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Chronic Pulmonary Hypertension

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Abstract

This chapter discusses the anatomical and physiological basis for chronic pulmonary arterial hypertension and its diagnosis and management. Pulmonary arterial hypertension (PAH) can lead to significant cardiac dysfunction and is associated with an increased risk of perioperative cardiovascular complications. The selection of appropriate therapies is complex, requiring familiarity with the underlying disease process, complicated delivery systems, dosing regimens, and medication complications. Recent therapeutic and surgical advances in the management of PAH have led to an improvement in prognosis.

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References

  1. Ivy DD, Abman SH, Barst RJ, Berger RM, Bonnet D, Fleming TR, Haworth SG, Raj JU, Rosenzweig EB, Schulze Neick I, Steinhorn RH, Beghetti M. Pediatric pulmonary hypertension. J Am Coll Cardiol. 2013;62:D117–D126.

    Google Scholar 

  2. Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D42–D50.

    Article  PubMed  Google Scholar 

  4. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–D41.

    Article  PubMed  Google Scholar 

  5. Lammers AE, Adatia I, Cerro MJ, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, Ivy D, Lopes AA, Raj JU, Sandoval J, Stenmark K, Haworth SG. Functional classification of pulmonary hypertension in children: report from the PVRI pediatric taskforce, Panama 2011. Pulm Circ. 2011;1:280–285.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cerro MJ, Abman S, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, Haworth SG, Ivy D, Lopes AA, Raj JU, Sandoval J, Stenmark K, Adatia I. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ. 2011;1:286–298.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol. 2007;2:369–399.

    Article  CAS  PubMed  Google Scholar 

  8. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation. 2006;114:1883–1891.

    Article  PubMed  Google Scholar 

  9. Heath D, Smith P, Gosney J, Mulcahy D, Fox K, Yacoub M, Harris P. The pathology of the early and late stages of primary pulmonary hypertension. Br Heart J. 1987;58:204–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kumar R, Graham B. How does inflammation contribute to pulmonary hypertension? Eur Respir J. 2018;51:1702403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rubin LJ. Targeting bone morphogenic protein receptor 2 (BMPR2) signalling to treat pulmonary arterial hypertension. Eur Respir J. 2017;50(3):1701370.

    Article  CAS  PubMed  Google Scholar 

  12. West J, Austin E, Fessel JP, Loyd J, Hamid R. Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension. Drug Discov Today. 2014;19:1241–1245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet. 2003;361:1533–1544.

    Article  PubMed  Google Scholar 

  14. Weinberg CE, Hertzberg JR, Ivy DD, Kirby KS, Chan KC, Valdes-Cruz L, Shandas R. Extraction of pulmonary vascular compliance, pulmonary vascular resistance, and right ventricular work from single-pressure and Doppler flow measurements in children with pulmonary hypertension: a new method for evaluating reactivity: in vitro and clinical studies. Circulation. 2004;110:2609–2617.

    Article  PubMed  Google Scholar 

  15. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62:D22–D33.

    Article  PubMed  Google Scholar 

  16. Beghetti M, Berger RM, Schulze-Neick I, Day RW, Pulido T, Feinstein J, Barst RJ, Humpl T. Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice. Eur Respir J. 2013;42:689–700.

    Article  CAS  PubMed  Google Scholar 

  17. Berger RM, Beghetti M, Humpl T, Raskob GE, Ivy DD, Jing ZC, Bonnet D, Schulze-Neick I, Barst RJ. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. 2012;379:537–546.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216–223.

    Article  CAS  PubMed  Google Scholar 

  19. Takatsuki S, Darst JR, Das BB, Fagan TE, Wolfe R, Ivy DD. Clinical manifestations and long-term follow-up in pediatric patients living at altitude with isolated pulmonary artery of ductal origin. Pediatr Cardiol. 2012;33:775–781.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Puchalski MD, Lozier JS, Bradley DJ, Minich LL, Tani LY. Electrocardiography in the diagnosis of right ventricular hypertrophy in children. Pediatrics. 2006;118:1052–1055.

    Article  PubMed  Google Scholar 

  21. Ivy D. Echocardiographic evaluation of pulmonary hypertension. Echocardiographic Diagnosis of Congenital Heat Disease An Embryologic and Anatomic Approach. Lippincott-Raven Publishers. 1999:537–547.

    Google Scholar 

  22. Zhu N, Gonzaga-Jauregui C, Welch CL, Ma L, Qi H, King AK, Krishnan U, Rosenzweig EB, Ivy DD, Austin ED, Hamid R, Nichols WC, Pauciulo MW, Lutz KA, Sawle A, Reid JG, Overton JD, Baras A, Dewey F, Shen Y, Chung WK. Exome sequencing in children with pulmonary arterial hypertension demonstrates differences compared with adults. Circ Genom Precis Med. 2018;11:e001887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Masuyama T, Kodama K, Kitabatake A, Sato H, Nanto S, Inoue M. Continuous-wave Doppler echocardiographic detection of pulmonary regurgitation and its application to noninvasive estimation of pulmonary artery pressure. Circulation. 1986;74:484–492.

    Article  CAS  PubMed  Google Scholar 

  24. Koestenberger M, Ravekes W, Everett AD, Stueger HP, Heinzl B, Gamillscheg A, Cvirn G, Boysen A, Fandl A, Nagel B. Right ventricular function in infants, children and adolescents: reference values of the tricuspid annular plane systolic excursion (TAPSE) in 640 healthy patients and calculation of z score values. J Am Soc Echocardiogr. 2009;22:715–719.

    Article  PubMed  Google Scholar 

  25. Jone PN, Ivy DD. Echocardiography in pediatric pulmonary hypertension. Front Pediatr. 2014;2:124.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jone PN, Patel SS, Cassidy C, Ivy DD. Three-dimensional echocardiography of right ventricular function correlates with severity of pediatric pulmonary hypertension. Congenit Heart Dis. 2016;11(6):562-569.

    Article  PubMed  Google Scholar 

  27. Ploegstra MJ, Roofthooft MT, Douwes JM, Bartelds B, Elzenga NJ, van de Weerd D, Hillege HL, Berger RM. Echocardiography in pediatric pulmonary arterial hypertension: early study on assessing disease severity and predicting outcome. Circ Cardiovasc Imaging. 2015;8(1):e000878.

    Article  PubMed  Google Scholar 

  28. Jone PN, Hinzman J, Wagner BD, Ivy DD, Younoszai A. Right ventricular to left ventricular diameter ratio at end-systole in evaluating outcomes in children with pulmonary hypertension. J Am Soc Echocardiogr. 2014;27:172–178.

    Article  PubMed  Google Scholar 

  29. Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, Ettinger NA, Hill NS, Summer WR, de Boisblanc B, Schwartz T, Koch G, Clayton LM, Jobsis MM, Crow JW, Long W. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214–1219.

    Article  PubMed  Google Scholar 

  30. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–172.

    Article  PubMed  Google Scholar 

  31. Alkon J, Humpl T, Manlhiot C, McCrindle BW, Reyes JT, Friedberg MK. Usefulness of the right ventricular systolic to diastolic duration ratio to predict functional capacity and survival in children with pulmonary arterial hypertension. Am J Cardiol. 2010;106:430–436.

    Article  PubMed  Google Scholar 

  32. Friedberg MK, Redington AN. Right versus left ventricular failure: differences, similarities, and interactions. Circulation. 2014;129:1033–1044.

    Article  PubMed  Google Scholar 

  33. Lammers AE, Haworth SG, Riley G, Maslin K, Diller GP, Marek J. Value of tissue Doppler echocardiography in children with pulmonary hypertension. J Am Soc Echocardiogr. 2012;25:504–510.

    Article  PubMed  Google Scholar 

  34. Takatsuki S, Nakayama T, Jone PN, Wagner BD, Naoi K, Ivy DD, Saji T. Tissue Doppler imaging predicts adverse outcome in children with idiopathic pulmonary arterial hypertension. J Pediatr. 2012;161:1126–1131.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ozawa K, Funabashi N, Takaoka H, Tanabe N, Yanagawa N, Tatsumi K, Kobayashi Y. Utility of three-dimensional global longitudinal strain of the right ventricle using transthoracic echocardiography for right ventricular systolic function in pulmonary hypertension. Int J Cardiol. 2014;174:426–430.

    Article  PubMed  Google Scholar 

  36. Lu X, Nadvoretskiy V, Bu L, Stolpen A, Ayres N, Pignatelli RH, Kovalchin JP, Grenier M, Klas B, Ge S. Accuracy and reproducibility of real-time three-dimensional echocardiography for assessment of right ventricular volumes and ejection fraction in children. J Am Soc Echocardiogr. 2008;21:84–89.

    Article  PubMed  Google Scholar 

  37. Lammers AE, Hislop AA, Flynn Y, Haworth SG. The 6-minute walk test: normal values for children of 4-11 years of age. Arch Dis Child. 2008;93:464–468.

    Article  CAS  PubMed  Google Scholar 

  38. Li AM, Yin J, Au JT, So HK, Tsang T, Wong E, Fok TF, Ng PC. Standard reference for the six-minute-walk test in healthy children aged 7 to 16 years. Am J Respir Crit Care Med. 2007;176:174–180.

    Article  PubMed  Google Scholar 

  39. Geiger R, Strasak A, Treml B, Gasser K, Kleinsasser A, Fischer V, Geiger H, Loeckinger A, Stein JI. Six-minute walk test in children and adolescents. J Pediatr. 2007;150:395–399, 399 e1-2.

    Article  PubMed  Google Scholar 

  40. Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96:1401–1406.

    Article  CAS  PubMed  Google Scholar 

  41. van Loon RL, Roofthooft MT, Delhaas T, van Osch-Gevers M, ten Harkel AD, Strengers JL, Backx A, Hillege HL, Berger RM. Outcome of pediatric patients with pulmonary arterial hypertension in the era of new medical therapies. Am J Cardiol. 2010;106:117–124.

    Article  PubMed  Google Scholar 

  42. Douwes JM, Hegeman AK, van der Krieke MB, Roofthooft MT, Hillege HL, Berger RM. Six-minute walking distance and decrease in oxygen saturation during the six-minute walk test in pediatric pulmonary arterial hypertension. Int J Cardiol. 2015;202:34–39.

    Article  PubMed  Google Scholar 

  43. Garofano RP, Barst RJ. Exercise testing in children with primary pulmonary hypertension. Pediatr Cardiol. 1999;20:61–64; discussion 65.

    Article  CAS  PubMed  Google Scholar 

  44. Yetman AT, Taylor AL, Doran A, Ivy DD. Utility of cardiopulmonary stress testing in assessing disease severity in children with pulmonary arterial hypertension. Am J Cardiol. 2005;95:697–699.

    Article  PubMed  Google Scholar 

  45. Rausch CM, Taylor AL, Ross H, Sillau S, Ivy DD. Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension. Int J Cardiol. 2013;169:445–448.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865–870.

    Article  CAS  PubMed  Google Scholar 

  47. Van Albada ME, Loot FG, Fokkema R, Roofthooft MT, Berger RM. Biological serum markers in the management of pediatric pulmonary arterial hypertension. Pediatr Res. 2008;63:321–327.

    Article  CAS  PubMed  Google Scholar 

  48. Lammers AE, Hislop AA, Haworth SG. Prognostic value of B-type natriuretic peptide in children with pulmonary hypertension. Int J Cardiol. 2009;135:21–26.

    Article  PubMed  Google Scholar 

  49. Bernus A, Wagner BD, Accurso F, Doran A, Kaess H, Ivy DD. Brain natriuretic peptide levels in managing pediatric patients with pulmonary arterial hypertension. Chest. 2009;135:745–751.

    Article  CAS  PubMed  Google Scholar 

  50. Amdani SM, Mian MUM, Thomas RL, Ross RD. NT-pro BNP-A marker for worsening respiratory status and mortality in infants and young children with pulmonary hypertension. Congenit Heart Dis. 2018;13(4):499-505.

    Article  PubMed  Google Scholar 

  51. Ploegstra MJ, Zijlstra WM, Douwes JM, Hillege HL, Berger RM. Prognostic factors in pediatric pulmonary arterial hypertension: a systematic review and meta-analysis. Int J Cardiol. 2015;184:198–207.

    Article  PubMed  Google Scholar 

  52. Del Cerro MJ, Moledina S, Haworth SG, Ivy D, Al Dabbagh M, Banjar H, Diaz G, Heath-Freudenthal A, Galal AN, Humpl T, Kulkarni S, Lopes A, Mocumbi AO, Puri GD, Rossouw B, Harikrishnan S, Saxena A, Udo P, Caicedo L, Tamimi O, Adatia I. Cardiac catheterization in children with pulmonary hypertensive vascular disease: consensus statement from the Pulmonary Vascular Research Institute, Pediatric and Congenital Heart Disease Task Forces. Pulm Circ. 2016;6:118–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197–1208.

    Article  CAS  PubMed  Google Scholar 

  54. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Herve P, Simonneau G. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105–3111.

    Article  CAS  PubMed  Google Scholar 

  55. Beghetti M. Current treatment options in children with pulmonary arterial hypertension and experiences with oral bosentan. Eur J Clin Investig. 2006;36(Suppl 3):16–24.

    Article  CAS  Google Scholar 

  56. O’Byrne ML, Kennedy KF, Kanter JP, Berger JT, Glatz AC. Risk factors for major early adverse events related to cardiac catheterization in children and young adults with pulmonary hypertension: an analysis of data from the IMPACT (Improving Adult and Congenital Treatment) registry. J Am Heart Assoc. 2018;7(5):e008142.

    PubMed  PubMed Central  Google Scholar 

  57. Douwes JM, van Loon RL, Hoendermis ES, Vonk-Noordegraaf A, Roofthooft MT, Talsma MD, Hillege HL, Berger RM. Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria. Eur Heart J. 2011;32(24):3137-3146.

    Article  PubMed  Google Scholar 

  58. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006. Heart. 2009;95:312–317.

    Article  CAS  PubMed  Google Scholar 

  59. Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Circulation. 2012;125:113–122.

    Article  PubMed  Google Scholar 

  60. Douwes JM, Humpl T, Bonnet D, Beghetti M, Ivy DD, Berger RM, Investigators T. Acute vasodilator response in pediatric pulmonary arterial hypertension: current clinical practice from the TOPP registry. J Am Coll Cardiol. 2016;67:1312–1323.

    Article  PubMed  Google Scholar 

  61. Carmosino MJ, Friesen RH, Doran A, Ivy DD. Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization. Anesth Analg. 2007;104:521–527.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425–1436.

    Article  CAS  PubMed  Google Scholar 

  63. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–349.

    Article  PubMed  Google Scholar 

  64. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110:660–665.

    Article  PubMed  Google Scholar 

  65. Barst RJ. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest. 1986;89:497–503.

    Article  CAS  PubMed  Google Scholar 

  66. van Loon RL, Roofthooft MT, Hillege HL, Ten Harkel AD, van Osch-Gevers M, Delhaas T, Kapusta L, Strengers JL, Rammeloo L, Clur SA, Mulder BJ, Berger RM. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124(16):1755-1764.

    Article  PubMed  Google Scholar 

  67. JE Loyd, MG Butler, TM Foroud. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;152:93–97.

    Article  CAS  PubMed  Google Scholar 

  68. Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014;115:189–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Harrison RE, Berger R, Haworth SG, Tulloh R, Mache CJ, Morrell NW, Aldred MA, Trembath RC. Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation. 2005;111:435–441.

    Article  CAS  PubMed  Google Scholar 

  70. Consortium TIP, Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-B receptor cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81–84.

    Article  CAS  Google Scholar 

  71. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737–744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA, 3rd, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001;68:92–102.

    Article  CAS  PubMed  Google Scholar 

  73. Trembath RC, Harrison R. Insights into the genetic and molecular basis of primary pulmonary hypertension. Pediatr Res. 2003;53:883–888.

    Article  PubMed  Google Scholar 

  74. Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, Hodge SE, Morse JH, Knowles JA. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med. 2000;161:1055–1059.

    Article  CAS  PubMed  Google Scholar 

  75. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Halme M, Raisanen-Sokolowski A, Laitinen T, Morrell NW, Trembath RC. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet. 2003;40:865–871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Roberts KE, McElroy JJ, Wong WP, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J. 2004;24:371–374.

    Article  CAS  PubMed  Google Scholar 

  77. Levy M, Eyries M, Szezepanski I, Ladouceur M, Nadaud S, Bonnet D, Soubrier F. Genetic analyses in a cohort of children with pulmonary hypertension. Eur Respir J. 2016;48:1118–1126.

    Article  CAS  PubMed  Google Scholar 

  78. Fujiwara M, Yagi H, Matsuoka R, Akimoto K, Furutani M, Imamura S, Uehara R, Nakayama T, Takao A, Nakazawa M, Saji T. Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J. 2008;72:127–133.

    Article  CAS  PubMed  Google Scholar 

  79. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, 3rd, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000;26:81–84.

    Article  CAS  PubMed  Google Scholar 

  80. Grunig E, Koehler R, Miltenberger-Miltenyi G, Zimmermann R, Gorenflo M, Mereles D, Arnold K, Naust B, Wilkens H, Benz A, von Hippel A, Ulmer HE, Kubler W, Katus HA, Bartram CR, Schranz D, Janssen B. Primary pulmonary hypertension in children may have a different genetic background than in adults. Pediatr Res. 2004;56:571–578.

    Article  PubMed  Google Scholar 

  81. Rosenzweig EB, Morse JH, Knowles JA, Chada KK, Khan AM, Roberts KE, McElroy JJ, Juskiw NK, Mallory NC, Rich S, Diamond B, Barst RJ. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant. 2008;27:668–674.

    Article  PubMed  Google Scholar 

  82. Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, West JD, Phillips JA, 3rd, Hamid R, Loyd JE. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:892–896.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ma L, Chung WK. The genetic basis of pulmonary arterial hypertension. Hum Genet. 2014;133:471–479.

    Article  CAS  PubMed  Google Scholar 

  84. Eddahibi S, Adnot S. The serotonin pathway in pulmonary hypertension. Arch Mal Coeur Vaiss. 2006;99:621–625.

    CAS  PubMed  Google Scholar 

  85. Vachharajani A, Saunders S. Allelic variation in the serotonin transporter (5HTT) gene contributes to idiopathic pulmonary hypertension in children. Biochem Biophys Res Commun. 2005;334:376–379.

    Article  CAS  PubMed  Google Scholar 

  86. Krishnan U, Rosenzweig EB. Pulmonary hypertension in chronic lung disease of infancy. Curr Opin Pediatr. 2015;27:177–183.

    Article  CAS  PubMed  Google Scholar 

  87. Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, Poindexter BB, Ingram DA, Abman SH. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;191:87–95.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, Mullen MP. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120:1260–1269.

    Article  PubMed  Google Scholar 

  89. del Cerro MJ, Sabate Rotes A, Carton A, Deiros L, Bret M, Cordeiro M, Verdu C, Barrios MI, Albajara L, Gutierrez-Larraya F. Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes. Pediatr Pulmonol. 2014;49:49–59.

    Article  PubMed  Google Scholar 

  90. Abman SH, Ivy DD. Hospitalizations of children with pulmonary hypertension: implications for improving care. Pediatrics. 2015;136:392–393.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Augustine S, Avey MT, Harrison B, Locke T, Ghannad M, Moher D, Thebaud B. Mesenchymal stromal cell therapy in bronchopulmonary dysplasia: systematic review and meta-analysis of preclinical studies. Stem Cells Transl Med. 2017;6:2079–2093.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Krishnan U, Feinstein JA, Adatia I, Austin ED, Mullen MP, Hopper RK, Hanna B, Romer L, Keller RL, Fineman J, Steinhorn R, Kinsella JP, Ivy DD, Rosenzweig EB, Raj U, Humpl T, Abman SH, Pediatric Pulmonary Hypertension N. Evaluation and management of pulmonary hypertension in children with bronchopulmonary dysplasia. J Pediatr. 2017;188:24–34 e1.

    Article  PubMed  Google Scholar 

  93. Beghetti M. Congenital heart disease and pulmonary hypertension. Rev Port Cardiol. 2004;23:273–281.

    PubMed  Google Scholar 

  94. Rosenzweig EB, Barst RJ. Congenital heart disease and pulmonary hypertension: pharmacology and feasibility of late surgery. Prog Cardiovasc Dis. 2012;55:128–133.

    Article  PubMed  Google Scholar 

  95. McMahon CJ, Penny DJ, Nelson DP, Ades A, Al Maskary S, Speer M, Katkin J, McKenzie D, Fraser CD, Chang AC. Preterm infants with congenital heart disease and bronchopulmonary dysplasia: postoperative course and outcome after cardiac surgery. Pediatrics. 2005;116:423–430.

    Article  PubMed  Google Scholar 

  96. Berman EB, Barst RJ. Eisenmenger’s syndrome: current management. Prog Cardiovasc Dis. 2002;45:129–138.

    Article  PubMed  Google Scholar 

  97. Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circulation. 1993;87:1954–1959.

    Article  CAS  PubMed  Google Scholar 

  98. 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. Predictors of death in contemporary adult patients with Eisenmenger syndrome: a multicenter study. Circulation. 2017;135:1432–1440.

    Article  PubMed  Google Scholar 

  99. Dimopoulos K, Inuzuka R, Goletto S, Giannakoulas G, Swan L, Wort SJ, Gatzoulis MA. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation. 2010;121:20–25.

    Article  PubMed  Google Scholar 

  100. La Gerche A, Gewillig M. What limits cardiac performance during exercise in normal subjects and in healthy Fontan patients? Int J Pediatr. 2010;2010:791291.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Haseyama K, Satomi G, Yasukochi S, Matsui H, Harada Y, Uchita S. Pulmonary vasodilation therapy with sildenafil citrate in a patient with plastic bronchitis after the Fontan procedure for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 2006;132:1232–1233.

    Article  PubMed  Google Scholar 

  102. John AS, Johnson JA, Khan M, Driscoll DJ, Warnes CA, Cetta F. Clinical outcomes and improved survival in patients with protein-losing enteropathy after the Fontan operation. J Am Coll Cardiol. 2014;64:54–62.

    Article  PubMed  Google Scholar 

  103. Malhotra SP, Ivy DD, Mitchell MB, Campbell DN, Dines ML, Miyamoto S, Kay J, Clarke DR, Lacour-Gayet F. Performance of cavopulmonary palliation at elevated altitude: midterm outcomes and risk factors for failure. Circulation. 2008;118:S177–S181.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Levy M, Danel C, Laval AM, Leca F, Vouhe PR, Israel-Biet D. Nitric oxide synthase expression by pulmonary arteries: a predictive marker of Fontan procedure outcome? J Thorac Cardiovasc Surg. 2003;125:1083–1090.

    Article  CAS  PubMed  Google Scholar 

  105. Morchi GS, Ivy DD, Duster MC, Claussen L, Chan KC, Kay J. Sildenafil increases systemic saturation and reduces pulmonary artery pressure in patients with failing Fontan physiology. Congenit Heart Dis. 2009;4:107–111.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Goldberg DJ, French B, Szwast AL, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM, Rychik J. Impact of sildenafil on echocardiographic indices of myocardial performance after the Fontan operation. Pediatr Cardiol. 2012;33:689–696.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Van De Bruaene A, La Gerche A, Claessen G, De Meester P, Devroe S, Gillijns H, Bogaert J, Claus P, Heidbuchel H, Gewillig M, Budts W. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging. 2014;7:265–273.

    Article  Google Scholar 

  108. Yamagishi M, Kurosawa H, Hashimoto K, Nomura K, Kitamura N. The role of plasma endothelin in the Fontan circulation. J Cardiovasc Surg. 2002;43:793–797.

    CAS  Google Scholar 

  109. Bowater SE, Weaver RA, Thorne SA, Clift PF. The safety and effects of bosentan in patients with a Fontan circulation. Congenit Heart Dis. 2012;7:243–249.

    Article  PubMed  Google Scholar 

  110. Derk G, Houser L, Miner P, Williams R, Moriarty J, Finn P, Alejos J, Aboulhosn J. Efficacy of endothelin blockade in adults with Fontan physiology. Congenit Heart Dis. 2015;10(1):E11-E16.

    Article  PubMed  Google Scholar 

  111. Hebert A, Mikkelsen UR, Thilen U, Idorn L, Jensen AS, Nagy E, Hanseus K, Sorensen KE, Sondergaard L. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation. 2014;130:2021–2030.

    Article  CAS  PubMed  Google Scholar 

  112. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350:886–895.

    Article  CAS  PubMed  Google Scholar 

  113. Sachdev V, Machado RF, Shizukuda Y, Rao YN, Sidenko S, Ernst I, St Peter M, Coles WA, Rosing DR, Blackwelder WC, Castro O, Kato GJ, Gladwin MT. Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease. J Am Coll Cardiol. 2007;49:472–479.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Klings ES, Machado RF, Barst RJ, Morris CR, Mubarak KK, Gordeuk VR, Kato GJ, Ataga KI, Gibbs JS, Castro O, Rosenzweig EB, Sood N, Hsu L, Wilson KC, Telen MJ, Decastro LM, Krishnamurti L, Steinberg MH, Badesch DB, Gladwin MT, American Thoracic Society Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell D. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med. 2014;189:727–740.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Barst RJ. Recent advances in the treatment of pediatric pulmonary artery hypertension. Pediatr Clin N Am. 1999;46:331–345.

    Article  CAS  Google Scholar 

  116. Rashid A, Ivy D. Severe paediatric pulmonary hypertension: new management strategies. Arch Dis Child. 2005;90:92–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Auger WR CR, Kerr KM, et al. Evaluation of patients with suspected chronic thromboembolic pulmonary hypertension. Semin Thorac Cardiovasc Surg. 1999;11:179–190.

    Article  CAS  PubMed  Google Scholar 

  118. Channick RN, Newhart JW, Johnson FW, Williams PJ, Auger WR, Fedullo PF, Moser KM. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests. Chest. 1996;109:1545–1549.

    Article  CAS  PubMed  Google Scholar 

  119. Katayama Y, Higenbottam TW, Cremona G, Akamine S, Demoncheaux EA, Smith AP, Siddons TE. Minimizing the inhaled dose of NO with breath-by-breath delivery of spikes of concentrated gas. Circulation. 1998;98:2429–2432.

    Article  CAS  PubMed  Google Scholar 

  120. Atz AM, Adatia I, Jonas RA, Wessel DL. Inhaled nitric oxide in children with pulmonary hypertension and congenital mitral stenosis. Am J Cardiol. 1996;77:316–319.

    Article  CAS  PubMed  Google Scholar 

  121. Pearl JM ND, Raake JL, Manning PB, Schwartz SM, Koons L, Shanley TP, Wong HR, Duffy JY. Inhaled nitric oxide increases endothelin-1 levels: a potential cause of rebound pulmonary hypertension. Crit Care Med. 2002;30:89–93.

    Article  CAS  PubMed  Google Scholar 

  122. Ivy DD, Griebel JL, Kinsella JP, Abman SH. Acute hemodynamic effects of pulsed delivery of low flow nasal nitric oxide in children with pulmonary hypertension. J Pediatr. 1998;133:453–456.

    Article  CAS  PubMed  Google Scholar 

  123. Atz AM, Adatia I, Lock JE, Wessel DL. Combined effects of nitric oxide and oxygen during acute pulmonary vasodilator testing. J Am Coll Cardiol. 1999;33:813–819.

    Article  CAS  PubMed  Google Scholar 

  124. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K, Jr., Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26:15–23.

    Article  CAS  PubMed  Google Scholar 

  125. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, 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.

    Article  CAS  PubMed  Google Scholar 

  126. Barst RJ, Galie N, Naeije R, Simonneau G, Jeffs R, Arneson C, Rubin LJ. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28:1195–1203.

    Article  CAS  PubMed  Google Scholar 

  127. Ivy DD, Claussen L, Doran A. Transition of stable pediatric patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil. Am J Cardiol. 2007;99:696–698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Voswinckel R, Enke B, Reichenberger F, Kohstall M, Kreckel A, Krick S, Gall H, Gessler T, Schmehl T, Ghofrani HA, Schermuly RT, Grimminger F, Rubin LJ, Seeger W, Olschewski H. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol. 2006;48:1672–1681.

    Article  CAS  PubMed  Google Scholar 

  129. Krishnan U, Takatsuki S, Ivy DD, Kerstein J, Calderbank M, Coleman E, Rosenzweig EB. Effectiveness and safety of inhaled treprostinil for the treatment of pulmonary arterial hypertension in children. Am J Cardiol. 2012;110:1704–1709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, Torbicki A, Xu KF, Yehle D, Laliberte K, Arneson C, Rubin LJ. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013;127:624–633.

    Article  CAS  PubMed  Google Scholar 

  131. Tapson VF, Jing ZC, Xu KF, Pan L, Feldman J, Kiely DG, Kotlyar E, McSwain CS, Laliberte K, Arneson C, Rubin LJ, Team F-CS. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144:952–958.

    Article  CAS  PubMed  Google Scholar 

  132. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S, Speich R, Hoeper MM, Behr J, Winkler J, Sitbon O, Popov W, Ghofrani HA, Manes A, Kiely DG, Ewert R, Meyer A, Corris PA, Delcroix M, Gomez-Sanchez M, Siedentop H, Seeger W. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322–329.

    Article  CAS  PubMed  Google Scholar 

  133. Beghetti M, Berner M, Rimensberger PC. Long term inhalation of iloprost in a child with primary pulmonary hypertension: an alternative to continuous infusion. Heart. 2001;86:E10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rimensberger PC, Spahr-Schopfer I, Berner M, Jaeggi E, Kalangos A, Friedli B, Beghetti M. Inhaled nitric oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease: vasodilator capacity and cellular mechanisms. Circulation. 2001;103:544–548.

    Article  CAS  PubMed  Google Scholar 

  135. Hallioglu O, Dilber E, Celiker A. Comparison of acute hemodynamic effects of aerosolized and intravenous iloprost in secondary pulmonary hypertension in children with congenital heart disease. Am J Cardiol. 2003;92:1007–1009.

    Article  CAS  PubMed  Google Scholar 

  136. Dahlem P, van Aalderen WM, de Neef M, Dijkgraaf MG, Bos AP. Randomized controlled trial of aerosolized prostacyclin therapy in children with acute lung injury. Crit Care Med. 2004;32:1055–1060.

    Article  PubMed  Google Scholar 

  137. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–1263.

    Article  CAS  PubMed  Google Scholar 

  138. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360:895–900.

    Article  CAS  PubMed  Google Scholar 

  139. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, Weissmann N, Ghofrani S, Enke B, Seeger W, Grimminger F. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol. 2003;42:158–164.

    Article  CAS  PubMed  Google Scholar 

  140. Gallotti R, Drogalis-Kim DE, Satou G, Alejos J. Single-center experience using selexipag in a pediatric population. Pediatr Cardiol. 2017;38:1405–1409.

    Article  PubMed  Google Scholar 

  141. Tanabe N, Ikeda S, Tahara N, Fukuda K, Hatano M, Ito H, Nakayama T, Anzai T, Hashimoto A, Inoue T, Kajinami K, Kihara Y, Kinoshita H, Kuwahara K, Murohara T, Okazaki O, Sakai S, Satoh T, Takeda Y, Takeishi Y, Taniguchi M, Watanabe H, Yamamoto T, Yamauchi-Takihara K, Yoshioka K, Sasayama S. Efficacy and safety of an orally administered selective prostacyclin receptor agonist, selexipag, in Japanese patients with pulmonary arterial hypertension. Circ J. 2017;81:1360–1367.

    Article  CAS  PubMed  Google Scholar 

  142. Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, Bingaman D, Nguyen N, Gaitonde M, van Giersbergen PL. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2003;73:372–382.

    Article  CAS  PubMed  Google Scholar 

  143. Badesch DB, McLaughlin VV, Delcroix M, Vizza CD, Olschewski H, Sitbon O, Barst RJ. Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:56S–61S.

    Article  CAS  PubMed  Google Scholar 

  144. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903.

    Article  CAS  PubMed  Google Scholar 

  145. Simpson CM, Penny DJ, Cochrane AD, Davis AM, Rose ML, Wilson SE, Weintraub RG. Preliminary experience with bosentan as initial therapy in childhood idiopathic pulmonary arterial hypertension. J Heart Lung Transplant. 2006;25:469–473.

    Article  PubMed  Google Scholar 

  146. Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:697–704.

    Article  CAS  PubMed  Google Scholar 

  147. Ivy DD, Doran A, Claussen L, Bingaman D, Yetman A. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan. Am J Cardiol. 2004;93:943–946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Maiya S, Hislop AA, Flynn Y, Haworth SG. Response to bosentan in children with pulmonary hypertension. Heart. 2006;92:664–670.

    Article  CAS  PubMed  Google Scholar 

  149. Sitbon O, Beghetti M, Petit J, Iserin L, Humbert M, Gressin V, Simonneau G. Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart defects. Eur J Clin Investig. 2006;36(Suppl 3):25–31.

    Article  CAS  Google Scholar 

  150. 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. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–818.

    Article  CAS  PubMed  Google Scholar 

  151. Aypar E, Alehan D, Karagoz T, Aykan HH, Ertugrul I. Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension. Cardiol Young. 2018;28:542–547.

    Article  PubMed  Google Scholar 

  152. Schulze-Neick I LJ, Reader JA, Shekerdemian L, Redington AN, Penny DJ. The endothelin antagonist BQ123 reduces pulmonary vascular resistance after surgical intervention for congenital heart disease. J Thorac Cardiovasc Surg. 2002;124:435–441.

    Article  CAS  PubMed  Google Scholar 

  153. Prendergast B, Newby DE, Wilson LE, Webb DJ, Mankad PS. Early therapeutic experience with the endothelin antagonist BQ-123 in pulmonary hypertension after congenital heart surgery. Heart. 1999;82:505–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, Frost AE, Zwicke D, Naeije R, Shapiro S, Olschewski H, Rubin LJ. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:529–535.

    Article  CAS  PubMed  Google Scholar 

  155. Zuckerman WA, Leaderer D, Rowan CA, Mituniewicz JD, Rosenzweig EB. Ambrisentan for pulmonary arterial hypertension due to congenital heart disease. Am J Cardiol. 2011;107:1381–1385.

    Article  CAS  PubMed  Google Scholar 

  156. Takatsuki S, Rosenzweig EB, Zuckerman W, Brady D, Calderbank M, Ivy DD. Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol. 2013;48:27–34.

    Article  PubMed  Google Scholar 

  157. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med. 2000;343:1342.

    Article  CAS  PubMed  Google Scholar 

  158. Kumar S. Indian doctor in protest after using Viagra to save “blue babies”. BMJ. 2002;325:181.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Michelakis ED, Tymchak W, Noga M, Webster L, Wu XC, Lien D, Wang SH, Modry D, Archer SL. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation. 2003;108:2066–2069.

    Article  CAS  PubMed  Google Scholar 

  160. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart. 2000;84:E4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Karatza AA, Bush A, Magee AG. Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int J Cardiol. 2005;100:267–273.

    Article  PubMed  Google Scholar 

  162. 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. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157.

    Article  CAS  PubMed  Google Scholar 

  163. Ivy DD, Kinsella JP, Ziegler JW, Abman SH. Dipyridamole attenuates rebound pulmonary hypertension after inhaled nitric oxide withdrawal in postoperative congenital heart disease. J Thorac Cardiovasc Surg. 1998;115:875–882.

    Article  CAS  PubMed  Google Scholar 

  164. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology. 1999;91:307–310.

    Article  CAS  PubMed  Google Scholar 

  165. Namachivayam P, Theilen U, Butt WW, Cooper SM, Penny DJ, Shekerdemian LS. Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children. Am J Respir Crit Care Med. 2006;174:1042–1047.

    Article  CAS  PubMed  Google Scholar 

  166. Atz Am LA, Fairbrother DL, Uber WE, Bradley SM. Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crisis. J Thorac Cardiovasc Surg. 2002;124:628–629.

    Article  PubMed  Google Scholar 

  167. Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, Butrous G, Petros A, Lange P, Redington AN. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation. 2003;108(Suppl 1):II167–II173.

    PubMed  Google Scholar 

  168. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med. 2003;29:1996–2003.

    Article  PubMed  Google Scholar 

  169. Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BK, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125:324–334.

    Article  CAS  PubMed  Google Scholar 

  170. Barst RJ, Beghetti M, Pulido T, Layton G, Konourina I, Zhang M, Ivy DD, Investigators S. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014;129:1914–1923.

    Article  CAS  PubMed  Google Scholar 

  171. Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012;33:683–688.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Yamazaki H, Kobayashi N, Taketsuna M, Tajima K, Suzuki N, Murakami M. Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance. Curr Med Res Opin. 2017;33:2241–2249.

    Article  CAS  PubMed  Google Scholar 

  173. Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs. 2011;20:567–576.

    Article  CAS  PubMed  Google Scholar 

  174. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C, Group C-S. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319–329.

    Article  CAS  PubMed  Google Scholar 

  175. Rosenkranz S, Ghofrani HA, Beghetti M, Ivy D, Frey R, Fritsch A, Weimann G, Saleh S, Apitz C. Riociguat for pulmonary arterial hypertension associated with congenital heart disease. Heart. 2015;101:1792–1799.

    Article  CAS  PubMed  Google Scholar 

  176. Spreemann T, Bertram H, Happel CM, Kozlik-Feldmann R, Hansmann G. First-in-child use of the oral soluble guanylate cyclase stimulator riociguat in pulmonary arterial hypertension. Pulm Circ. 2018;8:2045893217743123.

    Article  CAS  PubMed  Google Scholar 

  177. Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, Grunig E, Staehler G, Rosenkranz S, Halank M, Held M, Lange TJ, Behr J, Klose H, Claussen M, Ewert R, Opitz CF, Vizza CD, Scelsi L, Vonk-Noordegraaf A, Kaemmerer H, Gibbs JS, Coghlan G, Pepke-Zaba J, Schulz U, Gorenflo M, Pittrow D, Hoeper MM. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. 2014;129:57–65.

    Article  CAS  PubMed  Google Scholar 

  178. Sandoval J, Santos LE, Cordova J, Pulido T, Gutierrez G, Bautista E, Martinez Guerra ML, Pena H, Broberg CS. Does anticoagulation in Eisenmenger syndrome impact long-term survival? Congenit Heart Dis. 2012;7(3):268-276.

    Article  PubMed  Google Scholar 

  179. Chiu JS, Zuckerman WA, Turner ME, Richmond ME, Kerstein D, Krishnan U, Torres A, Vincent JA, Rosenzweig EB. Balloon atrial septostomy in pulmonary arterial hypertension: effect on survival and associated outcomes. J Heart Lung Transplant. 2015;34:376–380.

    Article  PubMed  Google Scholar 

  180. Baruteau AE, Serraf A, Levy M, Petit J, Bonnet D, Jais X, Vouhe P, Simonneau G, Belli E, Humbert M. Potts shunt in children with idiopathic pulmonary arterial hypertension: long-term results. Ann Thorac Surg. 2012;94:817–824.

    Article  PubMed  Google Scholar 

  181. Labombarda F, Maragnes P, Dupont-Chauvet P, Serraf A. Potts anastomosis for children with idiopathic pulmonary hypertension. Pediatr Cardiol. 2009;30(8):1143.

    Article  PubMed  Google Scholar 

  182. Blanc J, Vouhe P, Bonnet D. Potts shunt in patients with pulmonary hypertension. N Engl J Med. 2004;350:623.

    Article  CAS  PubMed  Google Scholar 

  183. Choong CK, Sweet SC, Guthrie TJ, Mendeloff EN, Haddad FJ, Schuler P, De La Morena M, Huddleston CB. Repair of congenital heart lesions combined with lung transplantation for the treatment of severe pulmonary hypertension: a 13-year experience. J Thorac Cardiovasc Surg. 2005;129:661–669.

    Article  PubMed  Google Scholar 

  184. Bridges ND, Clark BJ, Gaynor JW, Spray TL. Outcome of children with pulmonary hypertension referred for lung or heart and lung transplantation. Transplantation. 1996;62:1824–1828.

    Article  CAS  PubMed  Google Scholar 

  185. Bridges ND, Mallory GB, Jr., Huddleston CB, Canter CE, Sweet SC, Spray TL. Lung transplantation in children and young adults with cardiovascular disease. Ann Thorac Surg. 1995;59:813–820; discussion 820-1.

    Article  CAS  PubMed  Google Scholar 

  186. Clabby ML, Canter CE, Moller JH, Bridges ND. Hemodynamic data and survival in children with pulmonary hypertension. J Am Coll Cardiol. 1997;30:554–560.

    Article  CAS  PubMed  Google Scholar 

  187. Waddell TK, Bennett L, Kennedy R, Todd TR, Keshavjee SH. Heart-lung or lung transplantation for Eisenmenger syndrome. J Heart Lung Transplant. 2002;21:731–737.

    Article  PubMed  Google Scholar 

  188. Goldfarb SB, Levvey BJ, Cherikh WS, Chambers DC, Khush K, Kucheryavaya AY, Lund LH, Meiser B, Rossano JW, Yusen RD, Stehlik J, International Society for H and Lung T. Registry of the International Society for Heart and Lung Transplantation: twentieth pediatric lung and heart-lung transplantation report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36:1070–1079.

    Article  PubMed  Google Scholar 

  189. Thilenius OG, Nadas AS, Jockin H. Primary pulmonary vascular obstruction in children. Pediatrics. 1965;36:75–87.

    CAS  PubMed  Google Scholar 

  190. Sandoval J, Bauerle O, Gomez A, Palomar A, Martinez Guerra ML, Furuya ME. Primary pulmonary hypertension in children: clinical characterization and survival. J Am Coll Cardiol. 1995;25:466–474.

    Article  CAS  PubMed  Google Scholar 

  191. Zijlstra WM, Douwes JM, Rosenzweig EB, Schokker S, Krishnan U, Roofthooft MT, Miller-Reed K, Hillege HL, Ivy DD, Berger RM. Survival differences in pediatric pulmonary arterial hypertension: clues to a better understanding of outcome and optimal treatment strategies. J Am Coll Cardiol. 2014;63:2159–2169.

    Article  PubMed  Google Scholar 

  192. Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S, Ivy DD, Berger RM. Pediatric pulmonary arterial hypertension: updates on definition, classification, diganostics and management. Eur Respir J. 2019;53 (1):1801916.

    Article  PubMed  PubMed Central  Google Scholar 

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Frank, B.S., Rashid, A., Ivy, D. (2020). Chronic Pulmonary Hypertension. In: Munoz, R., Morell, V., da Cruz, E., Vetterly, C., da Silva, J. (eds) Critical Care of Children with Heart Disease . Springer, Cham. https://doi.org/10.1007/978-3-030-21870-6_43

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