New approaches to the treatment of pulmonary arterial hypertension

Pulmonary hypertension (PH) is a polyetiological disease characterized by an increase in mean pulmonary artery pressure (MPP) by more than 20 mm Hg at rest. Idiopathic pulmonary arterial hypertension (PAH), which is assigned to the first group according to the 2018 PH classification, is the most studied in terms of optimal therapy selection. This is a rare but fatal disease that occurs as a result of vascular remodeling of the distal pulmonary arteries. Currently, PAH treatments target three major metabolic cascades: prostacyclin, endothelin, and nitric oxide. The available therapies improve the symptoms and quality of life of patients with PAH, but, unfortunately, none of them directly affect the pathogenesis or allow to achieve complete control of the disease.

The aim of the review was to analyze the literature and demonstrate of the most promising methods and potential targets for the treatment of PAH.

Conclusion. At the moment, PAH therapy is a serious clinical problem, and therefore, it is essential to study new therapeutic targets and develop the corresponding drugs.

1. Humbert M., Kovacs G., Hoeper M.M. et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the 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 the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). Eur. Heart J. 2022; 43 (38): 3618–3731. DOI: 10.1093/eurheartj/ehac237.

2. Xiao Y., Chen P.P., Zhou R.L. et al. Pathological mechanisms and potential therapeutic targets of pulmonary arterial hypertension: a review. Aging. Dis. 2020; 11 (6): 1623–1639. DOI: 10.14336/AD.2020.0111.

3. Qaiser K.N., Tonelli A.R. Novel treatment pathways in pulmonary arterial hypertension. Methodist Debakey Cardiovasc. J. 2021; 17 (2): 106–114. DOI: 10.14797/CBHS2234.

4. Guignabert C., Humbert M. Targeting transforming growth factor-β receptors in pulmonary hypertension. Eur. Respir. J. 2021; 57 (2): 2002341. DOI: 10.1183/13993003.02341-2020.

5. Sherman M.L., Borgstein N.G., Mook L. et al. Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women. J. Clin. Pharmacol. 2013; 53 (11): 1121–1130. DOI: 10.1002/jcph.160.

6. Yung L.M., Yang P., Joshi S. et al. ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci. Transl. Med. 2020; 12 (543): eaaz5660. DOI: 10.1126/scitranslmed.aaz5660.

7. Hoeper M.M., Badesch D.B., Ghofrani H.A. et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N. Engl. J. Med. 2023; 388 (16): 1478–1490. DOI: 10.1056/NEJMoa2213558.

8. Araya A.A., Tasnif Y. Tacrolimus. Treasure Island (FL): StatPearls Publishing; 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK544318/

9. Spiekerkoetter E., Tian X., Cai J. et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J. Clin. Invest. 2013; 123 (8): 3600–3613. DOI: 10.1172/JCI65592.

10. Spiekerkoetter E., Sung Y.K., Sudheendra D. et al. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur. Respir. J. 2017; 50 (3): 1602449. DOI: 10.1183/13993003.02449-2016.

11. Perros F., Montani D., Dorfmüller P. et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2008; 178 (1): 81–88. DOI: 10.1164/rccm.200707-1037OC.

12. Medarametla V., Festin S., Sugarragchaa C. et al. PK10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension. Pulm. Circ. 2014; 4 (1): 82–102. DOI: 10.1086/674881.

13. Schermuly R.T., Dony E., Ghofrani H.A. et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 2005; 115 (10): 2811–2821. DOI: 10.1172/JCI24838.

14. Hoeper M.M., Barst R.J., Bourge R.C. et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013; 127 (10): 1128–1138. DOI: 10.1161/CIRCULATIONAHA.112.000765.

15. Shah A.M., Campbell P., Rocha G.Q. et al. Effect of imatinib as add-on therapy on echocardiographic measures of right ventricular function in patients with significant pulmonary arterial hypertension. Eur. Heart J. 2015; 36 (10): 623–632. DOI: 10.1093/eurheartj/ehu035.

16. Frantz R.P., Benza R.L., Channick R.N. et al. TORREY, a Phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension. Pulm. Circ. 2021; 11 (4): 20458940211057071. DOI: 10.1177/20458940211057071.

17. Gossamer Bio. Gossamer Bio announces seralutinib meets primary endpoint in phase 2 torrey study in pah. Available at: https://ir.gossamerbio.com/news-releases/news-release-details/gossamer-bio-announces-seralutinib-meets-primary-endpoint-phase/

18. Archer S.L. Acquired mitochondrial abnormalities, including epigenetic inhibition of superoxide dismutase 2, in pulmonary hypertension and cancer: therapeutic implications. Adv. Exp. Med. Biol. 2016; 903: 29–53. DOI: 10.1007/978-1-4899-7678-9_3.

19. Stephen Y. Chan, Lewis J. Rubin. Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice. Eur. Respir. Rev. 2017, 26 (146): 170094. DOI: 10.1183/16000617.0094-2017.

20. Michelakis E.D., McMurtry M.S., Wu X.C. et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation. 2002; 105 (2): 244–250. DOI: 10.1161/hc0202.101974.

21. Michelakis E.D., Gurtu V., Webster L. et al. Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients. Sci. Transl. Med. 2017; 9 (413): eaao4583. DOI: 10.1126/scitranslmed.aao4583.

22. Rouhana S., Virsolvy A., Fares N. et al. Ranolazine: an old drug with emerging potential; Lessons from pre-clinical and clinical investigations for possible repositioning. Pharmaceuticals (Basel). 2021; 15 (1): 31. DOI: 10.3390/ph15010031.

23. Han Y., Forfia P., Vaidya A. et al. Ranolazine improves right ventricular function in patients with precapillary pulmonary hypertension: results from a double-blind, randomized, placebo-controlled trial. J. Card. Fail. 2021; 27 (2): 253–257. DOI: 10.1016/j.cardfail.2020.10.006.

24. Zolty R. Novel experimental therapies for treatment of pulmonary arterial hypertension. J. Exp. Pharmacol. 2021; 13: 817–857. DOI: 10.2147/JEP.S236743.

25. 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.

26. ClinicalTrials.gov. Phase 2 study to assess safety, tolerability and efficacy of once weekly SC pemziviptadil (PB1046) in subjects with symptomatic PAH (VIP). 2022; No.NCT03556020. Available at: https://clinicaltrials.gov/study/NCT03556020

27. Liu Y., Fanburg B.L. Serotonin-induced growth of pulmonary artery smooth muscle requires activation of phosphatidylinositol 3-kinase/serine-threonine protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase 1. Am. J. Respir. Cell Mol. Biol. 2006; 34 (2): 182–191. DOI: 10.1165/rcmb.2005-0163OC.

28. Hervé P., Launay J.M., Scrobohaci M.L. et al. Increased plasma serotonin in primary pulmonary hypertension. Am. J. Med. 1995; 99 (3): 249–254. DOI: 10.1016/s0002-9343(99)80156-9.

29. Lazarus H.M., Denning J., Wring S. et al. A trial design to maximize knowledge of the effects of rodatristat ethyl in the treatment of pulmonary arterial hypertension (ELEVATE 2). Pulm. Circ. 2022; 12 (2): e12088. DOI: 10.1002/pul2.12088.

30. Cassady S.J., Soldin D., Ramani G.V. Novel and emerging therapies in pulmonary arterial hypertension. Front. Drug Dis. 2022; 2. DOI: 10.3389/fddsv.2022.1022971.

31. Kawut S.M., Archer-Chicko C.L., DeMichele A. et al. Anastrozole in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 2017; 195 (3): 360–368. DOI: 10.1164/rccm.201605-1024OC.

32. Sitbon O., Gomberg-Maitland M., Granton J. et al. Clinical trial design and new therapies for pulmonary arterial hypertension. Eur. Respir. J. 2019; 53 (1): 1801908. DOI: 10.1183/13993003.01908-2018.

33. ClinicalTrials.gov. Austin E. Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension (T3PAH). 2022; No.NCT03528902. Available at: https://clinicaltrials.gov/study/NCT03528902

34. Haryono A.; Ramadhiani R.; Ryanto G.R.T. Emoto N. Endothelin and the cardiovascular system: the long journey and where we are going. Biology (Basel). 2022; 11 (5): 759. DOI: 10.3390/biology11050759.

35. Zhang C., Jing S. Therapeutic antibody approach for pulmonary arterial hypertension. Int. J. Cardiol. Cardiovasc. Dis. 2021; 1 (1): 15–19. DOI: 10.46439/cardiology.1.002.

36. Christman B.W., McPherson C.D., Newman J.H. et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N. Engl. J. Med. 1992; 327 (2): 70–75. DOI: 10.1056/NEJM199207093270202.

37. Katugampola S.D., Davenport A.P. Thromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT(1) receptor antagonist losartan. Br. J. Pharmacol. 2001; 134 (7): 1385–1392. DOI: 10.1038/sj.bjp.0704416.

38. Mulvaney E.P., Reid H.M., Bialesova L. et al. NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension. BMC Pulm. Med. 2020; 20 (1): 85. DOI: 10.1186/s12890-020-1113-2.

39. Savai R., Pullamsetti S.S., Kolbe J. et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2012; 186 (9): 897–908. DOI: 10.1164/rccm.201202-0335OC.

40. Liang S., Desai A.A., Black S.M., Tang H. Cytokines, chemokines, and inflammation in pulmonary arterial hypertension. Adv. Exp. Med. Biol. 2021; 1303: 275–303. DOI: 10.1007/978-3-030-63046-1_15.

41. Prins K.W., Archer S.L., Pritzker M. et al. Interleukin-6 is independently associated with right ventricular function in pulmonary arterial hypertension. J. Heart Lung Transplant. 2018; 37 (3): 376–384. DOI: 10.1016/j.healun.2017.08.011.

42. Toshner M., Rothman A. IL-6 in pulmonary hypertension: why novel is not always best. Eur. Respir. J. 2020; 55 (4): 2000314. DOI: 10.1183/13993003.00314-2020.

43. Trankle C.R., Canada J.M., 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; 199 (3): 381–384. DOI: 10.1164/rccm.201809-1631LE.

44. Bell R.D., White R.J., Garcia-Hernandez M.L. et al. Tumor necrosis factor induces obliterative pulmonary vascular disease in a novel model of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheumatol. 2020; 72 (10): 1759–1770. DOI: 10.1002/art.41309.

45. O'Brien J., Hayder H., Zayed Y., Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. (Lausanne). 2018; 9: 402. DOI: 10.3389/fendo.2018.00402.

46. Sindi H.A., Russomanno G., Satta S. et al. Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension. Nat. Commun. 2020; 11 (1): 1185. DOI: 10.1038/s41467-020-14966-x.

47. Dhoble S., Patravale V., Weaver E. et al. Comprehensive review on novel targets and emerging therapeutic modalities for pulmonary arterial Hypertension. Int. J. Pharm. 2022; 621: 121792. DOI: 10.1016/j.ijpharm.2022.121792.