cardioКардиологияKardiologiia0022-90402412-5660Kardiomag10.18087/cardio.2019.7.10259cardio-754Research ArticleПРАКТИЧЕСКАЯ КАРДИОЛОГИЯ ПРИЛОЖЕНИЕ ДЛЯ ПРАКТИЧЕСКИХ ВРАЧЕЙ. КЛИНИЧЕСКИЕ СЕМИНАРЫPRACTICAL CARDIOLOGY SUPPLEMENT FOR PRACTISING PHYSICIANS. CLINICAL SEMINARSНовые биомаркеры легочной гипертензииNovel Biomarkers of Pulmonary HypertensionГайнитдиноваВ. В.GaynitdinovaV. V.

Москва

Gaynitdinova Viliya V. – MD, professor. 

Moscow

ivv_08@mail.ruАвдеевС. Н.AvdeevS. N.

Москва

Moscow

ФГАОУ ВО Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава России (Сеченовский Университет)РоссияPulmonology Research InstituteRussian FederationФГАОУ ВО Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава России (Сеченовский Университет); ФГБУ «НИИ пульмонологии» ФМБА РоссииРоссияSechenov First Moscow State Medical University (Sechenov University); Pulmonology Research InstituteRussian Federation2019190720195978494Copyright © Kardiomag, 20192019KardiomagKardiomaghttps://cardio.elpub.ru/jour/about/submissions#copyrightNoticehttps://cardio.elpub.ru/jour/article/view/754

Легочная гипертензия (ЛГ) представляет собой клинический синдром, характеризующийся прогрессирующим повышением легочного сосудистого сопротивления, которое приводит к ремоделированию правого желудочка, его недостаточности и преждевременной смерти пациентов. Ранняя диагностика и мониторинг прогрессирования заболевания имеют решающее значение для принятия решений о необходимой терапии. «Золотым стандартом» диагностики ЛГ является катетеризация правых отделов сердца. Для мониторирования течения болезни используется оценка систолического давления в легочной артерии с помощью трансторакальной эхокардиографии. В дополнение к этому существует потребность в неинвазивных биомаркерах, отражающих патологические изменения в сосудах легочной артерии и позволяющих диагностировать ЛГ. В обзоре излагаются данные о таких биомаркерах, как срединный фрагмент проадреномедулина, карбоксиконцевой проэндотелин-1, копептин, асимметричный диметиларгинин, 15-й фактор роста и дифференциации роста, которые классифицируются на основе их зависимости от дисфункции эндотелиальных клеток, воспаления, эпигенетики, функции сердца, окислительного стресса, внеклеточного матрикса. Определение биомаркеров, имеющих диагностическую ценность для прогнозирования тяжести, прогрессирования ЛГ и ответа на терапию, в простом анализе крови или конденсате выдыхаемого воздуха, значительно может снизить затраты на лечение и улучшить ведение больных ЛГ.

Pulmonary hypertension (PH) is a clinical syndrome characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to remodeling of the right ventricle (RV), right heart failure and premature death of patients. Early diagnosis and monitoring of disease progression are crucial for making decisions about the necessary therapy. The gold standard for the diagnosis of pulmonary hypertension is the right heart catheterization. The estimation of systolic pressure in pulmonary artery by means of transthoracic echocardiography is also used for monitoring the course of the disease. At present, there is still a need for non-invasive biomarkers that reflect pathological changes in pulmonary arterial vessels and allow diagnosing of PH. Our review outlines the new data about some biomarkers potentially useful for diagnosis and prognostication of PH. These biomarkers (mid-regional pro-adrenomedullin, carboxyterminal pro-endothelin-1, copeptin, asymmetric dimethylarginine, growth differentiation factor 15, and others) are classified based on their relationship to endothelial cell dysfunction, inflammation, epigenetics, cardiac function, oxidative stress, extracellular matrix. The determination of biomarkers that are of diagnostic value for predicting the severity, progression of PH and response to therapy, in a simple blood test or condensate of exhaled air, can significantly reduce treatment costs and improve PH management.

легочная гипертензиялегочная артериальная гипертензиябиомаркерыдиагностическаяпрогностическая значимостьpulmonary hypertensionpulmonary arterial hypertensionbiomarkersdiagnostic valueprognostic valueReferencesЧазова И. Е., Авдеев С. Н., Царева Н. А., Волков А. В., Мартынюк Т. В., Наконечников С. Н. Клинические рекомендации по диагностике и лечению легочной гипертонии. Терапевтический архив. 2014;86(9):4-23Chazova I. E., Avdeev S. N., Tsareva N. A., Volkov A. V., Martynyuk T. V., Nakonechnikov S. N. Clinical practice guidelines for the diagnosis and treatment of pulmonary hypertension. Therapeutic archive. 2014;86(9):4–23.Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European Heart Journal. 2016;37(1):67–119. DOI: 10.1093/eurheartj/ehv317Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European Heart Journal. 2016;37(1):67–119. DOI: 10.1093/eurheartj/ehv317Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F et al. Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Patients With Primary Pulmonary Hypertension. Circulation. 2000;102(8):865–70. DOI: 10.1161/01.CIR.102.8.865Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F et al. Plasma Brain Natriuretic Peptide as a Prognostic Indicator in Patients With Primary Pulmonary Hypertension. Circulation. 2000;102(8):865–70. DOI: 10.1161/01.CIR.102.8.865Williams MH, Handler CE, Akram R, Smith CJ, Das C, Smee J et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. European Heart Journal. 2006;27(12):1485–94. DOI: 10.1093/eurheartj/ehi891Williams MH, Handler CE, Akram R, Smith CJ, Das C, Smee J et al. Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. European Heart Journal. 2006;27(12):1485–94. DOI: 10.1093/eurheartj/ehi891Takatsuki S, Wagner BD, Ivy DD. B-type Natriuretic Peptide and Amino-terminal Pro-B-type Natriuretic Peptide in Pediatric Patients with Pulmonary Arterial Hypertension: Comparison of Brain Natriuretic Peptides. Congenital Heart Disease. 2012;7(3):259–67. DOI: 10.1111/j.1747-0803.2011.00620.xTakatsuki S, Wagner BD, Ivy DD. B-type Natriuretic Peptide and Amino-terminal Pro-B-type Natriuretic Peptide in Pediatric Patients with Pulmonary Arterial Hypertension: Comparison of Brain Natriuretic Peptides. Congenital Heart Disease. 2012;7(3):259–67. DOI: 10.1111/j.1747-0803.2011.00620.xНеклюдова Г. В., Авдеев С. Н., Баймаканова Г. Е. Хроническая обструктивная болезнь легких и легочная гипертензия: мозговой натрийуретический пептид как маркер легочной гипертензии. Пульмонология. 2013;3:31-5Neklyudova G. V., Avdeev S. N., Baymakanova G. E. Chronic obstructive pulmonary disease and pulmonary hypertension: natriuretic brain peptide as a marker of pulmonary hypertension. Pulmonology. 2013;3:31–5.Andreassen AK, Wergeland R, Simonsen S, Geiran O, Guevara C, Ueland T. N-Terminal Pro-B-Type Natriuretic Peptide as an Indicator of Disease Severity in a Heterogeneous Group of Patients With Chronic Precapillary Pulmonary Hypertension. The American Journal of Cardiology. 2006;98(4):525–9. DOI: 10.1016/j.amjcard.2006.02.061Andreassen AK, Wergeland R, Simonsen S, Geiran O, Guevara C, Ueland T. N-Terminal Pro-B-Type Natriuretic Peptide as an Indicator of Disease Severity in a Heterogeneous Group of Patients With Chronic Precapillary Pulmonary Hypertension. The American Journal of Cardiology. 2006;98(4):525–9. DOI: 10.1016/j.amjcard.2006.02.061Mauritz G-J, Rizopoulos D, Groepenhoff H, Tiede H, Felix J, Eilers P et al. Usefulness of Serial N-Terminal Pro-B-Type Natriuretic Peptide Measurements for Determining Prognosis in Patients With Pulmonary Arterial Hypertension. The American Journal of Cardiology. 2011;108(11):1645–50. DOI: 10.1016/j.amjcard.2011.07.025Mauritz G-J, Rizopoulos D, Groepenhoff H, Tiede H, Felix J, Eilers P et al. Usefulness of Serial N-Terminal Pro-B-Type Natriuretic Peptide Measurements for Determining Prognosis in Patients With Pulmonary Arterial Hypertension. The American Journal of Cardiology. 2011;108(11):1645–50. DOI: 10.1016/j.amjcard.2011.07.025Al-Naamani N, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Roberts KE et al. Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. Annals of the American Thoracic Society. 2016;13(1):25–30. DOI: 10.1513/AnnalsATS.201508-543OCAl-Naamani N, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Roberts KE et al. Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. Annals of the American Thoracic Society. 2016;13(1):25–30. DOI: 10.1513/AnnalsATS.201508-543OCZelniker T, Uhlmann L, Spaich S, Friedrich J, Preusch MR, Meyer FJ et al. Novel biomarkers for risk stratification in pulmonary arterial hypertension. ERJ Open Research. 2015;1(2):00008–2015. DOI: 10.1183/23120541.00008-2015Zelniker T, Uhlmann L, Spaich S, Friedrich J, Preusch MR, Meyer FJ et al. Novel biomarkers for risk stratification in pulmonary arterial hypertension. ERJ Open Research. 2015;1(2):00008–2015. DOI: 10.1183/23120541.00008-2015Sellitti DF, Koles N, Mendonça MC. Regulation of C-type natriuretic peptide expression. Peptides. 2011;32(9):1964–71. DOI: 10.1016/j.peptides.2011.07.013Sellitti DF, Koles N, Mendonça MC. Regulation of C-type natriuretic peptide expression. Peptides. 2011;32(9):1964–71. DOI: 10.1016/j.peptides.2011.07.013Suga S. Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells--evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells. Endocrinology. 1993;133(6):3038–41. DOI: 10.1210/en.133.6.3038Suga S. Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells--evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells. Endocrinology. 1993;133(6):3038–41. DOI: 10.1210/en.133.6.3038Cargill RI, Barr CS, Coutie WJ, Struthers AD, Lipworth BJ. C-type natriuretic peptide levels in cor pulmonale and in congestive heart failure. Thorax. 1994;49(12):1247–9. PMID: 7878562Cargill RI, Barr CS, Coutie WJ, Struthers AD, Lipworth BJ. C-type natriuretic peptide levels in cor pulmonale and in congestive heart failure. Thorax. 1994;49(12):1247–9. PMID: 7878562Kaiser R, Grotemeyer K, Lepper P, Stokes C, Bals R, Wilkens H. Associations of circulating natriuretic peptides with haemodynamics in precapillary pulmonary hypertension. Respiratory Medicine. 2015;109(9):1213–23. DOI: 10.1016/j.rmed.2015.02.014Kaiser R, Grotemeyer K, Lepper P, Stokes C, Bals R, Wilkens H. Associations of circulating natriuretic peptides with haemodynamics in precapillary pulmonary hypertension. Respiratory Medicine. 2015;109(9):1213–23. DOI: 10.1016/j.rmed.2015.02.014Гайнитдинова В. В., Авдеев С. Н., Шарафутдинова Л. А., Губайдуллина Р. Я. Диагностическая и прогностическая значимость N-концевого предшественника натрийуретического пептида С-типа у больных ХОБЛ с легочной гипертензии. Пульмонология. 2015;25(6):693-7Gaynitdinova V. V., Avdeev S. N., Sharafutdinova L. A., Gubay dullina R. Ya. Diagnostic and prognostic values of N-terminal pro-C type natriuretic peptide in patients with COPD and pulmonary hypertension. Pulmonology. 2015;25(6):693–7.Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJV, Pfeffer MA et al. Red Cell Distribution Width as a Novel Prognostic Marker in Heart Failure. Journal of the American College of Cardiology. 2007;50(1):40–7. DOI: 10.1016/j.jacc.2007.02.067Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJV, Pfeffer MA et al. Red Cell Distribution Width as a Novel Prognostic Marker in Heart Failure. Journal of the American College of Cardiology. 2007;50(1):40–7. DOI: 10.1016/j.jacc.2007.02.067Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M. Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease. Circulation. 2008;117(2):163–8. DOI: 10.1161/CIRCULATIONAHA.107.727545Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M. Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease. Circulation. 2008;117(2):163–8. DOI: 10.1161/CIRCULATIONAHA.107.727545Wen Y. High red blood cell distribution width is closely associated with risk of carotid artery atherosclerosis in patients with hypertension. Experimental and Clinical Cardiology. 2010;15(3):37–40. PMID: 20959889Wen Y. High red blood cell distribution width is closely associated with risk of carotid artery atherosclerosis in patients with hypertension. Experimental and Clinical Cardiology. 2010;15(3):37–40. PMID: 20959889Rhodes CJ, Wharton J, Howard LS, Gibbs JSR, Wilkins MR. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart. 2011;97(13):1054–60. DOI: 10.1136/hrt.2011.224857Rhodes CJ, Wharton J, Howard LS, Gibbs JSR, Wilkins MR. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart. 2011;97(13):1054–60. DOI: 10.1136/hrt.2011.224857Fenster BE, Lasalvia L, Schroeder JD, Smyser J, Silveira LJ, Buckner JK et al. Cystatin C: A potential biomarker for pulmonary arterial hypertension: Cystatin C for pulmonary hypertension. Respirology. 2014;19(4):583–9. DOI: 10.1111/resp.12259Fenster BE, Lasalvia L, Schroeder JD, Smyser J, Silveira LJ, Buckner JK et al. Cystatin C: A potential biomarker for pulmonary arterial hypertension: Cystatin C for pulmonary hypertension. Respirology. 2014;19(4):583–9. DOI: 10.1111/resp.12259Sanli C, Oguz D, Olgunturk R, Tunaoglu FS, Kula S, Pasaoglu H et al. Elevated Homocysteine and Asymmetric Dimethyl Arginine Levels in Pulmonary Hypertension Associated With Congenital Heart Disease. Pediatric Cardiology. 2012;33(8):1323–31. DOI: 10.1007/s00246-012-0321-9Sanli C, Oguz D, Olgunturk R, Tunaoglu FS, Kula S, Pasaoglu H et al. Elevated Homocysteine and Asymmetric Dimethyl Arginine Levels in Pulmonary Hypertension Associated With Congenital Heart Disease. Pediatric Cardiology. 2012;33(8):1323–31. DOI: 10.1007/s00246-012-0321-9Ozerol IH, Pac FA, Ozerol E, Ege E, Yologlu S, Temel I et al. Plasma endothelin-1, homocysteine and serum nitric oxide values in patients with left-to-right shunt. Indian Heart Journal. 2004;56(6):653–7. PMID: 15751522Ozerol IH, Pac FA, Ozerol E, Ege E, Yologlu S, Temel I et al. Plasma endothelin-1, homocysteine and serum nitric oxide values in patients with left-to-right shunt. Indian Heart Journal. 2004;56(6):653–7. PMID: 15751522Vélez-Martínez M, Ayers C, Mishkin JD, Bartolome SB, García CK, Torres F et al. Association of Cardiac Troponin I With Disease Severity and Outcomes in Patients With Pulmonary Hypertension. The American Journal of Cardiology. 2013;111(12):1812–7. DOI: 10.1016/j.amjcard.2013.02.036Vélez-Martínez M, Ayers C, Mishkin JD, Bartolome SB, García CK, Torres F et al. Association of Cardiac Troponin I With Disease Severity and Outcomes in Patients With Pulmonary Hypertension. The American Journal of Cardiology. 2013;111(12):1812–7. DOI: 10.1016/j.amjcard.2013.02.036Völkers M, Rohde D, Zelniker T, Weiss CS, Giannitsis E, Katus HA et al. High-sensitive Troponin T increase after exercise in patients with pulmonary arterial hypertension. BMC Pulmonary Medicine. 2013;13(1):28. DOI: 10.1186/1471-2466-13-28Völkers M, Rohde D, Zelniker T, Weiss CS, Giannitsis E, Katus HA et al. High-sensitive Troponin T increase after exercise in patients with pulmonary arterial hypertension. BMC Pulmonary Medicine. 2013;13(1):28. DOI: 10.1186/1471-2466-13-28Khan SQ, O’Brien RJ, Struck J, Quinn P, Morgenthaler N, Squire I et al. Prognostic Value of Midregional Pro-Adrenomedullin in Patients With Acute Myocardial Infarction. Journal of the American College of Cardiology. 2007;49(14):1525–32. DOI: 10.1016/j.jacc.2006.12.038Khan SQ, O’Brien RJ, Struck J, Quinn P, Morgenthaler N, Squire I et al. Prognostic Value of Midregional Pro-Adrenomedullin in Patients With Acute Myocardial Infarction. Journal of the American College of Cardiology. 2007;49(14):1525–32. DOI: 10.1016/j.jacc.2006.12.038Krüger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T. Cardiovascular and Inflammatory Biomarkers to Predict Short- and Long-Term Survival in Community-acquired Pneumonia: Results from the German Competence Network, CAPNETZ. American Journal of Respiratory and Critical Care Medicine. 2010;182(11):1426–34. DOI: 10.1164/rccm.201003-0415OCKrüger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T. Cardiovascular and Inflammatory Biomarkers to Predict Short- and Long-Term Survival in Community-acquired Pneumonia: Results from the German Competence Network, CAPNETZ. American Journal of Respiratory and Critical Care Medicine. 2010;182(11):1426–34. DOI: 10.1164/rccm.201003-0415OCSilva Marques J, Martins SR, Calisto C, Gonçalves S, Almeida AG, de Sousa JC et al. An exploratory panel of biomarkers for risk prediction in pulmonary hypertension: Emerging role of CT-proET-1. The Journal of Heart and Lung Transplantation. 2013;32(12):1214–21. DOI: 10.1016/j.healun.2013.06.020Silva Marques J, Martins SR, Calisto C, Gonçalves S, Almeida AG, de Sousa JC et al. An exploratory panel of biomarkers for risk prediction in pulmonary hypertension: Emerging role of CT-proET-1. The Journal of Heart and Lung Transplantation. 2013;32(12):1214–21. DOI: 10.1016/j.healun.2013.06.020Maisel A, Mueller C, Nowak R, Peacock WF, Landsberg JW, Ponikowski P et al. Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea. Journal of the American College of Cardiology. 2010;55(19):2062–76. DOI: 10.1016/j.jacc.2010.02.025Maisel A, Mueller C, Nowak R, Peacock WF, Landsberg JW, Ponikowski P et al. Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea. Journal of the American College of Cardiology. 2010;55(19):2062–76. DOI: 10.1016/j.jacc.2010.02.025Kolditz M, Seyfarth H-J, Wilkens H, Ewert R, Bollmann T, Dinter C et al. MR-proADM Predicts Exercise Capacity and Survival Superior to Other Biomarkers in PH. Lung. 2015;193(6):901–10. DOI: 10.1007/s00408-015-9802-yKolditz M, Seyfarth H-J, Wilkens H, Ewert R, Bollmann T, Dinter C et al. MR-proADM Predicts Exercise Capacity and Survival Superior to Other Biomarkers in PH. Lung. 2015;193(6):901–10. DOI: 10.1007/s00408-015-9802-yHeresi GA, Aytekin M, Newman J, DiDonato J, Dweik RA. Plasma Levels of High-Density Lipoprotein Cholesterol and Outcomes in Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. 2010;182(5):661–8. DOI: 10.1164/rccm.201001-0007OCHeresi GA, Aytekin M, Newman J, DiDonato J, Dweik RA. Plasma Levels of High-Density Lipoprotein Cholesterol and Outcomes in Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. 2010;182(5):661–8. DOI: 10.1164/rccm.201001-0007OCZhao Q-H, Peng F-H, Wei H, He J, Chen F-D, Di R-M et al. Serum High-Density Lipoprotein Cholesterol Levels as a Prognostic Indicator in Patients With Idiopathic Pulmonary Arterial Hypertension. The American Journal of Cardiology. 2012;110(3):433–9. DOI: 10.1016/j.amjcard.2012.03.042Zhao Q-H, Peng F-H, Wei H, He J, Chen F-D, Di R-M et al. Serum High-Density Lipoprotein Cholesterol Levels as a Prognostic Indicator in Patients With Idiopathic Pulmonary Arterial Hypertension. The American Journal of Cardiology. 2012;110(3):433–9. DOI: 10.1016/j.amjcard.2012.03.042Zhang S, Yang T, Xu X, Wang M, Zhong L, Yang Y et al. Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study. BMC Pulmonary Medicine. 2015;15(1):50. DOI: 10.1186/s12890-015-0045-8Zhang S, Yang T, Xu X, Wang M, Zhong L, Yang Y et al. Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study. BMC Pulmonary Medicine. 2015;15(1):50. DOI: 10.1186/s12890-015-0045-8Giannakoulas G, Mouratoglou S-A, Gatzoulis MA, Karvounis H. Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A systematic review. International Journal of Cardiology. 2014;174(3):618–23. DOI: 10.1016/j.ijcard.2014.04.156Giannakoulas G, Mouratoglou S-A, Gatzoulis MA, Karvounis H. Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A systematic review. International Journal of Cardiology. 2014;174(3):618–23. DOI: 10.1016/j.ijcard.2014.04.156Malhotra R, Paskin-Flerlage S, Zamanian RT, Zimmerman P, Schmidt JW, Deng DY et al. Circulating Angiogenic Modulatory Factors Predict Survival and Functional Class in Pulmonary Arterial Hypertension. Pulmonary Circulation. 2013;3(2):369–80. DOI: 10.4103/2045-8932.110445Malhotra R, Paskin-Flerlage S, Zamanian RT, Zimmerman P, Schmidt JW, Deng DY et al. Circulating Angiogenic Modulatory Factors Predict Survival and Functional Class in Pulmonary Arterial Hypertension. Pulmonary Circulation. 2013;3(2):369–80. DOI: 10.4103/2045-8932.110445Tiede SL, Gall H, Dörr O, Guilherme M dos S, Troidl C, Liebetrau C et al. New potential diagnostic biomarkers for pulmonary hypertension. European Respiratory Journal. 2015;46(5):1390–6. DOI: 10.1183/13993003.00187-2015Tiede SL, Gall H, Dörr O, Guilherme M dos S, Troidl C, Liebetrau C et al. New potential diagnostic biomarkers for pulmonary hypertension. European Respiratory Journal. 2015;46(5):1390–6. DOI: 10.1183/13993003.00187-2015Damico R, Kolb TM, Valera L, Wang L, Housten T, Tedford RJ et al. Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. 2015;191(2):208–18. DOI: 10.1164/rccm.201409-1742OCDamico R, Kolb TM, Valera L, Wang L, Housten T, Tedford RJ et al. Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. 2015;191(2):208–18. DOI: 10.1164/rccm.201409-1742OCKümpers P, Nickel N, Lukasz A, Golpon H, Westerkamp V, Olsson KM et al. Circulating angiopoietins in idiopathic pulmonary arterial hypertension. European Heart Journal. 2010;31(18):2291– 300. DOI: 10.1093/eurheartj/ehq226Kümpers P, Nickel N, Lukasz A, Golpon H, Westerkamp V, Olsson KM et al. Circulating angiopoietins in idiopathic pulmonary arterial hypertension. European Heart Journal. 2010;31(18):2291–300. DOI: 10.1093/eurheartj/ehq226Langleben D, Orfanos SE, Giovinazzo M, Hirsch A, Baron M, Senécal J-L et al. Pulmonary capillary endothelial metabolic dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension. Arthritis & Rheumatism. 2008;58(4):1156–64. DOI: 10.1002/art.23405Langleben D, Orfanos SE, Giovinazzo M, Hirsch A, Baron M, Senécal J-L et al. Pulmonary capillary endothelial metabolic dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension. Arthritis & Rheumatism. 2008;58(4):1156–64. DOI: 10.1002/art.23405Orfanos SE, Psevdi E, Stratigis N, Langleben D, Catravas JD, Kyriakidis M et al. Pulmonary capillary endothelial dysfunction in early systemic sclerosis. Arthritis & Rheumatism. 2001;44(4):902– 11. DOI: 10.1002/1529-0131(200104)44:4<902::AIDANR147>3.3.CO;2-0Orfanos SE, Psevdi E, Stratigis N, Langleben D, Catravas JD, Kyriakidis M et al. Pulmonary capillary endothelial dysfunction in early systemic sclerosis. Arthritis & Rheumatism. 2001;44(4):902– 11. DOI: 10.1002/1529-0131(200104)44:4<902::AIDANR147>3.3.CO;2-0Langleben D, Orfanos SE, Giovinazzo M, Schlesinger RD, Hirsch AM, Blenkhorn F et al. Acute Vasodilator Responsiveness and Microvascular Recruitment in Idiopathic Pulmonary Arterial Hypertension. Annals of Internal Medicine. 2015;162(2):154–6. DOI: 10.7326/M14-1402Langleben D, Orfanos SE, Giovinazzo M, Schlesinger RD, Hirsch AM, Blenkhorn F et al. Acute Vasodilator Responsiveness and Microvascular Recruitment in Idiopathic Pulmonary Arterial Hypertension. Annals of Internal Medicine. 2015;162(2):154–6. DOI: 10.7326/M14-1402Nickel N, Kempf T, Tapken H, Tongers J, Laenger F, Lehmann U et al. Growth Differentiation Factor-15 in Idiopathic Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. 2008;178(5):534–41. DOI: 10.1164/rccm.200802-235OCNickel N, Kempf T, Tapken H, Tongers J, Laenger F, Lehmann U et al. Growth Differentiation Factor-15 in Idiopathic Pulmonary Arterial Hypertension. American Journal of Respiratory and Critical Care Medicine. 2008;178(5):534–41. DOI: 10.1164/rccm.200802-235OCHo JE, Liu C, Lyass A, Courchesne P, Pencina MJ, Vasan RS et al. Galectin-3, a Marker of Cardiac Fibrosis, Predicts Incident Heart Failure in the Community. Journal of the American College of Cardiology. 2012;60(14):1249–56. DOI: 10.1016/j.jacc.2012.04.053Ho JE, Liu C, Lyass A, Courchesne P, Pencina MJ, Vasan RS et al. Galectin-3, a Marker of Cardiac Fibrosis, Predicts Incident Heart Failure in the Community. Journal of the American College of Cardiology. 2012;60(14):1249–56. DOI: 10.1016/j.jacc.2012.04.053Fenster BE, Lasalvia L, Schroeder JD, Smyser J, Silveira LJ, Buckner JK et al. Galectin-3 levels are associated with right ventricular functional and morphologic changes in pulmonary arterial hypertension. Heart and Vessels. 2016;31(6):939–46. DOI: 10.1007/s00380-015-0691-zFenster BE, Lasalvia L, Schroeder JD, Smyser J, Silveira LJ, Buckner JK et al. Galectin-3 levels are associated with right ventricular functional and morphologic changes in pulmonary arterial hypertension. Heart and Vessels. 2016;31(6):939–46. DOI: 10.1007/s00380-015-0691-zLi LС, Li J, Gao J. Functions of Galectin-3 and Its Role in Fibrotic Diseases. Journal of Pharmacology and Experimental Therapeutics. 2014;351(2):336–43. DOI: 10.1124/jpet.114.218370Li LС, Li J, Gao J. Functions of Galectin-3 and Its Role in Fibrotic Diseases. Journal of Pharmacology and Experimental Therapeutics. 2014;351(2):336–43. DOI: 10.1124/jpet.114.218370Nadadur RD, Umar S, Wong G, Eghbali M, Iorga A, Matori H et al. Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension. Journal of Applied Physiology. 2012;113(1):149–58. DOI: 10.1152/japplphysiol.01349.2011Nadadur RD, Umar S, Wong G, Eghbali M, Iorga A, Matori H et al. Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension. Journal of Applied Physiology. 2012;113(1):149–58. DOI: 10.1152/japplphysiol.01349.2011Lorenzen JM, Nickel N, Krämer R, Golpon H, Westerkamp V, Olsson KM et al. Osteopontin in Patients With Idiopathic Pulmonary Hypertension. Chest. 2011;139(5):1010–7. DOI: 10.1378/chest.10-1146Lorenzen JM, Nickel N, Krämer R, Golpon H, Westerkamp V, Olsson KM et al. Osteopontin in Patients With Idiopathic Pulmonary Hypertension. Chest. 2011;139(5):1010–7. DOI: 10.1378/chest.10-1146Le Hiress M, Tu L, Ricard N, Phan C, Thuillet R, Fadel E et al. Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex. American Journal of Respiratory and Critical Care Medicine. 2015;192(8):983–97. DOI: 10.1164/rccm.201402-0322OCLe Hiress M, Tu L, Ricard N, Phan C, Thuillet R, Fadel E et al. Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex. American Journal of Respiratory and Critical Care Medicine. 2015;192(8):983–97. DOI: 10.1164/rccm.201402-0322OCStefanantoni K, Sciarra I, Vasile M, Badagliacca R, Poscia R, Pendolino M et al. Elevated serum levels of macrophage migration inhibitory factor and stem cell growth factor β in patients with idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Reumatismo. 2015;66(4):270–6. DOI: 10.4081/reumatismo.2014.774Stefanantoni K, Sciarra I, Vasile M, Badagliacca R, Poscia R, Pendolino M et al. Elevated serum levels of macrophage migration inhibitory factor and stem cell growth factor β in patients with idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Reumatismo. 2015;66(4):270–6. DOI: 10.4081/reumatismo.2014.774Özpelit E, Akdeniz B, Özpelit ME, Tas S, Bozkurt S, Tertemiz KC et al. Prognostic value of neutrophil-to-lymphocyte ratio in pulmonary arterial hypertension. Journal of International Medical Research. 2015;43(5):661–71. DOI: 10.1177/0300060515589394Özpelit E, Akdeniz B, Özpelit ME, Tas S, Bozkurt S, Tertemiz KC et al. Prognostic value of neutrophil-to-lymphocyte ratio in pulmonary arterial hypertension. Journal of International Medical Research. 2015;43(5):661–71. DOI: 10.1177/0300060515589394Olsson KM, Olle S, Fuge J, Welte T, Hoeper MM, Lerch C et al. CXCL13 in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Respiratory Research. 2016;17(1):21. DOI: 10.1186/s12931-016-0336-5Olsson KM, Olle S, Fuge J, Welte T, Hoeper MM, Lerch C et al. CXCL13 in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Respiratory Research. 2016;17(1):21. DOI: 10.1186/s12931-016-0336-5Шайдаков Е. В., Евлахов В. И. Роль эндотелия в патогенезе хронической тромбо-эмболической лёгочной гипертензии. Ангиология и сосудистая хирургия. 2016;22(1):22-6Shaidakov E. V., Yevlakhov V. I. Role of endothelium in pathogenesis of chronic thromboembolic pulmonary hypertension. Angiology and vascular surgery. 2016;22(1):22–6.Sarrion I, Milian L, Juan G, Ramon M, Furest I, Carda C et al. Role of Circulating miRNAs as Biomarkers in Idiopathic Pulmonary Arterial Hypertension: Possible Relevance of miR-23a. Oxidative Medicine and Cellular Longevity. 2015;2015:792846. DOI: 10.1155/2015/792846Sarrion I, Milian L, Juan G, Ramon M, Furest I, Carda C et al. Role of Circulating miRNAs as Biomarkers in Idiopathic Pulmonary Arterial Hypertension: Possible Relevance of miR-23a. Oxidative Medicine and Cellular Longevity. 2015;2015:792846. DOI: 10.1155/2015/792846Paulin R, Sutendra G, Gurtu V, Dromparis P, Haromy A, Provencher S et al. A miR-208–Mef2 Axis Drives the Decom pensation of Right Ventricular Function in Pulmonary Hypertension. Circulation Research. 2015;116(1):56–69. DOI: 10.1161/CIRCRESAHA.115.303910Paulin R, Sutendra G, Gurtu V, Dromparis P, Haromy A, Provencher S et al. A miR-208–Mef2 Axis Drives the Decom pensation of Right Ventricular Function in Pulmonary Hypertension. Circulation Research. 2015;116(1):56–69. DOI: 10.1161/CIRCRESAHA.115.303910Reis GS, Augusto VS, Silveira APC, Jordão AA, Baddini-Martinez J, Neto OP et al. Oxidative-Stress Biomarkers in Patients with Pulmonary Hypertension. Pulmonary Circulation. 2013;3(4):856–61. DOI: 10.1086/674764Reis GS, Augusto VS, Silveira APC, Jordão AA, Baddini-Martinez J, Neto OP et al. Oxidative-Stress Biomarkers in Patients with Pulmonary Hypertension. Pulmonary Circulation. 2013;3(4):856– 61. DOI: 10.1086/674764Cracowski J-L, Degano B, Chabot F, Labarère J, Schwedhelm E, Monneret D et al. Independent Association of Urinary F2-Isoprostanes With Survival in Pulmonary Arterial Hypertension. Chest. 2012;142(4):869–76. DOI: 10.1378/chest.11-1267Cracowski J-L, Degano B, Chabot F, Labarère J, Schwedhelm E, Monneret D et al. Independent Association of Urinary F2-Isoprostanes With Survival in Pulmonary Arterial Hypertension. Chest. 2012;142(4):869–76. DOI: 10.1378/chest.11-1267Sharma S, Umar S, Potus F, Iorga A, Wong G, Meriwether D et al. Apolipoprotein A-I Mimetic Peptide 4F Rescues Pulmonary Hypertension by Inducing MicroRNA-193-3p. Circulation. 2014;130(9):776–85. DOI: 10.1161/CIRCULATIONAHA.114.007405Sharma S, Umar S, Potus F, Iorga A, Wong G, Meriwether D et al. Apolipoprotein A-I Mimetic Peptide 4F Rescues Pulmonary Hypertension by Inducing MicroRNA-193-3p. Circulation. 2014;130(9):776–85. DOI: 10.1161/CIRCULATIONAHA.114.007405Ross DJ, Hough G, Hama S, Aboulhosn J, Belperio JA, Saggar R et al. Proinflammatory High-Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension. Pulmonary Circulation. 2015;5(4):640–8. DOI: 10.1086/683695Ross DJ, Hough G, Hama S, Aboulhosn J, Belperio JA, Saggar R et al. Proinflammatory High-Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension. Pulmonary Circulation. 2015;5(4):640–8. DOI: 10.1086/683695Schumann C, Lepper PM, Frank H, Schneiderbauer R, Wibmer T, Kropf C et al. Circulating biomarkers of tissue remodelling in pulmonary hypertension. Biomarkers. 2010;15(6):523–32. DOI: 10.3109/1354750X.2010.492431Schumann C, Lepper PM, Frank H, Schneiderbauer R, Wibmer T, Kropf C et al. Circulating biomarkers of tissue remodelling in pulmonary hypertension. Biomarkers. 2010;15(6):523–32. DOI: 10.3109/1354750X.2010.492431Hessel M, Steendijk P, den Adel B, Schutte C, van der Laarse A. Pressure Overload-induced Right Ventricular Failure is Associated with Re-expression of Myocardial Tenascin-C and Elevated Plasma Tenascin-C Levels. Cellular Physiology and Biochemistry. 2009;24(3–4):201–10. DOI: 10.1159/000233246Hessel M, Steendijk P, den Adel B, Schutte C, van der Laarse A. Pressure Overload-induced Right Ventricular Failure is Associated with Re-expression of Myocardial Tenascin-C and Elevated Plasma Tenascin-C Levels. Cellular Physiology and Biochemistry. 2009;24(3–4):201–10. DOI: 10.1159/000233246Mansoor JK, Schelegle ES, Davis CE, Walby WF, Zhao W, Aksenov AA et al. Analysis of Volatile Compounds in Exhaled Breath Condensate in Patients with Severe Pulmonary Arterial Hypertension. PLoS ONE. 2014;9(4):e95331. DOI: 10.1371/journal.pone.0095331Mansoor JK, Schelegle ES, Davis CE, Walby WF, Zhao W, Aksenov AA et al. Analysis of Volatile Compounds in Exhaled Breath Condensate in Patients with Severe Pulmonary Arterial Hypertension. PLoS ONE. 2014;9(4):e95331. DOI: 10.1371/journal.pone.0095331

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