Treatments in Respiratory Medicine

, Volume 3, Issue 6, pp 339–352 | Cite as

Pulmonary Arterial Hypertension in Systemic Sclerosis

Clinical Manifestations, Pathophysiology, Evaluation, and Management
Leading Article

Abstract

It is increasingly recognized that significant pulmonary arterial hypertension (PAH) develops in more than 15% of patients with systemic sclerosis (SSc). As this complication of SSc may occur even in the absence of overt interstitial lung disease (isolated PAH), it has been likened to primary PAH and is attributable to intrinsic vascular pathology that is the hallmark of SSc. Deregulated activity of mediators controlling vasomotor tone has been implicated, and levels of endothelin-1 (ET-1) are elevated in the circulation and in the lungs. By causing enhanced vasoconstriction, vascular endothelial cell proliferation, smooth muscle hypertrophy, and irreversible vascular remodeling in the lungs, ET-1 appears to play a significant role in the pathogenesis of SSc-associated PAH.

Although patients with the limited cutaneous form of SSc are more likely to develop PAH than those with the diffuse form, the true prevalence of PAH in SSc, and the risk factors for its development, are not yet known. Because the prognosis of patients with SSc-associated PAH is substantially worse than that of patients without this complication, intensive efforts are underway to develop sensitive screening strategies and effective treatments. Serial evaluation of SSc patients with Doppler echocardiography appears to be prudent. Antibodies against the centromere or fibrillarin proteins may be useful in identifying those patients with SSc at highest risk for developing PAH.

The US FDA has approved a number of novel treatments, including long-acting oral ET-1 receptor antagonists such as bosentan and short-acting parenteral prostacyclin analogs, such as epoprostenol, for PAH. In particular, bosentan appear to be well tolerated, and short-term therapy results in improved exercise tolerance, improved hemodynamics, and possibly improved survival in patients with advanced PAH. These agents may be used alone, or possibly in combination with prostacyclin analogs. Therapeutic agents that modulate the synthesis of nitric oxide, and additional agents targeting the ET-1 signaling system are under preclinical development. Although the large-scale clinical trials that resulted in obtaining FDA approval for these agents were generally carried out in patients with primary PAH, it appears that patients with SSc-associated PAH respond similarly. Therefore, it is reasonable to conclude that ET-1 receptor antagonists and parenteral prostacyclin analogs should be used in SSc patients with moderate to severe PAH. The efficacy of these agents for treating patients with PAH who also experience significant interstitial lung disease, as occurs in many SSc patients, remains unknown. Additional important unresolved issues relate to the long-term efficacy of ET-1 receptor antagonists, and their effects on survival and progression of PAH. Additionally, it is not yet clear if early intervention for SSc patients with mild PAH is beneficial.

Notes

Acknowledgment

This review was supported by a grant from the National Institutes of Health (AR-42309). The authors have no conflicts of interest that are directly relevant to the content of this review

References

  1. 1.
    Steen VD, Conte C, Owens GR, et al. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994; 37: 1283–128PubMedCrossRefGoogle Scholar
  2. 2.
    Altman RD, Medsger Jr TA, Bloch DA, et al. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1991; 34(4): 403–19PubMedCrossRefGoogle Scholar
  3. 3.
    Rich S, editor. Primary pulmonary hypertension: executive summary from the world symposium. Geneva: World Health Organization, 1998Google Scholar
  4. 4.
    Maricq HR, Weinrich MC, Keil JE, et al. Prevalence of scleroderma spectrum disorders in the general population of South Carolina. Arthritis Rheum 1989 Aug; 32(8): 998–1006PubMedCrossRefGoogle Scholar
  5. 5.
    Kuwana M, Kaburaki J, Arnett FC, et al. Influence of ethnic background on clinical and serologic features in patients with systemic sclerosis and anti-DNA topoisomerase I antibody. Arthritis Rheum 1999 Mar; 42(3): 465–74PubMedCrossRefGoogle Scholar
  6. 6.
    Steen VD, Powell DL, Medsger Jr TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988 Feb; 31(2): 196–203PubMedCrossRefGoogle Scholar
  7. 7.
    Jiminez SA, Derk CT. Following the molecular pathways toward understanding the pathogenesis of systmic sclerosis. Ann Intern Med 2004; 140: 37–50Google Scholar
  8. 8.
    Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987; 107: 216–23PubMedGoogle Scholar
  9. 9.
    Stupi AM, Steen VD, Owens GR, et al. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 1986; 29(4): 515–24PubMedCrossRefGoogle Scholar
  10. 10.
    Salerni R, Rodnan GP, Leon DF, et al. Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Ann Intern Med 1977; 86: 394–9PubMedGoogle Scholar
  11. 11.
    Ungerer RG, Tashkin DP, Furst D, et al. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983; 75(1): 65–74PubMedCrossRefGoogle Scholar
  12. 12.
    Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest 1996 Dec; 110(6): 1515–9PubMedCrossRefGoogle Scholar
  13. 13.
    Young RH, Mark GJ. Pulmonary vascular changes in scleroderma. Am J Med 1978; 64: 998–1004PubMedCrossRefGoogle Scholar
  14. 14.
    Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990; 21: 467–74PubMedCrossRefGoogle Scholar
  15. 15.
    Kawut SM, Taichman DB, Archer-Chicko CL, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003 Feb; 123(2): 344–50PubMedCrossRefGoogle Scholar
  16. 16.
    Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine 1984; 63: 92–107PubMedCrossRefGoogle Scholar
  17. 17.
    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 2000 Feb; 161 (2 Pt 1): 487–92PubMedGoogle Scholar
  18. 18.
    Denton CP, Cailes JB, Phillips GD, et al. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997 Feb; 36(2): 239–43PubMedCrossRefGoogle Scholar
  19. 19.
    Koh ET, Lee P, Gladman DD, et al. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996 Oct; 35(10): 989–93PubMedCrossRefGoogle Scholar
  20. 20.
    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 2003 Feb 15; 167(4): 580–6PubMedCrossRefGoogle Scholar
  21. 21.
    Langevitz P, Buskila D, Gladman DD, et al. HLA alleles in systemic sclerosis: association with pulmonary hypertension and outcome. Br J Rheumatol 1992 Sep; 31(9): 609–13PubMedCrossRefGoogle Scholar
  22. 22.
    Reveille JD, Fischbach M, McNearney T, et al. Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum 2001; 30(5): 332–46PubMedCrossRefGoogle Scholar
  23. 23.
    Scorza R, Caronni M, Bazzi S, et al. Post-menopause is the main risk factor for developing isolated pulmonary hypertension in systemic sclerosis. Ann N Y Acad Sci 2002 Jun; 966: 238–46PubMedCrossRefGoogle Scholar
  24. 24.
    Launay D, Hachulla E, Hatron PY, et al. Pulmonary hypertension screening in systemic scleroderma: a cohort study of 67 patients. Rev Med Interne 2001 Sep; 22(9): 819–29PubMedCrossRefGoogle Scholar
  25. 25.
    Steen VD, Graham G, Conte C, et al. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992 Jul; 35(7): 765–70PubMedCrossRefGoogle Scholar
  26. 26.
    Steen V, Medsger Jr TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003 Feb; 48(2): 516–22PubMedCrossRefGoogle Scholar
  27. 27.
    Negi VS, Tripathy NK, Misra R, et al. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol 1998; 25: 462–6PubMedGoogle Scholar
  28. 28.
    Ulanet DB, Wigley FM, Gelber AC, et al. Autoantibodies against B23, a nucleolar phosphoprotein, occur in scleroderma and are associated with pulmonary hypertension. Arthritis Rheum 2003 Feb 15; 49(1): 85–92PubMedCrossRefGoogle Scholar
  29. 29.
    Okano Y, Steen VD, Medsger Jr TA. Autoantibody to U3 nucleolar ribonucleoprotein (fibrillarin) in patients with systemic sclerosis. Arthritis Rheum 1992; 35(1): 95–100PubMedCrossRefGoogle Scholar
  30. 30.
    Tormey VJ, Bunn CC, Denton CP, et al. Anti-fibrillarin antibodies in systemic sclerosis. Rheumatology 2001; 40(10): 1157–62PubMedCrossRefGoogle Scholar
  31. 31.
    Grigolo B, Mazzetti I, Meliconi R, et al. Anti-topoisomerase II alpha autoantibodies in systemic sclerosis-association with pulmonary hypertension and HLA-B35. Clin Exp Immunol 2000 Sep; 121(3): 539–43PubMedCrossRefGoogle Scholar
  32. 32.
    D’Angelo WA, Fries JF, Masi AT, et al. Pathologic observations in systemic sclerosis (scleroderma): a study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med 1969; 46: 428–40PubMedCrossRefGoogle Scholar
  33. 33.
    Norton WL, Nardo JM. Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med 1970; 73: 317PubMedGoogle Scholar
  34. 34.
    Al-Sabbagh MR, Steen VD, Zee BC, et al. Pulmonary arterial histology and morphometry in systemic sclerosis: a case-control autopsy study. J Rheumatol 1989; 16(8): 1038–42PubMedGoogle Scholar
  35. 35.
    Cool CD, Kennedy D, Voelkel NF, et al. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997 Apr; 28(4): 434–42PubMedCrossRefGoogle Scholar
  36. 36.
    Rubin LJ. In: Murray JF, Nadel JA, editors. Textbook of respiratory medicine. Philadelphia (PA): W.B Saunders and Company, 2000Google Scholar
  37. 37.
    Morse J, Barst R, Horn E, et al. Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations. J Rheumatol 2002 Nov; 29(11): 2379–81PubMedGoogle Scholar
  38. 38.
    Lunardi C, Bason C, Navone R, et al. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Med 2000; 6: 1183–6PubMedCrossRefGoogle Scholar
  39. 39.
    Carvalho D, Savage CO, Black CM, et al. IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro: induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest 1996; 97: 111–9PubMedCrossRefGoogle Scholar
  40. 40.
    Cacoub P, Dorent R, Nataf P, et al. Endothelin-1 in the lungs of patients with pulmonary hypertension. Cardiovasc Res 1997 Jan; 33(1): 196–200PubMedCrossRefGoogle Scholar
  41. 41.
    Kadono T, Kikuchi K, Sato S, et al. Elevated plasma endothelin levels in systemic sclerosis. Arch Dermatol Res 1995; 287(5): 439–42PubMedCrossRefGoogle Scholar
  42. 42.
    Vancheeswaran R, Magoulas T, Efrat G, et al. Circulating endothelin-1 levels in systemic sclerosis subsets: a marker of fibrosis or vascular dysfunction? J Rheumatol 1994; 21(10): 1838–44PubMedGoogle Scholar
  43. 43.
    Reichenberger F, Schauer J, Kellner K, et al. Different expression of endothelin in the bronchoalveolar lavage in patients with pulmonary diseases. Lung 2001; 179(3): 163–74PubMedCrossRefGoogle Scholar
  44. 44.
    Shi-Wen X, Denton CP, Dashwood MR, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol 2001; 116(3): 417–25PubMedCrossRefGoogle Scholar
  45. 45.
    Abraham DJ, Vancheeswaran R, Dashwood MR, et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. Am J Pathol 1997; 151(3): 831–41PubMedGoogle Scholar
  46. 46.
    Hampl V, Herget J. Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. Physiol Rev 2000 Oct; 80(4): 1337–72PubMedGoogle Scholar
  47. 47.
    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): 214–21PubMedCrossRefGoogle Scholar
  48. 48.
    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: 1925–32PubMedGoogle Scholar
  49. 49.
    Owen NE. Prostacyclin can inhibit DNA synthesis in vascular smooth muscle cells. In: Bailey JM, editor. Prostaglandins, leukotrienes and lipoxins. New York: Plenum Press, 1985: 193–204CrossRefGoogle Scholar
  50. 50.
    Yu AY, Shimoda LA, Iyer NV, et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha. J Clin Invest 1999; 103: 691–6PubMedCrossRefGoogle Scholar
  51. 51.
    Iwashina M, Shichiri M, Marumo F, et al. Transfection of inducible mitric oxide synthase gene causes apoptosis in vascular smooth muscle cells. Circulation 1998; 98: 1212–8PubMedCrossRefGoogle Scholar
  52. 52.
    Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987 Nov 7; II(8567): 1057–8CrossRefGoogle Scholar
  53. 53.
    Kharitonov SA, Cailes JB, Black CM, et al. Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension. Thorax 1997 Dec; 52(12): 1051–5PubMedCrossRefGoogle Scholar
  54. 54.
    Mayes MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum 2003 May; 48(5): 1190–9PubMedCrossRefGoogle Scholar
  55. 55.
    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: 70–5PubMedCrossRefGoogle Scholar
  56. 56.
    Karniguian A, Legrand YJ, Caen JP. Prostaglandins: specific inhibition of platelet adhesion to collagen and relationship with cAMP level. Prostaglandins 1982 Apr; 23(4): 437–57PubMedCrossRefGoogle Scholar
  57. 57.
    Fanburg BL, Lee SL. A role for the serotonin transporter in hypoxia-induced pulmonary hypertension. J Clin Invest 2000; 105: 1521–3PubMedCrossRefGoogle Scholar
  58. 58.
    Imokawa S, Sato A, Hayakawa H, et al. Tissue factor expression and fibrin deposition in the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis. Am J Respir Crit Care Med 1997; 156: 631–6PubMedGoogle Scholar
  59. 59.
    Ames PR, Lupoli S, Alves J, et al. The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress syndrome. Br J Rheumatol 1997 Oct; 36(10): 1045–50PubMedCrossRefGoogle Scholar
  60. 60.
    Botney MD, Bahadori L, Gold LI. Vascular remodeling in primary pulmonary hypertension: potential role for transforming growth factor-beta. Am J Pathol 1994 Feb; 144(2): 286–95PubMedGoogle Scholar
  61. 61.
    Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J 1995 Dec; 8(12): 2129–38PubMedCrossRefGoogle Scholar
  62. 62.
    Carducci MA, Nelson JB, Bowling MK, et al. Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol 2002 Apr 15; 20(8): 2171–80PubMedCrossRefGoogle Scholar
  63. 63.
    Luscher TF, Enseleit F, Pacher R, et al. Hemodynamic and neurohumoral effects of selective endothelin A (ET [A]) receptor blockade in chronic heart failure: the Heart Failure ET (A) Receptor Blockade Trial (HEAT). Circulation 2002 Nov 19; 106(21): 2666–72PubMedCrossRefGoogle Scholar
  64. 64.
    O’Connor CM, Gattis WA, Adams Jr KF, et al. Tezosentan in patients with acute heart failure and acute coronary syndromes: design of the Randomized Intravenous Tezosentan study (RITZ-4). Am Heart J 2002 Oct; 144(4): 583–8PubMedGoogle Scholar
  65. 65.
    Nakov R, Pfarr E, Eberle S. Darusentan: an effective endothelin A receptor antagonist for treatment of hypertension. J Hypertens 2002 Jul; 15 (7 Pt 1): 583–9CrossRefGoogle Scholar
  66. 66.
    Wanecek M, Oldner A, Rudehill A, et al. Cardiopulmonary dysfunction during porcine endotoxin shock is effectively counteracted by the endothelin receptor antagonist bosentan. Shock 1997 May; 7(5): 364–70PubMedCrossRefGoogle Scholar
  67. 67.
    Chen SJ, Chen YF, Meng QC, et al. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995 Dec; 79(6): 2122–31PubMedGoogle Scholar
  68. 68.
    Shimoyama H, Sabbah HN, Borzak S, et al. Short-term hemodynamic effects of endothelin receptor blockade in dogs with chronic heart failure. Circulation 1996; 94: 779–84PubMedCrossRefGoogle Scholar
  69. 69.
    Kiowski W, Sütsch G, Hunziker P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995 Sep 16; 346(8977): 732–6PubMedCrossRefGoogle Scholar
  70. 70.
    Sütsch G, Kiowski W, Yan XW, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998; 98: 2262–8PubMedCrossRefGoogle Scholar
  71. 71.
    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): 1119–23PubMedCrossRefGoogle Scholar
  72. 72.
    Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002 Mar 21; 346(12): 896–903PubMedCrossRefGoogle Scholar
  73. 73.
    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 2003 Apr 16; 41(8): 1380–6PubMedCrossRefGoogle Scholar
  74. 74.
    Sitbon O, Badesch DB, Channick RN, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest 2003 Jul; 124(1): 247–54PubMedCrossRefGoogle Scholar
  75. 75.
    Conte JV, Gaine SP, Orens JB, et al. The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation. J Heart Lung Transplant 1998; 17: 679–85PubMedGoogle Scholar
  76. 76.
    Rich S. Medical treatment of primary pulmonary hypertension: a bridge to transplantation? Am J Cardiol 1995 Jan 19; 75(3): 63A–6APubMedCrossRefGoogle Scholar
  77. 77.
    Jones K, Higenbottam T, Wallwork J. Pulmonary vasodilation with prostacyclin in primary and secondary pulmonary hypertension. Chest 1989 Oct; 96(4): 784–9PubMedCrossRefGoogle Scholar
  78. 78.
    Nootens M, Schrader B, Kaufmann E, et al. Comparative acute effects of adenosine and prostacyclin in primary pulmonary hypertension. Chest 1995 Jan; 107(1): 54–7PubMedCrossRefGoogle Scholar
  79. 79.
    Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension: a dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995 Feb; 151 (2 Pt 1): 384–9PubMedGoogle Scholar
  80. 80.
    Higenbottam T, Wheeldon D, Wells F, et al. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1984; I: 1046–7CrossRefGoogle Scholar
  81. 81.
    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: 485–91PubMedGoogle Scholar
  82. 82.
    Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994; 121: 409–15PubMedGoogle Scholar
  83. 83.
    McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002 Sep 17; 106(12): 1477–82PubMedCrossRefGoogle Scholar
  84. 84.
    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 Aug 21; 40(4): 780–8PubMedCrossRefGoogle Scholar
  85. 85.
    Klings ES, Hill NS, Ieong MH, et al. Systemic sclerosis-associated pulmonary hypertension: short- and long-term effects of epoprostenol (prostacyclin). Arthritis Rheum 1999; 42: 2638–45PubMedCrossRefGoogle Scholar
  86. 86.
    Strange C, Bolster M, Mazur J, et al. Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension. Chest 2000 Oct; 118(4): 1077–82PubMedCrossRefGoogle Scholar
  87. 87.
    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 Mar 21; 132(6): 425–34PubMedGoogle Scholar
  88. 88.
    Remodulin [package insert]. Research Triangle Park (NC): United Therapeutics Corporation, 2002 MayGoogle Scholar
  89. 89.
    McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 2003 Feb; 41(2): 293–9PubMedCrossRefGoogle Scholar
  90. 90.
    Gaine SP, Barst RJ, Rich S, et al. Acute hemodynamic effects of subcutaneous UT 15 in primary pulmonary hypertension [abstract]. Am J Crit Care Med 1999; 159: A161Google Scholar
  91. 91.
    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 2002 Mar 15; 165(6): 800–4PubMedGoogle Scholar
  92. 92.
    Hamilton G, Saba T, Corris P, et al. Improvement of exercise tolerance due to uniprost in patients with pulmonary arterial hypertension is related to baseline performance [abstract]. Am J Respir Crit Care Med 2001; 163: A540Google Scholar
  93. 93.
    Fleming T, Lindenfeld J, Lipicky R, et al. Report from the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting; 2001 Aug 9–10. Circulation 2001 Oct 9; 104(15): 1742PubMedCrossRefGoogle Scholar
  94. 94.
    Vachiery JL, Hill N, Zwicke D, et al. Transitioning from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest 2002 May; 121(5): 1561–5PubMedCrossRefGoogle Scholar
  95. 95.
    Ahn HS, Foster M, Cable M, et al. Ca/CaM-stimulated and cGMP-specific phosphodiesterases in vascular and non-vascular tissues. Adv Exp Med Biol 1991; 308: 191–7PubMedCrossRefGoogle Scholar
  96. 96.
    Zhao L, Mason NA, Morrell NW, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104: 424–8PubMedCrossRefGoogle Scholar
  97. 97.
    Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000 Nov 2; 343(18): 1342PubMedCrossRefGoogle Scholar
  98. 98.
    Schumacher YO, Zdebik A, Huonker M, et al. Sildenafil in HIV-related pulmonary hypertension. AIDS 2001 Sep 7; 15(13): 1747–8PubMedCrossRefGoogle Scholar
  99. 99.
    Littera R, La Nasa G, Derchi G, et al. Long-term treatment with sildenafil in a thalassemic patient with pulmonary hypertension. Blood 2002 Aug 15; 100(4): 1516–7PubMedCrossRefGoogle Scholar
  100. 100.
    Watanabe H, Ohashi K, Takeuchi K, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002 May; 71(5): 398–402PubMedCrossRefGoogle Scholar
  101. 101.
    Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002 Sep 15; 90(6): 677–80PubMedCrossRefGoogle Scholar
  102. 102.
    Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002 May 21; 105(20): 2398–403PubMedCrossRefGoogle Scholar
  103. 103.
    Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002 Sep 21; 360(9337): 895–900PubMedCrossRefGoogle Scholar
  104. 104.
    Givertz MM, Colucci WS, LeJemtel TH, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation 2000; 101: 2922–7PubMedCrossRefGoogle Scholar
  105. 105.
    Barst RJ, Rich S, Widlitz A, et al. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest 2002 Jun; 121(6): 1860–8PubMedCrossRefGoogle Scholar
  106. 106.
    Barst RJ, Langleben D, Frost A, et al. Sitaxsentan, a selective ETA receptor antagonist, improves exercise capacity and NYHA functional class in pulmonary arterial hypertension (PAH) [abstract]. Am J Crit Care Med 2003; 167(7): A440Google Scholar
  107. 107.
    Scott JP, Higenbottam T, Wallwork J. The acute effect of the synthetic prostacyclin analogue iloprost in primary pulmonary hypertension. Br J Clin Pract 1990 Jun; 44(6): 231–4PubMedGoogle Scholar
  108. 108.
    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): 356–65PubMedCrossRefGoogle Scholar
  109. 109.
    Gomez-Sanchez MA, de la Calzada CS, Gomez Pajuelo C, et al. Different hemodynamic responses between acute and chronic infusion of iloprost (prostacyclin-stable analogue) in severe pulmonary hypertension. Am Rev Respir Dis 1991 Dec; 144(6): 1404–5PubMedGoogle Scholar
  110. 110.
    Higenbottam TW, Butt AY, Dinh-Xaun AT, et al. Treatment of pulmonary hypertension with the continuous infusion of a prostacyclin analogue, iloprost. Heart 1998; 79: 175–9PubMedGoogle Scholar
  111. 111.
    Higenbottam T, Butt AY, McMahon A, et al. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart 1998; 80: 151–5PubMedGoogle Scholar
  112. 112.
    Olschewski H, Walmrath D, Schermuly R, et al. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med 1996; 124: 820–4PubMedGoogle Scholar
  113. 113.
    Olschewski H, Ghofrani HA, Walmrath D, et al. Recovery from circulatory shock in severe primary pulmonary hypertension (PPH) with aerosolization of iloprost. Intensive Care Med 1998 Jun; 24(6): 631–4PubMedCrossRefGoogle Scholar
  114. 114.
    Blumberg FC, Riegger GA, Pfeifer M. Hemodynamic effects of aerosolized iloprost in pulmonary hypertension at rest and during exercise. Chest 2002 May; 121(5): 1566–71PubMedCrossRefGoogle Scholar
  115. 115.
    Wensel R, Opitz CF, Ewert R, et al. Effects of iloprost inhalation on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension. Circulation 2000 May 23; 101(20): 2388–92PubMedCrossRefGoogle Scholar
  116. 116.
    Olschewski H, Ghofrani HA, Schmehl T, et al. Inhaled iloprost to treat severe pulmonary hypertension: an uncontrolled trial: German PPH Study Group. Ann Intern Med 2000 Mar 21; 132(6): 435–43PubMedGoogle Scholar
  117. 117.
    Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000 Nov 9; 343(19): 1421–2CrossRefGoogle Scholar
  118. 118.
    Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension: Aerosolized Iloprost Randomized (AIR) study group. N Engl J Med 2002 Aug 1; 347(5): 322–9PubMedCrossRefGoogle Scholar
  119. 119.
    de la Mata J, Gomez-Sanchez MA, Aranzana M, et al. Long-term iloprost infusion therapy for severe pulmonary hypertension in patients with connective tissue diseases. Arthritis Rheum 1994 Oct; 37(10): 1528–33PubMedCrossRefGoogle Scholar
  120. 120.
    Bartosik I, Eskilsson J, Scheja A, et al. Intermittent iloprost infusion therapy of pulmonary hypertension in scleroderma: a pilot study. Br J Rheumatol 1996 Nov; 35(11): 1187–8PubMedCrossRefGoogle Scholar
  121. 121.
    Launay D, Hachulla E, Hatron PY, et al. Aerosolized iloprost in CREST syndrome related pulmonary hypertension. J Rheumatol 2001 Oct; 28(10): 2252–6PubMedGoogle Scholar
  122. 122.
    Petkov V, Ziesche R, Mosgoeller W, et al. Aerosolised iloprost improves pulmonary haemodynamics in patients with primary pulmonary hypertension receiving continuous epoprostenol treatment. Thorax 2001 Sep; 56(9): 734–6PubMedCrossRefGoogle Scholar
  123. 123.
    Schenk P, Petkov V, Madl C, et al. Aerosolized iloprost therapy could not replace long-term IV epoprostenol (prostacyclin) administration in severe pulmonary hypertension. Chest 2001 Jan; 119(1): 296–300PubMedCrossRefGoogle Scholar
  124. 124.
    Hoeper MM, Spiekerkoetter E, Westerkamp V, et al. Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension. Eur Respir J 2002 Aug; 20(2): 339–43PubMedCrossRefGoogle Scholar
  125. 125.
    Saji T, Ozawa Y, Ishikita T, et al. Short-term hemodynamic effect of a new oral PGI2 analogue, beraprost, in primary and secondary pulmonary hypertension. Am J Cardiol 1996 Jul 15; 78(2): 244–7PubMedCrossRefGoogle Scholar
  126. 126.
    Ichida F, Uese K, Hashimoto I, et al. Acute effect of oral prostacyclin and inhaled nitric oxide on pulmonary hypertension in children. J Cardiol 1997 Apr; 29(4): 217–24PubMedGoogle Scholar
  127. 127.
    Ichida F, Uese K, Tsubata S, et al. Additive effect of beraprost on pulmonary vasodilation by inhaled nitric oxide in children with pulmonary hypertension. Am J Cardiol 1997 Sep 1; 80(5): 662–4PubMedCrossRefGoogle Scholar
  128. 128.
    Nagaya N, Shimizu Y, Satoh T, et al. Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension. Heart 2002 Apr; 87(4): 340–5PubMedCrossRefGoogle Scholar
  129. 129.
    Vizza CD, Sciomer S, Morelli S, et al. Long term treatment of pulmonary arterial hypertension with beraprost, an oral prostacyclin analogue. Heart 2001 Dec; 86(6): 661–5PubMedCrossRefGoogle Scholar
  130. 130.
    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: 1188–92PubMedCrossRefGoogle Scholar
  131. 131.
    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. Arterial Pulmonary Hypertension and Beraprost European Trial (ALPHABET) Study Group. J Am Coll Cardiol 2002 May 1; 39(9): 1496–502PubMedCrossRefGoogle Scholar
  132. 132.
    Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension: Beraprost Study Group. J Am Coll Cardiol 2003 Jun 18; 41(12): 2119–25PubMedCrossRefGoogle Scholar
  133. 133.
    Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002 Apr 2; 136(7): 515–22PubMedGoogle Scholar
  134. 134.
    Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001 Sep 11; 104(11): 1218–22PubMedCrossRefGoogle Scholar
  135. 135.
    Channick RN, Kim NHS, Lombardi S, et al. Addition of bosentan to patients with pulmonary arterial hypertension receiving chronic epoprostenol or treprostinil is well tolerated and allows weaning or discontinuation of prostacyclin in some patients [abstract]. Am J Crit Care Med 2003; 167(7): A441Google Scholar
  136. 136.
    Humbert M, Barst RJ, Robbins IM, et al. Safety and efficacy of bosentan combined with epoprostenol in patients with severe pulmonary hypertension [abstract]. Am J Crit Care Med 2003; 167(7): A441Google Scholar
  137. 137.
    Rich S, Kaufman E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76PubMedCrossRefGoogle Scholar
  138. 138.
    Sfikakis PP, Kyriakidis MK, Vergos CG, et al. Cardiopulmonary hemodynamics in systemic sclerosis and response to nifedipine and captopril. Am J Med 1991 May; 90(5): 541–6PubMedCrossRefGoogle Scholar
  139. 139.
    Pressly TA, Winkler A, Alpert MA, et al. Value and limitations of calcium channel blockade in the treatment of pulmonary hypertension associated with CREST: case reports. Angiology 1988 Apr; 39(4): 385–9PubMedCrossRefGoogle Scholar
  140. 140.
    Alpert MA, Pressly TA, Mukerji V, et al. Acute and long-term effects of nifedipine on pulmonary and systemic hemodynamics in patients with pulmonary hypertension associated with diffuse systemic sclerosis, the CREST syndrome and mixed connective tissue disease. Am J Cardiol 1991; 68: 1687–91PubMedCrossRefGoogle Scholar
  141. 141.
    Maurer JR, Frost AE, Estenne M, et al. International guidelines for the selection of lung transplant candidates: the International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. Transplantation 1998 Oct 15; 66(7): 951–6PubMedCrossRefGoogle Scholar
  142. 142.
    Rosas V, Conte JV, Yang SC, et al. Lung transplantation and systemic sclerosis. Ann Transplant 2000; 5(3): 38–43PubMedGoogle Scholar
  143. 143.
    Levine SM, Anzueto A, Peters JI, et al. Single lung transplantation in patients with systemic disease. Chest 1994 Mar; 105(3): 837–41PubMedCrossRefGoogle Scholar
  144. 144.
    Pigula FA, Griffith BP, Zenati MA, et al. Lung transplantation for respiratory failure resulting from systemic disease. Ann Thorac Surg 1997; 64: 1630–4PubMedCrossRefGoogle Scholar
  145. 145.
    Lau CL, Palmer SM, Howell DN, et al. Laparoscopic antireflux surgery in the lung transplant population. Surg Endosc 2002 Dec; 16(12): 1674–8PubMedCrossRefGoogle Scholar
  146. 146.
    Conte JV, Borja MJ, Patel CB, et al. Lung transplantation for primary and secondary pulmonary hypertension. Ann Thorac Surg 2001 Nov 1; 72(5): 1673–80PubMedCrossRefGoogle Scholar
  147. 147.
    Pasque MK, Trulock EP, Cooper JD, et al. Single lung transplantation for pulmonary hypertension: single institution experience in 34 patients. Circulation 1995 Oct 15; 92(8): 2252–8PubMedCrossRefGoogle Scholar
  148. 148.
    Gammie JS, Keenan RJ, Pham SM, et al. Single- versus double-lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1998 Feb 1; 115(2): 397–403PubMedCrossRefGoogle Scholar
  149. 149.
    Kerstein D, Levy PS, Hsu DT, et al. Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation 1995 Apr 1; 91(7): 2028–35PubMedCrossRefGoogle Scholar
  150. 150.
    Kramer MR, Valantine HA, Marshall SE, et al. Recovery of the right ventricle after single-lung transplantation in pulmonary hypertension. Am J Cardiol 1994 Mar 1; 73(7): 494–500PubMedCrossRefGoogle Scholar
  151. 151.
    Higenbottam TW, Spiegelhalter D, Scott JP, et al. Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J 1993; 70(4): 366–70PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Andrew J. McKelvey Lung Transplantation CenterEmory University School of MedicineAtlantaUSA
  2. 2.Division of Rheumatology (M/C 733)Northwestern University, Feinberg School of MedicineChicagoUSA

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