Pulmonary Arterial Hypertension and Therapeutic Interventions

Abstract

Pulmonary hypertension is an uncommon disease that carries a significant morbidity and mortality. Pulmonary arterial hypertension is a subtype of pulmonary hypertension that describes a group of disease entities that lead to an elevation in precapillary pulmonary artery pressure. Despite advances in the diagnosis and treatment of pulmonary arterial hypertension, it remains a difficult disease to recognize and manage. In this review article, we will discuss the definition and diagnosis of pulmonary arterial hypertension. Additionally, we will discuss the ever-expanding management options, their mechanisms and strategies, including combination therapy and the most recent advances and future directions.

Keywords

pulmonary hypertension - pulmonary arterial hypertension - phosphodiesterase-5 inhibitor - prostacyclin analog - endothelin receptor antagonists - combination therapy - calcium channel blockers

• References

• 1 Dodson MW, Brown LM, Elliott CG. Pulmonary arterial hypertension. Heart Fail Clin 2018; 14 (03) 255-269
• 2 Hoeper MM, Humbert M, Souza R. , et al. A global view of pulmonary hypertension. Lancet Respir Med 2016; 4 (04) 306-322
• 3 Hoeper MM, Bogaard HJ, Condliffe R. , et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62 (25, Suppl): D42-D50
• 4 McLaughlin VV, Archer SL, Badesch DB. , et al; ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119 (16) 2250-2294
• 5 Galiè N, Humbert M, Vachiery J-L. , et al; ESC Scientific Document Group. 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; 37 (01) 67-119
• 6 Galiè N, McLaughlin VV, Rubin LJ, Simonneau G. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J 2019; 53 (01) ):•••
• 7 Naeije R, Saggar R, Badesch D. , et al. Exercise-induced pulmonary hypertension: translating pathophysiological concepts into clinical practice. Chest 2018; 154 (01) 10-15
• 8 Herve P, Lau EM, Sitbon O. , et al. Criteria for diagnosis of exercise pulmonary hypertension. Eur Respir J 2015; 46 (03) 728-737
• 9 Wright LM, Dwyer N, Celermajer D, Kritharides L, Marwick TH. Follow-up of pulmonary hypertension with echocardiography. JACC Cardiovasc Imaging 2016; 9 (06) 733-746
• 10 Gorcsan III J, Edwards TD, Ziady GM, Katz WE, Griffith BP. Transesophageal echocardiography to evaluate patients with severe pulmonary hypertension for lung transplantation. Ann Thorac Surg 1995; 59 (03) 717-722
• 11 Wang M, Ma R, Wu D. , et al. Value of lung perfusion scintigraphy in patients with idiopathic pulmonary arterial hypertension: a patchy pattern to consider. Pulm Circ 2019; 9 (01) 2045894018816968
• 12 van Wolferen SA, Marcus JT, Boonstra A. , et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J 2007; 28 (10) 1250-1257
• 13 van de Veerdonk MC, Kind T, Marcus JT. , et al. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011; 58 (24) 2511-2519
• 14 Grignola JC. Hemodynamic assessment of pulmonary hypertension. World J Cardiol 2011; 3 (01) 10-17
• 15 Naeije R, Vachiery J-L, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J 2013; 41 (01) 217-223
• 16 Ascha M, Renapurkar RD, Tonelli AR. A review of imaging modalities in pulmonary hypertension. Ann Thorac Med 2017; 12 (02) 61-73
• 17 Peña E, Dennie C, Veinot J, Muñiz SH. Pulmonary hypertension: how the radiologist can help. Radiographics 2012; 32 (01) 9-32
• 18 Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004; 351 (16) 1655-1665
• 19 Prins KW, Thenappan T. World Health Organization Group I pulmonary hypertension: epidemiology and pathophysiology. Cardiol Clin 2016; 34 (03) 363-374
• 20 Lan NSH, Massam BD, Kulkarni SS, Lang CC. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases 2018; 6 (02) E38
• 21 Ryan JJ, Archer SL. The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circ Res 2014; 115 (01) 176-188
• 22 Tedford RJ, Mudd JO, Girgis RE. , et al. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 2013; 6 (05) 953-963
• 23 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333 (04) 214-221
• 24 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; 327 (02) 70-75
• 25 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; 159 (06) 1925-1932
• 26 Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?. Ann Intern Med 1991; 114 (06) 464-469
• 27 Hervé P, Launay JM, Scrobohaci ML. , et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99 (03) 249-254
• 28 Marcos E, Adnot S, Pham MH. , et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med 2003; 168 (04) 487-493
• 29 Abenhaim L, Moride Y, Brenot F. , et al; International Primary Pulmonary Hypertension Study Group. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335 (09) 609-616
• 30 Eddahibi S, Humbert M, Fadel E. , et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001; 108 (08) 1141-1150
• 31 Loscalzo J. Genetic clues to the cause of primary pulmonary hypertension. N Engl J Med 2001; 345 (05) 367-371
• 32 Best DH, Austin ED, Chung WK, Elliott CG. Genetics of pulmonary hypertension. Curr Opin Cardiol 2014; 29 (06) 520-527
• 33 Battle RW, Davitt MA, Cooper SM. , et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest 1996; 110 (06) 1515-1519
• 34 Minter KR, Gladwin MT. Pulmonary complications of sickle cell anemia. A need for increased recognition, treatment, and research. Am J Respir Crit Care Med 2001; 164 (11) 2016-2019
• 35 Platt OS, Brambilla DJ, Rosse WF. , et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330 (23) 1639-1644
• 36 Gabler NB, French B, Strom BL. , et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 2012; 126 (03) 349-356
• 37 Wensel R, Francis DP, Meyer FJ. , et al. Incremental prognostic value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial hypertension. Int J Cardiol 2013; 167 (04) 1193-1198
• 38 Warwick G, Thomas PS, Yates DH. Biomarkers in pulmonary hypertension. Eur Respir J 2008; 32 (02) 503-512
• 39 Jaïs X, Olsson KM, Barbera JA. , et al. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. Eur Respir J 2012; 40 (04) 881-885
• 40 Thorne S, Nelson-Piercy C, MacGregor A. , et al. Pregnancy and contraception in heart disease and pulmonary arterial hypertension. J Fam Plann Reprod Health Care 2006; 32 (02) 75-81
• 41 Cohn JN. Optimal diuretic therapy for heart failure. Am J Med 2001; 111 (07) 577
• 42 Roberts DH, Lepore JJ, Maroo A, Semigran MJ, Ginns LC. Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension. Chest 2001; 120 (05) 1547-1555
• 43 Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70 (04) 580-587
• 44 Sitbon O, Humbert M, Jaïs X. , et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111 (23) 3105-3111
• 45 Galiè N, Ussia G, Passarelli P, Parlangeli R, Branzi A, Magnani B. Role of pharmacologic tests in the treatment of primary pulmonary hypertension. Am J Cardiol 1995; 75 (03) 55A-62A
• 46 Montani D, Savale L, Natali D. , et al. Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J 2010; 31 (15) 1898-1907
• 47 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; 327 (02) 76-81
• 48 Hoeper MM, Apitz C, Grünig E. , et al. Targeted therapy of pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018. Int J Cardiol 2018; 272S: 37-45
• 49 Valerio CJ, Coghlan JG. Bosentan in the treatment of pulmonary arterial hypertension with the focus on the mildly symptomatic patient. Vasc Health Risk Manag 2009; 5: 607-619
• 50 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; 358 (9288): 1119-1123
• 51 Rubin LJ, Badesch DB, Barst RJ. , et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346 (12) 896-903
• 52 Humbert M, Barst RJ, Robbins IM. , et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004; 24 (03) 353-359
• 53 Galiè N, Beghetti M, Gatzoulis MA. , et al; Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006; 114 (01) 48-54
• 54 Galiè N, Rubin Lj, Hoeper M. , et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008; 371 (9630): 2093-2100
• 55 McLaughlin V, Channick RN, Ghofrani H-A. , et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J 2015; 46 (02) 405-413
• 56 Galié N, Badesch D, Oudiz R. , et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46 (03) 529-535
• 57 Galiè N, Olschewski H, Oudiz RJ. , et al; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117 (23) 3010-3019
• 58 Pulido T, Adzerikho I, Channick RN. , et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369 (09) 809-818
• 59 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; 353 (20) 2148-2157
• 60 Rubin LJ, Badesch DB, Fleming TR. , et al; SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 2011; 140 (05) 1274-1283
• 61 Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, Søndergaard L. Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. Eur Heart J 2010; 31 (09) 1124-1131
• 62 Galiè N, Brundage BH, Ghofrani HA. , et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119 (22) 2894-2903
• 63 Oudiz RJ, Brundage BH, Galiè N. , et al; PHIRST Study Group. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol 2012; 60 (08) 768-774
• 64 Jing Z-C, Yu Z-X, Shen J-Y. , et al; Efficacy and Safety of Vardenafil in the Treatment of Pulmonary Arterial Hypertension (EVALUATION) Study Group. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 2011; 183 (12) 1723-1729
• 65 Ghofrani H-A, Galiè N, Grimminger F. , et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369 (04) 330-340
• 66 Rubin LJ, Galiè N, Grimminger F. , et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015; 45 (05) 1303-1313
• 67 Sitbon O, Delcroix M, Bergot E. , et al. EPITOME-2: An open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension. Am Heart J 2014; 167 (02) 210-217
• 68 Barst RJ, Rubin LJ, Long WA. , et al; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334 (05) 296-301
• 69 Sitbon O, Humbert M, Nunes H. , et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002; 40 (04) 780-788
• 70 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; 112 (07) 485-491
• 71 Badesch DB, Tapson VF, McGoon MD. , et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132 (06) 425-434
• 72 Doran AK, Ivy DD, Barst RJ, Hill N, Murali S, Benza RL. ; Scientific Leadership Council of the Pulmonary Hypertension Association. Guidelines for the prevention of central venous catheter-related blood stream infections with prostanoid therapy for pulmonary arterial hypertension. Int J Clin Pract Suppl 2008; (160) 5-9
• 73 Barst RJ, McGoon M, McLaughlin V. , et al; Beraprost Study Group. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003; 41 (12) 2119-2125
• 74 Hoeper MM, Gall H, Seyfarth HJ. , et al. Long-term outcome with intravenous iloprost in pulmonary arterial hypertension. Eur Respir J 2009; 34 (01) 132-137
• 75 Olschewski H, Simonneau G, Galiè N. , et al; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347 (05) 322-329
• 76 Simonneau G, Barst RJ, Galie N. , et al; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165 (06) 800-804
• 77 White RJ, Levin Y, Wessman K, Heininger A, Frutiger K. Subcutaneous treprostinil is well tolerated with infrequent site changes and analgesics. Pulm Circ 2013; 3 (03) 611-621
• 78 Hiremath J, Thanikachalam S, Parikh K. , et al; TRUST Study Group. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant 2010; 29 (02) 137-149
• 79 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; 55 (18) 1915-1922
• 80 Jing Z-C, 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 2013; 127 (05) 624-633
• 81 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; 142 (06) 1383-1390
• 82 Tapson VF, Jing Z-C, Xu K-F. , 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; 144 (03) 952-958
• 83 Sitbon O, Channick R, Chin KM. , et al; GRIPHON Investigators. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015; 373 (26) 2522-2533
• 84 Galiè N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J 2010; 31 (17) 2080-2086
• 85 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; 373 (09) 834-844
• 86 Prior DL, Adams H, Williams TJ. Update on pharmacotherapy for pulmonary hypertension. Med J Aust 2016; 205 (06) 271-276
• 87 Yoon KL. New therapeutic target for pulmonary arterial hypertension. Korean Circ J 2018; 48 (12) 1145-1147
• 88 Marcu R, Kotha S, Zhi Z. , et al. The mitochondrial permeability transition pore regulates endothelial bioenergetics and angiogenesis. Circ Res 2015; 116 (08) 1336-1345
• 89 Pullamsetti SS, Savai R, Seeger W, Goncharova EA. Translational advances in the field of pulmonary hypertension. from cancer biology to new pulmonary arterial hypertension therapeutics. targeting cell growth and proliferation signaling hubs. Am J Respir Crit Care Med 2017; 195 (04) 425-437
• 90 Satoh K, Kikuchi N, Satoh T. , et al. Identification of novel therapeutic targets for pulmonary arterial hypertension. Int J Mol Sci 2018; 19 (12) 4081
• 91 Noda K, Nakajima S, Godo S. , et al. Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice. PLoS One 2014; 9 (11) e110446
• 92 Satoh K, Satoh T, Kikuchi N. , et al. Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circ Res 2014; 115 (08) 738-750
• 93 Chang SA, Kim HK, Chang HJ, Kim DK. Acute hemodynamic changes after single administration of udenafil in pulmonary arterial hypertension: a phase IIa study. Korean Circ J 2019; 49 (04) 353-360