Advances in the discovery of drugs that treat pulmonary arterial hypertension

References

• D’alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991 Sep 1;115(5):343–349. PMID: 1863023. 10.7326/0003-4819-115-5-343.
   PubMedGoogle Scholar
• Galiè N, McLaughlin VV, Rubin LJ, et al. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J. 2019 Jan 24;53(1):1802148. PMID: 30552088. PMID: 30552088: 10.1183/13993003.02148-2018
   PubMed Web of Science ®Google Scholar
• Humbert M, Kovacs G, Hoeper MM, et al.ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43(38):3618–373136017548. 10.1093/eurheartj/ehac237
   PubMedGoogle Scholar
• Tuder RM, Archer SL, Dorfmüller P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol PMID: 24355640. 2013;62:D4–12. doi: 10.1016/j.jacc.2013.10.025.
   PubMed Web of Science ®Google Scholar
• Humbert M, Montani D, Perros F, et al. Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension. Vasc Pharmacol. 2008;49:113–118. PMID: 18606248. DOI:10.1016/j.vph.2008.06.003.
   PubMed Web of Science ®Google Scholar
• Rabinovitch MMolecular pathogenesis of pulmonary arterial hypertensionJ Clin Investig20121224306–431310.1172/JCI60658 PMID: 23202738
   PubMed Web of Science ®Google Scholar
• Cohen-Kaminsky S, Hautefort A, Price L, et al. Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first. Drug Discov Today. 2014;19:1251–1256. PMID: 24747559. DOI:10.1016/j.drudis.2014.04.007.
   PubMed Web of Science ®Google Scholar
• Ryan J, Dasgupta A, Huston J, et al. Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med. 2015;93:229–242. PMID: 25672499. DOI:10.1007/s00109-015-1263-5.
   PubMed Web of Science ®Google Scholar
• Potus F, Ruffenach G, Dahou A, et al. Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension. Circulation. 2015;132:932–943. PMID: 26162916. DOI:10.1161/CIRCULATIONAHA.115.016382.
   PubMed Web of Science ®Google Scholar
• Potus F, Malenfant S, Graydon C, et al. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014;190:318–328. PMID: 2497762. DOI:10.1164/rccm.201402-0383OC.
   PubMed Web of Science ®Google Scholar
• Ranchoux B, Antigny F, Rucker-Martin C, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation. 2015;131:1006–1018. PMID: 25593290. DOI:10.1161/CIRCULATIONAHA.114.008750.
   PubMed Web of Science ®Google Scholar
• Kherbeck N, Tamby MC, Bussone G, et al. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin Rev Allergy Immunol. 2013;44:31–38. PMID: 21394427. DOI:10.1007/s12016-011-8265-z.
   PubMed Web of Science ®Google Scholar
• Malenfant S, Neyron AS, Paulin R, et al. Signal transduction in the development of pulmonary arterial hypertension. Pulm Circ. 2013;3:278–293. PMID: 24015329. DOI:10.4103/2045-8932.114752.
   PubMed Web of Science ®Google Scholar
• Perros F, Humbert M, Cohen-Kaminsky S. Pulmonary arterial hypertension: a flavor of autoimmunity. Méd Sci. 2013;29:607–616. 12. PMID: 23859515. DOI:10.1051/medsci/2013296013.
   Google Scholar
• Montani D, Günther S, Dorfmüller P, et al. Pulmonary arterial hypertension. Orphan et J Rare Dis. 2013;8:97. PMID: 23829793. DOI:10.1186/1750-1172-8-97.
   PubMed Web of Science ®Google Scholar
• Smits AJ, Botros L, Mol MAE, et al. A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension. ERJ Open Res. 2022 May 30;8(2):00009–2022. PMID: 35651362. DOI:10.1183/23120541.00009-2022.
   PubMedGoogle Scholar
• Andreassen AK, Wergeland R, Simonsen S, et al. N-terminal pro-B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension. Am J Cardiol. 2006;98:525–529.
   PubMedGoogle Scholar
• Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest. 2006;129:1313–1321.
   PubMed Web of Science ®Google Scholar
• Yang D, Liu Z, Yang Z. Ghrelin and its relation with N-terminal brain natriuretic peptide, Endothelin-1 and nitric oxide in patients with idiopathic pulmonary hypertension. Cardiology (Switzerland). 2013;124:241–245. PMID: 23571554. DOI:10.1159/000348368.
   PubMedGoogle Scholar
• Calvier L, Legchenko E, Grimm L, et al. Galectin-3 and aldosterone as potential tandem biomarkers in pulmonary arterial hypertension. Heart. 2016;102:390–396. PMID: 26869635. DOI:10.1136/heartjnl-2015-308365.
   PubMedGoogle Scholar
• Rhodes CJ, Wharton J, Swietlik EM, et al. Using the plasma proteome for risk stratifying patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2022 May 1;205(9):1102–1111. PMID: 35081018. 10.1164/rccm.202105-1118OC.
   PubMedGoogle Scholar
• Harbaum L, Rhodes CJ, Wharton J, et al. U.K. national institute for health research bioresource rare diseases consortium, U.k. pulmonary arterial hypertension cohort study consortium, and U.S. pulmonary arterial hypertension biobank consortium. mining the plasma proteome for insights into the molecular pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2022 Jun 15;205(12):1449–1460. PMID: 35394406. 10.1164/rccm.202109-2106OC.
   PubMedGoogle Scholar
• Boucherat O, Yokokawa T, Krishna V, et al. Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension. Nat Cardiovasc Res. 2022 Aug 11;1:748–760. DOI:10.1038/s44161-022-00113-w.
   Google Scholar
• Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 114(14). PMID: 16982941. 1482–1489. 2006 Oct 3. 10.1161/CIRCULATIONAHA.106.618397.
   PubMedGoogle Scholar
• McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol. 2009 Apr 28;53(17):1573–1619. PMID: 19389575. 10.1016/j.jacc.2009.01.004.
   PubMedGoogle Scholar
• Fogel MR, Sawhney VK, Neal EA, et al. Diuresis in the ascitic patient: a randomized controlled trial of three regimens. PMID: 7035545 J Clin Gastroenterol. 1981;3Suppl 1:73–80. 10.1097/00004836-198100031-00016
   PubMedGoogle Scholar
• Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998 Sep;114(3):787–792. PMID: 9743167. DOI:10.1378/chest.114.3.787.
   PubMed Web of Science ®Google Scholar
• Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992 Jul 9;327(2):76–81. PMID: 1603139. DOI:10.1056/NEJM199207093270203.
   PubMed Web of Science ®Google Scholar
• Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. PMID: 30545968. 10.1183/13993003.01913-2018
   PubMed Web of Science ®Google Scholar
• Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992 Jul 9;327(2):70–75. PMID: 1603138. DOI:10.1056/NEJM199207093270202.
   PubMedGoogle Scholar
• Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999 Jun;159(6):1925–1932. PMID: 10351941. DOI:10.1164/ajrccm.159.6.9804054.
   PubMed Web of Science ®Google Scholar
• Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990 Apr 1;112(7):485–491. PMID: 2107780. 10.7326/0003-4819-112-7-485.
   PubMed Web of Science ®Google Scholar
• Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994 Sep 15;121(6):409–415. PMID: 8053614. DOI:10.7326/0003-4819-121-6-199409150-00003.
   PubMedGoogle Scholar
• Barst RJ, Rubin LJ, Long WA, et al.Primary Pulmonary Hypertension Study GroupA comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertensionN Engl J Med1996 Feb 13345296–30110.1056/NEJM199602013340504 PMID: 8532025
   PubMed Web of Science ®Google Scholar
• Shapiro SM, Oudiz RJ, Cao T, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol. 1997 Aug;30(2):343–349. PMID: 9247503. DOI:10.1016/s0735-1097(97)00187-3.
   PubMed Web of Science ®Google Scholar
• McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 106(12): PMID: 12234951:1477–1482. 2002 Sep 17. 10.1161/01.cir.0000029100.82385.58
   PubMedGoogle Scholar
• Olschewski H, Walmrath D, Schermuly R, et al. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med. 1996 May 1;124(9):820–824. PMID: 8610951. DOI:10.7326/0003-4819-124-9-199605010-00006.
   PubMedGoogle Scholar
• Olschewski H, Simonneau G, Galiè N, et al.Aerosolized Iloprost Randomized Study GroupInhaled iloprost for severe pulmonary hypertensionN Engl J Med2002 Aug 13475322–32910.1056/NEJMoa020204 PMID: 12151469
   PubMed Web of Science ®Google Scholar
• Opitz CF, Wensel R, Winkler J, et al. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J. 2005 Sep;26(18):1895–1902. Epub 2005 May 11. PMID: 15888496. DOI:10.1093/eurheartj/ehi283.
   PubMed Web of Science ®Google Scholar
• Higenbottam T, Butt AY, McMahon A, et al. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart. 1998 Aug;80(2):151–155. PMID: 9813561. DOI:10.1136/hrt.80.2.151.
   PubMed Web of Science ®Google Scholar
• Olschewski H, Rohde B, Behr J, et al. Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest. 2003 Oct;124(4):1294–1304. PMID: 14555558. DOI:10.1378/chest.124.4.1294.
   PubMed Web of Science ®Google Scholar
• Opitz CF, Wensel R, Bettmann M, et al. Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation. Eur Heart J. 2003 Feb;24(4):356–365. PMID: 12581683. DOI:10.1016/s0195-668x(02)00302-0.
   PubMed Web of Science ®Google Scholar
• Higenbottam TW, Butt AY, Dinh-Xaun AT, et al. Treatment of pulmonary hypertension with the continuous infusion of a prostacyclin analogue, iloprost. Heart. 1998 Feb;79(2):175–179. PMID: 9538312. DOI:10.1136/hrt.79.2.175.
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Gall H, Seyfarth HJ, et al. Long-term outcome with intravenous iloprost in pulmonary arterial hypertension. Eur Respir J. 2009 Jul;34(1):132–137. PMID: 19251782. DOI:10.1183/09031936.00130408.
   PubMed Web of Science ®Google Scholar
• Simonneau G, Barst RJ, Galie N, et al.Treprostinil Study GroupContinuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trialAm J Respir Crit Care Med2002 Mar 151656800–80410.1164/ajrccm.165.6.2106079 PMID: 11897647
   PubMed Web of Science ®Google Scholar
• Channick RN, Olschewski H, Seeger W, et al. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006 Oct 3;48(7):1433–1437. PMID: 17010807. DOI:10.1016/j.jacc.2006.05.070.
   PubMedGoogle Scholar
• McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010 May 4;55(18):1915–1922. PMID: 20430262. 10.1016/j.jacc.2010.01.027.
   PubMed Web of Science ®Google Scholar
• Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012 Dec;142(6):1383–1390. PMID: 22628490 Clinical Trial. DOI:10.1378/chest.11-2212
   PubMed Web of Science ®Google Scholar
• Tapson VF, Jing ZC, Xu KF, et al. FREEDOM-C2 study team. oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013 Sep;144(3):952–958. PMID: 23669822. DOI:10.1378/chest.12-2875.
   PubMed Web of Science ®Google Scholar
• Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. PMID: 23307827 2013;127: 624–633.doi: 10.1161/CIRCULATIONAHA.112.124388
   PubMed Web of Science ®Google Scholar
• White RJ, Jerjes-Sanchez C, Bohns Meyer GM, et al. FREEDOM-EV investigators. combination therapy with oral treprostinil for pulmonary arterial hypertension: a double-blind placebo-controlled clinical trial. Am J Respir Crit Care Med. 2020;201:707–717. PMID: 31765604. DOI:10.1164/rccm.201908-1640OC.
   PubMed Web of Science ®Google Scholar
• Moncada S, Gryglewski R, Bunting S, et al. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976;263:663–665.
   PubMed Web of Science ®Google Scholar
• Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev. 1978;30:293–331. PMID: 116251.
   PubMed Web of Science ®Google Scholar
• Km F, Martin KA, Hwa J. Cardioprotective prostacyclin signaling in vascular smooth muscle. Prostaglandins Other Lipid Mediators. 2007;82:109–118. PMID: 17164138. DOI:10.1016/j.prostaglandins.2006.05.011.
   PubMedGoogle Scholar
• Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev. 1994;46:205–229. PMID: 7938166.
   PubMed Web of Science ®Google Scholar
• Asaki T, Kuwano K, Morrison K, et al. Selexipag: an oral and selective IP prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. J Med Chem. 2015 Sep 24;58(18):7128–7137. Epub 2015 Sep 16. PMID: 26291199. DOI:10.1021/acs.jmedchem.5b00698.
   PubMedGoogle Scholar
• Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015 Dec 24;373(26):2522–2533. PMID: 26699168. 10.1056/NEJMoa1503184.
   PubMed Web of Science ®Google Scholar
• European Medicines AgencyEMA concludes safety review of Uptravi EMA 2017http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/04/news_detail_002726.jsp&mid=WC0b01ac058004d5c1“mid=WC0b01ac058004d5c1
   Google Scholar
• Torres F, Farber H, Ristic A, et al. Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial. Eur Respir J. 2019 Oct 10;54(4):1901030. PMID: 31391223. 10.1183/13993003.01030-2019.
   PubMedGoogle Scholar
• Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993 Jun 17;328(24):1732–1739. PMID: 8497283. 10.1056/NEJM199306173282402.
   PubMedGoogle Scholar
• Seo B, Oemar BS, Siebenmann R, et al. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation. 1994 Mar;89(3):1203–1208. PMID: 8124808. DOI:10.1161/01.cir.89.3.1203.
   PubMedGoogle Scholar
• Hirata Y, Emori T, Eguchi S, et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest. 1993 Apr;91(4):1367–1373. PMID: 7682570. DOI:10.1172/JCI116338.
   PubMed Web of Science ®Google Scholar
• Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001 Oct 6;358(9288):1119–1123. PMID: 11597664. 10.1016/S0140-6736(01)06250-X.
   PubMed Web of Science ®Google Scholar
• Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21;346(12):896–903. PMID: 11907289. 10.1056/NEJMoa012212.
   PubMed Web of Science ®Google Scholar
• Humbert M, Segal ES, Kiely DG, et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J. 2007 Aug;30(2):338–344. Epub 2007 May 15. PMID: 17504794. DOI:10.1183/09031936.00138706.
   PubMed Web of Science ®Google Scholar
• Simonneau G, Galiè N, Jansa P, et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol. 2014 Mar 15;172(2):332–339. Epub 2014 Jan 9. PMID: 24525158. 10.1016/j.ijcard.2013.12.179.
   PubMedGoogle Scholar
• Opitz CF, Ewert R, Kirch W, et al. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J. 2008 Aug;29(16):1936–1948. Epub 2008 Jun 17. PMID: 18562303. DOI:10.1093/eurheartj/ehn234.
   PubMedGoogle Scholar
• Wu C, Decker ER, Blok N, et al. Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist. J Med Chem. 2004 Apr 8;47(8):1969–1986. PMID: 15055997. 10.1021/jm030528p.
   PubMedGoogle Scholar
• Oudiz RJ, Galiè N, Olschewski H, et al.ARIES Study GroupLong-term ambrisentan therapy for the treatment of pulmonary arterial hypertensionJ Am Coll Cardiol2009 Nov 1754211971–198110.1016/j.jacc.2009.07.033 PMID: 19909879
   PubMedGoogle Scholar
• Hoeper MM, Olsson KM, Schneider A, et al. Severe hepatitis associated with sitaxentan and response to glucocorticoid therapy. Eur Respir J. 2009 Jun;33(6):1518–1519. PMID: 19483056. DOI:10.1183/09031936.00193308.
   PubMedGoogle Scholar
• Lavelle A, Sugrue R, Lawler G, et al. Gaine SP Sitaxentan-induced hepatic failure in two patients with pulmonary arterial hypertension. Eur Respir J. 2009 Sep;34(3):770–771. PMID: 19720812. DOI:10.1183/09031936.00058409.
   PubMed Web of Science ®Google Scholar
• Lee WT, Kirkham N, Johnson MK, et al. Sitaxentan-related acute liver failure in a patient with pulmonary arterial hypertension. Eur Respir J. 2011 Feb;37(2):472–474. PMID: 21282815. DOI:10.1183/09031936.00091610.
   PubMedGoogle Scholar
• Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008 Dec;327(3):736–745. PMID: 18780830. DOI:10.1124/jpet.108.142976.
   PubMed Web of Science ®Google Scholar
• Pulido T, Adzerikho I, Channick RN, et al. SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809–818. 23984728. 10.1056/NEJMoa1213917.
   PubMedGoogle Scholar
• Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995 Jul 27;333(4):214–221. PMID: 7540722. DOI:10.1056/NEJM199507273330403.
   PubMed Web of Science ®Google Scholar
• Galiè N, Ghofrani HA, Torbicki A, et al. SildenafiL use in pulmonary arterial hypertension (SUPER) study group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov 17;353(20):2148–2157. PMID: 16291984. 10.1056/NEJMoa050010.
   PubMedGoogle Scholar
• Rubin LJ, Badesch DB, Fleming TR, et al.SUPER-2 Study GroupLong-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study.Chest2011Nov14051274–128310.1378/chest.10-0969 PMID: 21546436
   Google Scholar
• Galiè N, Brundage BH, Ghofrani HA, et al.Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study GroupTadalafil therapy for pulmonary arterial hypertension.Circulation2009 Jun 9119222894–290310.1161/CIRCULATIONAHA.108.839274 PMID: 19470885
   Google Scholar
• BarstRJ, Oudiz RJ, Beardsworth, A, et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2011 Jun;30(6):632–643. Epub 2011 Jan 21. PMID: 21256048. Doi:10.1016/j.healun.2010.11.009
   PubMed Web of Science ®Google Scholar
• Stasch JP, Becker EM, Alonso-Alija C, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature. 2001 Mar 8;410(6825):212–215. PMID: 11242081. 10.1038/35065611.
   PubMedGoogle Scholar
• Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.Circulation. Circulation. 123(20): PMID: 21606405:2263–2273. 2011 May 24. 10.1161/CIRCULATIONAHA.110.981738
   PubMedGoogle Scholar
• Ghofrani HA, Galie N, Grimminger F, et al.PATENT-1 Study GroupRiociguat for the treatment of pulmonary arterial hypertensionN Engl J Med2013 Jul 253694330–34010.1056/NEJMoa1209655 PMID: 23883378
   PubMed Web of Science ®Google Scholar
• Humbert M, Coghlan JG, Ghofrani HA, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017 Feb;76(2):422–426. PMID: 27457511. DOI:10.1136/annrheumdis-2015-209087.
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, D’armini AM, Grimminger F, et al.CHEST-1 Study GroupRiociguat for the treatment of chronic thromboembolic pulmonary hypertensionN Engl J Med2013 Jul 253694319–32910.1056/NEJMoa1209657 PMID: 23883377
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Simonneau G, Corris PA, et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017 Sep 9;50(3):1602425. PMID: 28889107. 10.1183/13993003.02425-2016.
   PubMedGoogle Scholar
• Hoeper MM, Al-Hiti H, Benza RL, et al. REPLACE investigators. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2021 Jun;9(6):573–584. PMID: 33773120. DOI:10.1016/S2213-2600(20)30532-4.
   PubMed Web of Science ®Google Scholar
• Galiè N, Barberà JA, Frost AE, et al. AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27;373(9):834–844. PMID: 26308684. 10.1056/NEJMoa1413687.
   PubMedGoogle Scholar
• Sitbon O, Cottin V, Canuet M, et al. Initial combination therapy of macitentan and tadalafil in pulmonary arterial hypertension. Eur Respir J. 2020 Sep;56(3):2000673. PMID: 32350101. DOI:10.1183/13993003.00673-2020.
   PubMed Web of Science ®Google Scholar
• Chin KM, Sitbon O, Doelberg M, et al. Three- versus two-drug therapy for patients with newly diagnosed pulmonary arterial hypertension. J Am Coll Cardiol. 2021 Oct 5;78(14):1393–1403. PMID: 34593120. 10.1016/j.jacc.2021.07.057.
   PubMed Web of Science ®Google Scholar
• Farber HW, Benza RL. Risk assessment tools in pulmonary arterial hypertension. prognosis for prospective trials? Am J Respir Crit Care Med. 2018 Apr 1;197(7):843–845. PMID: 29373796. DOI:10.1164/rccm.201801-0042ED.
   PubMedGoogle Scholar
• Weatherald J, Boucly A, Sahay S, et al. The low-risk profile in pulmonary arterial hypertension. Time for a paradigm shift to goal-oriented clinical trial endpoints? Am J Respir Crit Care Med. 2018 Apr 1;197(7):860–868. PMID: 29256625. DOI:10.1164/rccm.201709-1840PP.
   PubMedGoogle Scholar
• Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL). Circulation. 122(2). PMID: 20585012. 164–172. 2010 Jul 13. 10.1161/CIRCULATIONAHA.109.898122.
   PubMedGoogle Scholar
• Lee WT, Ling Y, Sheares KK, et al. Predicting survival in pulmonary arterial hypertension in the UK. Eur Respir J. 2012 Sep;40(3):604–611. PMID: 22556026. DOI:10.1183/09031936.00196611.
   PubMed Web of Science ®Google Scholar
• Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012 Oct 15;186(8):790–796. PMID: 22798320. 10.1164/rccm.201203-0383OC.
   PubMed Web of Science ®Google Scholar
• Thenappan T, Glassner C, Gomberg-Maitland M. Validation of the pulmonary hypertension connection equation for survival prediction in pulmonary arterial hypertension. Chest. 2012 Mar;141(3):642–650. PMID: 21885728. DOI:10.1378/chest.11-0969.
   PubMedGoogle Scholar
• Humbert M, Sitbon O, Yaïci A, et al. French pulmonary arterial hypertension network. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010 Sep;36(3):549–555. PMID: 20562126. DOI:10.1183/09031936.00057010.
   PubMed Web of Science ®Google Scholar
• Sitbon O, Benza RL, Badesch DB, et al. Validation of two predictive models for survival in pulmonary arterial hypertension. Eur Respir J. 2015 Jul;46(1):152–164. 25837032. DOI:10.1183/09031936.00004414.
   PubMed Web of Science ®Google Scholar
• Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012 Feb;141(2):354–362. PMID: 21680644. DOI:10.1378/chest.11-0676
   PubMed Web of Science ®Google Scholar
• Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting survival in patients with pulmonary arterial hypertension: the REVEAL risk score calculator 2.0 and Comparison with ESC/ERS-Based Risk Assessment Strategies. Chest. 2019 Aug;156(2):323–337. PMID: 30772387. DOI:10.1016/j.chest.2019.02.004
   PubMed Web of Science ®Google Scholar
• Benza RL, Kanwar MK, Raina A, et al. Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for Use in Patients with Pulmonary Arterial Hypertension. Chest. 2021 Jan;159(1):337–346. PMID: 32882243. DOI:10.1016/j.chest.2020.08.2069
   PubMed Web of Science ®Google Scholar
• Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017 Aug 3;50(2):1700889. PMID: 28775050. 10.1183/13993003.00889-2017.
   PubMedGoogle Scholar
• Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017 Aug 3;50(2):1700740. PMID: 28775047. 10.1183/13993003.00740-2017.
   PubMedGoogle Scholar
• Kylhammar D, Kjellström B, Hjalmarsson C, et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur Heart J. 2018 Dec 14;39(47):4175–4181. PMID: 28575277. 10.1093/eurheartj/ehx257.
   PubMed Web of Science ®Google Scholar
• Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives: state of the art and research perspectivesEur Respir J. 2019 Jan 24;53(1):1801887. PMID: 30545970. 10.1183/13993003.01887-2018
   PubMedGoogle Scholar
• Machado RD, Eickelberg O, Elliott CG, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S32–42. PMID: 19555857. 10.1016/j.jacc.2009.04.015.
   PubMedGoogle Scholar
• Valdimarsdottir G, Goumans MJ, Rosendahl A, et al. Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein–induced activation of endothelial cells. Circulation. 106(17). PMID: 12390958. 2263–2270. 2002 Oct 22. 10.1161/01.cir.0000033830.36431.46.
   PubMedGoogle Scholar
• Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res. 2006 Feb 3;98(2):209–217. PMID: 16357305. 10.1161/01.RES.0000200180.01710.e6.
   PubMedGoogle Scholar
• Soon E, Crosby A, Southwood M, et al. Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(7):859–872. 18. PMID: 26073741 DOI:10.1164/rccm.201408-1509OC.
   PubMed Web of Science ®Google Scholar
• de Jesus Perez Va, Alastalo T-P, Wu JC, et al. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. PMID: 19139264 J Cell Biol. 2009;1841:83–99. 10.1083/jcb.200806049
   PubMedGoogle Scholar
• Hansmann G, de Jesus Perez VA, Alastalo TP, et al. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest. 2008;118:1846–1857. PMID: 18382765. DOI:10.1172/jci32503.
   PubMed Web of Science ®Google Scholar
• Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737–744. PMID: 10903931. DOI:10.1086/303059.
   PubMed Web of Science ®Google Scholar
• Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000;37:741–745. PMID: 11015450. DOI:10.1136/jmg.37.10.741.
   PubMed Web of Science ®Google Scholar
• Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105(14):1672–1678. PMID: 11940546 10.1161/01.CIR.0000012754.72951.3D.
   PubMed Web of Science ®Google Scholar
• Austin ED, Hamid R, Hemnes AR, et al. BMPR2 expression is suppressed by signaling through the estrogen receptor. Biol Sex Differ. 2012;3(1):6. PMID: 22348410 DOI:10.1186/2042-6410-3-6.
   PubMed Web of Science ®Google Scholar
• Long L, Ormiston ML, Yang X, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med. 2015 Jul;21(7):777–785. PMID: 26076038. DOI:10.1038/nm.3877.
   PubMed Web of Science ®Google Scholar
• Nikolic I, Yung L-M, Yang P, et al. Bone morphogenetic protein 9 is a mechanistic biomarker of portopulmonary hypertension. Am J Respir Crit Care Med. 2019 Apr 1;199(7):891–902. PMID: 30312106. 10.1164/rccm.201807-1236OC.
   PubMedGoogle Scholar
• Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013 Aug;123(8):3600–3613. PMID: 23867624. DOI:10.1172/JCI65592.
   PubMed Web of Science ®Google Scholar
• Spiekerkoetter E, Sung YK, Sudheendra D, et al. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J. 2017 Sep 11;50(3):1602449. PMID: 28893866. 10.1183/13993003.02449-2016.
   PubMedGoogle Scholar
• Thomas M, Docx C, Holmes AM, et al. Activin-like kinase 5 (ALK5) mediates abnormal proliferation of vascular smooth muscle cells from patients with familial pulmonary arterial hypertension and is involved in the progression of experimental pulmonary arterial hypertension induced by monocrotaline. Am J Pathol. 2009 Feb;174(2):380–389. PMID: 19116361. DOI:10.2353/ajpath.2009.080565.
   PubMedGoogle Scholar
• Yung L-M, Nikolic I, Paskin-Flerlage SD, et al. A selective transforming growth factor-β ligand trap attenuates pulmonary hypertension. Am J Respir Crit Care Med. 2016 Nov 1;194(9):1140–1151. PMID: 27115515. DOI:10.1164/rccm.201510-1955OC.
   PubMedGoogle Scholar
• Zaiman AL, Podowski M, Medicherla S, et al. Role of the TGF-β/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med. 2008 Apr 15;177(8):896–905. PMID: 18202349. 10.1164/rccm.200707-1083OC.
   PubMedGoogle Scholar
• Chen YF, Feng JA, Li P, et al. Dominant negative mutation of the TGF-β receptor blocks hypoxia-induced pulmonary vascular remodeling. J Appl Physiol (1985). 2006 Feb;100(2):564–571. PMID: 16223981. DOI:10.1152/japplphysiol.00595.2005.
   PubMedGoogle Scholar
• Sheares KK, Jeffery TK, Long L, et al. Differential effects of TGF-β1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2004 Nov;287(5):L919–27. PMID: 15220111. DOI:10.1152/ajplung.00012.2004.
   PubMedGoogle Scholar
• Graham BB, Chabon J, Gebreab L, et al. Transforming growth factor-β signaling promotes pulmonary hypertension caused by Schistosoma mansoni. Circulation. 128(12). PMID: 23958565. 1354–1364. 2013 Sep 17. 10.1161/CIRCULATIONAHA.113.003072.
   PubMedGoogle Scholar
• Yan Y, Wang XJ, Li SQ, et al. Elevated levels of plasma transforming growth factor-β1 in idiopathic and heritable pulmonary arterial hypertension. Int J Cardiol. 2016 Nov 1:222:368–374. DOI:10.1016/j.ijcard.2016.07.192 PMID: 27500766.
   PubMedGoogle Scholar
• Long L, Crosby A, Yang X, et al. Altered bone morphogenetic protein and transforming growth factor-β signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation. 119(4): PMID: 19153267:566–576. 2009 Feb 3. 10.1161/CIRCULATIONAHA.108.821504
   PubMedGoogle Scholar
• Yndestad A, Larsen K-O, Øie E, et al. Elevated levels of activin a in clinical and experimental pulmonary hypertension. J Appl Physiol (1985). 2009 Apr;106(4):1356–1364. PMID: 19196915. DOI:10.1152/japplphysiol.90719.2008.
   PubMedGoogle Scholar
• Kudryashova TV, Shen Y, Pena A, et al. Inhibitory antibodies against activin a and TGF-β reduce self-supported, but not soluble factors-induced growth of human pulmonary arterial vascular smooth muscle cells in pulmonary arterial hypertension. Int J Mol Sci. 2018 Sep 28;19(10):2957. PMID: 30274147. DOI:10.3390/ijms19102957.
   PubMedGoogle Scholar
• Yung LM, Yang P, Joshi S, et al.ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertensionSci Transl Med2020 May 1312543eaaz566010.1126/scitranslmed.aaz5660 PMID: 32404506
   PubMedGoogle Scholar
• Gomberg-Maitland M, Hoeper MM, Preston IR, et al. PULSAR Trial Investigators. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021 Apr 1;384(13):1204–1215. PMID: 33789009. 10.1056/NEJMoa2024277.
   PubMedGoogle Scholar
• Waxman AB, Risbano MG, Frantz RP, et al. The SPECTRA Study: a Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study to Assess the Effects of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH). Am J Respir Crit Care Med. 2021;203:A1187.
   Google Scholar
• Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S10–19. PMID: 19555853. 10.1016/j.jacc.2009.04.006.
   PubMedGoogle Scholar
• Adnot SLessons learned from cancer may help in the treatment of pulmonary hypertensionJ Clin Invest2005Jun11561461–146310.1172/JCI25399 PMID: 15931382
   PubMedGoogle Scholar
• Perros F, Montani D, Dorfmuller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008 Jul 1;178(1):81–88. Epub 2008 Apr 17. PMID: 18420966. 10.1164/rccm.200707-1037OC.
   PubMedGoogle Scholar
• Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005 Oct;115(10):2811–2821. PMID: 16200212. DOI:10.1172/JCI24838.
   PubMed Web of Science ®Google Scholar
• Merklinger SL, Jones PL, Martinez EC, et al. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation. 112(3): PMID: 16027270:423–431. 2005 Jul 19. 10.1161/CIRCULATIONAHA.105.540542
   PubMedGoogle Scholar
• Redner RL. Why doesn’t imatinib cure chronic myeloid leukemia? PMID: 20124443 Oncology. 2010;152:182–186. 10.1634/theoncologist.2009-0297
   Google Scholar
• Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition Clin Invest. J Clin Investig. 2005 Oct;115(10):2811–2821. PMID: 16200212. DOI:10.1172/JCI24838
   PubMed Web of Science ®Google Scholar
• Frost AE, Barst RJ, Hoeper MM, et al. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant. 2015 Nov;34(11):1366–1375. PMID: 26210752. DOI:10.1016/j.healun.2015.05.025.
   PubMed Web of Science ®Google Scholar
• Pitsiou G, Zarogoulidis P, Petridis D, et al. Inhaled tyrosine kinase inhibitors for pulmonary hypertension: a possible future treatment. Drug Des Devel Ther. 2014 Oct 7:8:1753–1763. DOI:10.2147/DDDT.S70277 PMID: 25336919.
   PubMedGoogle Scholar
• Sitapara R, Slee D, Salter-Cid L, et al. In vivo efficacy of a novel, inhaled Pdgfra/b inhibitor, Gb002, in the rat monocrotaline and pneumonectomy model of pulmonary arterial hypertension. Circulation. 2019;140:A12947.
   Google Scholar
• Galkin A, Clemons B, Garcia E, et al. GB002, a Novel Inhaled Pdgfr Kinase Inhibitor, Demonstrates Efficacy in the Su5416 Hypoxia Rat Model of Pulmonary Arterial Hypertension (PAH). Circulation. 2019;140:A11102.
   Google Scholar
• Fanburg BL, Lee SLA new role for an old molecule: serotonin as a mitogenAm J Physiol1997May2725 Pt 1L795–80610.1152/ajplung.1997.272.5.L795 PMID: 9176241
   PubMed Web of Science ®Google Scholar
• Hervé P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am j med. 1995 Sep;99(3):249–254. PMID: 7653484. DOI:10.1016/s0002-9343(99)80156-9.
   PubMed Web of Science ®Google Scholar
• Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996 Aug 29;335(9):609–616. PMID: 8692238. 10.1056/NEJM199608293350901.
   PubMedGoogle Scholar
• Marcos E, Adnot S, Pham MH, et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension.Am. J Respir Crit Care Med. 2003 Aug 15;168(4):487–493. Epub 2003 May 28. PMID: 12773327. DOI:10.1164/rccm.200210-1212OC.
   PubMedGoogle Scholar
• Marcos E, Fadel E, Sanchez O, et al. Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res. 2004;94:1263–1270. PMID: 15059929. DOI:10.1161/01.RES.0000126847.27660.69.
   PubMed Web of Science ®Google Scholar
• Dempsie Y, Morecroft I, Welsh DJ, et al. Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation. 2008;117:2928–2937. PMID: 18506000. DOI:10.1161/CIRCULATIONAHA.108.767558.
   PubMed Web of Science ®Google Scholar
• Marcos E, Adnot S, Pham MH, et al. Eddahibi SSerotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med. 2003;168:487. PMID: 12773327. DOI:10.1164/rccm.200210-1212OC.
   PubMed Web of Science ®Google Scholar
• Guignabert C, Raffestin B, Benferhat R, et al. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation. 2005;111:2812–2819. 15927991. DOI:10.1161/CIRCULATIONAHA.104.524926.
   PubMed Web of Science ®Google Scholar
• Sodimu A, Bartolome S, Igenoza OP, et al. Hemodynamic effects of fluoxetine in pulmonary arterial hypertension: an open label pilot study. Pulm Circ. 2020 Nov 25;10(4):2045894020971954. PMID: 33282204. DOI:10.1177/2045894020971954.
   Google Scholar
• Bader M. Inhibition of serotonin synthesis: a novel therapeutic paradigm. Pharmacol Ther. 2020 Jan;205:107423. Epub 2019 Oct 17. PMID: 31629717. DOI:10.1016/j.pharmthera.2019.107423.
   PubMed Web of Science ®Google Scholar
• Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987 Aug;107(2):216–223. PMID: 3605900. DOI:10.7326/0003-4819-107-2-216.
   PubMed Web of Science ®Google Scholar
• Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how reveal differs from historic and non‐us contemporary registries. Chest. 2011 Jan;139(1):128–137. Epub 2010 Jun 17. PMID: 20558556. DOI:10.1378/chest.10-0075
   PubMed Web of Science ®Google Scholar
• McGoon MD, Benza RL, Escribano‐subias P, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D51–9. PMID: 24355642. 10.1016/j.jacc.2013.10.023.
   PubMedGoogle Scholar
• Prins KW, Thenappan T. World health organization group i pulmonary hypertension: epidemiology and pathophysiology. Cardiol Clin. 2016 Aug;34(3):363–374. PMID: 27443134. DOI:10.1016/j.ccl.2016.04.001.
   PubMed Web of Science ®Google Scholar
• Chen X, Austin ED, Talati M, et al.Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defectsEur Respir J2017 Aug 3502160233710.1183/13993003.02337-2016 PMID: 28775043
   PubMedGoogle Scholar
• Simpson ER, Clyne C, Rubin G, et al. Aromatase—a brief overview. Annu Rev Physiol. 2002;64:93–127. PMID: 11826265. DOI:10.1146/annurev.physiol.64.081601.142703.
   PubMed Web of Science ®Google Scholar
• Burstein HJ, Griggs JJ, Prestrud AA, et al. American Society of Clinical Oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor‐positive breast cancer. J Oncol Pract. 2010;6:243–246. PMID: 21197188. DOI:10.1200/JOP.000082.
   PubMedGoogle Scholar
• Mair KM, Wright AF, Duggan N, et al. Sex‐dependent influence of endogenous estrogen in pulmonary hypertension. Am J Respir Crit Care Med. 2014;190:456–467. PMID: 24956156. DOI:10.1164/rccm.201403-0483OC.
   PubMed Web of Science ®Google Scholar
• de Man FS, Tu L, Handoko ML, et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:780–789. PMID: 22859525. DOI:10.1164/rccm.201203-0411OC.
   PubMed Web of Science ®Google Scholar
• Morrell NW, Danilov SM, Satyan KB, et al. Right ventricular angiotensin converting enzyme activity and expression is increased during hypoxic pulmonary hypertension. Cardiovasc Res. 1997;34:393–403. PMID: 9205554. DOI:10.1016/s0008-6363(97)00049-7.
   PubMed Web of Science ®Google Scholar
• Morrell NW, Atochina EN, Morris KG, et al. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. J Clin Invest. 1995;96:1823–1833. PMID: 7560074. DOI:10.1172/JCI118228.
   PubMed Web of Science ®Google Scholar
• Morrell NW, Morris KG, Stenmark KR. Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension. Am J Physiol. 1995;269:H1186–94. PMID: 7485548. DOI:10.1152/ajpheart.1995.269.4.H1186.
   PubMed Web of Science ®Google Scholar
• Alpert MA, Pressly TA, Mukerji V, et al. Short- and long-term hemodynamic effects of captopril in patients with pulmonary hypertension and selected connective tissue disease. Chest. 1992;102:1407–1412. PMID: 1424860. DOI:10.1378/chest.102.5.1407.
   PubMed Web of Science ®Google Scholar
• Ikram H, Maslowski AH, Nicholls MG, et al. Haemodynamic and hormonal effects of captopril in primary pulmonary hypertension. Br Heart J. 1982;48:541–545. PMID: 6756445. DOI:10.1136/hrt.48.6.541.
   PubMedGoogle Scholar
• Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. Biochem Pharmacol. 2008;75:781–786. PMID: 17897633. DOI:10.1016/j.bcp.2007.08.012.
   PubMed Web of Science ®Google Scholar
• Tallant EA, Lu X, Weiss RB, et al. Bovine aortic endothelial cells contain an angiotensin-(1–7) receptor. Hypertension. 1997;29:388–393. PMID: 9039132. DOI:10.1161/01.hyp.29.1.388.
   PubMed Web of Science ®Google Scholar
• Ferrario CM, Chappell MC, Tallant EA, et al. Counterregulatory actions of angiotensin-(1–7). Hypertension. 1997;30:535–541. PMID: 9322978. DOI:10.1161/01.hyp.30.3.535.
   PubMed Web of Science ®Google Scholar
• Brosnihan KB, Li P, Ferrario CM. Angiotensin-(1–7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996;27:523–528. PMID: 8613197. DOI:10.1161/01.hyp.27.3.523.
   PubMed Web of Science ®Google Scholar
• Nakamoto H, Ferrario CM, Fuller SB, et al. Angiotensin-(1–7) and nitric oxide interaction in renovascular hypertension. Hypertension. 1995;25:796–802. PMID: 7536715. DOI:10.1161/01.hyp.25.4.796.
   PubMed Web of Science ®Google Scholar
• Simon MA, Hanrott K, Budd DC, et al. An open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of GSK2586881 in participants with pulmonary arterial hypertension. Pulm Circ. 2022 Jan 20;12(1):e12024. PMID: 35506108. 10.1002/pul2.12024.
   PubMedGoogle Scholar
• Henning RJ. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001 Jan;49(1):27–37. PMID: 11121793. DOI:10.1016/s0008-6363(00)00229-7.
   PubMed Web of Science ®Google Scholar
• Dewachter L, Dewachter C, Naeije R. New therapies for pulmonary arterial hypertension: an update on current bench to bedside translation. Expert Opin Investig Drugs. 2010 Apr;19(4):469–488. PMID: 20367190. DOI:10.1517/13543781003727099.
   PubMed Web of Science ®Google Scholar
• Labrie F, Luu-The V, Labrie C, et al. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol. 2001;22:185–212. PMID: 11456468. DOI:10.1006/frne.2001.0216.
   PubMed Web of Science ®Google Scholar
• Bonnet S, Dumas-de-La-Roque E, Bégueret H, et al. Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension Proc Natl Acad Sci U S A2003Aug5100169488–949310.1073/pnas.1633724100 PMID: 12878719
   Google Scholar
• Bonnet S, Paulin R, Sutendra G, et al. Dehydroepiandrosterone reverses systemic vascular remodeling through the inhibition of the Akt/GSK3-β/NFAT axis. Circulation. 2009 Sep 29;120(13):1231–1240. PMID: 19752325. 10.1161/CIRCULATIONAHA.109.848911.
   PubMedGoogle Scholar
• Liu D, Si H, Reynolds KA, Zhen W, Jia Z, Dillon JS. Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a Gαi protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression. Endocrinology. 2007;148:3068–3076. PMID: 17395704. doi: 10.1210/en.2006-1378.
   PubMed Web of Science ®Google Scholar
• Liu D, Dillon JS. Dehydroepiandrosterone stimulates nitric oxide releasing vascular endothelial cells: evidence for a cell surface receptor.Steroids. 2004;69:279–289. PMID: 15183694. doi: 10.1016/j.steroids.2004.02.004.
   Google Scholar
• Alzoubi A, Toba M, Abe K, et al.Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertensionAm J Physiol Heart Circ Physiol2013 Jun 1530412H1708–1810.1152/ajpheart.00746.2012 PMID: 23585128
   PubMedGoogle Scholar
• Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109:3122–3131. 0000133187.74800.B9. PMID: 15226229. DOI:10.1161/01.CIR.0000133187.74800.B9.
   PubMed Web of Science ®Google Scholar
• Pascal JM The comings and goings of PARP-1 in response to DNA damage. DNA Repair (Amst). 2018 Nov;71:177–182. doi:10.1016/j.dnarep.2018.08.022. PMID: 30177435
   PubMed Web of Science ®Google Scholar
• Meloche J, Pflieger A, Vaillancourt M, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation PMID: 24270264. 2014;129:786–797. doi: 10.1161/CIRCULATIONAHA.113.006167.
   PubMed Web of Science ®Google Scholar
• Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009 Sep;27(5):351–357. PMID: 19711245. DOI:10.1055/s-0029-1237423.
   PubMed Web of Science ®Google Scholar
• Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020 Apr 24;126(9):1190–1208. PMID: 32324495. DOI:10.1161/CIRCRESAHA.120.315929.
   PubMedGoogle Scholar
• Meloche J, Potus F, Vaillancourt M, et al. Bromodomain-containing protein 4: the epigenetic origin of pulmonary arterial hypertension. Circ Res. 2015 Aug 28;117(6):525–535. PMID: 26224795. 10.1161/CIRCRESAHA.115.307004.
   PubMed Web of Science ®Google Scholar
• Provencher S, Potus F, Blais-Lecours P, et al. BET protein inhibition for pulmonary arterial hypertension: a pilot clinical trial. Am J Respir Crit Care Med. 2022 Jun 1;205(11):1357–1360. PMID: 35289736. 10.1164/rccm.202109-2182LE.
   PubMed Web of Science ®Google Scholar
• Handoko ML, De Man FS, Allaart CP, et al. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev. 2010;19:72–82. PMID: 20956170. DOI:10.1183/09059180.00007109.
   PubMedGoogle Scholar
• Tello K, Dalmer A, Vanderpool R, et al. Impaired right ventricular lusitropy is associated with ventilatory inefficiency in pulmonary arterial hypertension. Eur Respir J. 2019;54:1900342. PMID: 31515402. DOI:10.1183/13993003.00342-2019.
   PubMedGoogle Scholar
• Borgdorff MA, Bartelds B, Dickinson MG, et al. Sildenafil treatment in established right ventricular dysfunction improves diastolic function and attenuates interstitial fibrosis independent from afterload. Am J Physiol Heart Circ Physiol. 2014;307:H361–9. PMID: 24878769. DOI:10.1152/ajpheart.00843.2013.
   PubMedGoogle Scholar
• Gomez-Arroyo J, Sakagami M, Syed AA, et al. Iloprost reverses established fibrosis in experimental right ventricular failure. Eur Respir J. 2015;45:449–462. PMID: 25261325. DOI:10.1183/09031936.00188013.
   PubMedGoogle Scholar
• Rai N, Veeroju S, Schymura Y, et al. Effect of riociguat and sildenafil on right heart remodeling and function in pressure overload induced model of pulmonary arterial banding. BioMed Res Int. 2018;2018:3293584. PMID: 29511676. DOI:10.1155/2018/3293584.
   PubMedGoogle Scholar
• Borgdorff MAJ, Bartelds B, Dickinson MG, et al. Sildenafil enhances systolic adaptation, but does not prevent diastolic dysfunction, in the pressure-loaded right ventricle. Eur J Heart Fail. 2012;14:1067–1074. PMID: 22730335. DOI:10.1093/eurjhf/hfs094.
   PubMedGoogle Scholar
• Dai H, Jiang L, Xiao Z, et al. ACE2-angiotensin-(1-7)-Mas axis might be a promising therapeutic target for pulmonary arterial hypertension. Nat Rev Cardiol. 2015;12:374. PMID: 25940924. DOI:10.1038/nrcardio.2015.6-c1.
   PubMed Web of Science ®Google Scholar
• Spiekerkoetter E, Kawut SM, de Jesus Perez VA. New and emerging therapies for pulmonary arterial hypertension. Annu Rev Med. 2019;70:45–59. PMID: 30216732. DOI:10.1146/annurev-med-041717-085955.
   PubMed Web of Science ®Google Scholar
• Shenoy V, Kwon KC, Rathinasabapathy A, et al. Oral delivery of angiotensin-converting enzyme 2 and angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension. Hypertension. 2014;64:1248–1259. PMID: 25225206. DOI:10.1161/HYPERTENSIONAHA.114.03871.
   PubMed Web of Science ®Google Scholar
• Shenoy V, Gjymishka A, Jarajapu YP, et al. Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med. 2013;187:648–657. PMID: 23370913. DOI:10.1164/rccm.201205-0880OC.
   PubMed Web of Science ®Google Scholar