Emerging pharmacotherapies for the treatment of pulmonary arterial hypertension

References

• Galie N, Humbert M, Vachiery JL, 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). Eur Heart J. 2016 [cited 2016 Jan 1];37(1):67–119.
   PubMed Web of Science ®Google Scholar
• Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010 May 11;121(18):2045–2066. doi: 10.1161/CIRCULATIONAHA.108.847707
   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 Jan;53(1):1801913. doi: 10.1183/13993003.01913-2018
   PubMed Web of Science ®Google Scholar
• Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 [2022 Oct 11];43(38):3618–3731. doi: 10.1093/eurheartj/ehac237
   PubMed Web of Science ®Google Scholar
• McLaughlin VV, SP G, Howard LS, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D73–81. doi: 10.1016/j.jacc.2013.10.034
   PubMed Web of Science ®Google Scholar
• Channick R, Preston I, Klinger JR. Oral therapies for pulmonary arterial hypertension: endothelin receptor antagonists and phosphodiesterase-5 inhibitors. Clin Chest Med. 2013 Dec;34(4):811–824. doi: 10.1016/j.ccm.2013.09.005
   PubMed Web of Science ®Google Scholar
• Munyombwe T, Hofer S, Fitzsimons D, et al. An evaluation of the Minnesota living with heart failure questionnaire using Rasch analysis. Qual Life Res. 2014 Aug;23(6):1753–1765. doi: 10.1007/s11136-013-0617-0
   PubMed Web of Science ®Google Scholar
• Gomberg-Maitland M, Thenappan T, Rizvi K, et al. United States validation of the Cambridge pulmonary hypertension outcome Review (CAMPHOR). J Heart Lung Transplant. 2008 Jan;27(1):124–130. doi: 10.1016/j.healun.2007.10.004
   PubMed Web of Science ®Google Scholar
• Peacock AJ, Naeije R, Galie N, et al. End-points and clinical trial design in pulmonary arterial hypertension: have we made progress? Eur Respir J. 2009 Jul;34(1):231–242. doi: 10.1183/09031936.00107108
   PubMed Web of Science ®Google Scholar
• Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010 Jul 13;122(2):156–163. doi: 10.1161/CIRCULATIONAHA.109.911818
   PubMed Web of Science ®Google Scholar
• Tremblay E, Gosselin C, Mai V, et al. Assessment of clinical worsening end points as a surrogate for mortality in pulmonary arterial hypertension: a systematic review and meta-analysis of randomized controlled trials. Circulation. 2022 Aug 23;146(8):597–612. doi: 10.1161/CIRCULATIONAHA.121.058635
   PubMed Web of Science ®Google Scholar
• Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension: a review. JAMA. 2022 Apr 12;327(14):1379–1391. doi: 10.1001/jama.2022.4402
   PubMed Web of Science ®Google Scholar
• Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011 Jun 15;183(12):1723–1729. doi: 10.1164/rccm.201101-0093OC
   PubMed Web of Science ®Google Scholar
• Blount MA, Beasley A, Zoraghi R, et al. Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol. 2004 Jul;66(1):144–152. doi: 10.1124/mol.66.1.144
   PubMed Web of Science ®Google Scholar
• Eldon MA, Parsley EL, Maurer M, et al. Safety, tolerability, and pharmacokinetics of RT234 (vardenafil inhalation powder): a first-in-human, ascending single- and multiple-dose study in healthy subjects. J Aerosol Med Pulm Drug Deliv. 2021 Aug;34(4):251–261. doi: 10.1089/jamp.2020.1651
   PubMed Web of Science ®Google Scholar
• Benza RL, Franco V, Aras MA, et al. Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design. Respir Res. 2022 Dec 17;23(1):355. doi: 10.1186/s12931-022-02262-9
   PubMed Web of Science ®Google Scholar
• Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov 17;353(20):2148–2157. doi: 10.1056/NEJMoa050010
   PubMed Web of Science ®Google Scholar
• Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008 Oct 21;149(8):521–530. doi: 10.7326/0003-4819-149-8-200810210-00004
   PubMed Web of Science ®Google Scholar
• Vizza CD, Sastry BK, Safdar Z, et al. Efficacy of 1, 5, and 20 mg oral sildenafil in the treatment of adults with pulmonary arterial hypertension: a randomized, double-blind study with open-label extension. BMC Pulm Med. 2017 Feb 23;17(1):44. doi: 10.1186/s12890-017-0374-x
   PubMedGoogle Scholar
• Chang SA, Kim HK, Chang HJ, et al. Acute hemodynamic changes after single administration of Udenafil in pulmonary arterial hypertension: a Phase IIa study. Korean Circ J. 2019 Apr;49(4):353–360. doi: 10.4070/kcj.2018.0281
   PubMed Web of Science ®Google Scholar
• Chang HJ, Song S, Chang SA, et al. Efficacy and safety of Udenafil for the treatment of pulmonary arterial hypertension: a placebo-controlled, double-blind, Phase IIb clinical trial. Clin Ther. 2019 Aug;41(8):1499–1507. doi: 10.1016/j.clinthera.2019.05.006
   PubMed Web of Science ®Google Scholar
• Bajwa EK, Cislak D, Palcza J, et al. Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). Respir med. 2023 Jan;206:107065.
   PubMed Web of Science ®Google Scholar
• A study of the efficacy and safety of MK-5475 in participants with pulmonary arterial hypertension (INSIGNIA-PAH: phase 2/3 study of an inhaled sGC Stimulator in PAH) (p. MK-5475–007 ClinicalTrials.gov: National Library of Medicine 2021 [cited 2023 Sept 2023]. Available from: https://clinicaltrials.gov/study/NCT04732221
   Google Scholar
• Becker-Pelster EM, Hahn MG, Delbeck M, et al. Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC. Respir Res. 2022 Oct 1;23(1):272. doi: 10.1186/s12931-022-02189-1
   PubMed Web of Science ®Google Scholar
• This study tests the safety of inhaled BAY1237592, how the drug is tolerated and how it effects patients with high blood pressure in the arteries of the lungs in the two different disease groups pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) (ATMOS) ClinicalTrial.gov: National Library of Medicine 2019 [cited 2023 Sept 23]. Available from: https://clinicaltrials.gov/study/NCT03754660
   Google Scholar
• Belge C, Delcroix M. Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience. Ther Adv Respir Dis. 2019 Jan;13:1753466618823440. doi: 10.1177/1753466618823440
   Web of Science ®Google Scholar
• Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809–818. doi: 10.1056/NEJMoa1213917
   PubMed Web of Science ®Google Scholar
• Bagnato A, Rosano L. The endothelin axis in cancer. Int J Biochem Cell Biol. 2008;40(8):1443–1451. doi: 10.1016/j.biocel.2008.01.022
   PubMed Web of Science ®Google Scholar
• Weathers SP, Rood-Breithaupt J, de Groot J, et al. Results of a phase I trial to assess the safety of macitentan in combination with temozolomide for the treatment of recurrent glioblastoma. Neurooncol Adv. 2021 Jan;3(1):vdab141. doi: 10.1093/noajnl/vdab141
   PubMedGoogle Scholar
• Outcome study assessing a 75 milligrams (mg) dose of macitentan in patients with pulmonary arterial hypertension (UNISUS) clinicaltrials.Gov National Library of Medicine 2023 [cited 2023 Apr 2]. Available from: https://clinicaltrials.gov/study/NCT04273945
   Google Scholar
• Melian EB, Goa KL. Beraprost: a review of its pharmacology and therapeutic efficacy in the treatment of peripheral arterial disease and pulmonary arterial hypertension. Drugs. 2002;62(1):107–133. doi: 10.2165/00003495-200262010-00005
   PubMed Web of Science ®Google Scholar
• Yoon HS, Choi WJ, Sung IH, et al. Effects of beraprost sodium on subjective symptoms in diabetic patients with peripheral arterial disease. Clin Orthop Surg. 2013 Jun;5(2):145–151. doi: 10.4055/cios.2013.5.2.145
   PubMedGoogle Scholar
• Sakao S, Tanabe N, Kasahara Y, et al. Long-term survival of Japanese patients with pulmonary arterial hypertension treated with beraprost sodium, an oral prostacyclin analogue. Intern Med. 2014;53(17):1913–1920. doi: 10.2169/internalmedicine.53.2573
   PubMed Web of Science ®Google Scholar
• Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003 Jun 18;41(12):2119–2125. doi: 10.1016/S0735-1097(03)00463-7
   PubMed Web of Science ®Google Scholar
• Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002 May 1;39(9):1496–1502. doi: 10.1016/S0735-1097(02)01786-2
   PubMed Web of Science ®Google Scholar
• Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension. J Am Coll Cardiol. 1999 Oct;34(4):1188–1192. doi: 10.1016/S0735-1097(99)00312-5
   PubMed Web of Science ®Google Scholar
• Kumar P, Thudium E, Laliberte K, et al. A comprehensive Review of treprostinil pharmacokinetics via four routes of administration. Clin Pharmacokinet. 2016 Dec;55(12):1495–1505. doi: 10.1007/s40262-016-0409-0
   PubMed Web of Science ®Google Scholar
• Roscigno RF, Vaughn T, Parsley E, et al. Comparative bioavailability of inhaled treprostinil administered as LIQ861 and Tyvaso(R) in healthy subjects. Vasc Pharmacol. 2021 Jun;138:106840.
   PubMed Web of Science ®Google Scholar
• A study to evaluate the efficacy, safety and pharmacokinetics of treprostinil Palmitil inhalation powder in participants with pulmonary arterial hypertension ClinicalTrials.Gov: national Library of Medicine 2022 [updated August 24 2022 cited 2023 April 29]. Available from: https://clinicaltrials.gov/study/NCT05147805
   Google Scholar
• A study to assess the safety, tolerability, and effectiveness of the long-term use of treprostinil palmitil inhalation powder (TPIP) in participants with pulmonary arterial hypertension (PAH): Clinicaltrials.gov; 2022 [cited 2023 Apr 29]. Available from: https://clinicaltrials.gov/study/NCT05649748
   Google Scholar
• Clapp LH, Gurung R. The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: role of membrane versus nuclear receptors. Prosta Other Lipid Mediat. 2015 Jul;120:56–71. doi: 10.1016/j.prostaglandins.2015.04.007
   PubMed Web of Science ®Google Scholar
• Grundy JS, King CD, Adams JW, et al. Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers. Pulm Circ. 2020 Apr;10(2):2045894020922814. doi: 10.1177/2045894020922814
   Web of Science ®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;54(4):1901030. doi: 10.1183/13993003.01030-2019
   PubMed Web of Science ®Google Scholar
• Klings E, Barbera J, Grover R, et al. Long-term data from study APD811-007, an open-label extension study Evaluating ralinepag for the treatment of pulmonary arterial hypertension. In: A96. GIANTS STADIUM: tREATMENTS and TRIALS in PULMONARY. HYPERTENSION: American Thoracic Society; 2022. p. A2149–A2149.
   Google Scholar
• A study evaluating the efficacy and safety of ralinepag to improve treatment outcomes in PAH patients ClinicalTrials.Gov: National Library of Medicine 2018 [cited 2023 Sept 24]. Available from: https://clinicaltrials.gov/study/NCT03626688
   Google Scholar
• A study of ralinepag to evaluate effects on exercise capacity by CPET in subjects with WHO group 1 PH (CAPACITY) ClinicalTrials.gov: National Library of Medicine 2020 [cited 2023 Sept 24]. Available from: https://clinicaltrials.gov/study/NCT04084678?tab=history&a=25
   Google Scholar
• Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015 Aug 27;373(9):834–844. doi: 10.1056/NEJMoa1413687
   PubMed Web of Science ®Google Scholar
• Johnson S, Sommer N, Cox-Flaherty K, et al. Pulmonary hypertension: a contemporary review. Am J Respir Crit Care Med. 2023 Sep 1;208(5):528–548. doi: 10.1164/rccm.202302-0327SO
   PubMed Web of Science ®Google Scholar
• In: Chin K. editor. Macitentan/Tadalafil fixed-dose combination in pulmonary arterial hypertension - a DUE. The American College of Cardiology annual scientific session 2023. New Orleans LA
   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. doi: 10.1016/j.jacc.2021.07.057
   PubMed Web of Science ®Google Scholar
• McLaughlin V, Chin K, Doelberg M, et al. Initial triple Oral therapy in pulmonary arterial hypertension (PAH): extended long-term outcome data from TRITON. J Heart Lung Transplant. 2021;40(4):S108. doi: 10.1016/j.healun.2021.01.349
   PubMedGoogle Scholar
• Lyle MA, Davis JP, Brozovich FV. Regulation of pulmonary vascular smooth muscle contractility in pulmonary arterial hypertension: implications for therapy. Front Physiol. 2017;8:614. doi: 10.3389/fphys.2017.00614
   PubMed Web of Science ®Google Scholar
• Yamamura A, Nayeem MJ, Sato M. The rho kinase 2 (ROCK2)-specific inhibitor KD025 ameliorates the development of pulmonary arterial hypertension. Biochem Biophys Res Commun. 2021 Jan 1;534:795–801. doi: 10.1016/j.bbrc.2020.10.106
   PubMed Web of Science ®Google Scholar
• Homma N, Nagaoka T, Morio Y, et al. Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation. J Cardiovasc Pharmacol. 2007 Dec;50(6):697–702. doi: 10.1097/FJC.0b013e3181593774
   PubMed Web of Science ®Google Scholar
• Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J. 2013;77(10):2619–2625. doi: 10.1253/circj.CJ-13-0443
   PubMed Web of Science ®Google Scholar
• Ruan H, Zhang Y, Liu R, et al. The acute effects of 30 mg vs 60 mg of intravenous fasudil on patients with congenital heart defects and severe pulmonary arterial hypertension. Congenit Heart Dis. 2019;14(4):645–650. doi: 10.1111/chd.12764
   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. Eur Respir J. 2019 Jan;53(1):1801887. doi: 10.1183/13993003.01887-2018
   PubMed Web of Science ®Google Scholar
• Eddahibi S, Humbert M, Sediame S, et al. Imbalance between platelet vascular endothelial growth factor and platelet-derived growth factor in pulmonary hypertension. Effect of prostacyclin therapy. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1493–1499. doi: 10.1164/ajrccm.162.4.2003124
   PubMed Web of Science ®Google Scholar
• Xiao Y, Chen PP, Zhou RL, et al. Pathological mechanisms and potential therapeutic targets of pulmonary arterial hypertension: a review. Aging Dis. 2020 Dec;11(6):1623–1639. doi: 10.14336/AD.2020.0111
   PubMed Web of Science ®Google Scholar
• de Miguel I M, Cruz-Utrilla A, Oliver E, et al. Novel molecular mechanisms involved in the Medical treatment of pulmonary arterial hypertension. Int J Mol Sci. 2023 Feb 19;24(4):4147. doi: 10.3390/ijms24044147
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013 Mar 12;127(10):1128–1138. doi: 10.1161/CIRCULATIONAHA.112.000765
   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. doi: 10.1016/j.healun.2015.05.025
   PubMed Web of Science ®Google Scholar
• Positioning imatinib for pulmonary arterial hypertension (PIPAH) ClinicalTrials.Gov: National Library of Medicine 2020 [cited 2023 Jun 5]. Available from: https://clinicaltrials.gov/ct2/show/NCT04416750
   Google Scholar
• A study of AV-101 (dry powder inhaled imatinib) in patients with pulmonary arterial hypertension (PAH) (IMPAHCT) ClinicalTrials.gov: National Library of Medicine 2021 [cited 2023 Sep 5]. Available from: https://clinicaltrials.gov/study/NCT05036135
   Google Scholar
• Galkin A, Sitapara R, Clemons B, et al. Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension. Eur Respir J. 2022 Dec;60(6):2102356. doi: 10.1183/13993003.02356-2021
   PubMed Web of Science ®Google Scholar
• Frantz RP, VV M, Sahay S, et al. Seralutinib for the treatment of pulmonary arterial hypertension (PAH): results from the phase 2 TORREY trial. Am J Respir Crit Care Med. 2023;207:A6726.
   Web of Science ®Google Scholar
• Fessel JP, Loyd JE, Austin ED. The genetics of pulmonary arterial hypertension in the post-BMPR2 era. Pulm Circ. 2011 Jul;1(3):305–319. doi: 10.4103/2045-8932.87293
   PubMedGoogle Scholar
• Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019 Jan;53(1):1801899. doi: 10.1183/13993003.01899-2018
   PubMed Web of Science ®Google Scholar
• Theobald V, Benjamin N, Seyfarth HJ, et al. Reduction of BMPR2 mRNA expression in peripheral blood of pulmonary arterial hypertension patients: a Marker for disease severity? Genes (Basel). 2022 Apr 26;13(5):759. doi: 10.3390/genes13050759
   PubMed Web of Science ®Google Scholar
• Rol N, Kurakula KB, Happe C, et al. TGF-β and BMPR2 signaling in PAH: two black sheep in one family. Int J Mol Sci. 2018 Aug 31;19(9):2585. doi: 10.3390/ijms19092585
   PubMed Web of Science ®Google Scholar
• Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003 Jun 13;113(6):685–700. doi: 10.1016/S0092-8674(03)00432-X
   PubMed Web of Science ®Google Scholar
• Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol. 2001 Jun;187(3):265–276. doi: 10.1002/jcp.1080
   PubMed Web of Science ®Google Scholar
• Guignabert C, Humbert M. Targeting transforming growth factor-β receptors in pulmonary hypertension. Eur Respir J. 2021 Feb;57(2):2002341. doi: 10.1183/13993003.02341-2020
   PubMed Web of Science ®Google Scholar
• Condon DF, Agarwal S, Chakraborty A, et al. Novel mechanisms targeted by drug trials in pulmonary arterial hypertension. Chest. 2022 Apr;161(4):1060–1072. doi: 10.1016/j.chest.2021.10.010
   PubMed Web of Science ®Google Scholar
• Yung LM, Yang P, Joshi S, et al. ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci Transl Med. 2020 May 13;12(543). doi: 10.1126/scitranslmed.aaz5660
   PubMed Web of Science ®Google Scholar
• Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2021 Apr 1;384(13):1204–1215. doi: 10.1056/NEJMoa2024277
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023 Apr 20;388(16):1478–1490. doi: 10.1056/NEJMoa2213558
   PubMed Web of Science ®Google Scholar
• A long-term follow-up study of sotatercept for PAH treatment (MK-7962-004) (SOTERIA) ClinicalTrials.gov: National Library of Medicine 2021 [cited 2023 Sept 24]. Available from: https://clinicaltrials.gov/study/NCT04796337
   Google Scholar
• Study to evaluate sotatercept (MK-7962) in children with pulmonary arterial hypertension (PAH) (MK-7962-008) (MOONBEAM) (MOONBEAM) ClinicalTrials.Gov: national Library of Medicine 2023. Available from: https://clinicaltrials.gov/study/NCT05587712
   Google Scholar
• Study of sotatercept in newly diagnosed intermediate- and high-risk PAH participants (MK-7962-005/A011-13) (HYPERION) ClinicalTrials.Gov: national Library of Medicine 2022. Available from: https://clinicaltrials.gov/study/NCT04811092
   Google Scholar
• A study of sotatercept for the treatment of pulmonary arterial hypertension (SPECTRA) ClinicalTrials.gov: National Library of Medicine 2019 [cited 2023 Sept 24]. Available from: https://clinicaltrials.gov/study/NCT03738150
   Google Scholar
• A study of sotatercept in participants with PAH WHO FC III or FC IV at high risk of mortality (MK-7962-006/ZENITH) (ZENITH) ClinicalTrials.gov: National Library of Medicine 2021 [cited 2023 Sept 24]. Available from: https://clinicaltrials.gov/study/NCT04896008
   Google 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. doi: 10.1172/JCI65592
   PubMed Web of Science ®Google Scholar
• Spiekerkoetter E, Sung YK, Sudheendra D, et al. Low-dose FK506 (tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015 Jul 15;192(2):254–257. doi: 10.1164/rccm.201411-2061LE
   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;50(3):1602449. doi: 10.1183/13993003.02449-2016
   PubMed Web of Science ®Google Scholar
• Wright AF, Ewart MA, Mair K, et al. Oestrogen receptor alpha in pulmonary hypertension. Cardiovasc Res. 2015 May 1;106(2):206–216. doi: 10.1093/cvr/cvv106
   PubMed Web of Science ®Google Scholar
• Ventetuolo CE, Mitra N, Wan F, et al. Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function. Eur Respir J. 2016 Feb;47(2):553–563. doi: 10.1183/13993003.01083-2015
   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. doi: 10.1186/2042-6410-3-6
   PubMed Web of Science ®Google Scholar
• Kawut SM, Archer-Chicko CL, DeMichele A, et al. Anastrozole in pulmonary arterial hypertension. A randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med. 2017 Feb 1;195(3):360–368. doi: 10.1164/rccm.201605-1024OC
   PubMed Web of Science ®Google Scholar
• Pulmonary hypertension and anastrozole trial (PHANTOM) ClinicalTrials.Gov: National Library of Medicine 2017 [cited 2023 Jun 5]. Available from: https://clinicaltrials.gov/ct2/show/NCT03229499
   Google Scholar
• Tamoxifen therapy to treat pulmonary arterial hypertension (T3PAH) ClinicalTrials.Gov: National Library of Medicine 2018 [cited 2023 Jun 5]. Available from: https://clinicaltrials.gov/ct2/show/NCT03528902
   Google Scholar
• Baird GL, Archer-Chicko C, Barr RG, et al. Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension. Eur Respir J. 2018 Jun;51(6):1800467. doi: 10.1183/13993003.00467-2018
   PubMed Web of Science ®Google Scholar
• Effects of DHEA in pulmonary hypertension (EDIPHY) ClinicalTrials.Gov: National Library of Medicine 2019 [cited 2023 Sept 23]. Available from: https://clinicaltrials.gov/study/NCT03648385
   Google Scholar
• Olschewski A, Berghausen EM, Eichstaedt CA, et al. Pathobiology, pathology and genetics of pulmonary hypertension: update from the cologne consensus conference 2018. Int J Cardiol. 2018 Dec 1;272S:p. 4–10.
   Google 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. doi: 10.1161/CIRCRESAHA.115.307004
   PubMed Web of Science ®Google Scholar
• Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. 2012 Jun 22;12(7):465–477. doi: 10.1038/nrc3256
   PubMed Web of Science ®Google Scholar
• Van der Feen DE, Kurakula K, Tremblay E, et al. Multicenter preclinical validation of BET inhibition for the treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2019 Oct 1;200(7):910–920. doi: 10.1164/rccm.201812-2275OC
   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. doi: 10.1164/rccm.202109-2182LE
   PubMed Web of Science ®Google Scholar
• Bochum S, Berger S, Olaparib MU. Recent results cancer Res. 2018;211:217–233.
   Google Scholar
• Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1274–1284. doi: 10.1016/S1470-2045(17)30469-2
   PubMed Web of Science ®Google Scholar
• Sharma S, Aldred MA. DNA damage and repair in pulmonary arterial hypertension. Genes (Basel). 2020 Oct 19;11(10):1224. doi: 10.3390/genes11101224
   PubMed Web of Science ®Google Scholar
• Olaparib for PAH: a multicenter clinical trial (OPTION) ClinicalTrials.Gov: National Library of Medicine 2018 [cited 2023 Jun 5]. Available from: https://clinicaltrials.gov/study/NCT03782818
   Google Scholar
• MacLean MR, Fanburg B, Hill N, et al. Serotonin and pulmonary hypertension; sex and drugs and ROCK and rho. Compr Physiol. 2022 Aug 29;12(4):4103–4118.
   PubMed Web of Science ®Google Scholar
• Bader M. Inhibition of serotonin synthesis: a novel therapeutic paradigm. Pharmacol Ther. 2020 Jan;205:107423. doi: 10.1016/j.pharmthera.2019.107423
   PubMed Web of Science ®Google Scholar
• A study of rodatristat ethyl in patients with pulmonary arterial hypertension (ELEVATE2) ClinicalTrial.gov: National Library of Medicine 2021 [cited 2023 Jun 6]. Available from: https://clinicaltrials.gov/study/NCT04712669
   Google Scholar
• Abdul-Ghani MA, Norton L, DeFronzo RA. Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Curr Diab Rep. 2012 Jun;12(3):230–238. doi: 10.1007/s11892-012-0275-6
   PubMed Web of Science ®Google Scholar
• Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016 Sep 6;134(10):752–772. doi: 10.1161/CIRCULATIONAHA.116.021887
   PubMed Web of Science ®Google Scholar
• Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117–2128. doi: 10.1056/NEJMoa1504720
   PubMed Web of Science ®Google Scholar
• Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020 Oct 8;383(15):1413–1424. doi: 10.1056/NEJMoa2022190
   PubMed Web of Science ®Google Scholar
• McMurray JJV, Docherty KF, Jhund PS. Dapagliflozin in patients with heart failure and reduced ejection fraction. Reply N Engl J Med. 2020 Mar 5;382(10):973.
   PubMedGoogle Scholar
• Yurista SR, Sillje HHW, Oberdorf-Maass SU, et al. Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail. 2019 Jul;21(7):862–873. doi: 10.1002/ejhf.1473
   PubMed Web of Science ®Google Scholar
• Chowdhury B, Luu AZ, Luu VZ, et al. The SGLT2 inhibitor empagliflozin reduces mortality and prevents progression in experimental pulmonary hypertension. Biochem Biophys Res Commun. 2020 Mar 26;524(1):50–56. doi: 10.1016/j.bbrc.2020.01.015
   PubMed Web of Science ®Google Scholar
• Tang Y, Tan S, Li M, et al. Dapagliflozin, sildenafil and their combination in monocrotaline-induced pulmonary arterial hypertension. BMC Pulm Med. 2022 Apr 12;22(1):142. doi: 10.1186/s12890-022-01939-7
   PubMed Web of Science ®Google Scholar
• Feasibility study of empagliflozin as treatment for idiopathic pulmonary arterial hypertension ClinicalTrials.Gov: National Library of Medicine 2022 [cited 2023 May 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT05493371
   Google Scholar
• Dapagliflozin in pulmonary arterial hypertension (DAPAH) ClinicalTrials.Gov: National Library of Medicine 2023 [cited 2023 Sept 23]. Available from: https://clinicaltrials.gov/study/NCT05179356
   Google Scholar
• Safdar Z, Cho E. Effect of spironolactone use in pulmonary arterial hypertension - analysis from pivotal trial databases. Pulm Circ. 2021 Oct;11(4):20458940211045618. doi: 10.1177/20458940211045618
   Web of Science ®Google Scholar
• Hayashi T, Matsumoto S, Hosokawa A, et al. P2501 Rivaroxaban combined with spironolactone attenuates cardiovascular remodeling due to hypoxia in pulmonary arterial hypertension. Eur Heart J. 2018;39(suppl_1):ehy565. P2501. doi: 10.1093/eurheartj/ehy565.P2501
   Google Scholar
• Bendtzen K, Hansen PR, Rieneck K. Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis. Clin Exp Immunol. 2003 Oct;134(1):151–158. doi: 10.1046/j.1365-2249.2003.02249.x
   PubMed Web of Science ®Google Scholar
• Spironolactone for pulmonary arterial hypertension ClinicalTrials.Gov: National Library of Medicine 2014 [cited 2023 Sept 23]. Available from: https://clinicaltrials.gov/study/NCT01712620
   Google Scholar
• Verdejo HE, Rojas A, Lopez-Crisosto C, et al. Effects of Trimetazidine on right ventricular function and ventricular remodeling in patients with pulmonary artery hypertension: a randomised controlled trial. J Clin Med. 2023 Feb 16;12(4):1571. doi: 10.3390/jcm12041571
   PubMed Web of Science ®Google Scholar
• Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008 Nov;32(5):1289–1294. doi: 10.1183/09031936.00050008
   PubMed Web of Science ®Google Scholar
• Phase 2 study to assess safety, tolerability and efficacy of Once weekly SC pemziviptadil (PB1046) in subjects with symptomatic PAH (VIP) ClinicalTrials.gov: National Library of Medicine 2022 [cited 2023 Sept 23]. Available from: https://clinicaltrials.gov/study/NCT03556020
   Google Scholar
• Rabinovitch M, Guignabert C, Humbert M, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):165–175. doi: 10.1161/CIRCRESAHA.113.301141
   PubMed Web of Science ®Google Scholar
• Cero FT, Hillestad V, Sjaastad I, et al. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol. 2015 Aug 15;309(4):L378–87. doi: 10.1152/ajplung.00342.2014
   PubMed Web of Science ®Google Scholar
• Lee S, Suh GY, Ryter SW, et al. Regulation and function of the nucleotide binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 inflammasome in lung disease. Am J Respir Cell Mol Biol. 2016 Feb;54(2):151–160. doi: 10.1165/rcmb.2015-0231TR
   PubMed Web of Science ®Google Scholar
• Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995 May;151(5):1628–1631. doi: 10.1164/ajrccm.151.5.7735624
   PubMed Web of Science ®Google Scholar
• Kawut SM, Bagiella E, Lederer DJ, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011 Jun 28;123(25):2985–2993. doi: 10.1161/CIRCULATIONAHA.110.015693
   PubMed Web of Science ®Google Scholar
• Cordasco EM Jr., Ahmad M, Mehta A, et al. The effects of steroid therapy on pulmonary hypertension secondary to fibrosing mediastinitis. Cleve Clin J Med. 1990 Oct;57(7):647–652. doi: 10.3949/ccjm.57.7.647
   PubMed Web of Science ®Google Scholar
• Trankle CR, Canada JM, Kadariya D, et al. IL-1 blockade reduces inflammation in pulmonary arterial hypertension and right ventricular failure: a single-arm, open-label, Phase IB/II Pilot study. Am J Respir Crit Care Med. 2019 Feb 1;199(3):381–384. doi: 10.1164/rccm.201809-1631LE
   PubMed Web of Science ®Google Scholar
• Hernandez-Sanchez J, Harlow L, Church C, et al. Clinical trial protocol for TRANSFORM-UK: a therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension. Pulm Circ. 2018 Jan;8(1):2045893217735820. doi: 10.1177/2045893217735820
   Web of Science ®Google Scholar
• Tian W, Jiang X, Tamosiuniene R, et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013 Aug 28;5(200):200ra117. doi: 10.1126/scitranslmed.3006674
   PubMed Web of Science ®Google Scholar
• Yamazaki T, Sugiyama K, Ichihara K. Effect of ubenimex on the immune system of patients with hematological malignancies. Biomed Pharmacother. 1991;45(2–3):105–112. doi: 10.1016/0753-3322(91)90129-H
   PubMed Web of Science ®Google Scholar
• Open-label extension study of Ubenimex in patients with pulmonary arterial hypertension (WHO group 1) (LIBERTY2) ClinicalTrial.gov: National Library of Medicine 2023. Available from: https://clinicaltrials.gov/study/NCT02736149
   Google Scholar
• Zamanian RT, Badesch D, Chung L, et al. Safety and efficacy of B-Cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension: a multicenter, double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2021 Jul 15;204(2):209–221. doi: 10.1164/rccm.202009-3481OC
   PubMed Web of Science ®Google Scholar
• Medrek S, Melendres-Groves L. Evolving nonvasodilator treatment options for pulmonary arterial hypertension. Curr Opin Pulm Med. 2022 Sep 1;28(5):361–368. doi: 10.1097/MCP.0000000000000887
   PubMed Web of Science ®Google Scholar
• A study of sotatercept for the treatment of cpc-PH due to HFpEF (MK-7962-007/A011-16) (CADENCE) ClinicalTrials.gov: National Library of Medicine 2021 [cited 2023 Sept 15]. Available from: https://clinicaltrials.gov/study/NCT04945460
   Google Scholar
• Gurtu V, Michelakis ED. A paradigm shift is needed in the field of pulmonary arterial hypertension for its entrance into the precision Medicine era. Circ Res. 2016 Dec 9;119(12):1276–1279. doi: 10.1161/CIRCRESAHA.116.309689
   PubMed Web of Science ®Google Scholar
• Hemnes AR. Using omics to understand and treat pulmonary vascular disease. Front Med. 2018;5:157. doi: 10.3389/fmed.2018.00157
   Web of Science ®Google Scholar
• Savale L, Guignabert C, Weatherald J, et al. Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era. Eur Respir Rev. 2018 Jun 30;27(148):180004. doi: 10.1183/16000617.0004-2018
   PubMed Web of Science ®Google Scholar
• Jiang J, Liu S, Yang H, et al. Application of transcriptomics and proteomics in pulmonary arterial hypertension. Per Med. 2023 Mar;20(2):183–192. doi: 10.2217/pme-2023-0020
   PubMedGoogle Scholar
• Rhodes CJ, Sweatt AJ, Maron BA. Harnessing big data to advance treatment and understanding of pulmonary hypertension. Circ Res. 2022 Apr 29;130(9):1423–1444. doi: 10.1161/CIRCRESAHA.121.319969
   PubMed Web of Science ®Google Scholar
• Fazal S, Bisserier M, Hadri L. Molecular and genetic profiling for precision Medicines in pulmonary arterial hypertension. Cells. 2021 Mar 13;10(3):638. doi: 10.3390/cells10030638
   PubMed Web of Science ®Google Scholar