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Management of Pulmonary Arterial Hypertension Associated with Congenital Systemic-to-Pulmonary Shunts and Eisenmenger’s Syndrome

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Abstract

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger’s syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis.

The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed.

The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25–50% of this population affected by Eisenmenger’s syndrome.

Clinically, Eisenmenger’s syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger’s syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger’s syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class.

The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger’s syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis.

The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger’s syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger’s syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger’s syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger’s syndrome.

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References

  1. Galie N, Rubin L. Pulmonary arterial hypertension: epidemiology, pathobiology, assessment and therapy. J Am Coll Cardiol 2004; 43: S1–90

    Google Scholar 

  2. Eisenmenger V. Die angeboren Defects des Kammerscheidewand des Herzen. Z Klin Med 1897; 32: 1–28

    Google Scholar 

  3. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults: second of two parts [published erratum appears in N Engl J Med 2000 Mar 30; 342 (13): 988]. N Engl J Med 2000; 342: 334–342

    PubMed  CAS  Google Scholar 

  4. Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period: The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005; 26: 2325–33

    PubMed  Google Scholar 

  5. Duffels MGJ, Engelfriet PM, Berger RMF, et al. Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry. Int J Cardiol 2007; 120: 198–204

    PubMed  CAS  Google Scholar 

  6. Engelfriet PM, Duffels MGJ, Moller T, et al. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007; 93: 682–7

    PubMed  Google Scholar 

  7. Simonneau G, Galie N, Rubin L, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43: S5–12

    Google Scholar 

  8. Lee SD, Shroyer KR, Markham NE, et al. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998; 101: 927–34

    PubMed  CAS  Google Scholar 

  9. Galie N. Classification of patients with congenital systemic-to-pulmonary shunts associated with pulmonary hypertension: current status and future directions. In: Beghetti M, Barst R, Naeije R, et al., editors. Pulmonary arterial hypertension related to congenital heart disease. Munchen: Elsevier, 2006: 11–7

    Google Scholar 

  10. Gatzoulis MA, Barst RJ, Fineman J, et al. Eisenmenger’s syndrome and pulmonary arterial hypertension in adults with congenital heart disease. Curr Med Res Opin 2007; 23 Suppl. 2: S19–25

    Google Scholar 

  11. van Albada ME, Berger RMF. Pulmonary hypertension in the setting of the congenital cardiac disease: the need for refinement of the Evian-Venice classification. Cardiol Young 2008; 18: 10–17

    PubMed  Google Scholar 

  12. Schulze-Neick I, Beghetti M. Classifying pulmonary hypertension in the setting of the congenitally malformed heart: cleaning up a dog’s dinner. Cardiol Young 2008; 18: 22–25

    PubMed  Google Scholar 

  13. Daliento L, Somerville J, Presbitero P, et al. Eisenmenger’s syndrome: factors relating to deterioration and death. Eur Heart J 1998; 19: 1845–55

    PubMed  CAS  Google Scholar 

  14. Besterman E. Atrial septal defects with pulmonary hypertension. Br Heart J 1961; 23: 587–98

    PubMed  CAS  Google Scholar 

  15. Hoffman JE, Rudolph AM. The natural history of ventricular septal defects in infancy. Am J Cardiol 1985; 16: 634–53

    Google Scholar 

  16. Steele P, Fuster V, Cohen M, et al. Isolated atrial septal defect with pulmonary vascular obstructive disease: long-term follow-up and prediction of outcome after surgical correction. Circulation 1987; 76: 1037–42

    PubMed  CAS  Google Scholar 

  17. Vogel M, Berger F, Kramer A, et al. Incidence of secondary pulmonary hypertension in adults with atrial septal or sinus venosus defects. Heart 1999; 82: 30–3

    PubMed  CAS  Google Scholar 

  18. Kidd L, Driscoll D, Gersony W, et al. Second natural history study of congenital heart defects: results of treatment of patients with ventricular septal defects. Circulation 1993; 87: 138–51

    Google Scholar 

  19. Neumayer U, Stone S, Somerville J. Small ventricular septal defects in adults. Eur Heart J 1988; 19: 1573–82

    Google Scholar 

  20. Task FM, Galie N, Torbicki A, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004; 25: 2243–78

    Google Scholar 

  21. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006; 173: 1023–30

    PubMed  Google Scholar 

  22. Peacock AJ, Murphy NF, McMurray JJV, et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007; 30: 104–9

    PubMed  CAS  Google Scholar 

  23. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004; 43 (12 Suppl. 1): S25–32

    Google Scholar 

  24. Humbert M, Morrell N, Archer S, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43 (12 Suppl. 1): S13–24

    Google Scholar 

  25. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004; 109: 159–65

    PubMed  Google Scholar 

  26. Cowan KN, Heilbut A, Humpl T, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000; 6: 698–702

    PubMed  CAS  Google Scholar 

  27. Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 2003; 348: 500–9

    PubMed  CAS  Google Scholar 

  28. Vongpatanasin W, Brickner ME, Hillis LD, et al. The Eisenmenger’s syndrome in adults. Ann Intern Med 1998; 128: 745–55

    PubMed  CAS  Google Scholar 

  29. Diller GP, Dimopoulos K, Okonko D, et al. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation 2005; 112: 828–35

    PubMed  Google Scholar 

  30. Diller GP, Gatzoulis MA. Pulmonary vascular disease in adults with congenital heart disease. Circulation 2007; 115: 1039–50

    PubMed  Google Scholar 

  31. Broberg C, Ujita M, Babu-Narayan S, et al. Massive pulmonary artery thrombosis with haemoptysis in adults with Eisenmenger’s syndrome: a clinical dilemma. Heart 2004; 90: e63

    PubMed  CAS  Google Scholar 

  32. Broberg CS, Ujita M, Prasad S, et al. Pulmonary arterial thrombosis in eisenmenger’s syndrome is associated with biventricular dysfunction and decreased pulmonary flow velocity. J Am Coll Cardiol 2007; 50: 634–42

    PubMed  Google Scholar 

  33. Diller GP, Dimopoulos K, Broberg CS, et al. Presentation, survival prospects, and predictors of death in Eisenmenger’s syndrome: a combined retrospective and case-control study. Eur Heart J 2006; 27: 1737–42

    PubMed  Google Scholar 

  34. Hopkins WE, Ochoa LL, Richardson GW, et al. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger’s syndrome. J Heart Lung Transplant 1996; 15: 100–5

    PubMed  CAS  Google Scholar 

  35. Berman EB, Barst RJ. Eisenmenger’s syndrome: current management. Prog Cardiovasc Dis 2002; 45: 129–38

    PubMed  Google Scholar 

  36. Deanfield J, Thaulow E, Warnes C, et al. Management of grown up congenital heart disease. Eur Heart J 2003; 24: 1035–84

    PubMed  Google Scholar 

  37. Galie N, Beghetti M, Gatzoulis MA, et al., for the Bosentan Randomized Trial of Endothelin Antagonist Therapy. Bosentan therapy in patients with eisenmenger’s syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006; 114: 48–54

    PubMed  CAS  Google Scholar 

  38. Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation 2006; 114: 1482–9

    PubMed  Google Scholar 

  39. Avila WS, Grinberg M, Snitcowsky R, et al. Maternal and fetal outcome in pregnant women with Eisenmenger’s syndrome. Eur Heart J 1995; 16: 460–4

    PubMed  CAS  Google Scholar 

  40. Uebing A, Steer PJ, Yentis SM, et al. Pregnancy and congenital heart disease. BMJ 2006; 332: 401–6

    PubMed  Google Scholar 

  41. Yentis SM, Steer PJ, Plaat F. Eisenmenger’s syndrome in pregnancy: maternal and fetal mortality in the 1990s. Br J Obstet Gynaecol 1998; 105: 921–2

    PubMed  CAS  Google Scholar 

  42. Oakley C, Child A, Lung B, et al. Expert consensus document on management of cardiovascular diseases during pregnancy. Eur Heart J 2003; 24: 761–81

    Google Scholar 

  43. Kiely DG, Charles EA, Webster VJ, et al. Pregnancy and pulmonary hypertension: new approaches to the management of a lifethreatening combination. In: Steer PJ, Gatzoulis MA, Baker P, editors. Heart disease and pregnancy. London: RCOG press, 2006: 211–30

    Google Scholar 

  44. Broberg CS, Uebing A, Cuomo L, et al. Adult patients with Eisenmenger’s syndrome report flying safely on commercial airlines. Heart 2007 Dec; 93(12): 1599–603

    PubMed  Google Scholar 

  45. Girgis A, Sanson-Fisher RW. Breaking bad news: consensus guidelines for medical practitioners. J Clin Oncol 1995; 13: 2449–56

    PubMed  CAS  Google Scholar 

  46. Stewart M, Davidson K, Meade D, et al. Group support for couples coping with a cardiac condition. J Adv Nurs 2001; 33: 190–9

    PubMed  CAS  Google Scholar 

  47. Broberg CS, Bax BE, Okonko DO, et al. Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease. J Am Coll Cardiol 2006; 48: 356–65

    PubMed  Google Scholar 

  48. Sandoval J, Aguirre JS, Pulido T, et al. Nocturnal oxygen therapy in patients with the Eisenmenger’s syndrome. Am J Respir Crit Care Med 2001; 164: 1682–7

    PubMed  CAS  Google Scholar 

  49. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105–11

    PubMed  CAS  Google Scholar 

  50. Post MC, Janssens S, Van de Werf F, et al. Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with congenital heart defects and pulmonary arterial hypertension. Eur Heart J 2004; 25: 1651–6

    PubMed  CAS  Google Scholar 

  51. 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: 485–91

    PubMed  CAS  Google Scholar 

  52. 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 1996; 334: 296–302

    CAS  Google Scholar 

  53. 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: 425–34

    PubMed  CAS  Google Scholar 

  54. 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: 1119–23

    PubMed  CAS  Google Scholar 

  55. 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 2002; 143: E4

    PubMed  Google Scholar 

  56. 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; 165: 800–4

    PubMed  Google Scholar 

  57. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903

    PubMed  CAS  Google Scholar 

  58. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomised, double-blind placebo-controlled trial. J Am Coll Cardiol 2002; 39: 1496–502

    PubMed  CAS  Google Scholar 

  59. Olschewski H, Simonneau G, Galie N, et al., for the AIR Study Group. Inhaled iloprost in severe pulmonary hypertension. N Engl J Med 2002; 347: 322–9

    PubMed  CAS  Google Scholar 

  60. Barst RJ, McGoon M, McLaughlin VV, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003; 41(12): 2119–25

    PubMed  CAS  Google Scholar 

  61. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004; 24: 353–9

    PubMed  CAS  Google Scholar 

  62. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004; 169: 441–7

    PubMed  Google Scholar 

  63. Sastry BKS, Narasimhan C, Reddy NK, et al. Clinical efficacy of sildenafil in primary pulmonary hypertension-1: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43: 1149–53

    PubMed  CAS  Google Scholar 

  64. Galie N, Ghofrani HA, Torbicki A, et al., and the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148–57

    PubMed  CAS  Google Scholar 

  65. Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-a receptor antagonist sitaxsentan. J Am Coll Cardiol 2006; 47: 2049–56

    PubMed  CAS  Google Scholar 

  66. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174: 1257–63

    PubMed  CAS  Google Scholar 

  67. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351: 1425–36

    PubMed  CAS  Google Scholar 

  68. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 1999; 99: 1858–65

    PubMed  CAS  Google Scholar 

  69. Barst R, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Resp Crit Care Med 2004; 169(4): 441–7

    PubMed  Google Scholar 

  70. Fernandes SM, Newburger JW, Lang P, et al. Usefulness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger’s physiology. Am J Cardiol 2003; 91: 632–5

    PubMed  CAS  Google Scholar 

  71. 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 1996; 334: 296–302

    CAS  Google Scholar 

  72. 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: 780–788

    PubMed  CAS  Google Scholar 

  73. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106: 1477–82

    PubMed  CAS  Google Scholar 

  74. Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 2004; 61: 227–37

    PubMed  CAS  Google Scholar 

  75. Cacoub P, Dorent R, Maistre G, et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger’s syndrome. Am J Cardiol 1993; 71: 448–50

    PubMed  CAS  Google Scholar 

  76. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328: 1732–9

    PubMed  CAS  Google Scholar 

  77. Christensen DD, McConnell ME, Book WM, et al. Initial experience with bosentan therapy in patients with the Eisenmenger’s syndrome. Am J Cardiol 2004; 94: 261–3

    PubMed  CAS  Google Scholar 

  78. Gatzoulis MA, Rogers P, Li W, et al. Safety and tolerability of bosentan in adults with Eisenmenger’s physiology. Int J Cardiol 2005; 98: 147–51

    PubMed  Google Scholar 

  79. Apostolopoulou SC, Manginas A, Cokkinos DV, et al. Effect of the oral endothelin antagonist bosentan on the clinical, exercise, and haemodynamic status of patients with pulmonary arterial hypertension related to congenital heart disease. Heart 2005; 91(11): 1447–52

    PubMed  CAS  Google Scholar 

  80. Schulze-Neick I, Gilbert N, Ewert R, et al. Adult patients with congenital heart disease and pulmonary arterial hypertension: first open prospective multicenter study of bosentan therapy. Am Heart J 2005; 150: 716-e7-12

    PubMed  Google Scholar 

  81. Diller GP, Dimopoulos K, Kaya MG, et al. Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease. Heart 2007; 93: 974–6

    PubMed  CAS  Google Scholar 

  82. Apostolopoulou SC, Manginas A, Cokkinos DV, et al. Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2007; 93: 350–4

    PubMed  CAS  Google Scholar 

  83. Gatzoulis MA, Beghetti M, Galie N, et al. Longer-term bosentan therapy improves functional capacity in Eisenmenger’s syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol. Epub 2007. doi:10.1016/j.ijcard.2007.04.078

  84. van Loon RLE, Hoendermis ES, Duffels MG, et al. Long-term effect of bosentan in adults versus children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: does the beneficial effect persist? Am Heart J 2007; 154: 776–82

    PubMed  Google Scholar 

  85. Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 1999; 274: 13729–32

    PubMed  CAS  Google Scholar 

  86. Tantini B, Manes A, Fiumana E, et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 2005; 100(2): 131–8

    PubMed  CAS  Google Scholar 

  87. Nagendran J, Archer SL, Soliman D, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 2007; 116: 238–48

    PubMed  CAS  Google Scholar 

  88. Ghofrani HA, Pepke-Zaba J, Barbera JA, et al. Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: S68–72

    Google Scholar 

  89. Celermajer DS, Cullen S, Deanfild JE. Impairment of endothelium-dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Circulation 1993; 87: 440–6

    PubMed  CAS  Google Scholar 

  90. Singh T, Rohit M, Grover A, et al. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006; 151: 851-el-5

    PubMed  Google Scholar 

  91. Lim ZS, Salmon AP, Vettukattil JJ, et al. Sildenafil therapy for pulmonary arterial hypertension associated with atrial septal defects. Int J Cardiol 2007; 118: 178–82

    PubMed  Google Scholar 

  92. Chau EMC, Fan KYY, Chow WH. Effects of chronic sildenafil in patients with Eisenmenger’s syndrome versus idiopathic pulmonary arterial hypertension. Int J Cardiol 2007; 120: 301–5

    PubMed  Google Scholar 

  93. Garg N, Sharma MK, Sinha N. Role of oral sildenafil in severe pulmonary arterial hypertension: clinical efficacy and dose response relationship. Int J Cardiol 2007; 120: 306–13

    PubMed  Google Scholar 

  94. Humpl T, Reyes JT, Holtby H, et al. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation 2005; 111: 3274–80

    PubMed  CAS  Google Scholar 

  95. Mukhopadhyay S, Sharma M, Ramakrishnan S, et al. Phosphodiesterase-5 inhibitor in Eisenmenger’s syndrome: a preliminary observational study. Circulation 2006; 114: 1807–10

    PubMed  CAS  Google Scholar 

  96. Palazzini M, Manes A, Romanazzi S, et al. Effects of sildenafil treatment in patients with pulmonary hypertension associated with congenital cardiac shunts [abstract]. Eur Heart J 2007; 28: 308

    Google Scholar 

  97. Hoeper M, Taha N, Bekjarova A, et al. Bosentan treatment in patients with primary pulmonary hypertension receiving non-parenteral prostanoids. Eur Respir J 2003; 22: 339–43

    Google Scholar 

  98. Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003; 42: 158–64

    PubMed  CAS  Google Scholar 

  99. Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004; 24: 1007–10

    PubMed  CAS  Google Scholar 

  100. Hoeper M, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006; 4(28): 691–4

    Google Scholar 

  101. Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007; 29: 469–75

    PubMed  CAS  Google Scholar 

  102. Humbert M, Barst R, Robbins I, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004; 24(3): 353–9

    PubMed  CAS  Google Scholar 

  103. Simonneau G, Rubin L, Galie N, et al. Safety and efficacy of sildenafil-epoprostenol combination therapy in patients with pulmonary arterial hypertension [abstract]. Am J Respir Crit Care Med 2007; 175: A300

    Google Scholar 

  104. Therrien J, Warnes C, Daliento L, et al. Canadian Cardiovascular Society Consensus Conference 2001 update: recommendations for the management of adults with congenital heart disease part III. Can. J Cardiol 2001; 17: 1135–58

    PubMed  CAS  Google Scholar 

  105. Frost AE, Quinones MA, Zoghbi WA, et al. Reversal of pulmonary hypertension and subsequent repair of atrial septal defect after treatment with continuous intravenous epoprostenol. J Heart Lung Transplant 2005; 24: 501–3

    PubMed  Google Scholar 

  106. Schwerzmann M, Zafar M, McLaughlin PR, et al. Atrial septal defect closure in a patient with ‘irreversible’ pulmonary hypertensive arteriopathy. Int J Cardiol 2006; 110: 104–7

    PubMed  Google Scholar 

  107. Eicken A, Balling G, Gielden HP et al. Transcatheter closure of a non-restrictive patent ductus arteriosus with an Amplatzer muscular ventricular septal defect occluder. Int J Cardiol 2007; 117: c40–2

    Google Scholar 

  108. Dimopoulos K, Peset A, Gatzouulis MA. Evaluating operability in adults with congenital heart disease and the role of pretreatment with targeted pulmonary arterial hypertension therapy. Int J Cardiol. Epub 2008. doi: 10.1016/j.ijcardio.2008.02.004

  109. Klepetko W, Mayer E, Sandoval J, et al. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43 (12 Suppl. S): 73–80S

    Google Scholar 

  110. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based guidelines for clinical practice. Chest 2004; 126: 35–62S

    Google Scholar 

  111. Galie N, Torbicki A, Barst R, et al. Pocket guidelines on the diagnosis and treatment of pulmonary arterial hypertension. Sophia Antipolis: European Society of Cardiology, 2006

    Google Scholar 

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Acknowledgements

Dr Galie reports having served on the advisory boards of Pfizer, Actelion, Schering, Encysive, Myogen, GlaxoSmithKline and Mondobiotec, and that the Institute of Cardiology has received grant support from Pfizer, Actelion, Schering, Encysive, United Therapeutics and Myogen. The other authors report no conflicts of interest that are directly relevant to the content of this review. No sources of funding were used to assist specifically in the preparation of this review.

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Galie, N., Manes, A., Palazzini, M. et al. Management of Pulmonary Arterial Hypertension Associated with Congenital Systemic-to-Pulmonary Shunts and Eisenmenger’s Syndrome. Drugs 68, 1049–1066 (2008). https://doi.org/10.2165/00003495-200868080-00004

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