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Review

Medical therapeutics for pulmonary arterial hypertension: from basic science and clinical trial design to evidence-based medicine

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Pages 347-360 | Published online: 10 Jan 2014

References

  • Simonneau G, Galie N, Rubin LJ et al. Clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 43, S5–S 12 (2004).
  • 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. 115, 343–349 (1991).
  • 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. 327, 76–81 (1992).
  • Barst RJ, McGoon M, Torbicki A et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 43, S40–S47 (2004).
  • Sitbon O, Humbert M, Ioos V et al. Who benefits from long-term calcium channel-blocker therapy in primary pulmonary arterial hypertension? Am. J. Respir. Crit. Care Med. 167 (2003) (Abstract 440).
  • Fuster V, Steele PM, Edwards WD et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 70, 580–587 (1984).
  • Frank H, Mlczoch J, Huber K et al. The effect of anticoagulant therapy in primary and anorectic-induced pulmonary hypertension. Chest 112, 714–721 (1997).
  • Jeffrey TK, Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog. Cardiovasc. Dis.45, 173–202 (2002).
  • 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. 327, 70–75 (1992).
  • Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 333, 214–221 (1995).
  • Giaid A, Yanagisawa M, Langleben D et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 328, 1732–1739 (1993).
  • Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 114(Suppl. 3), S208–S212 (1998).
  • 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. 159, 1925–1932 (1999).
  • 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. 112, 485–491 (1990).
  • Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N. Engl. J. Med. 334, 296–302 (1996).
  • 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. 132, 425–434 (2000).
  • Barst RJ, Rubin LJ, McGoon MD et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann. Intern. Med. 121, 409–415 (1994).
  • 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. 30, 343–349 (1997).
  • McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 106, 1477–1482 (2002).
  • 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. 40, 780–788 (2002).
  • Kuhn KP, Byrne DW, Arbogast PG et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am. J. Respir. Crit. Care Med. 167, 580–586 (2003).
  • McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N. Engl. J. Med. 338, 273–277 (1998).
  • Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J. Am. Coll. Cardiol. 34, 1184–1187 (1999).
  • McLaughlin VV, Genthner DE, Panella MM et al. Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann. Intern. Med. 130, 740–743 (1999).
  • Robbins IM, Gaine SP, Schilz R et al. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest 117, 14–18 (2000).
  • Horn EM, Barst RJ, Poon M. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest 118, 1229–1230 (2000).
  • Krowka MJ, Frantz RP, McGoon MD et al. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate-to-severe portopulmonary hypertension. Hepatology 30, 641–648 (1999).
  • Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 99, 1858–1865 (1999).
  • Simonneau G, Barst RJ, Galie N et al. 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. 165, 800–804 (2002).
  • Olschewski H, Simonneau G, Galie N et al. Inhaled iloprost for severe pulmonary hypertension. N. Engl. J. Med. 347, 322–329 (2002).
  • 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. 39, 1496–1502 (2002).
  • Barst RJ, McGoon M, McLaughlin VV et al. Beraprost therapy for pulmonary arterial hypertension. J. Am. Coll. Cardiol. 41, 2119–2125 (2003).
  • Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet 358, 1119–1123 (2001).
  • Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346, 896–903 (2002).
  • Barst RJ, Langleben D, Frost A et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 169, 441–447 (2004).
  • Rubin LJ, Galie N, Badesch D et al. Ambrisentan improves exercise capacity and clinical measures in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 169(7) (2004) (Abstract 210).
  • Ghofrani HA. Sildenafil use in pulmonary arterial hypertension (SUPER-1 trial). Presented at the 70th Annual Meeting of the American College of Chest Physicians. Seattle, WA, USA 23–28 October 2004.
  • Galie N, Rubin LJ. Pulmonary arterial hypertension. Epidemiology, pathobiology, assessment, and therapy. J. Am. Coll. Cardiol. 43(12 Suppl S), S89–S90 (2004).
  • Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126(Suppl.) (2004).
  • Humbert M, Barst RJ, Robbins IM et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur. Respir. J. 24, 353–359 (2004).
  • Channick RN, Kim N, Lombardi S et al. Addition of bosentan to patients with pulmonary arterial hypertension receiving chronic epoprostenol or treprostinil is well tolerated and allows for weaning or discontinuation of prostacyclin in some patients. Am. J. Respir. Crit. Care Med. 167(7), A441 (2003).
  • Rayburn BK, Benza RL, Tallaj JA et al. The use of bosentan and a prostacyclin analog in the treatment of primary pulmonary hypertension. International Society for Heart and Lung Transplantation Meeting. Vienna, Austria, 8–12 April 2003 (Abstract 241).
  • Suleman N, Frost AE. Transition from epoprostenol and treprostinil to the oral endothelin receptor antagonist bosentan in patients with pulmonary hypertension. Chest 126, 808–815 (2004).
  • Ghofrani HA, Wiedemann R, Rose F et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann. Intern. Med. 136(7), 515–522 (2002).
  • Stiebellehner L, Petkov V, Vonbank K et al. Long-term treatment with oral sildenafil in addition to continuous iv. epoprostenol in patients with pulmonary arterial hypertension. Chest 123, 1293–1295 (2003).
  • Wilkens H, Guth A, Konig J et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 104, 1218–1222 (2001).
  • Gomberg-Maitland M, Gulati M, Rich S. Combination therapy of subcutaneous treprostinil and oral sildenafil: a proof of concept of pilot trial. Am. J. Respir. Crit. Care Med. 169(Suppl. 7), A211 (2004).
  • Vachiery JL, Hill N, Zwicke D et al. Transitioning from iv. epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest 121, 1561–1565 (2002).
  • Kim NK, Channick RN, Rubin LJ. Successful withdrawal of long-term epoprostenol therapy for pulmonary arterial hypertension. Chest 124, 1612–1615 (2003).
  • Tapson V, Barst R, Horn E et al. Safety and efficacy of chronic intravenous treprostinil in patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 169(Suppl. 7), A172 (2004).
  • Voswinckel R, Enke B, Kreckel A et al. Inhaled treprostinil sodium for the treatment of pulmonary hypertension. Circulation 110(Suppl. 17), 1414 (2004).
  • Arai H, Hori S, Aramori I et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348, 730–732 (1990).
  • Seo B, Oemar BS, Siebenmann R et al. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89, 1203–1208 (1994).
  • Davie N, Haleen SJ, Upton PD et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am. J. Respir. Crit. Care Med. 165, 398–405 (2002).
  • de Nucci G, Thomas R, D’Orleans-Juste P et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc. Natl Acad. Sci. USA 85, 9797–9800 (1988).
  • MacLean MR, Docherty CC, McCulloch KM et al. Effect of novel mixed ETA/ETB antagonists on responses to ET-1 in human small muscular pulmonary arteries. Pulm. Pharmacol. Ther. 11, 147–149 (1998).
  • Jasmin JF, Lucas M, Cernacek P et al. Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation 103, 314–318 (2001).
  • Miyamoto S, Nagaya N, Satoh T et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am. J. Respir. Crit. Care Med. 161(2 Pt 1), 487–492 (2000).
  • Paciocco G, Martinez FJ, Bossone E et al. Oxygen desaturation on the 6-minute walk test and mortality in untreated primary pulmonary hypertension. Eur. Respir. J. 17, 647–652 (2001).
  • Sun XG, Hansen JE, Oudiz RJ et al. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 104, 429–435 (2001).
  • Wax D, Garifano R, Barst RJ. Effects of long-term infusion of prostacyclin on exercise performance in patients with primary pulmonary hypertension. Chest 116, 914–920 (1999).
  • Wensel R, Opitz C, Anker SD et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation 106, 319–324 (2002).
  • Oudiz R, Barst R, Hansen JE et al. Cause of correlation failure between cardiopulmonary exercise testing and 6-minute walk distance in patients with pulmonary arterial hypertension. Circulation 110(17 Suppl.), 2496 (2004).
  • Hansen JE, Sun X, Yasunobu Y et al. Reproducibility of cardiopulmonary exercise measurements in patients with pulmonary arterial hypertension. Chest 126, 816–824 (2004).
  • Hinderliter AL, Willis PW IV, Barst RJ et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right-ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation 95, 1479–1486 (1997).
  • Galie N, Hinderliter AL, Torbicki A et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. J. Am. Coll. Cardiol. 41, 1380–1386 (2003).
  • Bellenger NG, Grothues F, Smith GC, Pennell DJ. Quantification of right and left-ventricular function by cardiovascular magnetic resonance. Herz 25, 392–399 (2000).
  • Marcus JT, Vonk-Noordegraaf A, Roeleveld RJ et al. Impaired left-ventricular filling due to right-ventricular pressure overload in primary pulmonary hypertension: noninvasive monitoring using MRI. Chest 119, 1761–1765 (2001).
  • Sulica R, Rosenbluth A, Goldman J et al. A novel noninvasive marker of pulmonary hypertension using magnetic resonance imaging. Am. J. Respir. Crit. Care Med. 165(Suppl. 8), A336 (2002).
  • Sulica R, Sanz J, Fearon-Clarke J et al. Intravenous nesiritide improves hemodynamics in a randomized, double-blind, placebo-controlled trial in patients with pulmonary hypertension and right-ventricular failure. Right atrial dimension by cardiac MRI is a reliable, novel treatment end point in pulmonary hypertension. Circulation 110(Suppl. 17), 2414 (2004).
  • Nagaya N, Nishikimi T, Uematsu M et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 102, 865–870 (2000).
  • Kakishita M, Nishikimi T, Okano Y et al. Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. Clin. Sci. (Lond) 96, 33–39 (1999).
  • Nagaya N, Uematsu M, Satoh T et al. Serum uric acid levels correlate with severity and mortality of primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 160, 487–492 (1999).
  • Torbicki A, Kurzyna M, Kuca P et al. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 108, 844–848 (2003).
  • Davie NJ, Crossno JT Jr, Frid MG et al. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L668–L678 (2004).
  • Takahashi M, Nakamura T, Toba T et al. Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs. Tissue Eng. 10, 771–779 (2004).
  • Yeager ME, Halley GR, Golpon HA et al. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res. 88, E2–E11 (2001).
  • Taraseviciene-Stewart L, Kasahara Y, Alger L et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 15, 427–438 (2001).
  • Campbell AI, Zhao Y, Sandhu R et al. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 104, 2242–2248 (2001).
  • Deng Z, Morse JH, Slager SL et al. Familial primary pulmonary hypertension is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet. 67, 737–744 (2000).
  • 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 of the TGF-β family. J. Med. Genet 37, 741–745 (2000).
  • Humbert M, Deng Z, Simonneau G et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur. Respir. J. 20, 518–523 (2002).
  • Roberts KE, McElroy JJ, Wong WPK et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur. Respir. J. 24, 371–374 (2004).
  • Du L, Sullivan CC, Chu D et al. Signaling molecules in nonfamilial pulmonary hypertension. N. Engl. J. Med. 348, 500–509 (2003).
  • Zhao YD, Campbell AI, Robb M et al. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ. Res. 92, 984–991 (2003).
  • 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. 108, 1141–1150 (2001).
  • Eddahibi S, Chaouat A, Morrell N et al. Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease. Circulation 108, 1839–1844 (2003).
  • Marcos E, Fadel E, Sanchez O et al. Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ. Res. 94, 1263–1270 (2004).
  • Petkov V, Mosgoeller W, Ziesche R et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J. Clin. Invest. 111, 1339–1346 (2003).
  • Nagaya N, Nishikimi T, Uematsu M et al. Hemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart 84, 653–658 (2000).
  • Nagaya N, Kyotani S, Uematsu M et al. Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Circulation 109, 351–356 (2004).
  • Nagaya N, Okumura H, Uematsu M et al. Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats. Am. J. Physiol. Heart Circ. Physiol. 285, H2125–H2131 (2003).
  • Herve P, Launay JM, Scrobohaci LM et al. Increased plasma serotonin in primary pulmonary hypertension. Am. J. Med. 99, 249–254 (1995).
  • Morecroft I, Heeley RP, Prentice HM et al. 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br. J. Pharmacol. 128, 730–734 (1999).
  • Welsh DJ, Harnett M, MacLean M et al. Proliferation and signaling in fibroblasts: role of 5-hydroxytryptamine-2A receptor and transporter. Am. J. Respir. Crit. Care Med. 170, 252–259 (2004).
  • Keegan A, Morecroft I, Smillie D et al. Contribution of the 5-HT (1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT (1B)-receptor knockout mice and the 5-HT (1B/1D)-receptor antagonist GR 127935. Circ. Res. 89, 1231–1239 (2001).
  • Hironaka E, Hongo M, Sakai A et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res. 60, 692–699 (2003).
  • Marcos E, Adnot S, Pham MH et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am. J. Respir. Crit. Care Med. 168, 487–493 (2003).
  • Yuan JX, Wang J, Juhaszova M et al. Attenuated K-channel gene transcription in primary pulmonary hypertension. Lancet 351, 726–727 (1998).
  • Geraci MW, Moore M, Gessell T et al. Gene expression pattern in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ. Res. 88, 555–562 (2001).
  • Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J. Clin. Invest. 105(1), 21–34 (2000).
  • Cowan KN, Heilbut A, Humpl T et al. Complete reversal of fatal pulmonary hypertension in rats by serine elastase inhibitor. Nature Med. 6, 698–702 (2000).
  • Nishimura T, Faul JL, Berry GJ et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 166, 1403–1408 (2002).
  • Nishimura T, Vaszar LT, Faul JL et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 108, 1640–1645 (2003).
  • Nagaya N, Uematsu M, Oya H et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 163, 887–891 (2001).
  • Surdacki A, Zmudka K, Bieron K et al. Lack of beneficial effects of L-arginine infusion in primary pulmonary hypertension. Wien Klin Wochenschr. 106, 521–526 (1994).
  • Boger RH, Mugge A, Bode-Boger SM et al. Differential systemic and pulmonary hemodynamic effects of L-arginine in patients with coronary artery disease or primary pulmonary hypertension. Int. J. Clin. Pharmacol. Ther. 34, 323–328 (1996).
  • Langleben D, Christman BW, Barst RJ et al. Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension. Am. Heart J. 143, E4 (2002).

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