Advances in the management of pediatric pulmonary hypertension

Respiratory Care

Volumn 56, Issue 9, 2011, Pages 1314-1339

  Oishi, Peter ^a   Datar, Sanjeev A ^a   Fineman, Jeffrey R ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Children; Endothelium; Infants; Neonatal; Pediatric; Pulmonary hypertension; Pulmonary vascular disease; Rho kinase; ROCK

Indexed keywords

ADRENOMEDULLIN; AMBRISENTAN; ARGININE; BAY 63 251; BERAPROST; BOSENTAN; CALCIUM CHANNEL BLOCKING AGENT; CICLETANINE; CITRULLINE; CYCLIC GMP; ENDOTHELIN 1; FASUDIL; ILOPROST; IMATINIB; NITRIC OXIDE; OXYGEN; PLACEBO; PRAVASTATIN; PROSTACYCLIN; PROSTANOID; RIOCIGUAT; SILDENAFIL; SIMVASTATIN; SITAXSENTAN; SORAFENIB; SUPEROXIDE DISMUTASE; TADALAFIL; UNCLASSIFIED DRUG; UNINDEXED DRUG; UNIPROST; VARDENAFIL; VASOACTIVE INTESTINAL POLYPEPTIDE; ANTIHYPERTENSIVE AGENT; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHODIESTERASE V INHIBITOR; PIPERAZINE DERIVATIVE; PROSTAGLANDIN; PURINE DERIVATIVE; SULFONAMIDE; SULFONE;

ADD ON THERAPY; CHILD; CONTINUOUS INFUSION; DEATH; DRUG HALF LIFE; DRUG MEGADOSE; DRUG METABOLISM; DRUG POTENTIATION; DRUG SUBSTITUTION; HEART RIGHT VENTRICLE FAILURE; HEART RIGHT VENTRICLE FUNCTION; HUMAN; INFANT; INFECTION; INJECTION SITE PAIN; LIVER TOXICITY; LUNG BLOOD VESSEL; LUNG VASCULAR RESISTANCE; LUNG VASOCONSTRICTION; MORBIDITY; MORTALITY; NEWBORN; PATHOPHYSIOLOGY; PATIENT CARE; PERSISTENT PULMONARY HYPERTENSION; PULMONARY HYPERTENSION; REVIEW; SINGLE DRUG DOSE; THROMBOSIS; VASCULAR ENDOTHELIUM; ANIMAL; CLASSIFICATION; DRUG COMBINATION; HEMODYNAMICS; MUSCLE CONTRACTION; PHYSIOLOGY; VASCULAR RESISTANCE; VASOCONSTRICTION;

ANIMALS; ANTIHYPERTENSIVE AGENTS; CHILD; CITRULLINE; DRUG THERAPY, COMBINATION; ENDOTHELIUM, VASCULAR; HEMODYNAMICS; HUMANS; HYPERTENSION, PULMONARY; INFANT; INFANT, NEWBORN; MUSCLE CONTRACTION; PERSISTENT FETAL CIRCULATION SYNDROME; PHOSPHODIESTERASE 5 INHIBITORS; PIPERAZINES; PPAR GAMMA; PROSTAGLANDINS; PURINES; SULFONAMIDES; SULFONES; VASCULAR RESISTANCE; VASOCONSTRICTION; VENTRICULAR FUNCTION, RIGHT;

EID: 82255163770     PISSN: 00201324     EISSN: 19433654     Source Type: Journal    
DOI: 10.4187/respcare.01297     Document Type: Review

References (347)

1. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S43-S54.
2. Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart 2010;96(17):1401-1406.
3. Fraisse A, Jais X, Schleich JM, di Filippo S, Maragnes P, Beghetti M, et al. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis 2010;103(2):66-74.
4. 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(4):312-317.
5. Fasnacht MS, Tolsa JF, Beghetti M. The Swiss registry for pulmonary arterial hypertension: the paediatric experience. Swiss Med Wkly 2007;137(35-36):510-513.
6. Beghetti M, Hoeper MM, Kiely DG, Carlsen J, Schwierin B, Segal ES, et al. Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension: results from the European Postmarketing Surveillance program. Pediatr Res 2008; 64(2):200-204.
7. Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005;46(4):697-704.
8. Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000;105(1 Pt 1):14-20.
9. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006(4): CD000399.
10. Anthi A, Machado RF, Jison ML, Taveira-Dasilva AM, Rubin LJ, Hunter L, et al. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med 2007;175(12):1272-1279.
11. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350(9):886-895.
12. Chaudry RA, Cikes M, Karu T, Hutchinson C, Ball S, Sutherland G, et al. Paediatric sickle cell disease: pulmonary hypertension but normal vascular resistance. Arch Dis Child 2011;96(2):131-136.
13. Celermajer DS, Cullen S, Deanfield JE. Impairment of endothelium- dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Circulation 1993;87(2):440-446.
14. Lincoln CR, Rigby ML, Mercanti C, Al-Fagih M, Joseph MC, Miller GA, et al. Surgical risk factors in total anomalous pulmonary venous connection. Am J Cardiol 1988;61(8):608-611.
15. Miller OI, Tang SF, Keech A, Pigott NB, Beller E, Celermajer DS. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. Lancet 2000;356(9240):1464-1469.
16. Semigran MJ, Cockrill BA, Kacmarek R, Thompson BT, Zapol WM, Dec GW, et al. Hemodynamic effects of inhaled nitric oxide in heart failure. J Am Coll Cardiol 1994;24(4):982-988.
17. Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 1994;90(6):2780-2785.
18. Creagh-Brown BC, Nicholson AG, Showkathali R, Gibbs JS, Howard LS. Pulmonary veno-occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil. Thorax 2008;63(10):933-934.
19. Oudiz RJ. Pulmonary hypertension associated with left-sided heart disease. Clin Chest Med 2007;28(1):233-241.
20. Delgado JF, Conde E, Sanchez V, Lopez-Rios F, Gomez-Sanchez MA, Escribano P, et al. Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure. Eur J Heart Fail 2005;7(6):1011-1016.
21. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 2000;102(14):1718-1723.
22. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation 1992; 85(2):504-509.
23. Ben Driss A, Devaux C, Henrion D, Duriez M, Thuillez C, Levy BI, et al. Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure. Circulation 2000;101(23):2764-2770.
24. Maeda K, Yamaki S, Yokota M, Murakami A, Takamoto S. Hypoplasia of the small pulmonary arteries in total anomalous pulmonary venous connection with obstructed pulmonary venous drainage. J Thorac Cardiovasc Surg 2004;127(2):448-456.
25. Endo M, Yamaki S, Ohmi M, Tabayashi K. Pulmonary vascular changes induced by congenital obstruction of pulmonary venous return. Ann Thorac Surg 2000;69(1):193-197.
26. Lantuejoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol 2006;30(7):850-857.
27. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JW, et al. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest 2007; 132(6):1906-1912.
28. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol 2006; 47(4):799-803.
29. Dyer K, Lanning C, Das B, Lee PF, Ivy DD, Valdes-Cruz L, et al. Noninvasive Doppler tissue measurement of pulmonary artery compliance in children with pulmonary hypertension. J Am Soc Echocardiogr 2006;19(4):403-412.
30. Hunter KS, Lee PF, Lanning CJ, Ivy DD, Kirby KS, Claussen LR, et al. Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pulmonary vascular resistance alone in pediatric patients with pulmonary hypertension. AmHeart J 2008;155(1): 166-174.
31. Weinberg CE, Hertzberg JR, Ivy DD, Kirby KS, Chan KC, Valdes- Cruz L, et al. Extraction of pulmonary vascular compliance, pulmonary vascular resistance, and right ventricular work from singlepressure and Doppler flow measurements in children with pulmonary hypertension: a new method for evaluating reactivity: in vitro and clinical studies. Circulation 2004;110(17):2609-2617.
32. Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med 2009;30(4):376-385.
33. Yamaki S, Wagenvoort CA. Comparison of primary plexogenic arteriopathy in adults and children. A morphometric study in 40 patients. Br Heart J 1985;54(4):428-434.
34. Rabinovitch M, Keane JF, Norwood WI, Castaneda AR, Reid L. Vascular structure in lung tissue obtained at biopsy correlated with pulmonary hemodynamic findings after repair of congenital heart defects. Circulation 1984;69(4):655-667.
35. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288(5789):373-376.
36. Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 1998;114(3 Suppl):208S-212S.
37. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333(4):214-221.
38. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328(24):1732-1739.
39. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327(2):70-75.
40. Adatia I, Barrow SE, Stratton PD, Miall-Allen VM, Ritter JM, Haworth SG. Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease. Circulation 1993;88(5 Pt 1):2117-2122.
41. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109(2):159-165.
42. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332(6163):411-415.
43. Bradley LM, Czaja JF, Goldstein RE. Circulatory effects of endothelin in newborn piglets. Am J Physiol 1990;259(5 Pt 2):H1613-H1617.
44. Cassin S, Kristova V, Davis T, Kadowitz P, Gause G. Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ. J Appl Physiol 1991;70(3):1228-1234.
45. Wong J, Vanderford PA, Fineman JR, Chang R, Soifer SJ. Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb. Am J Physiol 1993;265(4 Pt 2):H1318-H1325.
46. Wong J, Vanderford PA, Fineman JR, Soifer SJ. Developmental effects of endothelin-1 on the pulmonary circulation in sheep. Pediatr Res 1994;36(3):394-401.
47. Perreault T, De Marte J. Maturational changes in endotheliumderived relaxations in newborn piglet pulmonary circulation. Am J Physiol 1993;264(2 Pt 2):H302-H309.
48. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990;348(6303):730-732.
49. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 1990;348(6303):732-735.
50. Morris CR, Vichinsky EP. Pulmonary hypertension in thalassemia. Ann N Y Acad Sci 2010;1202:205-213.
51. Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens 2010;28(2): 201-212.
52. Spiekermann S, Schenk K, Hoeper MM. Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension. Eur Respir J 2009;34(1):276.
53. Gupte SA, Wolin MS. Oxidant and redox signaling in vascular oxygen sensing: implications for systemic and pulmonary hypertension. Antioxid Redox Signal 2008;10(6):1137-1152.
54. Black SM, Fineman JR. Oxidative and nitrosative stress in pediatric pulmonary hypertension: roles of endothelin-1 and nitric oxide. Vascul Pharmacol 2006;45(5):308-316.
55. Birukov KG. Cyclic stretch, reactive oxygen species, and vascular remodeling. Antioxid Redox Signal 2009;11(7):1651-1667.
56. Durmowicz AG, St Cyr JA, Clarke DR, Stenmark KR. Unilateral pulmonary hypertension as a result of chronic high flow to one lung. Am Rev Respir Dis 1990;142(1):230-233.
57. Ghorishi Z, Milstein JM, Poulain FR, Moon-Grady A, Tacy T, Bennett SH, et al. Shear stress paradigm for perinatal fractal arterial network remodeling in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol Heart Circ Physiol 2007;292(6):H3006-H3018.
58. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009;54(1 Suppl):S10-S19.
59. Marecki JC, Cool CD, Parr JE, Beckey VE, Luciw PA, Tarantal AF, et al. HIV-1 Nef is associated with complex pulmonary vascular lesions in SHIV-nef-infected macaques. Am J Respir Crit Care Med 2006;174(4):437-445.
60. Graham BB, Mentink-Kane MM, El-Haddad H, Purnell S, Zhang L, Zaiman A, et al. Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am J Pathol; 177(3):1549-1561.
61. Souza R, Humbert M, Sztrymf B, Jais X, Yaici A, Le Pavec J, et al. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J 2008;31(2):343-348.
62. Humbert M, Monti G, Fartoukh M, Magnan A, Brenot F, Rain B, et al. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J 1998;11(3):554-559.
63. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115(10):2811-2821.
64. + precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells. FASEB J 2007;21(13):3640-3652.
65. Abman SH. Impaired vascular endothelial growth factor signaling in the pathogenesis of neonatal pulmonary vascular disease. Adv Exp Med Biol 2010;661:323-335.
66. Tang JR, Markham NE, Lin YJ, McMurtry IF, Maxey A, Kinsella JP, et al. Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. Am J Physiol Lung Cell Mol Physiol 2004;287(2):L344-L351.
67. Pak O, Aldashev A, Welsh D, Peacock A. The effects of hypoxia on the cells of the pulmonary vasculature. Eur Respir J 2007;30(2): 364-372.
68. Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension. Pharmacol Ther 2001;92(1):1-20.
69. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98(3):322-334.
70. Nagaoka T, Fagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H, et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005;171(5):494-499.
71. Fagan KA, Oka M, Bauer NR, Gebb SA, Ivy DD, Morris KG, et al. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol 2004;287(4):L656-L664.
72. McMurtry IF, Bauer NR, Fagan KA, Nagaoka T, Gebb SA, Oka M. Hypoxia and Rho/Rho-kinase signaling. Lung development versus hypoxic pulmonary hypertension. Adv Exp Med Biol 2003;543: 127-137.
73. Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004;94(3):385-393.
74. Nagaoka T, Morio Y, Casanova N, Bauer N, Gebb S, McMurtry I, et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2004;287(4):L665-L672.
75. Mouchaers KT, Schalij I, de Boer MA, Postmus PE, van Hinsbergh VW, van Nieuw Amerongen GP, et al. Fasudil reduces monocrotaline- induced pulmonary arterial hypertension: comparison with bosentan and sildenafil. Eur Respir J 2010;36(4):800-807.
76. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002;105(14):1672-1678.
77. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, 3rd, Loyd JE, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 2000; 26(1):81-84.
78. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. American Journal of Human Genetics 2001;68(1):92-102.
79. Morse JH, Deng Z, Knowles JA. Genetic aspects of pulmonary arterial hypertension. Annals of Medicine 2001;33(9):596-603.
80. Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA 3rd, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 2001;345(5):319-324.
81. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000; 37(10):741-745.
82. Thomson J, Machado R, Pauciulo M, Morgan N, Yacoub M, Corris P, et al. Familial and sporadic primary pulmonary hypertension is caused by BMPR2 gene mutations resulting in haploinsufficiency of the bone morphogenetic protein type II receptor. J Heart Lung Transplant 2001;20(2):149.
83. Grunig E, Koehler R, Miltenberger-Miltenyi G, Zimmermann R, Gorenflo M, Mereles D, et al. Primary pulmonary hypertension in children may have a different genetic background than in adults. Pediatr Res 2004;56(4):571-578.
84. Rosenzweig EB, Morse JH, Knowles JA, Chada KK, Khan AM, Roberts KE, et al. 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(6): 668-674.
85. Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, et al. Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 2004;59(5):446-448.
86. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345(5):325-334.
87. Hoffman JI, Rudolph AM, Heymann MA. Pulmonary vascular disease with congenital heart lesions: pathologic features and causes. Circulation 1981;64(5):873-877.
88. Burrows FA, Klinck JR, Rabinovitch M, Bohn DJ. Pulmonary hypertension in children: perioperative management. Can Anaesth Soc J 1986;33(5):606-628.
89. Wheller J, George BL, Mulder DG, Jarmakani JM. Diagnosis and management of postoperative pulmonary hypertensive crisis. Circulation 1979;60(7):1640-1644.
90. Heidersbach RS, Johengen MJ, Bekker JM, Fineman JR. Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension. Pediatr Pulmonol 1999; 28(1):3-11.
91. Brierley J, Carcillo JA, Choong K, Cornell T, Decaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Crit Care Med Crit Care Med 2009;37(2):666-688.
92. Dworetz AR, Moya FR, Sabo B, Gladstone I, Gross I. Survival of infants with persistent pulmonary hypertension without extracorporeal membrane oxygenation. Pediatrics 1989;84(1):1-6.
93. Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 1985;76(4):488-494.
94. Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. The Journal of pediatrics 1997;131(1 Pt 1):55-62.
95. Gupta A, Rastogi S, Sahni R, Bhutada A, Bateman D, Rastogi D, et al. Inhaled nitric oxide and gentle ventilation in the treatment of pulmonary hypertension of the newborn: a single-center, 5-year experience. J Perinatology 2002;22(6):435-441.
96. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation 1999;99(9):1197-1208.
97. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111(23):3105-3111.
98. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med 1997;336(9):597-604.
99. Clark R, Kueser T, Walker M, Southgate W, Huckaby J, Perez J, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 2000;342(7):469-474.
100. Roberts JD Jr, Fineman JR, Morin FC 3rd, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med 1997;336(9):605-610.
101. Wessel DL, Adatia I, Giglia TM, Thompson JE, Kulik TJ. Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary hypertension and endothelial function after cardiopulmonary bypass. Circulation 1993;88(5 Pt 1):2128-2138.
102. Curran RD, Mavroudis C, Backer CL, Sautel M, Zales VR, Wessel DL. Inhaled nitric oxide for children with congenital heart disease and pulmonary hypertension. Ann Thorac Surg 1995;60(6):1765-1771.
103. Russell IA, Zwass MS, Fineman JR, Balea M, Rouine-Rapp K, Brook M, et al. The effects of inhaled nitric oxide on postoperative pulmonary hypertension in infants and children undergoing surgical repair of congenital heart disease. Anesth Analg 1998;87(1):46-51.
104. Day RW, Allen EM, Witte MK. A randomized, controlled study of the 1-hour and 24-hour effects of inhaled nitric oxide therapy in children with acute hypoxemic respiratory failure. Chest 1997; 112(5):1324-1331.
105. Bizzarro M, Gross I. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. Cochrane Database Syst Rev 2005(4): CD005055.
106. Goldman AP, Delius RE, Deanfield JE, Miller OI, de Leval MR, Sigston PE, et al. Pharmacological control of pulmonary blood flow with inhaled nitric oxide after the fenestrated Fontan operation. Circulation 1996;94(9 Suppl):II44-II48.
107. Gamillscheg A, Zobel G, Urlesberger B, Berger J, Dacar D, Stein JI, et al. Inhaled nitric oxide in patients with critical pulmonary perfusion after Fontan-type procedures and bidirectional Glenn anastomosis. J Thorac Cardiovasc Surg 1997;113(3):435-442.
108. Cai J, Su Z, Shi Z, Zhou Y, Xu Z, Yang Y. Nitric oxide and milrinone: combined effect on pulmonary circulation after Fontantype procedure: a prospective, randomized study. Ann Thorac Surg 2008;86(3):882-888.
109. Balzer DT, Kort HW, Day RW, Corneli HM, Kovalchin JP, Cannon BC, et al. Inhaled Nitric Oxide as a Preoperative Test (INOP Test I): the INOP Test Study Group. Circulation 2002;106(12 Suppl 1):I76-I81.
110. Adatia I, Perry S, Landzberg M, Moore P, Thompson JE, Wessel DL. Inhaled nitric oxide and hemodynamic evaluation of patients with pulmonary hypertension before transplantation. J Am Coll Cardiol 1995;25(7):1656-1664.
111. 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(3):813-819.
112. Barst RJ, Agnoletti G, Fraisse A, Baldassarre J, Wessel DL. Vasodilator testing with nitric oxide and/or oxygen in pediatric pulmonary hypertension. Pediatr Cardiol 2010;31(5):598-606.
113. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 2007;116(3): 238-248.
114. Bharani A, Mathew V, Sahu A, Lunia B. The efficacy and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertension. Indian Heart J 2003;55(1):55-59.
115. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353(20):2148-2157.
116. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo- controlled, double-blind, crossover study. J Am Coll Cardiol 2004;43(7):1149-1153.
117. Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006;151(4):851. e851-e855.
118. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, openlabel, pilot study. Circulation 2005;111(24):3274-3280.
119. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999;91(1):307-310.
120. 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(9):1042-1047.
121. Lee JE, Hillier SC, Knoderer CA. Use of sildenafil to facilitate weaning from inhaled nitric oxide in children with pulmonary hypertension following surgery for congenital heart disease. J Intensive Care Med 2008;23(5):329-334.
122. Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, et al. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 2003;108(Suppl 1):II167-II173.
123. 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(11):1996-2003.
124. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117(4):1077-1083.
125. Steinhorn RH, Kinsella JP, Pierce C, Butrous G, Dilleen M, Oakes M, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009;155(6):841-847. e841.
126. Jing ZC, Yu ZX, Shen JY, Wu BX, Xu KF, Zhu XY, et al. Vardenafil in pulmonary arterial hypertension: a randomized, doubleblind, placebo-controlled study. Am J Respir Crit Care Med 2011; 183(12):1723-1729.
127. Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med 2001;163(4):887-891.
128. Mehta S, Stewart DJ, Langleben D, Levy RD. Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension. Circulation 1995;92(6):1539-1545.
129. Vosatka RJ, Kashyap S, Trifiletti RR. Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate 1994;66(2-3):65-70.
130. Morris CR, Kuypers FA, Larkin S, Vichinsky EP, Styles LA. Patterns of arginine and nitric oxide in patients with sickle cell disease with vaso-occlusive crisis and acute chest syndrome. J Pediatr Hematol Oncol 2000;22(6):515-520.
131. Pearson DL, Dawling S, Walsh WF, Haines JL, Christman BW, Bazyk A, et al. Neonatal pulmonary hypertension-urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 2001;344(24):1832-1838.
132. Barr FE, Beverley H, VanHook K, Cermak E, Christian K, Drinkwater D, et al. Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery. J Pediatr 2003;142(1):26-30.
133. McCaffrey MJ, Bose CL, Reiter PD, Stiles AD. Effect of L-arginine infusion on infants with persistent pulmonary hypertension of the newborn. Biol Neonate 1995;67(4):240-243.
134. Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 2003;168(1):63-69.
135. Schulze-Neick I, Penny DJ, Rigby ML, Morgan C, Kelleher A, Collins P, et al. L-arginine and substance P reverse the pulmonary endothelial dysfunction caused by congenital heart surgery. Circulation 1999;100(7):749-755.
136. Smith HA, Canter JA, Christian KG, Drinkwater DC, Scholl FG, Christman BW, et al. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg 2006;132(1):58-65.
137. Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Muller D, Schluter KD, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008; 32(4):881-891.
138. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, et al. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation 2006;113(2):286-295.
139. Pankey EA, Bhartiya M, Badejo AM Jr, Haider U, Stasch JP, Murthy SN, et al. Pulmonary and Systemic Vasodilator Responses to the Soluble Guanylyl Cyclase Activator, Bay 60-2770, Are Not Dependent On Endogenous Nitric Oxide or Reduced Heme. Am J Physiol Heart Circ Physiol 2011.
140. Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bolkow D, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33(4):785-792.
141. Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, et al. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 2009;4(5):853-865.
142. Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010;36(4):792-799.
143. Braughler JM, Mittal CK, Murad F. Effects of thiols, sugars, and proteins on nitric oxide activation of guanylate cyclase. J Biol Chem 1979;254(24):12450-12454.
144. Schmidt HH, Schmidt PM, Stasch JP. NO- and haem-independent soluble guanylate cyclase activators. Handb Exp Pharmacol 2009; (191):309-339.
145. Higenbottam T, Wheeldon D, Wells F, Wallwork J. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1984;1(8385):1046-1047.
146. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, 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(5):296-302.
147. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40(4):780-788.
148. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998;338(5):273-277.
149. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation 2004;110(6):660-665.
150. D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115(5):343-349.
151. Tapson VF, Gomberg-Maitland M, McLaughlin VV, Benza RL, Widlitz AC, Krichman A, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest 2006;129(3):683-688.
152. 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(5):696-698.
153. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 1999;99(14):1858-1865.
154. Katz SL, Adatia I, Louca E, Leung K, Humpl T, Reyes JT, et al. Nebulized therapies for childhood pulmonary hypertension: an in vitro model. Pediatr Pulmonol 2006;41(7):666-673.
155. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr 2002; 141(6):830-832.
156. Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000;342(25):1866-1870.
157. Ivy DD, Doran AK, Smith KJ, Mallory GB Jr, Beghetti M, Barst RJ, et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol 2008;51(2):161-169.
158. Rimensberger PC, Spahr-Schopfer I, Berner M, Jaeggi E, Kalangos A, Friedli B, et al. Inhaled nitric oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease: vasodilator capacity and cellular mechanisms. Circulation 2001;103(4):544-548.
159. Limsuwan A, Wanitkul S, Khosithset A, Attanavanich S, Samankatiwat P. Aerosolized iloprost for postoperative pulmonary hypertensive crisis in children with congenital heart disease. Int J Cardiol 2008;129(3):333-338.
160. Channick RN, Olschewski H, Seeger W, Staub T, Voswinckel R, Rubin LJ. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol 2006;48(7):1433-1437.
161. Voswinckel R, Enke B, Reichenberger F, Kohstall M, Kreckel A, Krick S, et al. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol 2006;48(8):1672-1681.
162. Voswinckel R, Reichenberger F, Enke B, Kreckel A, Krick S, Gall H, et al. Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension. Pulm Pharmacol Ther 2008;21(5):824-832.
163. McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010;55(18):1915-1922.
164. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double- blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165(6):800-804.
165. Barst RJ, Galie N, Naeije R, Simonneau G, Jeffs R, Arneson C, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J 2006;28(6): 1195-1203.
166. Lang I, Gomez-Sanchez M, Kneussl M, Naeije R, Escribano P, Skoro-Sajer N, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest 2006;129(6): 1636-1643.
167. Gomberg-Maitland M, Tapson VF, Benza RL, McLaughlin VV, Krichman A, Widlitz AC, et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med 2005;172(12):1586-1589.
168. Oudiz RJ, Schilz RJ, Barst RJ, Galie N, Rich S, Rubin LJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 2004;126(2): 420-427.
169. McLaughlin VV, Gaine SP, Barst RJ, Oudiz RJ, Bourge RC, Frost A, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 2003; 41(2):293-299.
170. Levy M, Celermajer DS, Bourges-Petit E, Del Cerro MJ, Bajolle F, Bonnet D. Add-On Therapy with Subcutaneous Treprostinil for Refractory Pediatric Pulmonary Hypertension. J Pediatr 2010.
171. Ivy DD, Rosenzweig EB, Lemarie JC, Brand M, Rosenberg D, Barst RJ. Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings. Am J Cardiol 2010;106(9):1332-1338.
172. Barst RJ, McGoon M, McLaughlin V, Tapson V, Rich S, Rubin L, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41(12):2119-2125.
173. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 2002; 39(9):1496-1502.
174. Kunieda T, Nakanishi N, Matsubara H, Ohe T, Okano Y, Kondo H, et al. Effects of long-acting beraprost sodium (TRK-100STP) in Japanese patients with pulmonary arterial hypertension. Int Heart J 2009;50(4):513-529.
175. Schulze-Neick I, Li J, 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(3):435-441.
176. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358(9288):1119-1123.
177. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346(12):896-903.
178. Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114(1):48-54.
179. Maiya S, Hislop AA, Flynn Y, Haworth SG. Response to bosentan in children with pulmonary hypertension. Heart 2006;92(5):664-670.
180. Black SM, Mata-Greenwood E, Dettman RW, Ovadia B, Fitzgerald RK, Reinhartz O, et al. Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow. Circulation 2003;108(13):1646-1654.
181. Bauer M, Wilkens H, Langer F, Schneider SO, Lausberg H, Schafers HJ. Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension. Circulation 2002;105(9): 1034-1036.
182. Benza RL, Barst RJ, Galie N, Frost A, Girgis RE, Highland KB, et al. Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival. Chest 2008;134(4):775-782.
183. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006;47(10):2049-2056.
184. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169(4):441-447.
185. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest 2002;121(6):1860-1868.
186. Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 2004; 43(15):1089-1115.
187. Horn EM, Widlitz AC, Barst RJ. Sitaxsentan, a selective endothelin- A receptor antagonist for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs 2004;13(11):1483-1492.
188. Spence R, Mandagere A, Dufton C, Venitz J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J Clin Pharmacol 2008;48(12):1451-1459.
189. McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest 2009;135(1):122-129.
190. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004; 24(3):353-359.
191. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174(11):1257-1263.
192. Hoeper MM, Leuchte H, Halank M, Wilkens H, Meyer FJ, Seyfarth HJ, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006;28(4): 691-694.
193. Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149(8):521-530.
194. Ghofrani HA, Rose F, Schermuly RT, Olschewski H, Wiedemann R, Kreckel A, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003;42(1):158-164.
195. Galie N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371(9630):2093-2100.
196. Black SM, Ross PA, Levic S, Hallmark O. Reactive oxygen species inhibit endothelial NOS by mutiple mechanisms (abstract). Pediatr Res 1999;44:A1742.
197. Kalinowski L, Dobrucki IT, Malinski T. Cicletanine stimulates nitric oxide release and scavenges superoxide in endothelial cells. J Cardiovasc Pharmacol 2001;37(6):713-724.
198. Saadjian A, Philip-Joet F, Paganelli F, Arnaud A, Levy S. Longterm effects of cicletanine on secondary pulmonary hypertension. J Cardiovasc Pharmacol 1998;31(3):364-371.
199. Waxman AB, Lawler L, Cornett G. Cicletanine for the treatment of pulmonary arterial hypertension. Arch Intern Med 2008;168(19): 2164-2166.
200. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000;87(10):840-844.
201. Garcia CE, Kilcoyne CM, Cardillo C, Cannon RO, 3rd, Quyyumi AA, Panza JA. Effect of copper-zinc superoxide dismutase on endothelium- dependent vasodilation in patients with essential hypertension. Hypertension 1995;26(6 Pt 1):863-868.
202. Rosenfeld WN, Davis JM, Parton L, Richter SE, Price A, Flaster E, et al. Safety and pharmacokinetics of recombinant human superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome. Pediatrics 1996;97(6 Pt 1):811-817.
203. Davis JM, Rosenfeld WN, Richter SE, Parad MR, Gewolb IH, Spitzer AR, et al. Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome. Pediatrics 1997;100(1):24-30.
204. Steinhorn RH, Albert G, Swartz DD, Russell JA, Levine CR, Davis JM. Recombinant human superoxide dismutase enhances the effect of inhaled nitric oxide in persistent pulmonary hypertension. Am J Respir Crit Care Med 2001;164(5):834-839.
205. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275(5302):964-967.
206. Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, et al. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 2007;292(2): H1120-H1128.
207. Kanki-Horimoto S, Horimoto H, Mieno S, Kishida K, Watanabe F, Furuya E, et al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation 2006;114(1 Suppl):I181-I185.
208. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 2005;96(4):442-450.
209. Junhui Z, Xingxiang W, Guosheng F, Yunpeng S, Furong Z, Junzhu C. Reduced number and activity of circulating endothelial progenitor cells in patients with idiopathic pulmonary arterial hypertension. Respir Med 2008;102(7):1073-1079.
210. Diller GP, van Eijl S, Okonko DO, Howard LS, Ali O, Thum T, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 2008;117(23):3020-3030.
211. Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM, et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol 2007; 49(14):1566-1571.
212. Zhu JH, Wang XX, Zhang FR, Shang YP, Tao QM, Chen JZ. Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: open-label pilot study. Pediatr Transplant 2008;12(6):650-655.
213. Smadja DM, Mauge L, Gaussem P, d'Audigier C, Israel-Biet D, Celermajer DS, et al. Treprostinil increases the number and angiogenic potential of endothelial progenitor cells in children with pulmonary hypertension. Angiogenesis 2010.
214. Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, et al. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation 2007;115(10): 1260-1268.
215. Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003; 111(9):1339-1346.
216. Murakami S, Kimura H, Kangawa K, Nagaya N. Physiological significance and therapeutic potential of adrenomedullin in pulmonary hypertension. Cardiovasc Hematol Disord Drug Targets 2006; 6(2):125-132.
217. Kakishita M, Nishikimi T, Okano Y, Satoh T, Kyotani S, Nagaya N, et al. Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. Clin Sci (Lond) 1999;96(1):33-39.
218. Nagaya N, Kyotani S, Uematsu M, Ueno K, Oya H, Nakanishi N, et al. Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Circulation 2004;109(3):351-356.
219. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984;70(4):580-587.
220. Frank H, Mlczoch J, Huber K, Schuster E, Gurtner HP, Kneussl M. The effect of anticoagulant therapy in primary and anorectic druginduced pulmonary hypertension. Chest 1997;112(3):714-721.
221. Rich S, Kaufmann E, Levy PS. The effect of high doses of calciumchannel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327(2):76-81.
222. Montani D, Savale L, Natali D, Jais X, Herve P, Garcia G, et al. Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J 2010;31(15):1898-1907.
223. Guilluy C, Eddahibi S, Agard C, Guignabert C, Izikki M, Tu L, et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med 2009; 179(12):1151-1158.
224. Oka M, Homma N, Taraseviciene-Stewart L, Morris KG, Kraskauskas D, Burns N, et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007;100(6):923-929.
225. McNamara PJ, Murthy P, Kantores C, Teixeira L, Engelberts D, van Vliet T, et al. Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide. Am J Physiol Lung Cell Mol Physiol 2008;294(2):L205-L213.
226. Fujita H, Fukumoto Y, Saji K, Sugimura K, Demachi J, Nawata J, et al. Acute vasodilator effects of inhaled fasudil, a specific Rhokinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels 2010;25(2):144-149.
227. Li F, Xia W, Yuan S, Sun R. Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease. Pediatr Cardiol 2009;30(3):363-366.
228. Ishikura K, Yamada N, Ito M, Ota S, Nakamura M, Isaka N, et al. Beneficial acute effects of rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J 2006;70(2):174-178.
229. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005;91(3): 391-392.
230. Nagendran J, Sutendra G, Haromy A, Fu DZ, Ross DB, Rebeyka IM, et al. Endothelin receptor inhibitors decrease contractility in the hypertrophied right ventricle (abstract). Am J Respir Crit Care Med 2007;179:A4141.
231. Yerebakan C, Klopsch C, Niefeldt S, Zeisig V, Vollmar B, Liebold A, et al. Acute and chronic response of the right ventricle to surgically induced pressure and volume overload: an analysis of pressure- volume relations. Interact Cardiovasc Thorac Surg 2010;10(4): 519-525.
232. de Vroomen M, Cardozo RH, Steendijk P, van Bel F, Baan J. Improved contractile performance of right ventricle in response to increased RV afterload in newborn lamb. Am J Physiol Heart Circ Physiol 2000;278(1):H100-H105.
233. Hopkins WE, Waggoner AD. Severe pulmonary hypertension without right ventricular failure: the unique hearts of patients with Eisenmenger syndrome. Am J Cardiol 2002;89(1):34-38.
234. Watts JA, Marchick MR, Kline JA. Right ventricular heart failure from pulmonary embolism: key distinctions from chronic pulmonary hypertension. J Card Fail 2010;16(3):250-259.
235. Belenkie I, Dani R, Smith ER, Tyberg JV. Ventricular interaction during experimental acute pulmonary embolism. Circulation 1988; 78(3):761-768.
236. Gan CT, Lankhaar JW, Marcus JT, Westerhof N, Marques KM, Bronzwaer JG, et al. Impaired left ventricular filling due to rightto- left ventricular interaction in patients with pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 2006;290(4):H1528-1533.
237. Belenkie I, Horne SG, Dani R, Smith ER, Tyberg JV. Effects of aortic constriction during experimental acute right ventricular pres- sure loading. Further insights into diastolic and systolic ventricular interaction. Circulation 1995;92(3):546-554.
238. Yamaguchi S, Harasawa H, Li KS, Zhu D, Santamore WP. Comparative significance in systolic ventricular interaction. Cardiovasc Res 1991;25(9):774-783.
239. Santamore WP, Dell'Italia LJ. Ventricular interdependence: significant left ventricular contributions to right ventricular systolic function. Prog Cardiovasc Dis 1998;40(4):289-308.
240. Chockalingam A, Mehra A, Dorairajan S, Dellsperger KC. Acute left ventricular dysfunction in the critically ill. Chest 2010;138(1): 198-207.
241. Lepore JJ, Maroo A, Bigatello LM, Dec GW, Zapol WM, Bloch KD, et al. Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. Chest 2005;127(5):1647-1653.
242. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 2007;116(14):1555-1562.
243. Mathru M, Venus B, Smith RA, Shirakawa Y, Sugiura A. Treatment of low cardiac output complicating acute pulmonary hypertension in normovolemic goats. Crit Care Med 1986;14(2):120-124.
244. Molloy WD, Lee KY, Girling L, Schick U, Prewitt RM. Treatment of shock in a canine model of pulmonary embolism. Am Rev Respir Dis 1984;130(5):870-874.
245. Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology 1984;60(2):132-135.
246. Belenkie I, Dani R, Smith ER, Tyberg JV. Effects of volume loading during experimental acute pulmonary embolism. Circulation 1989;80(1):178-188.
247. Mercat A, Diehl JL, Meyer G, Teboul JL, Sors H. Hemodynamic effects of fluid loading in acute massive pulmonary embolism. Crit Care Med 1999;27(3):540-544.
248. Siva A, Shah AM. Moderate mitral stenosis in pregnancy: the haemodynamic impact of diuresis. Heart 2005;91(1):e3.
249. Ducas J, Prewitt RM. Pathophysiology and therapy of right ventricular dysfunction due to pulmonary embolism. Cardiovasc Clin 1987;17(2):191-202.
250. Holloway EL, Polumbo RA, Harrison DC. Acute circulatory effects of dopamine in patients with pulmonary hypertension. Br Heart J 1975;37(5):482-485.
251. Liet JM, Boscher C, Gras-Leguen C, Gournay V, Debillon T, Roze JC. Dopamine effects on pulmonary artery pressure in hypotensive preterm infants with patent ductus arteriosus. J Pediatr 2002;140(3): 373-375.
252. Barrington KJ, Finer NN, Chan WK. A blind, randomized comparison of the circulatory effects of dopamine and epinephrine infusions in the newborn piglet during normoxia and hypoxia. Crit Care Med 1995;23(4):740-748.
253. Leier CV, Heban PT, Huss P, Bush CA, Lewis RP. Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure. Circulation 1978;58(3 Pt 1):466-475.
254. Acosta F, Sansano T, Palenciano CG, Falcon L, Domenech P, Robles R, et al. Effects of dobutamine on right ventricular function and pulmonary circulation in pulmonary hypertension during liver transplantation. Transplant Proc 2005;37(9):3869-3870.
255. Ferrario M, Poli A, Previtali M, Lanzarini L, Fetiveau R, Diotallevi P, et al. Hemodynamics of volume loading compared with dobutamine in severe right ventricular infarction. Am J Cardiol 1994; 74(4):329-333.
256. Kihara S, Kawai A, Fukuda T, Yamamoto N, Aomi S, Nishida H, et al. Effects of milrinone for right ventricular failure after left ventricular assist device implantation. Heart Vessels 2002;16(2): 69-71.
257. Fukazawa K, Poliac LC, Pretto EA. Rapid assessment and safe management of severe pulmonary hypertension with milrinone during orthotopic liver transplantation. Clin Transplant 2010;24(4): 515-519.
258. Eichhorn EJ, Konstam MA, Weiland DS, Roberts DJ, Martin TT, Stransky NB, et al. Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1987;60(16):1329-1333.
259. Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation 2000;102(18):2222-2227.
260. Russ MA, Prondzinsky R, Carter JM, Schlitt A, Ebelt H, Schmidt H, et al. Right ventricular function in myocardial infarction complicated by cardiogenic shock: improvement with levosimendan. Crit Care Med 2009;37(12):3017-3023.
261. Poelzl G, Zwick RH, Grander W, Metzler B, Jonetzko P, Frick M, et al. Safety and effectiveness of levosimendan in patients with predominant right heart failure. Herz 2008;33(5):368-373.
262. Cicekcioglu F, Parlar AI, Ersoy O, Yay K, Hijazi A, Katircioglu SF. Levosimendan and severe pulmonary hypertension during open heart surgery. Gen Thorac Cardiovasc Surg 2008;56(11):563-565.
263. Kleber FX, Bollmann T, Borst MM, Costard-Jackle A, Ewert R, Kivikko M, et al. Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study. J Clin Pharmacol 2009;49(1): 109-115.
264. Kerbaul F, Rondelet B, Motte S, Fesler P, Hubloue I, Ewalenko P, et al. Effects of norepinephrine and dobutamine on pressure loadinduced right ventricular failure. Crit Care Med 2004;32(4):1035-1040.
265. Hirsch LJ, Rooney MW, Wat SS, Kleinmann B, Mathru M. Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism. Chest 1991;100(3): 796-801.
266. Tourneux P, Rakza T, Bouissou A, Krim G, Storme L. Pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension. J Pediatr 2008;153(3):345-349.
267. Kwak YL, Lee CS, Park YH, Hong YW. The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension*. Anaesthesia 2002;57(1):9-14.
268. Vlahakes GJ, Turley K, Hoffman JI. The pathophysiology of failure in acute right ventricular hypertension: hemodynamic and biochemical correlations. Circulation 1981;63(1):87-95.
269. Tayama E, Ueda T, Shojima T, Akasu K, Oda T, Fukunaga S, et al. Arginine vasopressin is an ideal drug after cardiac surgery for the management of low systemic vascular resistant hypotension concomitant with pulmonary hypertension. Interact Cardiovasc Thorac Surg 2007;6(6):715-719.
270. Jeon Y, Ryu JH, Lim YJ, Kim CS, Bahk JH, Yoon SZ, et al. Comparative hemodynamic effects of vasopressin and norepinephrine after milrinone-induced hypotension in off-pump coronary artery bypass surgical patients. Eur J Cardiothorac Surg 2006;29(6): 952-956.
271. Smith AM, Elliot CM, Kiely DG, Channer KS. The role of vasopressin in cardiorespiratory arrest and pulmonary hypertension. QJM 2006;99(3):127-133.
272. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358(9):877-887.
273. Walker BR, Haynes J Jr, Wang HL, Voelkel NF. Vasopressininduced pulmonary vasodilation in rats. Am J Physiol 1989;257(2 Pt 2):H415-422.
274. Eichinger MR, Walker BR. Enhanced pulmonary arterial dilation to arginine vasopressin in chronically hypoxic rats. Am J Physiol 1994;267(6 Pt 2):H2413-2419.
275. Rich S, Lam W. Atrial septostomy as palliative therapy for refractory primary pulmonary hypertension. Am J Cardiol 1983;51(9): 1560-1561.
276. Mullins CE, Nihill MR, Vick GW, 3rd, Ludomirsky A, O'Laughlin MP, Bricker JT, et al. Double balloon technique for dilation of valvular or vessel stenosis in congenital and acquired heart disease. J Am Coll Cardiol 1987;10(1):107-114.
277. Hausknecht MJ, Sims RE, Nihill MR, Cashion WR. Successful palliation of primary pulmonary hypertension by atrial septostomy. Am J Cardiol 1990;65(15):1045-1046.
278. Kerstein D, Levy PS, Hsu DT, Hordof AJ, Gersony WM, Barst RJ. Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation 1995;91(7):2028-2035.
279. Sandoval J, Gaspar J, Pulido T, Bautista E, Martinez-Guerra ML, Zeballos M, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol 1998;32(2):297-304.
280. Barst RJ. Role of atrial septostomy in the treatment of pulmonary vascular disease. Thorax 2000;55(2):95-96.
281. Labombarda F, Maragnes P, Dupont-Chauvet P, Serraf A. Potts anastomosis for children with idiopathic pulmonary hypertension. Pediatr Cardiol 2009;30(8):1143-1145.
282. Hoffman JI. Natural history of congenital heart disease. Problems in its assessment with special reference to ventricular septal defects. Circulation 1968;37(1):97-125.
283. Hanley FL, Heinemann MK, Jonas RA, Mayer JE Jr, Cook NR, Wessel DL, et al. Repair of truncus arteriosus in the neonate. J Thorac Cardiovasc Surg 1993;105(6):1047-1056.
284. Kolosionek E, Crosby A, Harhay MO, Morrell N, Butrous G. Pulmonary vascular disease associated with schistosomiasis. Expert Rev Anti Infect Ther 2010;8(12):1467-1473.
285. Cicalini S, Almodovar S, Grilli E, Flores S. Pulmonary hypertension and human immunodeficiency virus infection: epidemiology, pathogenesis, and clinical approach. Clin Microbiol Infect 2011; 17(1):25-33.
286. Bandara M, Gordon FD, Sarwar A, Knauft ME, Pomfret EA, Freeman RB, et al. Successful outcomes following living donor liver transplantation for portopulmonary hypertension. Liver Transpl 2010;16(8):983-989.
287. Saleemi S. Portopulmonary hypertension. Ann Thorac Med 2010; 5(1):5-9.
288. Traynor AE, Corbridge TC, Eagan AE, Barr WG, Liu Q, Oyama Y, et al. Prevalence and reversibility of pulmonary dysfunction in refractory systemic lupus: improvement correlates with disease remission following hematopoietic stem cell transplantation. Chest 2005;127(5):1680-1689.
289. Kamata Y, Nara H, Sato H, Masuyama JI, Minota S, Yoshio T. Effect of steroid pulse therapy on mixed connective tissue disease with pulmonary arterial hypertension. Ann Rheum Dis 2005;64(8): 1236-1237.
290. Jouve P, Humbert M, Chauveheid MP, Jais X, Papo T. POEMS syndrome-related pulmonary hypertension is steroid-responsive. Respir Med 2007;101(2):353-355.
291. Benyounes B, Crestani B, Couvelard A, Vissuzaine C, Aubier M. Steroid-responsive pulmonary hypertension in a patient with Langerhans' cell granulomatosis (histiocytosis X). Chest 1996;110(1): 284-286.
292. Rodman DM, Lindenfeld J. Successful treatment of sarcoidosisassociated pulmonary hypertension with corticosteroids. Chest 1990; 97(2):500-502.
293. Adatia I, Shekerdemian L. The role of calcium channel blockers, steroids, anticoagulation, antiplatelet drugs, and endothelin receptor antagonists. Pediatr Crit Care Med 2010;11(2 Suppl):S46-S52.
294. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376(9757):2018-2031.
295. Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr ClinNorth Am 2009;56(3):579-600, Table of Contents.
296. Gozal D, Kheirandish-Gozal L, Serpero LD, Sans Capdevila O, Dayyat E. Obstructive sleep apnea and endothelial function in schoolagednonobese children: effect of adenotonsillectomy. Circulation 2007;116(20):2307-2314.
297. Yilmaz MD, Onrat E, Altuntas A, Kaya D, Kahveci OK, Ozel O, etal. The effects of tonsillectomy and adenoidectomy on pulmonaryarterial pressure in children. Am J Otolaryngol 2005;26(1):18-21.
298. Mucklow ES. Obstructive sleep apnoea causing severe pulmonaryhypertension reversed by emergency tonsillectomy. Br J Clin Pract 1989;43(7):260-263.
299. Penaloza D, Arias-Stella J. The heart and pulmonary circulation athigh altitudes: healthy highlanders and chronic mountain sickness. Circulation 2007;115(9):1132-1146.
300. Munhoz AS, Adde FV, Nakaie CM, Doria Filho U, Silva Filho LV, Rodrigues JC. Long-term home oxygen therapy in children andadolescents: analysis of clinical use and costs of a home care program. J Pediatr (Rio J) 2011;87(1):13-18.
301. Ohashi N, Matsushima M, Maeda M, Yamaki S. Advantages of oxygen inhalation therapy for postoperative pulmonary hypertension. Pediatr Cardiol 2005;26(1):90-92.
302. Marvisi M, Zambrelli P, Brianti M, Civardi G, Lampugnani R, Delsignore R. Pulmonary hypertension is frequent in hyperthyroidism and normalizes after therapy. Eur J Intern Med 2006;17(4): 267-271.
303. Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010;182(9):1171-1177.
304. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006;5(10):835-844.
305. Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Nikolova S, et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 2008;118(20): 2081-2090.
306. Altieri DC. Survivin and IAP proteins in cell-death mechanisms. Biochem J 2010;430(2):199-205.
307. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005;115(6):1479-1491.
308. Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res 2005;97(12):1232-1235.
309. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 2002;106(1):57-62.
310. Ongini E, Impagnatiello F, Bonazzi A, Guzzetta M, Govoni M, Monopoli A, et al. Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced antiproliferative and antiinflammatory properties. Proc Natl Acad Sci USA 2004;101(22):8497-8502.
311. Girgis RE, Li D, Zhan X, Garcia JG, Tuder RM, Hassoun PM, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 2003;285(3):H938-945.
312. Girgis RE, Mozammel S, Champion HC, Li D, Peng X, Shimoda L, et al. Regression of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol 2007;292(5): L1105-L1110.
313. Nishimura T, Vaszar LT, Faul JL, Zhao G, Berry GJ, Shi L, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 2003;108(13):1640-1645.
314. Nishimura T, Faul JL, Berry GJ, Vaszar LT, Qiu D, Pearl RG, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 2002; 166(10):1403-1408.
315. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Cool C, Wood K, Tuder RM, et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2006;291(4):L668-L76.
316. Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest 2005;127(4):1446-1452.
317. Lee TM, Chen CC, Shen HN, Chang NC. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci (Lond) 2009;116(6): 497-505.
318. Wilkins MR, Ali O, Bradlow W, Wharton J, Taegtmeyer A, Rhodes CJ, et al. Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med 2010;181(10):1106-1113.
319. King WT, Day RW. Treatment of pediatric pulmonary hypertension with simvastatin: an observational study. Pediatr Pulmonol 2010.
320. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 2000;405(6785):421-424.
321. Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 2003;92(10):1162-1169.
322. Falcetti E, Hall SM, Phillips PG, Patel J, Morrell NW, Haworth SG, et al. Smooth muscle proliferation and role of the prostacyclin (IP) receptor in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2010;182(9):1161-1170.
323. Hansmann G, Wagner RA, Schellong S, Perez VA, Urashima T, Wang L, et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor- gamma activation. Circulation 2007;115(10):1275-1284.
324. Wakino S, Hayashi K, Tatematsu S, Hasegawa K, Takamatsu I, Kanda T, et al. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens Res 2005;28(3):255-262.
325. Delerive P, Martin-Nizard F, Chinetti G, Trottein F, Fruchart JC, Najib J, et al. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 1999;85(5):394-402.
326. Subbaramaiah K, Lin DT, Hart JC, Dannenberg AJ. Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300. J Biol Chem 2001;276(15):12440-12448.
327. Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 2003;23(1):52-57.
328. Polikandriotis JA, Mazzella LJ, Rupnow HL, Hart CM. Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferatoractivated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol 2005;25(9):1810-1816.
329. Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, et al. An antiproliferative BMP-2/PPARgamma/ apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 2008;118(5):1846-1857.
330. Hansmann G, Zamanian RT. PPARgamma activation: a potential treatment for pulmonary hypertension. Sci Transl Med 2009;1(12):12ps14.
331. Lu X, Murphy TC, Nanes MS, Hart CM. PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol 2010;299(4):L559-566.
332. Matsuda Y, Hoshikawa Y, Ameshima S, Suzuki S, Okada Y, Tabata T, et al. [Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats]. Nihon Kokyuki Gakkai Zasshi 2005;43(5):283-288. Article in Japanese.
333. Crossno JT Jr, Morris KG Jr, Klemm DJ. Attenuation of hypoxiainduced pulmonary artery remodeling by a peroxisome proliferatoractivated receptor-gamma agonist. Chest 2005;128(6 Suppl):580S.
334. Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, Sutliff RL, et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 2010;42(4):482-490.
335. Kim EK, Lee JH, Oh YM, Lee YS, Lee SD. Rosiglitazone attenuates hypoxia-induced pulmonary arterial hypertension in rats. Respirology 2010;15(4):659-668.
336. Yuan XJ, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K_ channel gene transcription in primary pulmonary hypertension. Lancet 1998;351(9104):726-727.
337. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 2007;104(27):11418-11423.
338. Paulin R, Courboulin A, Meloche J, Mainguy V, Dumas de la Roque E, Saksouk N, et al. Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension. Circulation 2011;123(11): 1205-1215.
339. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000;6(6):698-702.
340. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 2005;112(3):423-431.
341. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 2006;117(5): 1519-1531.
342. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004;95(8):830-840.
343. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 2002;105(2):244-250.
344. Huddleston CB. Lung transplantation for pulmonary hypertension in children. Pediatr Crit Care Med 2010;11(2 Suppl):S53-S56.
345. Aurora P, Edwards LB, Kucheryavaya AY, Christie JD, Dobbels F, Kirk R, et al. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official pediatric lung and heart-lung transplantation report, 2010. J Heart Lung Transplant 2010;29(10):1129-1141.
346. Clabby ML, Canter CE, Moller JH, Bridges ND. Hemodynamic data and survival in children with pulmonary hypertension. J Am Coll Cardiol 1997;30(2):554-560.
347. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 2009;297(6):L1013-L1032.