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Adult congenital heart disease with pulmonary arterial hypertension: mechanisms and management

  • Michail Papamichalis
  • Andrew Xanthopoulos
  • Panagiotis Papamichalis
  • John Skoularigis
  • Filippos TriposkiadisEmail author
Article

Abstract

Adult congenital heart disease (ACHD) encompasses a range of structural cardiac abnormalities present before birth attributable to abnormal foetal cardiac development. The pulmonary circulation of patients with ACHD and intracardiac or extracardiac defects is often exposed to increased blood flow and occasionally to systemic pressures. Depending on the location and magnitude of the defect as well as the time of surgical correction, the patient with ACHD is at risk of developing pulmonary arterial hypertension (PAH), which dramatically increases morbidity and mortality. It is encouraging that therapies applied in idiopathic PAH and significantly improve outcome are also effective in ACHD-related PAH (ACHD-PAH). This review summarizes the challenges encountered in the diagnosis and management of ACHD-PAH.

Keywords

Eisenmenger syndrome Pulmonary arterial hypertension Pulmonary hypertension Congenital heart disease Pathophysiology Treatment 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Stout KK, Daniels CJ, Aboulhosn JA, Bozkurt B, Broberg CS, Colman JM, Crumb SR, Dearani JA, Fuller S, Gurvitz M, Khairy P, Landzberg MJ, Saidi A, Valente AM, Van Hare GF (2019) 2018 AHA/ACC guideline for the management of adults with congenital heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol 73(12):1494–1563.  https://doi.org/10.1016/j.jacc.2018.08.1028 CrossRefPubMedGoogle Scholar
  2. 2.
    Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Group ESCSD (2016) 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 37(1):67–119.  https://doi.org/10.1093/eurheartj/ehv317 CrossRefPubMedGoogle Scholar
  3. 3.
    Schuijt MTU, Blok IM, Zwinderman AH, van Riel A, Schuuring MJ, de Winter RJ, Duijnhouwer AL, van Dijk APJ, Mulder BJM, Bouma BJ (2017) Mortality in pulmonary arterial hypertension due to congenital heart disease: serial changes improve prognostication. Int J Cardiol 243:449–453.  https://doi.org/10.1016/j.ijcard.2017.05.101 CrossRefPubMedGoogle Scholar
  4. 4.
    van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 58(21):2241–2247.  https://doi.org/10.1016/j.jacc.2011.08.025 CrossRefPubMedGoogle Scholar
  5. 5.
    Duffels MG, Engelfriet PM, Berger RM, van Loon RL, Hoendermis E, Vriend JW, van der Velde ET, Bresser P, Mulder BJ (2007) Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry. Int J Cardiol 120(2):198–204CrossRefPubMedGoogle Scholar
  6. 6.
    Lowe BS, Therrien J, Ionescu-Ittu R, Pilote L, Martucci G, Marelli AJ (2011) Diagnosis of pulmonary hypertension in the congenital heart disease adult population impact on outcomes. J Am Coll Cardiol 58(5):538–546.  https://doi.org/10.1016/j.jacc.2011.03.033 CrossRefPubMedGoogle Scholar
  7. 7.
    van Dissel AC, Mulder BJ, Bouma BJ (2017) The changing landscape of pulmonary arterial hypertension in the adult with congenital heart disease. J Clin Med 6(4).  https://doi.org/10.3390/jcm6040040
  8. 8.
    Ntiloudi D, Zanos S, Gatzoulis MA, Karvounis H, Giannakoulas G (2019) How to evaluate patients with congenital heart disease-related pulmonary arterial hypertension. Expert Rev Cardiovasc Ther 17(1):11–18.  https://doi.org/10.1080/14779072.2019.1550716 CrossRefPubMedGoogle Scholar
  9. 9.
    van Riel AC, Schuuring MJ, van Hessen ID, Zwinderman AH, Cozijnsen L, Reichert CL, Hoorntje JC, Wagenaar LJ, Post MC, van Dijk AP, Hoendermis ES, Mulder BJ, Bouma BJ (2014) Contemporary prevalence of pulmonary arterial hypertension in adult congenital heart disease following the updated clinical classification. Int J Cardiol 174(2):299–305.  https://doi.org/10.1016/j.ijcard.2014.04.072 CrossRefPubMedGoogle Scholar
  10. 10.
    Strange G, Rose M, Kermeen F, O'Donnell C, Keogh A, Kotlyar E, Grigg L, Bullock A, Disney P, Dwyer N, Whitford H, Tanous D, Frampton C, Weintraub R, Celermajer DS (2015) A binational registry of adults with pulmonary arterial hypertension complicating congenital heart disease. Intern Med J 45(9):944–950.  https://doi.org/10.1111/imj.12821 CrossRefPubMedGoogle Scholar
  11. 11.
    Arnott C, Strange G, Bullock A, Kirby AC, O’Donnell C, Radford DJ, Grigg LE, Celermajer DS (2017) Pulmonary vasodilator therapy is associated with greater survival in Eisenmenger syndrome. Heart 104:732–737.  https://doi.org/10.1136/heartjnl-2017-311876 CrossRefGoogle Scholar
  12. 12.
    Ramjug S, Hussain N, Hurdman J, Billings C, Charalampopoulos A, Elliot CA, Sabroe I, Kiely DG, Condliffe R (2016) Pulmonary arterial hypertension associated with congenital heart disease: comparison of clinical and anatomic-pathophysiologic classification. J Heart Lung Transplant 35(5):610–618.  https://doi.org/10.1016/j.healun.2015.12.016 CrossRefPubMedGoogle Scholar
  13. 13.
    Dimopoulos K, Wort SJ, Gatzoulis MA (2014) Pulmonary hypertension related to congenital heart disease: a call for action. Eur Heart J 35(11):691–700.  https://doi.org/10.1093/eurheartj/eht437 CrossRefPubMedGoogle Scholar
  14. 14.
    Dimopoulos K, Diller GP, Opotowsky AR, D'Alto M, Gu H, Giannakoulas G, Budts W, Broberg CS, Veldtman G, Swan L, Beghetti M, Gatzoulis MA (2018) Definition and management of segmental pulmonary hypertension. J Am Heart Assoc 7(14).  https://doi.org/10.1161/JAHA.118.008587
  15. 15.
    Diller GP, Gatzoulis MA (2007) Pulmonary vascular disease in adults with congenital heart disease. Circulation 115(8):1039–1050CrossRefPubMedGoogle Scholar
  16. 16.
    Roberts KE, McElroy JJ, Wong WP, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH (2004) BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 24(3):371–374.  https://doi.org/10.1183/09031936.04.00018604 CrossRefPubMedGoogle Scholar
  17. 17.
    Harrison RE, Berger R, Haworth SG, Tulloh R, Mache CJ, Morrell NW, Aldred MA, Trembath RC (2005) Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation 111(4):435–441.  https://doi.org/10.1161/01.cir.0000153798.78540.87 CrossRefGoogle Scholar
  18. 18.
    Kulik TJ (2012) Pulmonary blood flow and pulmonary hypertension: is the pulmonary circulation flowophobic or flowophilic? Pulm Circ 2(3):327–339.  https://doi.org/10.4103/2045-8932.101644 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    van der Feen DE, Bartelds B, de Boer RA, Berger RMF (2018) Assessment of reversibility in pulmonary arterial hypertension and congenital heart disease. Heart 105:276–282.  https://doi.org/10.1136/heartjnl-2018-314025 CrossRefGoogle Scholar
  20. 20.
    Righini FM, Apostolo A, Heck PB, Farina S, Hager A, Correale M, Badagliacca R, Barbieri S, Sciomer S, Agostoni P (2019) Exercise physiology in pulmonary hypertension patients with and without congenital heart disease. Eur J Prev Cardiol 26(1):86–93.  https://doi.org/10.1177/2047487318809479 CrossRefPubMedGoogle Scholar
  21. 21.
    Hopkins WE (2005) The remarkable right ventricle of patients with Eisenmenger syndrome. Coron Artery Dis 16(1):19–25CrossRefPubMedGoogle Scholar
  22. 22.
    Becker-Grunig T, Klose H, Ehlken N, Lichtblau M, Nagel C, Fischer C, Gorenflo M, Tiede H, Schranz D, Hager A, Kaemmerer H, Miera O, Ulrich S, Speich R, Uiker S, Grunig E (2013) Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. Int J Cardiol 168(1):375–381.  https://doi.org/10.1016/j.ijcard.2012.09.036 CrossRefPubMedGoogle Scholar
  23. 23.
    Blok IM, van Riel AC, Mulder BJ, Bouma BJ (2015) Management of patients with pulmonary arterial hypertension due to congenital heart disease: recent advances and future directions. Expert Rev Cardiovasc Ther 13(12):1377–1392.  https://doi.org/10.1586/14779072.2015.1101341 CrossRefPubMedGoogle Scholar
  24. 24.
    Cacoub P, Dorent R, Maistre G, Nataf P, Carayon A, Piette C, Godeau P, Cabrol C, Gandjbakhch I (1993) Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 71(5):448–450CrossRefPubMedGoogle Scholar
  25. 25.
    Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M (2006) Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 114(1):48–54CrossRefPubMedGoogle Scholar
  26. 26.
    Gatzoulis MA, Beghetti M, Galie N, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M (2008) Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol 127(1):27–32CrossRefPubMedGoogle Scholar
  27. 27.
    Gatzoulis MA, Landzberg M, Beghetti M, Berger RM, Efficace M, Gesang S, He J, Papadakis K, Pulido T, Galie N, Investigators MS (2019) Evaluation of macitentan in patients with Eisenmenger syndrome. Circulation 139(1):51–63.  https://doi.org/10.1161/CIRCULATIONAHA.118.033575 CrossRefPubMedGoogle Scholar
  28. 28.
    Dimopoulos K, Inuzuka R, Goletto S, Giannakoulas G, Swan L, Wort SJ, Gatzoulis MA (2010) Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 121(1):20–25.  https://doi.org/10.1161/CIRCULATIONAHA.109.883876 CrossRefPubMedGoogle Scholar
  29. 29.
    Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, Sondergaard L (2010) Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: a randomized, placebo-controlled, double-blinded trial. Eur Heart J 31(9):1124–1131.  https://doi.org/10.1093/eurheartj/ehq011 CrossRefPubMedGoogle Scholar
  30. 30.
    D'Alto M, Romeo E, Argiento P, Sarubbi B, Santoro G, Grimaldi N, Correra A, Scognamiglio G, Russo MG, Calabro R (2012) Bosentan-sildenafil association in patients with congenital heart disease-related pulmonary arterial hypertension and Eisenmenger physiology. Int J Cardiol 155(3):378–382.  https://doi.org/10.1016/j.ijcard.2010.10.051 CrossRefPubMedGoogle Scholar
  31. 31.
    Berger RM, Beghetti M, Galie N, Gatzoulis MA, Granton J, Lauer A, Chiossi E, Landzberg M (2010) Atrial septal defects versus ventricular septal defects in BREATHE-5, a placebo-controlled study of pulmonary arterial hypertension related to Eisenmenger’s syndrome: a subgroup analysis. Int J Cardiol 144(3):373–378.  https://doi.org/10.1016/j.ijcard.2009.04.037 CrossRefPubMedGoogle Scholar
  32. 32.
    Diller GP, Dimopoulos K, Kaya MG, Harries C, Uebing A, Li W, Koltsida E, Gibbs JS, Gatzoulis MA (2007) Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease. Heart 93(8):974–976CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Diaz-Caraballo E, Gonzalez-Garcia AE, Renones M, Sanchez-Recalde A, Garcia-Rio F, Oliver-Ruiz JM (2009) Long-term bosentan treatment of complex congenital heart disease and Eisenmenger’s syndrome. Rev Esp Cardiol 62(9):1046–1049CrossRefPubMedGoogle Scholar
  34. 34.
    Vis JC, Duffels MG, Mulder P, de Bruin-Bon RH, Bouma BJ, Berger RM, Hoendermis ES, van Dijk AP, Mulder BJ (2013) Prolonged beneficial effect of bosentan treatment and 4-year survival rates in adult patients with pulmonary arterial hypertension associated with congenital heart disease. Int J Cardiol 164(1):64–69.  https://doi.org/10.1016/j.ijcard.2011.06.064 CrossRefPubMedGoogle Scholar
  35. 35.
    Zuckerman WA, Leaderer D, Rowan CA, Mituniewicz JD, Rosenzweig EB (2011) Ambrisentan for pulmonary arterial hypertension due to congenital heart disease. Am J Cardiol 107(9):1381–1385.  https://doi.org/10.1016/j.amjcard.2010.12.051 CrossRefPubMedGoogle Scholar
  36. 36.
    Condliffe R, Elliot CA, Hurdman J, Sabroe I, Billings C, Kiely DG, Hamilton N (2014) Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre. Ther Adv Respir Dis 8(3):71–77.  https://doi.org/10.1177/1753465814532304 CrossRefPubMedGoogle Scholar
  37. 37.
    Blok IM, van Riel A, van Dijk APJ, Mulder BJM, Bouma BJ (2017) From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: further improvement? Int J Cardiol 227:51–52.  https://doi.org/10.1016/j.ijcard.2016.11.211 CrossRefPubMedGoogle Scholar
  38. 38.
    Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G, Investigators S (2013) Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 369(9):809–818.  https://doi.org/10.1056/NEJMoa1213917 CrossRefPubMedGoogle Scholar
  39. 39.
    Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S (2007) Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 93(3):350–354.  https://doi.org/10.1136/hrt.2006.100388 CrossRefPubMedGoogle Scholar
  40. 40.
    Crepaz R, Romeo C, Montanaro D, De Santis S (2013) Long-term results of treatment with bosentan in adult Eisenmenger’s syndrome patients with Down’s syndrome related to congenital heart disease. BMC Cardiovasc Disord 13:74.  https://doi.org/10.1186/1471-2261-13-74 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Diller GP, Alonso-Gonzalez R, Dimopoulos K, Alvarez-Barredo M, Koo C, Kempny A, Harries C, Parfitt L, Uebing AS, Swan L, Marino PS, Wort SJ, Gatzoulis MA (2013) Disease targeting therapies in patients with Eisenmenger syndrome: response to treatment and long-term efficiency. Int J Cardiol 167(3):840–847.  https://doi.org/10.1016/j.ijcard.2012.02.007 CrossRefPubMedGoogle Scholar
  42. 42.
    Giusca S, Jurcut R, Coman IM, Ghiorghiu I, Catrina D, Popescu BA, Dima L, Ginghina C (2013) Right ventricular function predicts clinical response to specific vasodilator therapy in patients with pulmonary hypertension. Echocardiography 30(1):17–26.  https://doi.org/10.1111/j.1540-8175.2012.01809.x CrossRefPubMedGoogle Scholar
  43. 43.
    Kaya MG, Lam YY, Erer B, Ayhan S, Vatankulu MA, Nurkalem Z, Meric M, Eren M, Eryol NK (2012) Long-term effect of bosentan therapy on cardiac function and symptomatic benefits in adult patients with Eisenmenger syndrome. J Card Fail 18(5):379–384.  https://doi.org/10.1016/j.cardfail.2012.02.004 CrossRefPubMedGoogle Scholar
  44. 44.
    Kopec G, Tyrka A, Miszalski-Jamka T, Mikolajczyk T, Waligora M, Guzik T, Podolec P (2012) Changes in exercise capacity and cardiac performance in a series of patients with Eisenmenger’s syndrome transitioned from selective to dual endothelin receptor antagonist. Heart Lung Circ 21(11):671–678.  https://doi.org/10.1016/j.hlc.2012.06.013 CrossRefPubMedGoogle Scholar
  45. 45.
    Schulze-Neick I, Gilbert N, Ewert R, Witt C, Gruenig E, Enke B, Borst MM, Lange PE, Hoeper MM (2005) Adult patients with congenital heart disease and pulmonary arterial hypertension: first open prospective multicenter study of bosentan therapy. Am Heart J 150(4):716–716.e12.  https://doi.org/10.1016/j.ahj.2005.07.005 CrossRefPubMedGoogle Scholar
  46. 46.
    Baptista R, Castro G, da Silva AM, Monteiro P, Providencia LA (2013) Long-term effect of bosentan in pulmonary hypertension associated with complex congenital heart disease. Rev Port Cardiol 32(2):123–129.  https://doi.org/10.1016/j.repc.2012.02.023 CrossRefPubMedGoogle Scholar
  47. 47.
    Duffels MG, Vis JC, van Loon RL, Nieuwkerk PT, van Dijk AP, Hoendermis ES, de Bruin-Bon RH, Bouma BJ, Bresser P, Berger RM, Mulder BJ (2009) Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down’s syndrome. Am J Cardiol 103(9):1309–1315CrossRefPubMedGoogle Scholar
  48. 48.
    Duffels MG, Vis JC, van Loon RL, Berger RM, Hoendermis ES, van Dijk AP, Bouma BJ, Mulder BJ (2009) Down patients with Eisenmenger syndrome: is bosentan treatment an option? Int J Cardiol 134(3):378–383CrossRefPubMedGoogle Scholar
  49. 49.
    Guo L, Liu YJ, Xie ZL (2014) Safety and tolerability evaluation of oral bosentan in adult congenital heart disease associated pulmonary arterial hypertension: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 18(5):638–645PubMedGoogle Scholar
  50. 50.
    Serino G, Guazzi M, Micheletti A, Lombardi C, Danesi R, Negura D, Carminati M, Chessa M (2013) Effect of bosentan on exercise capacity and clinical worsening in patients with dual down and Eisenmenger syndrome. Clin Med Insights Cardiol 7:29–34.  https://doi.org/10.4137/CMC.S10237 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Monfredi O, Griffiths L, Clarke B, Mahadevan VS (2011) Efficacy and safety of bosentan for pulmonary arterial hypertension in adults with congenital heart disease. Am J Cardiol 108(10):1483–1488.  https://doi.org/10.1016/j.amjcard.2011.07.006 CrossRefPubMedGoogle Scholar
  52. 52.
    Diller GP, Kempny A, Inuzuka R, Radke R, Wort SJ, Baumgartner H, Gatzoulis MA, Dimopoulos K (2014) Survival prospects of treatment naive patients with Eisenmenger: a systematic review of the literature and report of own experience. Heart 100(17):1366–1372.  https://doi.org/10.1136/heartjnl-2014-305690 CrossRefPubMedGoogle Scholar
  53. 53.
    Lu XL, Xiong CM, Shan GL, Zhu XY, Wu BX, Wu GH, Liu ZH, Ni XH, Cheng XS, Gu Q, Zhao ZH, Zhang DZ, Li WM, Zhang C, Tian HY, Guo YJ, Guo T, Liu HM, Zhang WJ, Gu H, Huang SA, Chen JY, Wu WF, Huang K, Li JJ, He JG (2010) Impact of sildenafil therapy on pulmonary arterial hypertension in adults with congenital heart disease. Cardiovasc Ther 28(6):350–355.  https://doi.org/10.1111/j.1755-5922.2010.00213.x CrossRefPubMedGoogle Scholar
  54. 54.
    Tay EL, Papaphylactou M, Diller GP, Alonso-Gonzalez R, Inuzuka R, Giannakoulas G, Harries C, Wort SJ, Swan L, Dimopoulos K, Gatzoulis MA (2011) Quality of life and functional capacity can be improved in patients with Eisenmenger syndrome with oral sildenafil therapy. Int J Cardiol 149(3):372–376.  https://doi.org/10.1016/j.ijcard.2010.02.020 CrossRefPubMedGoogle Scholar
  55. 55.
    Zeng WJ, Lu XL, Xiong CM, Shan GL, Liu ZH, Ni XH, Gu Q, Zhao ZH, Li JJ, He JG, Sildenafil Therapy on Pulmonary Arterial Hypertension Associated With Different Types of Congenital Heart Disease Study G (2011) The efficacy and safety of sildenafil in patients with pulmonary arterial hypertension associated with the different types of congenital heart disease. Clin Cardiol 34(8):513–518.  https://doi.org/10.1002/clc.20917 CrossRefPubMedGoogle Scholar
  56. 56.
    Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R (2006) A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 151(4):851 e851-855CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang ZN, Jiang X, Zhang R, Li XL, Wu BX, Zhao QH, Wang Y, Dai LZ, Pan L, Gomberg-Maitland M, Jing ZC (2011) Oral sildenafil treatment for Eisenmenger syndrome: a prospective, open-label, multicentre study. Heart 97(22):1876–1881.  https://doi.org/10.1136/heartjnl-2011-300344 CrossRefPubMedGoogle Scholar
  58. 58.
    Chau EM, Fan KY, Chow WH (2007) Effects of chronic sildenafil in patients with Eisenmenger syndrome versus idiopathic pulmonary arterial hypertension. Int J Cardiol 120(3):301–305CrossRefPubMedGoogle Scholar
  59. 59.
    Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353(20):2148–2157CrossRefPubMedGoogle Scholar
  60. 60.
    Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ, Group P-S (2013) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369(4):330–340.  https://doi.org/10.1056/NEJMoa1209655 CrossRefPubMedGoogle Scholar
  61. 61.
    Mukhopadhyay S, Sharma M, Ramakrishnan S, Yusuf J, Gupta MD, Bhamri N, Trehan V, Tyagi S (2006) Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study. Circulation 114(17):1807–1810CrossRefPubMedGoogle Scholar
  62. 62.
    Mukhopadhyay S, Nathani S, Yusuf J, Shrimal D, Tyagi S (2011) Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome--a randomized, placebo-controlled, double-blind crossover study. Congenit Heart Dis 6(5):424–431.  https://doi.org/10.1111/j.1747-0803.2011.00561.x CrossRefPubMedGoogle Scholar
  63. 63.
    Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ (2009) Tadalafil therapy for pulmonary arterial hypertension. Circulation 119(22):2894–2903CrossRefPubMedGoogle Scholar
  64. 64.
    Anand A, Srivastava N, Barwad P, Ramakrishnan S, Roy A, Bhargava B (2014) Dyspnea in Eisenmenger syndrome and its amelioration by sildenafil: role of J receptors. Int J Cardiol 174(3):574–578.  https://doi.org/10.1016/j.ijcard.2014.04.131 CrossRefPubMedGoogle Scholar
  65. 65.
    Diller GP, Korten MA, Bauer UM, Miera O, Tutarel O, Kaemmerer H, Berger F, Baumgartner H, German Competence Network for Congenital Heart Defects I (2016) Current therapy and outcome of Eisenmenger syndrome: data of the German National Register for congenital heart defects. Eur Heart J 37(18):1449–1455.  https://doi.org/10.1093/eurheartj/ehv743 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Garg N, Sharma MK, Sinha N (2007) Role of oral sildenafil in severe pulmonary arterial hypertension: clinical efficacy and dose response relationship. Int J Cardiol 120(3):306–313.  https://doi.org/10.1016/j.ijcard.2006.10.017 CrossRefPubMedGoogle Scholar
  67. 67.
    Garg N, Tripathy N, Sinha N (2011) Comparative efficacy of sildenafil in Eisenmenger's syndrome secondary to atrial septal defect versus ventricular septal defect: a cardiac catheterisation follow-up study. Cardiol Young 21(6):631–638.  https://doi.org/10.1017/S1047951111000497 CrossRefPubMedGoogle Scholar
  68. 68.
    Lim ZS, Salmon AP, Vettukattil JJ, Veldtman GR (2007) Sildenafil therapy for pulmonary arterial hypertension associated with atrial septal defects. Int J Cardiol 118(2):178–182.  https://doi.org/10.1016/j.ijcard.2006.06.045 CrossRefPubMedGoogle Scholar
  69. 69.
    Sun YJ, Yang T, Zeng WJ, Gu Q, Ni XH, Zhao ZH, Liu ZH, Xiong CM, He JG (2013) Impact of sildenafil on survival of patients with Eisenmenger syndrome. J Clin Pharmacol 53(6):611–618.  https://doi.org/10.1002/jcph.78 CrossRefPubMedGoogle Scholar
  70. 70.
    Rosenkranz S, Ghofrani HA, Beghetti M, Ivy D, Frey R, Fritsch A, Weimann G, Saleh S, Apitz C (2015) Riociguat for pulmonary arterial hypertension associated with congenital heart disease. Heart 101(22):1792–1799.  https://doi.org/10.1136/heartjnl-2015-307832 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Galie N, Muller K, Scalise AV, Grunig E (2015) PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J 45(5):1314–1322.  https://doi.org/10.1183/09031936.00105914 CrossRefPubMedGoogle Scholar
  72. 72.
    Mitchell JA, Ahmetaj-Shala B, Kirkby NS, Wright WR, Mackenzie LS, Reed DM, Mohamed N (2014) Role of prostacyclin in pulmonary hypertension. Glob Cardiol Sci Pract 2014(4):382–393.  https://doi.org/10.5339/gcsp.2014.53 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Thomas IC, Glassner-Kolmin C, Gomberg-Maitland M (2013) Long-term effects of continuous prostacyclin therapy in adults with pulmonary hypertension associated with congenital heart disease. Int J Cardiol 168(4):4117–4121.  https://doi.org/10.1016/j.ijcard.2013.07.072 CrossRefPubMedGoogle Scholar
  74. 74.
    Duarte AG, Thomas S, Safdar Z, Torres F, Pacheco LD, Feldman J, deBoisblanc B (2013) Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience. Chest 143(5):1330–1336.  https://doi.org/10.1378/chest.12-0528 CrossRefPubMedGoogle Scholar
  75. 75.
    Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G (2002) 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(9):1496–1502CrossRefPubMedGoogle Scholar
  76. 76.
    Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N, Degano B, Bonderman D, Kurzyna M, Efficace M, Giorgino R, Lang IM (2012) Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 40(4):874–880.  https://doi.org/10.1183/09031936.00137511 CrossRefPubMedGoogle Scholar
  77. 77.
    Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV, Investigators G (2015) Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 373(26):2522–2533.  https://doi.org/10.1056/NEJMoa1503184 CrossRefPubMedGoogle Scholar
  78. 78.
    Fernandes SM, Newburger JW, Lang P, Pearson DD, Feinstein JA, Gauvreau K, Landzberg MJ (2003) Usefulness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger physiology. Am J Cardiol 91(5):632–635CrossRefPubMedGoogle Scholar
  79. 79.
    Rosenzweig EB, Kerstein D, Barst RJ (1999) Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 99(14):1858–1865CrossRefPubMedGoogle Scholar
  80. 80.
    Cha KS, Cho KI, Seo JS, Choi JH, Park YH, Yang DH, Hong GR, Kim DS (2013) Effects of inhaled iloprost on exercise capacity, quality of life, and cardiac function in patients with pulmonary arterial hypertension secondary to congenital heart disease (the Eisenmenger syndrome) (from the EIGER Study). Am J Cardiol 112(11):1834–1839.  https://doi.org/10.1016/j.amjcard.2013.08.003 CrossRefPubMedGoogle Scholar
  81. 81.
    Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ (2002) 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(6):800–804CrossRefPubMedGoogle Scholar
  82. 82.
    Skoro-Sajer N, Gerges C, Balint OH, Kohalmi D, Kaldararova M, Simkova I, Jakowitsch J, Gabriel H, Baumgartner H, Gerges M, Sadushi-Kolici R, Celermajer DS, Lang IM (2018) Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension. Heart 104(14):1195–1199.  https://doi.org/10.1136/heartjnl-2017-312143 CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Adriaenssens T, Delcroix M, Van Deyk K, Budts W (2006) Advanced therapy may delay the need for transplantation in patients with the Eisenmenger syndrome. Eur Heart J 27(12):1472–1477.  https://doi.org/10.1093/eurheartj/ehl017 CrossRefPubMedGoogle Scholar
  84. 84.
    Barst RJ, McGoon M, McLaughlin V, Tapson V, Rich S, Rubin L, Wasserman K, Oudiz R, Shapiro S, Robbins IM, Channick R, Badesch D, Rayburn BK, Flinchbaugh R, Sigman J, Arneson C, Jeffs R, Beraprost Study G (2003) Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 41(12):2119–2125CrossRefPubMedGoogle Scholar
  85. 85.
    Chon MK, Cho KI, Cha KS, Seo JS, Kim DS (2017) Effects of long-term iloprost treatment on right ventricular function in patients with Eisenmenger syndrome. J Cardiol 69(5):741–746.  https://doi.org/10.1016/j.jjcc.2016.07.002 CrossRefPubMedGoogle Scholar
  86. 86.
    Duffels M, van Loon L, Berger R, Boonstra A, Vonk-Noordegraaf A, Mulder B (2007) Pulmonary arterial hypertension associated with a congenital heart defect: advanced medium-term medical treatment stabilizes clinical condition. Congenit Heart Dis 2(4):242–249CrossRefPubMedGoogle Scholar
  87. 87.
    El-Kersh K, Suliman S, Smith JS (2018) Selexipag in congenital heart disease-associated pulmonary arterial hypertension and Eisenmenger syndrome: first report. Am J Ther 25(6):e714–e715.  https://doi.org/10.1097/MJT.0000000000000727 CrossRefPubMedGoogle Scholar
  88. 88.
    Hopper RK, Wang Y, DeMatteo V, Santo A, Kawut SM, Elci OU, Hanna BD, Mercer-Rosa L (2018) Right ventricular function mirrors clinical improvement with use of prostacyclin analogues in pediatric pulmonary hypertension. Pulm Circ 8(2):2045894018759247.  https://doi.org/10.1177/2045894018759247 CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Yang SI, Chung WJ, Jung SH, Choi DY (2012) Effects of inhaled iloprost on congenital heart disease with Eisenmenger syndrome. Pediatr Cardiol 33(5):744–748.  https://doi.org/10.1007/s00246-012-0204-0 CrossRefPubMedGoogle Scholar
  90. 90.
    Farber HW, Miller DP, Meltzer LA, McGoon MD (2013) Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the REVEAL Registry. J Heart Lung Transplant 32(11):1114–1122.  https://doi.org/10.1016/j.healun.2013.08.010 CrossRefPubMedGoogle Scholar
  91. 91.
    Galie N, Barbera JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grunig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ, Investigators A (2015) Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 373(9):834–844.  https://doi.org/10.1056/NEJMoa1413687 CrossRefPubMedGoogle Scholar
  92. 92.
    Bendayan D, Shitrit D, Kramer MR (2008) Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study. Respirology 13(6):916–918.  https://doi.org/10.1111/j.1440-1843.2007.01176.x CrossRefPubMedGoogle Scholar
  93. 93.
    Fox BD, Shtraichman O, Langleben D, Shimony A, Kramer MR (2016) Combination therapy for pulmonary arterial hypertension: a systematic review and meta-analysis. Can J Cardiol 32(12):1520–1530.  https://doi.org/10.1016/j.cjca.2016.03.004 CrossRefPubMedGoogle Scholar
  94. 94.
    Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H, Kilner P, Meijboom F, Mulder BJ, Oechslin E, Oliver JM, Serraf A, Szatmari A, Thaulow E, Vouhe PR, Walma E, Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of C, Association for European Paediatric C, Guidelines ESCCfP (2010) ESC guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 31(23):2915–2957.  https://doi.org/10.1093/eurheartj/ehq249 CrossRefPubMedGoogle Scholar
  95. 95.
    Brida M, Gatzoulis MA (2018) Pulmonary arterial hypertension in adult congenital heart disease. Heart 104(19):1568–1574.  https://doi.org/10.1136/heartjnl-2017-312106 CrossRefPubMedGoogle Scholar
  96. 96.
    Opotowsky AR (2015) Clinical evaluation and management of pulmonary hypertension in the adult with congenital heart disease. Circulation 131(2):200–210.  https://doi.org/10.1161/CIRCULATIONAHA.114.006976 CrossRefPubMedGoogle Scholar
  97. 97.
    Daliento L, Somerville J, Presbitero P, Menti L, Brach-Prever S, Rizzoli G, Stone S (1998) Eisenmenger syndrome. Factors relating to deterioration and death. Eur Heart J 19(12):1845–1855CrossRefPubMedGoogle Scholar
  98. 98.
    Schuuring MJ, van Riel AC, Vis JC, Duffels MG, van Dijk AP, de Bruin-Bon RH, Zwinderman AH, Mulder BJ, Bouma BJ (2015) New predictors of mortality in adults with congenital heart disease and pulmonary hypertension: midterm outcome of a prospective study. Int J Cardiol 181:270–276.  https://doi.org/10.1016/j.ijcard.2014.11.222 CrossRefPubMedGoogle Scholar
  99. 99.
    Hjortshoj CMS, Kempny A, Jensen AS, Sorensen K, Nagy E, Dellborg M, Johansson B, Rudiene V, Hong G, Opotowsky AR, Budts W, Mulder BJ, Tomkiewicz-Pajak L, D'Alto M, Prokselj K, Diller GP, Dimopoulos K, Estensen ME, Holmstrom H, Turanlahti M, Thilen U, Gatzoulis MA, Sondergaard L (2017) Past and current cause-specific mortality in Eisenmenger syndrome. Eur Heart J 38(26):2060–2067.  https://doi.org/10.1093/eurheartj/ehx201 CrossRefPubMedGoogle Scholar
  100. 100.
    Diller G-P, Dimopoulos K, Kafka H, Ho SY, Gatzoulis MA (2007) Model of chronic adaptation: right ventricular function in Eisenmenger syndrome. Eur Heart J Suppl 9(suppl_H):H54–H60CrossRefGoogle Scholar
  101. 101.
    Diller GP, Dimopoulos K, Broberg CS, Kaya MG, Naghotra US, Uebing A, Harries C, Goktekin O, Gibbs JS, Gatzoulis MA (2006) Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: a combined retrospective and case-control study. Eur Heart J 27(14):1737–1742CrossRefPubMedGoogle Scholar
  102. 102.
    Diller GP, Alonso-Gonzalez R, Kempny A, Dimopoulos K, Inuzuka R, Giannakoulas G, Castle L, Lammers AE, Hooper J, Uebing A, Swan L, Gatzoulis M, Wort SJ (2012) B-type natriuretic peptide concentrations in contemporary Eisenmenger syndrome patients: predictive value and response to disease targeting therapy. Heart 98(9):736–742.  https://doi.org/10.1136/heartjnl-2011-301522 CrossRefPubMedGoogle Scholar
  103. 103.
    Giannakoulas G, Mouratoglou SA, Gatzoulis MA, Karvounis H (2014) Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A systematic review. Int J Cardiol 174(3):618–623.  https://doi.org/10.1016/j.ijcard.2014.04.156 CrossRefPubMedGoogle Scholar
  104. 104.
    Moceri P, Dimopoulos K, Liodakis E, Germanakis I, Kempny A, Diller GP, Swan L, Wort SJ, Marino PS, Gatzoulis MA, Li W (2012) Echocardiographic predictors of outcome in Eisenmenger syndrome. Circulation 126(12):1461–1468.  https://doi.org/10.1161/CIRCULATIONAHA.112.091421 CrossRefPubMedGoogle Scholar
  105. 105.
    Kempny A, Hjortshoj CS, Gu H, Li W, Opotowsky AR, Landzberg MJ, Jensen AS, Sondergaard L, Estensen ME, Thilen U, Budts W, Mulder BJ, Blok I, Tomkiewicz-Pajak L, Szostek K, D'Alto M, Scognamiglio G, Prokselj K, Diller GP, Dimopoulos K, Wort SJ, Gatzoulis MA (2017) Predictors of death in contemporary adult patients with Eisenmenger syndrome: a multicenter study. Circulation 135(15):1432–1440.  https://doi.org/10.1161/CIRCULATIONAHA.116.023033 CrossRefPubMedGoogle Scholar
  106. 106.
    Van De Bruaene A, De Meester P, Voigt JU, Delcroix M, Pasquet A, De Backer J, De Pauw M, Naeije R, Vachiery JL, Paelinck BP, Morissens M, Budts W (2013) Worsening in oxygen saturation and exercise capacity predict adverse outcome in patients with Eisenmenger syndrome. Int J Cardiol 168(2):1386–1392.  https://doi.org/10.1016/j.ijcard.2012.12.021 CrossRefGoogle Scholar
  107. 107.
    Broberg CS, Ujita M, Prasad S, Li W, Rubens M, Bax BE, Davidson SJ, Bouzas B, Gibbs JS, Burman J, Gatzoulis MA (2007) Pulmonary arterial thrombosis in Eisenmenger syndrome is associated with biventricular dysfunction and decreased pulmonary flow velocity. J Am Coll Cardiol 50(7):634–642CrossRefPubMedGoogle Scholar
  108. 108.
    Ntiloudi D, Apostolopoulou S, Vasiliadis K, Frogoudaki A, Tzifa A, Ntellos C, Brili S, Manginas A, Pitsis A, Kolios M, Karvounis H, Tsioufis C, Goudevenos J, Rammos S, Giannakoulas G, investigators C (2019) Hospitalisations for heart failure predict mortality in pulmonary hypertension related to congenital heart disease. Heart 105(6):465–469.  https://doi.org/10.1136/heartjnl-2018-313613 CrossRefPubMedGoogle Scholar
  109. 109.
    Drakopoulou M, Nashat H, Kempny A, Alonso-Gonzalez R, Swan L, Wort SJ, Price LC, McCabe C, Wong T, Gatzoulis MA, Ernst S, Dimopoulos K (2018) Arrhythmias in adult patients with congenital heart disease and pulmonary arterial hypertension. Heart 104(23):1963–1969.  https://doi.org/10.1136/heartjnl-2017-312881 CrossRefPubMedGoogle Scholar
  110. 110.
    Van De Bruaene A, Delcroix M, Pasquet A, De Backer J, De Pauw M, Naeije R, Vachiery JL, Paelinck B, Morissens M, Budts W (2011) Iron deficiency is associated with adverse outcome in Eisenmenger patients. Eur Heart J 32(22):2790–2799.  https://doi.org/10.1093/eurheartj/ehr130 CrossRefGoogle Scholar
  111. 111.
    Tay EL, Peset A, Papaphylactou M, Inuzuka R, Alonso-Gonzalez R, Giannakoulas G, Tzifa A, Goletto S, Broberg C, Dimopoulos K, Gatzoulis MA (2011) Replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/or the Eisenmenger syndrome. Int J Cardiol 151(3):307–312.  https://doi.org/10.1016/j.ijcard.2010.05.066 CrossRefPubMedGoogle Scholar
  112. 112.
    D'Alto M, Romeo E, Argiento P, Santoro G, Sarubbi B, Gaio G, Melot C, Russo MG, Naeije R, Calabro R (2010) Pulmonary vasoreactivity predicts long-term outcome in patients with Eisenmenger syndrome receiving bosentan therapy. Heart 96(18):1475–1479.  https://doi.org/10.1136/hrt.2010.199661 CrossRefPubMedGoogle Scholar
  113. 113.
    Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, Del Nido P, Fasules JW, Graham TP Jr, Hijazi ZM, Hunt SA, King ME, Landzberg MJ, Miner PD, Radford MJ, Walsh EP, Webb GD (2008) ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Developed in collaboration with the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 52(23):e143–e263CrossRefPubMedGoogle Scholar
  114. 114.
    D'Alto M, Romeo E, Argiento P, Correra A, Santoro G, Gaio G, Sarubbi B, Calabro R, Russo MG (2013) Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure. Int J Cardiol 168(4):3797–3801.  https://doi.org/10.1016/j.ijcard.2013.06.036 CrossRefPubMedGoogle Scholar
  115. 115.
    Manes A, Palazzini M, Leci E, Bacchi Reggiani ML, Branzi A, Galie N (2014) Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. Eur Heart J 35(11):716–724.  https://doi.org/10.1093/eurheartj/eht072 CrossRefPubMedGoogle Scholar
  116. 116.
    Mitropoulos FA, Apostolopoulou SC, Kanakis MA, Rammos S, Anagnostopoulos CE (2007) Bosentan treatment in an adult with pulmonary hypertension due to patent ductus arteriosus permits surgical repair. J Heart Lung Transplant 26(12):1345–1346CrossRefPubMedGoogle Scholar
  117. 117.
    Frost AE, Quinones MA, Zoghbi WA, Noon GP (2005) Reversal of pulmonary hypertension and subsequent repair of atrial septal defect after treatment with continuous intravenous epoprostenol. J Heart Lung Transplant 24(4):501–503CrossRefPubMedGoogle Scholar
  118. 118.
    Balzer DT, Kort HW, Day RW, Corneli HM, Kovalchin JP, Cannon BC, Kaine SF, Ivy DD, Webber SA, Rothman A, Ross RD, Aggarwal S, Takahashi M, Waldman JD (2002) Inhaled nitric oxide as a preoperative test (INOP test I): the INOP test study group. Circulation 106(12 Suppl 1):I76–I81PubMedGoogle Scholar
  119. 119.
    Greutmann M, Pieper PG (2015) Pregnancy in women with congenital heart disease. Eur Heart J 36(37):2491–2499.  https://doi.org/10.1093/eurheartj/ehv288 CrossRefPubMedGoogle Scholar
  120. 120.
    Ntiloudi D, Giannakoulas G (2019) Pregnancy still contraindicated in pulmonary arterial hypertension related to congenital heart disease: true or false? Eur J Prev Cardiol 26(10):1064–1066.  https://doi.org/10.1177/2047487318825347 CrossRefPubMedGoogle Scholar
  121. 121.
    Weiss BM, Zemp L, Seifert B, Hess OM (1998) Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol 31(7):1650–1657CrossRefPubMedGoogle Scholar
  122. 122.
    Niwa K, Perloff JK, Kaplan S, Child JS, Miner PD (1999) Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus, univentricular heart. J Am Coll Cardiol 34(1):223–232.  https://doi.org/10.1016/S0735-1097(99)00153-9 CrossRefPubMedGoogle Scholar
  123. 123.
    Li Q, Dimopoulos K, Liu T, Xu Z, Liu Q, Li Y, Zhang J, Gu H (2019) Peripartum outcomes in a large population of women with pulmonary arterial hypertension associated with congenital heart disease. Eur J Prev Cardiol 26(10):1067–1076.  https://doi.org/10.1177/2047487318821246 CrossRefPubMedGoogle Scholar
  124. 124.
    Bedard E, Dimopoulos K, Gatzoulis MA (2009) Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Eur Heart J 30(3):256–265CrossRefPubMedGoogle Scholar
  125. 125.
    Katsurahgi S, Kamiya C, Yamanaka K, Neki R, Miyoshi T, Iwanaga N, Horiuchi C, Tanaka H, Yoshimatsu J, Niwa K, Takagi Y, Ogo T, Nakanishi N, Ikeda T (2019) Maternal and fetal outcomes in pregnancy complicated with Eisenmenger syndrome. Taiwan J Obstet Gynecol 58(2):183–187.  https://doi.org/10.1016/j.tjog.2019.01.002 CrossRefPubMedGoogle Scholar
  126. 126.
    Ladouceur M, Benoit L, Radojevic J, Basquin A, Dauphin C, Hascoet S, Moceri P, Bredy C, Iserin L, Gouton M, Nizard J (2017) Pregnancy outcomes in patients with pulmonary arterial hypertension associated with congenital heart disease. Heart 103(4):287–292.  https://doi.org/10.1136/heartjnl-2016-310003 CrossRefPubMedGoogle Scholar
  127. 127.
    Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM, Gibbs JS, Gohlke-Baerwolf C, Gorenek B, Iung B, Kirby M, Maas AH, Morais J, Nihoyannopoulos P, Pieper PG, Presbitero P, Roos-Hesselink JW, Schaufelberger M, Seeland U, Torracca L (2011) ESC guidelines on the management of cardiovascular diseases during pregnancy: the task force on the management of cardiovascular diseases during pregnancy of the European Society of Cardiology (ESC). Eur Heart J 32(24):3147–3197.  https://doi.org/10.1093/eurheartj/ehr218 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Michail Papamichalis
    • 1
  • Andrew Xanthopoulos
    • 1
  • Panagiotis Papamichalis
    • 2
  • John Skoularigis
    • 1
  • Filippos Triposkiadis
    • 1
    Email author
  1. 1.Department of CardiologyLarissa University General HospitalLarissaGreece
  2. 2.Intensive Care UnitGeneral Hospital of LarissaLarissaGreece

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