Pulmonary arterial hypertension: Challenges in translational research and a vision for change

Science Translational Medicine

Volumn 5, Issue 208, 2013, Pages

  Sutendra, Gopinath ^a   Michelakis, Evangelos D ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANASTROZOLE; APELIN; ATORVASTATIN; BOSENTAN; CARBON MONOXIDE; DICHLOROACETIC ACID; ENDOTHELIN RECEPTOR ANTAGONIST; ESCITALOPRAM; FLUOXETINE; HYDROXYUREA; IMMUNOSUPPRESSIVE AGENT; PHOSPHODIESTERASE V INHIBITOR; PIOGLITAZONE; PRASTERONE; PROSTACYCLIN; PROTEIN TYROSINE KINASE INHIBITOR; PRX 08066; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; RITUXIMAB; ROSUVASTATIN; SEROTONIN; SEROTONIN 2 ANTAGONIST; SILDENAFIL; SIMVASTATIN; SORAFENIB; TACROLIMUS; UNCLASSIFIED DRUG;

CAUSAL ATTRIBUTION; DISEASE COURSE; DRUG APPROVAL; DRUG COST; DRUG EFFICACY; DRUG RESPONSE; DRUG TARGETING; DRUG TREATMENT FAILURE; GLUCOSE OXIDATION; HEART LUNG TRANSPLANTATION; HEART RIGHT VENTRICLE FUNCTION; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; INFLAMMATION; LUNG ARTERY PRESSURE; LUNG BLOOD VESSEL; LUNG CIRCULATION; MEAN ARTERIAL PRESSURE; METABOLIC DISORDER; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRACTICE GUIDELINE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REVIEW; STEM CELL TRANSPLANTATION; SURVIVAL RATE; TREATMENT DURATION; TREATMENT INDICATION; VASCULAR RESISTANCE; VASOCONSTRICTION;

ANIMALS; HUMANS; HYPERTENSION, PULMONARY; PHYSICIANS; RESEARCH PERSONNEL; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84886437293     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3005428     Document Type: Review

References (139)

1. A. J. Peacock, N. F. Murphy, J. J. McMurray, L. Caballero, S. Stewart, An epidemiological study of pulmonary arterial hypertension. Eur. Respir. J. 30, 104-109 (2007).
2. V. V. McLaughlin, S. L. Archer, D. B. Badesch, R. J. Barst, H. W. Farber, J. R. Lindner, M. A. Mathier, M. D. McGoon, M. H. Park, R. S. Rosenson, L. J. Rubin, V. F. Tapson, J. Varga, R. A. Harrington, J. L. Anderson, E. R. Bates, C. R. Bridges, M. J. Eisenberg, V. A. Ferrari, C. L. Grines, M. A. Hlatky, A. K. Jacobs, S. Kaul, R. C. Lichtenberg, D. J. Moliterno, D. Mukherjee, G. M. Pohost, R. S. Schofield, S. J. Shubrooks, J. H. Stein, C. M. Tracy, H. H. Weitz, D. J. Wesley; ACCF/AHA, ACCF/AHA 2009 expert consensus document on pulmonary hypertension: A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 119, 2250-2294 (2009).
3. O. Sitbon, C. Lascoux-Combe, J. F. Delfraissy, P. G. Yeni, F. Raffi, D. De Zuttere, V. Gressin, P. Clerson, D. Sereni, G. Simonneau, Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am. J. Respir. Crit. Care Med. 177, 108-113 (2008).
4. E. Hachulla, V. Gressin, L. Guillevin, P. Carpentier, E. Diot, J. Sibilia, A. Kahan, J. Cabane, C. Francès, D. Launay, L. Mouthon, Y. Allanore, K. P. Tiev, P. Clerson, P. de Groote, M. Humbert, Early detection of pulmonary arterial hypertension in systemic sclerosis: A French nationwide prospective multicenter study. Arthritis Rheum. 52, 3792-3800 (2005).
5. F. Haddad, R. Doyle, D. J. Murphy, S. A. Hunt, Right ventricular function in cardiovascular disease, part II: Pathophysiology, clinical importance, and management of right ventricular failure. Circulation 117, 1717-1731 (2008).
6. G. Simonneau, I. M. Robbins, M. Beghetti, R. N. Channick, M. Delcroix, C. P. Denton, C. G. Elliott, S. P. Gaine, M. T. Gladwin, Z. C. Jing, M. J. Krowka, D. Langleben, N. Nakanishi, R. Souza, Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S43-S54 (2009).
7. G. E. D 'Alonzo, R. J. Barst, S. M. Ayres, E. H. Bergofsky, B. H. Brundage, K. M. Detre, A. P. Fishman, R. M. Goldring, B. M. Groves, J. T. Kernis, P. S. Levy, G. G. Pietra, L. M. Reid, J. T. Reeves, S. Rich, C. E. Vreim, G. W. Williams, M. Wu, Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann. Intern. Med. 115, 343-349 (1991).
8. R. L. Benza, D. P. Miller, R. J. Barst, D. B. Badesch, A. E. Frost, M. D. McGoon, An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 142, 448-456 (2012).
9. A. Macchia, R. Marchioli, G. Tognoni, M. Scarano, R. Marfisi, L. Tavazzi, S. Rich, Systematic review of trials using vasodilators in pulmonary arterial hypertension: Why a new approach is needed. Am. Heart J. 159, 245-257 (2010).
10. A. Macchia, R. Marchioli, R. Marfisi, M. Scarano, G. Levantesi, L. Tavazzi, G. Tognoni, A meta-analysis of trials of pulmonary hypertension: A clinical condition looking for drugs and research methodology. Am. Heart J. 153, 1037-1047 (2007).
11. Y. F. Chen, S. Jowett, P. Barton, K. Malottki, C. Hyde, J. S. Gibbs, J. Pepke-Zaba, A. Fry-Smith, J. Roberts, D. Moore, Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: A systematic review and economic evaluation. Health Technol. Assess. 13, 1-320 (2009).
12. M. Angalakuditi, E. Edgell, A. Beardsworth, E. Buysman, T. Bancroft, Treatment patterns and resource utilization and costs among patients with pulmonary arterial hypertension in the United States. J. Med. Econ. 13, 393-402 (2010).
13. R. Copher, A. Cerulli, A. Watkins, M. Laura Monsalvo, Treatment patterns and healthcare system burden of managed care patients with suspected pulmonary arterial hypertension in the United States. J. Med. Econ. 15, 947-955 (2012).
14. A. Giaid, M. Yanagisawa, D. Langleben, R. P. Michel, R. Levy, H. Shennib, S. Kimura, T. Masaki, W. P. Duguid, D. J. Stewart, Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 328, 1732-1739 (1993).
15. A. Giaid, D. Saleh, Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 333, 214-221 (1995).
16. R. J. Barst, L. J. Rubin, W. A. Long, M. D. McGoon, S. Rich, D. B. Badesch, B. M. Groves, V. F. Tapson, R. C. Bourge, B. H. Brundage, S. K. Koerner, D. Langleben, C. A. Keller, S. Murali, B. F. Uretsky, L. M. Clayton, M. M. Jöbsis, S. D. Blackburn, D. Shortino, J. W. Crow; Primary Pulmonary Hypertension Study Group, A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N. Engl. J. Med. 334, 296-301 (1996).
17. L. J. Rubin, D. B. Badesch, R. J. Barst, N. Galie, C. M. Black, A. Keogh, T. Pulido, A. Frost, S. Roux, I. Leconte, M. Landzberg, G. Simonneau, Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346, 896-903 (2002).
18. S. L. Archer, E. K. Weir, M. R. Wilkins, Basic science of pulmonary arterial hypertension for clinicians: New concepts and experimental therapies. Circulation 121, 2045-2066 (2010).
19. E. D. Michelakis, M. R. Wilkins, M. Rabinovitch, Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation 118, 1486-1495 (2008).
20. N. Galiè, H. A. Ghofrani, A. Torbicki, R. J. Barst, L. J. Rubin, D. Badesch, T. Fleming, T. Parpia, G. Burgess, A. Branzi, F. Grimminger, M. Kurzyna, G. Simonneau; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group, Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med. 353, 2148-2157 (2005).
21. R. M. Califf, K. F. Adams, W. J. McKenna, M. Gheorghiade, B. F. Uretsky, S. E. McNulty, H. Darius, K. Schulman, F. Zannad, E. Handberg-Thurmond, F. E. Harrell Jr., W. Wheeler, J. Soler-Soler, K. Swedberg, A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am. Heart J. 134, 44-54 (1997).
22. P. R. Kalra, J. C. Moon, A. J. Coats, Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for nonselective endothelin antagonism in heart failure? Int. J. Cardiol. 85, 195-197 (2002).
23. P. Mylona, J. G. Cleland, Update of REACH-1 and MERIT-HF clinical trials in heart failure. Cardio.net Editorial Team. Eur. J. Heart Fail. 1, 197-200 (1999).
24. R. D. Machado, M. W. Pauciulo, J. R. Thomson, K. B. Lane, N. V. Morgan, L. Wheeler, J. A. Phillips III, J. Newman, D. Williams, N. Galiè, A. Manes, K. McNeil, M. Yacoub, G. Mikhail, P. Rogers, P. Corris, M. Humbert, D. Donnai, G. Martensson, L. Tranebjaerg, J. E. Loyd, R. C. Trembath, W. C. Nichols, BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am. J. Hum. Genet. 68, 92-102 (2001).
25. J. H. Newman, L. Wheeler, K. B. Lane, E. Loyd, R. Gaddipati, J. A. Phillips III, J. E. Loyd, 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. 345, 319-324 (2001).
26. M. Rabinovitch, Molecular pathogenesis of pulmonary arterial hypertension. J. Clin. Invest. 122, 4306-4313 (2012).
27. + channel gene transcription in primary pulmonary hypertension. Lancet 351, 726-727 (1998).
28. S. Eddahibi, N. Hanoun, L. Lanfumey, K. P. Lesch, B. Raffestin, M. Hamon, S. Adnot, Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J. Clin. Invest. 105, 1555-1562 (2000).
29. C. Guignabert, M. Izikki, L. I. Tu, Z. Li, P. Zadigue, A. M. Barlier-Mur, N. Hanoun, D. Rodman, M. Hamon, S. Adnot, S. Eddahibi, Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ. Res. 98, 1323-1330 (2006).
30. V. Petkov, W. Mosgoeller, R. Ziesche, M. Raderer, L. Stiebellehner, K. Vonbank, G. C. Funk, G. Hamilton, C. Novotny, B. Burian, L. H. Block, Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J. Clin. Invest. 111, 1339-1346 (2003).
31. M. S. McMurtry, S. L. Archer, D. C. Altieri, S. Bonnet, A. Haromy, G. Harry, S. Bonnet, L. Puttagunta, E. D. Michelakis, Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J. Clin. Invest. 115, 1479-1491 (2005).
32. X. Li, X. Zhang, R. Leathers, A. Makino, C. Huang, P. Parsa, J. Macias, J. X. Yuan, S. W. Jamieson, P. A. Thistlethwaite, Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat. Med. 15, 1289-1297 (2009).
33. R. T. Schermuly, E. Dony, H. A. Ghofrani, S. Pullamsetti, R. Savai, M. Roth, A. Sydykov, Y. J. Lai, N. Weissmann, W. Seeger, F. Grimminger, Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115, 2811-2821 (2005).
34. K. N. Cowan, A. Heilbut, T. Humpl, C. Lam, S. Ito, M. Rabinovitch, Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat. Med. 6, 698-702 (2000).
35. M. S. McMurtry, S. Bonnet, X. Wu, J. R. Dyck, A. Haromy, K. Hashimoto, E. D. Michelakis, Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 95, 830-840 (2004).
36. E. D. Michelakis, M. S. McMurtry, X. C. Wu, J. R. Dyck, R. Moudgil, T. A. Hopkins, G. D. Lopaschuk, L. Puttagunta, R. Waite, S. L. Archer, 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 105, 244-250 (2002).
37. G. Sutendra, S. Bonnet, G. Rochefort, A. Haromy, K. D. Folmes, G. D. Lopaschuk, J. R. Dyck, E. D. Michelakis, Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci. Transl. Med. 2, 44ra58 (2010).
38. G. Sutendra, P. Dromparis, P. Wright, S. Bonnet, A. Haromy, Z. Hao, M. S. McMurtry, M. Michalak, J. E. Vance, W. C. Sessa, E. D. Michelakis, The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci. Transl. Med. 3, 88ra55 (2011).
39. T. P. Alastalo, M. Li, J. Perez Vde, D. Pham, H. Sawada, J. K. Wang, M. Koskenvuo, L. Wang, B. A. Freeman, H. Y. Chang, M. Rabinovitch, Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J. Clin. Invest. 121, 3735-3746 (2011).
40. S. Bonnet, G. Rochefort, G. Sutendra, S. L. Archer, A. Haromy, L. Webster, K. Hashimoto, S. N. Bonnet, E. D. Michelakis, The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc. Natl. Acad. Sci. U.S.A. 104, 11418-11423 (2007).
41. S. Bonnet, E. D. Michelakis, C. J. Porter, M. A. Andrade-Navarro, B. Thébaud, S. Bonnet, A. Haromy, G. Harry, R. Moudgil, M. S. McMurtry, E. K. Weir, S. L. Archer, An abnormal mitochondrial-hypoxia inducible factor-1α-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. Circulation 113, 2630-2641 (2006).
42. G. Hansmann, R. A. Wagner, S. Schellong, V. A. Perez, T. Urashima, L. Wang, A. Y. Sheikh, R. S. Suen, D. J. Stewart, M. Rabinovitch, Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-γ activation. Circulation 115, 1275-1284 (2007).
43. R. Paulin, A. Courboulin, J. Meloche, V. Mainguy, E. Dumas de la Roque, N. Saksouk, J. Côté, S. Provencher, M. A. Sussman, S. Bonnet, Signal transducers and activators of transcription-3/Pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension. Circulation 123, 1205-1215 (2011).
44. F. A. Masri, W. Xu, S. A. Comhair, K. Asosingh, M. Koo, A. Vasanji, J. Drazba, B. Anand-Apte, S. C. Erzurum, Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L548-L554 (2007).
45. E. K. Weir, J. López-Barneo, K. J. Buckler, S. L. Archer, Acute oxygen-sensing mechanisms. N. Engl. J. Med. 353, 2042-2055 (2005).
46. E. D. Michelakis, V. Hampl, A. Nsair, X. Wu, G. Harry, A. Haromy, R. Gurtu, S. L. Archer, Diversity in mitochondrial function explains differences in vascular oxygen sensing. Circ. Res. 90, 1307-1315 (2002).
47. P. Dromparis, E. D. Michelakis, Mitochondria in vascular health and disease. Annu. Rev. Physiol. 75, 95-126 (2013).
48. M. G. Vander Heiden, L. C. Cantley, C. B. Thompson, Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324, 1029-1033 (2009).
49. W. Xu, T. Koeck, A. R. Lara, D. Neumann, F. P. DiFilippo, M. Koo, A. J. Janocha, F. A. Masri, A. C. Arroliga, C. Jennings, R. A. Dweik, R. M. Tuder, D. J. Stuehr, S. C. Erzurum, Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc. Natl. Acad. Sci. U.S.A. 104, 1342-1347 (2007).
50. J. W. Kim, C. V. Dang, Multifaceted roles of glycolytic enzymes. Trends Biochem. Sci. 30, 142-150 (2005).
51. + channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37-51 (2007).
52. E. D. Michelakis, G. Sutendra, P. Dromparis, L. Webster, A. Haromy, E. Niven, C. Maguire, T. L. Gammer, J. R. Mackey, D. Fulton, B. Abdulkarim, M. S. McMurtry, K. C. Petruk, Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).
53. G. Sutendra, P. Dromparis, S. Bonnet, A. Haromy, M. S. McMurtry, R. C. Bleackley, E. D. Michelakis, Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension. J. Mol. Med. 89, 771-783 (2011).
54. G. Sutendra, P. Dromparis, A. Kinnaird, T. H. Stenson, A. Haromy, J. M. Parker, M. S. McMurtry, E. D. Michelakis, Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. Oncogene 32, 1638-1650 (2013).
55. N. Zamzami, G. Kroemer, The mitochondrion in apoptosis: How Pandora's box opens. Nat. Rev. Mol. Cell Biol. 2, 67-71 (2001).
56. 2-sensor in resistance artery smooth muscle cells. J. Mol. Cell. Cardiol. 37, 1119-1136 (2004).
57. J. G. Pastorino, J. B. Hoek, N. Shulga, Activation of glycogen synthase kinase 3β disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res. 65, 10545-10554 (2005).
58. F. Macian, NFAT proteins: Key regulators of T-cell development and function. Nat. Rev. Immunol. 5, 472-484 (2005).
59. O. Kepp, L. Galluzzi, G. Kroemer, Mitochondrial control of the NLRP3 inflammasome. Nat. Immunol. 12, 199-200 (2011).
60. L. C. Price, S. J. Wort, F. Perros, P. Dorfmüller, A. Huertas, D. Montani, S. Cohen-Kaminsky, M. Humbert, Inflammation in pulmonary arterial hypertension. Chest 141, 210-221 (2012).
61. M. E. Yeager, M. B. Reddy, C. M. Nguyen, K. L. Colvin, D. D. Ivy, K. R. Stenmark, Activation of the unfolded protein response is associated with pulmonary hypertension. Pulm. Circ. 2, 229-240 (2012).
62. R. T. Zamanian, G. Hansmann, S. Snook, D. Lilienfeld, K. M. Rappaport, G. M. Reaven, M. Rabinovitch, R. L. Doyle, Insulin resistance in pulmonary arterial hypertension. Eur. Respir. J. 33, 318-324 (2009).
63. K. Morino, K. F. Petersen, S. Dufour, D. Befroy, J. Frattini, N. Shatzkes, S. Neschen, M. F. White, S. Bilz, S. Sono, M. Pypaert, G. I. Shulman, Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J. Clin. Invest. 115, 3587-3593 (2005).
64. K. F. Petersen, S. Dufour, D. Befroy, R. Garcia, G. I. Shulman, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664-671 (2004).
65. T. Hitosugi, S. Kang, M. G. Vander Heiden, T. W. Chung, S. Elf, K. Lythgoe, S. Dong, S. Lonial, X. Wang, G. Z. Chen, J. Xie, T. L. Gu, R. D. Polakiewicz, J. L. Roesel, T. J. Boggon, F. R. Khuri, D. G. Gilliland, L. C. Cantley, J. Kaufman, J. Chen, Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
66. J. W. Kim, I. Tchernyshyov, G. L. Semenza, C. V. Dang, HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177-185 (2006).
67. C. D. Cool, P. R. Rai, M. E. Yeager, D. Hernandez-Saavedra, A. E. Serls, T. M. Bull, M. W. Geraci, K. K. Brown, J. M. Routes, R. M. Tuder, N. F. Voelkel, Expression of human herpesvirus 8 in primary pulmonary hypertension. N. Engl. J. Med. 349, 1113-1122 (2003).
68. G. S. Hotamisligil, Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900-917 (2010).
69. P. B. Sehgal, S. Mukhopadhyay, K. Patel, F. Xu, S. Almodóvar, R. M. Tuder, S. C. Flores, Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L729-L737 (2009).
70. A. Sobolewski, N. Rudarakanchana, P. D. Upton, J. Yang, T. K. Crilley, R. C. Trembath, N. W. Morrell, Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: Potential for rescue. Hum. Mol. Genet. 17, 3180-3190 (2008).
71. N. F. Voelkel, C. D. Cool, S. Flores, From viral infection to pulmonary arterial hypertension: A role for viral proteins? AIDS 22 (Suppl. 3), S49-S53 (2008).
72. J. J. Ryan, G. Marsboom, Y. H. Fang, P. T. Toth, E. Morrow, N. Luo, L. Piao, Z. Hong, K. Ericson, H. J. Zhang, M. Han, C. R. Haney, C. T. Chen, W. W. Sharp, S. L. Archer, PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 187, 865-878 (2013).
73. M. D. Hirschey, T. Shimazu, E. Jing, C. A. Grueter, A. M. Collins, B. Aouizerat, A. Stančáková, E. Goetzman, M. M. Lam, B. Schwer, R. D. Stevens, M. J. Muehlbauer, S. Kakar, N. M. Bass, J. Kuusisto, M. Laakso, F. W. Alt, C. B. Newgard, R. V. Farese Jr., C. R. Kahn, E. Verdin, SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 44, 177-190 (2011).
74. J. J. Jia, X. Zhang, C. R. Ge, M. Jois, The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes. Obes. Rev. 10, 519-526 (2009).
75. P. Dromparis, R. Paulin, G. Sutendra, A. C. Qi, S. Bonnet, E. D. Michelakis, Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ. Res. 113, 126-136 (2013).
76. E. D. Michelakis, L. Webster, J. R. Mackey, Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer 99, 989-994 (2008).
77. P. Dromparis, R. Paulin, T. H. Stenson, A. Haromy, G. Sutendra, E. D. Michelakis, Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension. Circulation 1, 115-125 (2013).
78. P. Dorfmüller, F. Perros, K. Balabanian, M. Humbert, Inflammation in pulmonary arterial hypertension. Eur. Respir. J. 22, 358-363 (2003).
79. N. F. Voelkel, C. Cool, S. D. Lee, L. Wright, M. W. Geraci, R. M. Tuder, Primary pulmonary hypertension between inflammation and cancer. Chest 114, 225S-230S (1998).
80. E. Stacher, B. B. Graham, J. M. Hunt, A. Gandjeva, S. D. Groshong, V. V. McLaughlin, M. Jessup, W. E. Grizzle, M. A. Aldred, C. D. Cool, R. M. Tuder, Modern age pathology of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 186, 261-272 (2012).
81. V. V. McLaughlin, K. W. Presberg, R. L. Doyle, S. H. Abman, D. C. McCrory, T. Fortin, G. Ahearn; American College of Chest Physicians, Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126, 78S-92S (2004).
82. O. Sanchez, M. Humbert, O. Sitbon, G. Simonneau, Treatment of pulmonary hypertension secondary to connective tissue diseases. Thorax 54, 273-277 (1999).
83. 3C chemokine fractalkine in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 165, 1419-1425 (2002).
84. A. W. Caslin, D. Heath, B. Madden, M. Yacoub, J. R. Gosney, P. Smith, The histopathology of 36 cases of plexogenic pulmonary arteriopathy. Histopathology 16, 9-19 (1990).
85. R. M. Tuder, B. Groves, D. B. Badesch, N. F. Voelkel, Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol. 144, 275-285 (1994).
86. L. Taraseviciene-Stewart, M. R. Nicolls, D. Kraskauskas, R. Scerbavicius, N. Burns, C. Cool, K. Wood, J. E. Parr, S. A. Boackle, N. F. Voelkel, Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am. J. Respir. Crit. Care Med. 175, 1280-1289 (2007).
87. D. Heath, M. Yacoub, Lung mast cells in plexogenic pulmonary arteriopathy. J. Clin. Pathol. 44, 1003-1006 (1991).
88. E. Soon, A. M. Holmes, C. M. Treacy, N. J. Doughty, L. Southgate, R. D. Machado, R. C. Trembath, S. Jennings, L. Barker, P. Nicklin, C. Walker, D. C. Budd, J. Pepke-Zaba, N. W. Morrell, Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122, 920-927 (2010).
89. M. M. Hoeper, T. Welte, Systemic inflammation, COPD, and pulmonary hypertension. Chest 131, 634-635 (2007).
90. E. Daley, C. Emson, C. Guignabert, R. de Waal Malefyt, J. Louten, V. P. Kurup, C. Hogaboam, L. Taraseviciene-Stewart, N. F. Voelkel, M. Rabinovitch, E. Grunig, G. Grunig, Pulmonary arterial remodeling induced by a Th2 immune response. J. Exp. Med. 205, 361-372 (2008).
91. N. F. Voelkel, R. M. Tuder, J. Bridges, W. P. Arend, Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am. J. Respir. Cell Mol. Biol. 11, 664-675 (1994).
92. R. Zhou, A. S. Yazdi, P. Menu, J. Tschopp, A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221-225 (2011).
93. H17 and Treg cells. J. Exp. Med. 208, 1367-1376 (2011).
94. S. Y. Lunt, M. G. Vander Heiden, Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441-464 (2011).
95. S. Lenna, A. G. Farina, V. Martyanov, R. B. Christmann, T. A. Wood, H. W. Farber, R. Scorza, M. L. Whitfield, R. Lafyatis, M. Trojanowska, Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension. Arthritis Rheum. 65, 1357-1366 (2013).
96. S. Banka, W. G. Newman, R. K. Ozgül, A. Dursun, Mutations in the G6PC3 gene cause Dursun syndrome. Am. J. Med. Genet. A 152A, 2609-2611 (2010).
97. A. Dursun, R. K. Ozgul, A. Soydas, T. Tugrul, A. Gurgey, A. Celiker, R. J. Barst, J. A. Knowles, M. Mahesh, J. H. Morse, Familial pulmonary arterial hypertension, leucopenia, and atrial septal defect: A probable new familial syndrome with multisystem involvement. Clin. Dysmorphol. 18, 19-23 (2009).
98. D. Heath, J. E. Edwards, The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18, 533-547 (1958).
99. A. Rothman, D. M. Mann, C. A. Behling, R. G. Konopka, P. G. Chiles, C. A. Pedersen, K. M. Moser, Percutaneous pulmonary endoarterial biopsy in an experimental model of pulmonary hypertension. Chest 114, 241-250 (1998).
100. G. Niu, X. Chen, Apoptosis imaging: Beyond annexin V. J. Nucl. Med. 51, 1659-1662 (2010).
101. F. Haddad, S. A. Hunt, D. N. Rosenthal, D. J. Murphy, Right ventricular function in cardiovascular disease, part I: Anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation 117, 1436-1448 (2008).
102. M. C. van de Veerdonk, T. Kind, J. T. Marcus, G. J. Mauritz, M. W. Heymans, H. J. Bogaard, A. Boonstra, K. M. Marques, N. Westerhof, A. Vonk-Noordegraaf, Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J. Am. Coll. Cardiol. 58, 2511-2519 (2011).
103. B. H. Freed, M. Gomberg-Maitland, S. Chandra, V. Mor-Avi, S. Rich, S. L. Archer, E. B. Jamison Jr., R. M. Lang, A. R. Patel, Late gadolinium enhancement cardiovascular magnetic resonance predicts clinical worsening in patients with pulmonary hypertension. J. Cardiovasc. Magn. Reson. 14, 11 (2012).
104. G. Sutendra, P. Dromparis, R. Paulin, S. Zervopoulos, A. Haromy, J. Nagendran, E. D. Michelakis, A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J. Mol. Med. 10.1007/s00109-013-1059-4 (2013).
105. J. Nagendran, E. Michelakis, MRI: One-stop shop for the comprehensive assessment of pulmonary arterial hypertension? Chest 132, 2-5 (2007).
106. H. C. Champion, E. D. Michelakis, P. M. Hassoun, Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: State of the art and clinical and research implications. Circulation 120, 992-1007 (2009).
107. J. Nagendran, S. L. Archer, D. Soliman, V. Gurtu, R. Moudgil, A. Haromy, C. St Aubin, L. Webster, I. M. Rebeyka, D. B. Ross, P. E. Light, J. R. Dyck, E. D. Michelakis, Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116, 238-248 (2007).
108. J. Nagendran, G. Sutendra, I. Paterson, H. C. Champion, L. Webster, B. Chiu, A. Haromy, I. M. Rebeyka, D. B. Ross, E. D. Michelakis, Endothelin axis is upregulated in human and rat right ventricular hypertrophy. Circ. Res. 112, 347-354 (2013).
109. S. Rich, The 6-minute walk test as a primary endpoint in clinical trials for pulmonary hypertension. J. Am. Coll. Cardiol. 60, 1202-1203 (2012).
110. G. Savarese, S. Paolillo, P. Costanzo, C. D'Amore, M. Cecere, T. Losco, F. Musella, P. Gargiulo, C. Marciano, P. Perrone-Filardi, Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J. Am. Coll. Cardiol. 60, 1192-1201 (2012).
111. L. Chan, L. M. Chin, M. Kennedy, J. Woolstenhulme, S. D. Nathan, A. A. Weinstein, G. Connors, N. Weir, B. Drinkard, J. Lamberti, R. Keyser, Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension. Chest 143, 333-343 (2013).
112. http://www.orpha.net/consor/cgi-bin/index.php
113. C. Printz, BATTLE to personalize lung cancer treatment. Novel clinical trial design and tissue gathering procedures drive biomarker discovery. Cancer 116, 3307-3308 (2010).
114. A. S. Zandvliet, M. O. Karlsson, J. H. Schellens, W. Copalu, J. H. Beijnen, A. D. Huitema, Two-stage model-based clinical trial design to optimize phase I development of novel anticancer agents. Invest. New Drugs 28, 61-75 (2010).
115. E. L. Korn, L. M. McShane, B. Freidlin, Statistical challenges in the evaluation of treatments for small patient populations. Sci. Transl. Med. 5, 178sr3 (2013).
116. M. A. Schroeder, L. E. Cochlin, L. C. Heather, K. Clarke, G. K. Radda, D. J. Tyler, In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc. Natl. Acad. Sci. U.S.A. 105, 12051-12056 (2008).
117. 13C-labeled pyruvate for noninvasive assessment of mitochondrial function. Ann. N. Y. Acad. Sci. 1201, 111-120 (2010).
118. S. Rich, Future of clinical trials for pulmonary hypertension. Circulation 123, 2919-2921 (2011).
119. S. Rich, What is pulmonary arterial hypertension? Pulm. Circ. 2, 271-272 (2012).
120. J. Gomez-Arroyo, S. J. Saleem, S. Mizuno, A. A. Syed, H. J. Bogaard, A. Abbate, L. Taraseviciene-Stewart, Y. Sung, D. Kraskauskas, D. Farkas, D. H. Conrad, M. R. Nicolls, N. F. Voelkel, A brief overview of mouse models of pulmonary arterial hypertension: Problems and prospects. Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L977-L991 (2012).
121. K. R. Stenmark, B. Meyrick, N. Galie, W. J. Mooi, I. F. McMurtry, Animal models of pulmonary arterial hypertension: The hope for etiological discovery and pharmacological cure. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L1013-L1032 (2009).
122. L. Taraseviciene-Stewart, Y. Kasahara, L. Alger, P. Hirth, G. Mc Mahon, J. Waltenberger, N. F. Voelkel, R. M. Tuder, Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 15, 427-438 (2001).
123. R. M. Tuder, M. Chacon, L. Alger, J. Wang, L. Taraseviciene-Stewart, Y. Kasahara, C. D. Cool, A. E. Bishop, M. Geraci, G. L. Semenza, M. Yacoub, J. M. Polak, N. F. Voelkel, Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: Evidence for a process of disordered angiogenesis. J. Pathol. 195, 367-374 (2001).
124. M. Gomberg-Maitland, M. L. Maitland, R. J. Barst, L. Sugeng, S. Coslet, T. J. Perrino, L. Bond, M. E. Lacouture, S. L. Archer, M. J. Ratain, A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin. Pharmacol. Ther. 87, 303-310 (2010).
125. H. A. Ghofrani, N. W. Morrell, M. M. Hoeper, H. Olschewski, A. J. Peacock, R. J. Barst, S. Shapiro, H. Golpon, M. Toshner, F. Grimminger, S. Pascoe, Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am. J. Respir. Crit. Care Med. 182, 1171-1177 (2010).
126. T. D. Le Cras, D. H. Kim, S. Gebb, N. E. Markham, J. M. Shannon, R. M. Tuder, S. H. Abman, Abnormal lung growth and the development of pulmonary hypertension in the Fawn-Hooded rat. Am. J. Physiol. 277, L709-L718 (1999).
127. S. L. Merklinger, R. A. Wagner, E. Spiekerkoetter, A. Hinek, R. H. Knutsen, M. G. Kabir, K. Desai, S. Hacker, L. Wang, G. M. Cann, N. S. Ambartsumian, E. Lukanidin, D. Bernstein, M. Husain, R. P. Mecham, B. Starcher, H. Yanagisawa, M. Rabinovitch, Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension. Circ. Res. 97, 596-604 (2005).
128. H. Beppu, F. Ichinose, N. Kawai, R. C. Jones, P. B. Yu, W. M. Zapol, K. Miyazono, E. Li, K. D. Bloch, BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L1241-L1247 (2004).
129. L. Long, M. R. MacLean, T. K. Jeffery, I. Morecroft, X. Yang, N. Rudarakanchana, M. Southwood, V. James, R. C. Trembath, N. W. Morrell, Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ. Res. 98, 818-827 (2006).
130. Y. Song, J. E. Jones, H. Beppu, J. F. Keaney Jr., J. Loscalzo, Y. Y. Zhang, Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 112, 553-562 (2005).
131. D. Liu, J. Wang, B. Kinzel, M. Müeller, X. Mao, R. Valdez, Y. Liu, E. Li, Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity. Blood 110, 1502-1510 (2007).
132. J. West, J. Harral, K. Lane, Y. Deng, B. Ickes, D. Crona, S. Albu, D. Stewart, K. Fagan, Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L744-L755 (2008).
133. S. L. Archer, E. D. Michelakis, An evidence-based approach to the management of pulmonary arterial hypertension. Curr. Opin. Cardiol. 21, 385-392 (2006).
134. N. F. Voelkel, J. Gomez-Arroyo, A. Abbate, H. J. Bogaard, M. R. Nicolls, Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur. Respir. J. 40, 1555-1565 (2012).
135. E. Braunwald, M. S. Sabatine, The Thrombolysis in Myocardial Infarction (TIMI) Study Group experience. J. Thorac. Cardiovasc. Surg. 144, 762-770 (2012).
136. J. Mendelsohn, A national cancer clinical trials system for targeted therapies. Sci. Transl. Med. 3, 75cm8 (2011).
137. S. J. Nass, E. Balogh, J. Mendelsohn, A National Cancer Clinical Trials Network: Recommendations from the Institute of Medicine. Am. J. Ther. 18, 382-391 (2011).
138. G. Butrous, H. A. Ghofrani, F. Grimminger, Pulmonary vascular disease in the developing world. Circulation 118, 1758-1766 (2008).
139. M. Gomberg-Maitland, E. D. Michelakis, A global pulmonary arterial hypertension registry: Is it needed? Is it feasible? Pulmonary vascular disease: the global perspective. Chest 137, 95S-101S (2010).