF and Its Receptors in the Regulation of Inflammatory Response. Int J Mol Sci. 2017;18(5):1028. doi:10.3390/ijms18051028.of Inflammatory Response. Int J Mol Sci. 2017;18(5):1028. doi:10.3390/ijms18051028.Prakash Y, Thompson MA, Meuchel L, et al. Neurotrophins in lung health and disease. Expert Rev Respir Med. 2010;4(3):395-411. doi:10.1586/ers.10.29.Prakash Y, Thompson MA, Meuchel L, et al. Neurotrophins in lung health and disease. Expert Rev Respir Med. 2010;4(3):395-411. doi:10.1586/ers.10.29.Urzua U, Tapia V, Geraldo MP, et al. Nerve growth factor stimulates cellular proliferation of human epithelial ovarian cancer. Horm Metab Res. 2012;44(9):656-61. doi:10.1055/s-0032-1304617.Urzua U, Tapia V, Geraldo MP, et al. Nerve growth factor stimulates cellular proliferation of human epithelial ovarian cancer. Horm Metab Res. 2012;44(9):656-61. doi:10.1055/s-0032-1304617.Kawaguchi-Manabe H, Ieda M, Kimura K, et al. A novel cardiac hypertrophic factor, neurotrophin-3, is paradoxically downregulated in cardiac hypertrophy. Life Sci. 2007;81(5):385-92. doi:10.1016/j.lfs.2007.05.024.Kawaguchi-Manabe H, Ieda M, Kimura K, et al. A novel cardiac hypertrophic factor, neurotrophin-3, is paradoxically downregulated in cardiac hypertrophy. Life Sci. 2007;81(5):385-92. doi:10.1016/j.lfs.2007.05.024.Prakash YS, Iyanoye A, Ay B, et al. Neurotrophin effects on intracellular Ca2+ and force in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2006;291(3):L447-56. doi:10.1152/ajplung.00501.2005.Prakash YS, Iyanoye A, Ay B, et al. Neurotrophin effects on intracellular Ca2+ and force in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2006;291(3):L447-56. doi:10.1152/ajplung.00501.2005.Hartman W, Helan M, Smelter D, et al. Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle. PLoS One. 2015;10(7): e0129489. doi:10.1371/journal.pone.0129489.Hartman W, Helan M, Smelter D, et al. Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle. PLoS One. 2015;10(7): e0129489. doi:10.1371/journal.pone.0129489.Blum R, Konnerth A. Neurotrophin-mediated rapid signaling in the central nervous system: mechanisms and functions. Physiology (Bethesda). 2005;20:70-8. doi:10.1152/physiol.00042.2004.Blum R, Konnerth A. Neurotrophin-mediated rapid signaling in the central nervous system: mechanisms and functions. Physiology (Bethesda). 2005;20:70-8. doi:10.1152/physiol.00042.2004.Freeman MR, Sathish V, Manlove L, et al. Brain-derived neurotrophic factor and airway fibrosis in asthma. Am J Physiol Lung Cell Mol Physiol. 2017;313(2):L360-L370. doi:10.1152/ajplung.00580.2016.Freeman MR, Sathish V, Manlove L, et al. Brain-derived neurotrophic factor and airway fibrosis in asthma. Am J Physiol Lung Cell Mol Physiol. 2017;313(2):L360-L370. doi:10.1152/ajplung.00580.2016.Lee TH, Yeh CF, Lee YT, et al. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization. Nat Commun. 2020;11(1):4254. doi:10.1038/s41467-020-18047-x.Lee TH, Yeh CF, Lee YT, et al. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization. Nat Commun. 2020;11(1):4254. doi:10.1038/s41467-020-18047-x.Dagnell C, Kemi C, Klominek J, et al. Effects of neurotrophins on human bronchial smooth muscle cell migration and matrix metalloproteinase-9 secretion. Transl Res.Dagnell C, Kemi C, Klominek J, et al. Effects of neurotrophins on human bronchial smooth muscle cell migration and matrix metalloproteinase-9 secretion. Transl Res. 2007;150(5):303-10. doi:10.1016/j.trsl.2007.05.001.2007;150(5):303-10. doi:10.1016/j.trsl.2007.05.001.Goten C, Usui S, Takashima SI, et al. Circulating nerve growth factor receptor positive cells are associated with severity and prognosis of pulmonary arterial hypertension. Pulm Circ. 2021;11(1):2045894021990525. doi:10.1177/2045894021990525.Goten C, Usui S, Takashima SI, et al. Circulating nerve growth factor receptor positive cells are associated with severity and prognosis of pulmonary arterial hypertension. Pulm Circ. 2021;11(1):2045894021990525. doi:10.1177/2045894021990525.Drilon A. TRK inhibitors in TRK fusion-positive cancers. Ann Oncol. 2019;30(Suppl_8): viii23-viii30. doi:10.1093/annonc/mdz282.Drilon A. TRK inhibitors in TRK fusion-positive cancers. Ann Oncol. 2019;30(Suppl_8): viii23-viii30. doi:10.1093/annonc/mdz282.She W, Mei Z, Zhao H, et al. Nebulized Inhalation of Anti-Nerve Growth Factor Microspheres Inhibits Airway Remodeling in an Ovalbumin-Induced Rat Asthma Model. J Aerosol Med Pulm Drug Deliv. 2019;32(2):70-7. doi:10.1089/jamp.2018.1453.She W, Mei Z, Zhao H, et al. Nebulized Inhalation of Anti-Nerve Growth Factor Microspheres Inhibits Airway Remodeling in an Ovalbumin-Induced Rat Asthma Model. J Aerosol Med Pulm Drug Deliv. 2019;32(2):70-7. doi:10.1089/jamp.2018.1453.Wise BL, Seidel MF, Lane NE. The evolution of nerve growth factor inhibition in clinical medicine. Nat Rev Rheumatol. 2021;17(1):34-46. doi:10.1038/s41584-020-00528-4.Wise BL, Seidel MF, Lane NE. The evolution of nerve growth factor inhibition in clinical medicine. Nat Rev Rheumatol. 2021;17(1):34-46. doi:10.1038/s41584-020-00528-4.Oo WM, Hunter DJ. Nerve Growth Factor (NGF) Inhibitors and Related Agents for Chronic Musculoskeletal Pain: A Comprehensive Review. BioDrugs. 2021;35(6):611-41. doi:10.1007/s40259-021-00504-8.Oo WM, Hunter DJ. Nerve Growth Factor (NGF) Inhibitors and Related Agents for Chronic Musculoskeletal Pain: A Comprehensive Review. BioDrugs. 2021;35(6):611-41. doi:10.1007/s40259-021-00504-8.Sun F, Lu Z, Zhang Y, et al. Stagedependent changes of β2adrenergic receptor signaling in right ventricular remodeling in monocrotalineinduced pulmonary arterial hypertension. Int J Mol Med. 2018;41(5):2493-504. doi:10.3892/ijmm.2018.3449.Sun F, Lu Z, Zhang Y, et al. Stagedependent changes of β2adrenergic receptor signaling in right ventricular remodeling in monocrotalineinduced pulmonary arterial hypertension. Int J Mol Med. 2018;41(5):2493-504. doi:10.3892/ijmm.2018.3449.Liang CS, Fan TH, Sullebarger JT, et al. Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation. J Clin Invest. 1989;84(4):1267-75. doi:10.1172/JCI114294.Liang CS, Fan TH, Sullebarger JT, et al. Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation. J Clin Invest. 1989;84(4):1267-75. doi:10.1172/JCI114294.Peters EL, Bogaard HJ, Vonk Noordegraaf A, et al. Neurohormonal modulation in pul­monary arterial hypertension. Eur Respir J. 2021;58(4):2004633. doi:10.1183/13993003.04633-2020.Peters EL, Bogaard HJ, Vonk Noordegraaf A, et al. Neurohormonal modulation in pul­monary arterial hypertension. Eur Respir J. 2021;58(4):2004633. doi:10.1183/13993003.04633-2020.Kreusser MM, Buss SJ, Krebs J, et al. Differential expression of cardiac neurotrophic factors and sympathetic nerve ending abnormalities within the failing heart. J Mol Cell Cardiol. 2008;44(2):380-7. doi:10.1016/j.yjmcc.2007.10.019.Kreusser MM, Buss SJ, Krebs J, et al. Differential expression of cardiac neurotrophic factors and sympathetic nerve ending abnormalities within the failing heart. J Mol Cell Cardiol. 2008;44(2):380-7. doi:10.1016/j.yjmcc.2007.10.019.Bahls M, Könemann S, Markus MRP, et al. Brain-derived neurotrophic factor is related with adverse cardiac remodeling and high NTproBNP. Sci Rep. 2019;9(1):15421. doi:10.1038/s41598-019-51776-8.Bahls M, Könemann S, Markus MRP, et al. Brain-derived neurotrophic factor is related with adverse cardiac remodeling and high NTproBNP. Sci Rep. 2019;9(1):15421. doi:10.1038/s41598-019-51776-8.

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