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Pulmonary Hypertension: Biomarkers

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Pharmacotherapy of Pulmonary Hypertension

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

Physicians look to biomarkers to inform the management of pulmonary hypertension (PH) at all stages, from assessing susceptibility through screening, diagnosis, and risk stratification to drug selection and monitoring. PH is a heterogeneous disorder and currently there are no accepted blood biomarkers specific to any manifestation of the condition. Brain natriuretic peptide and its N-terminal peptide have been most widely studied. Other candidate prognostic biomarkers in patients with pulmonary arterial hypertension (PAH) include growth and differentiation factor-15, red cell distribution width, uric acid, creatinine, inflammatory markers such as interleukin-6, angiopoietins, and microRNAs. Combining the measurement of biomarkers reflecting different components of the pathology with other modalities may enable better molecular characterisation of PH subtypes and permit improved targeting of therapeutic strategies and disease monitoring.

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References

  • Abdul-Salam VB, Paul GA, Ali JO, Gibbs SR, Rahman D, Taylor GW, Wilkins MR, Edwards RJ (2006) Identification of plasma protein biomarkers associated with idiopathic pulmonary arterial hypertension. Proteomics 6:2286–2294

    Article  PubMed  CAS  Google Scholar 

  • Amabile N, Heiss C, Real WM, Minasi P, McGlothlin D, Rame EJ, Grossman W, De Marco T, Yeghiazarians Y (2008) Circulating endothelial microparticle levels predict hemodynamic severity of pulmonary hypertension. Am J Respir Crit Care Med 177:1268–1275

    Article  PubMed  CAS  Google Scholar 

  • Amabile N, Heiss C, Chang V, Angeli FS, Damon L, Rame EJ, McGlothlin D, Grossman W, De Marco T, Yeghiazarians Y (2009) Increased CD62e+ endothelial microparticle levels predict poor outcome in pulmonary hypertension patients. J Heart Lung Transplant 28:1081–1086

    Article  PubMed  Google Scholar 

  • Amaki M, Nakatani S, Kanzaki H, Kyotani S, Nakanishi N, Shigemasa C, Hisatome I, Kitakaze M (2009) Usefulness of three-dimensional echocardiography in assessing right ventricular function in patients with primary pulmonary hypertension. Hypertens Res 32:419–422

    Article  PubMed  Google Scholar 

  • Asosingh K, Aldred MA, Vasanji A, Drazba J, Sharp J, Farver C, Comhair SA, Xu W, Licina L, Huang L, Anand-Apte B, Yoder MC, Tuder RM, Erzurum SC (2008) Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension. Am J Pathol 172:615–627

    Article  PubMed  CAS  Google Scholar 

  • Atkinson AJ, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth DF, Oates JA, Peck CC, Schooley RT, Spilker BA, Woodcock J, Zeger SL (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95

    Article  Google Scholar 

  • Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177

    Article  PubMed  CAS  Google Scholar 

  • Bendayan D, Shitrit D, Ygla M, Huerta M, Fink G, Kramer MR (2003) Hyperuricemia as a prognostic factor in pulmonary arterial hypertension. Respir Med 97:130–133

    Article  PubMed  CAS  Google Scholar 

  • Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD (2010) Predicting survival in pulmonary arterial hypertension. Circulation 122:164–172

    Article  PubMed  Google Scholar 

  • Benza RL, Gomberg-Maitland M, Miller DP, Frost A, Frantz RP, Foreman AJ, Badesch DB, McGoon MD (2012) The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest 141:354–362

    Article  PubMed  Google Scholar 

  • Bogdan M, Humbert M, Francoual J, Claise C, Duroux P, Simonneau G, Lindenbaum A (1998) Urinary cGMP concentrations in severe primary pulmonary hypertension. Thorax 53:1059–1062

    Article  PubMed  CAS  Google Scholar 

  • Bokhari S, Raina A, Berman Rosenweig E, Schulze PC, Bokhari J, Einstein AJ, Barst RJ, Johnson LL (2011) PET imaging may provide a novel biomarker and understanding of right ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension/clinical perspective. Circ Cardiovasc Imaging 4:641–647

    Article  PubMed  Google Scholar 

  • Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci USA 94:11514–11519

    Article  PubMed  CAS  Google Scholar 

  • Bradlow WM, Gibbs JSR, Mohiaddin RH (2012) Cardiovascular magnetic resonance in pulmonary hypertension. J Cardiovasc Magn Reson 14:6

    Article  PubMed  Google Scholar 

  • Braghiroli A, Sacco C, Erbetta M, Ruga V, Donner CF (1993) Overnight urinary uric acid: creatinine ratio for detection of sleep hypoxemia. Validation study in chronic obstructive pulmonary disease and obstructive sleep apnea before and after treatment with nasal continuous positive airway pressure. Am Rev Respir Dis 148:173–178

    Article  PubMed  CAS  Google Scholar 

  • Brock M, Trenkmann M, Gay RE, Michel BA, Gay S, Fischler M, Ulrich S, Speich R, Huber LC (2009) Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res 104:1184–1191

    Article  PubMed  CAS  Google Scholar 

  • Brock M, Samillan VJ, Trenkmann M, Schwarzwald C, Ulrich S, Gay RE, Gassmann M, Ostergaard L, Gay S, Speich R, Huber LC (2012) AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur Heart J. doi:10.1093/eurheartj/ehs060

  • Cacoub P, Dorent R, Maistre G, Nataf P, Carayon A, Piette C, Godeau P, Cabrol C, Gandjbakhch I (1993) Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 71:448–450

    Article  PubMed  CAS  Google Scholar 

  • Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, MacDonald RA, Greig JA, Robertson KE, Masson R, Denby L, Dempsie Y, Long L, Morrell NW, Baker AH (2010) Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol 30:716–723

    Article  PubMed  CAS  Google Scholar 

  • Chu D, Sullivan CC, Du L, Cho AJ, Kido M, Wolf PL, Weitzman MD, Jamieson SW, Thistlethwaite PA (2004) A new animal model for pulmonary hypertension based on the overexpression of a single gene, angiopoietin-1. Ann Thorac Surg 77:449–456

    Article  PubMed  Google Scholar 

  • Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JS, Vrapi F, Das C, Elliot CA, Johnson M, DeSoyza J, Torpy C, Goldsmith K, Hodgkins D, Hughes RJ, Pepke-Zaba J, Coghlan JG (2009) Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 179:151–157

    Article  PubMed  Google Scholar 

  • Condliffe R, Pickwoth J, Hopkinson K, Walker S, Hameed A, Suntharaligam J, Soon E, Treacy C, Pepke-Zaba J, Francis S, Crossman D, Newman C, Elliot C, Morton A, Morrell N, Lawrie A (2012) Serum osteoprotegerin is increased and predicts survival in idiopathic pulmonary arterial hypertension. Pulm Circ 2:21–27

    Article  PubMed  CAS  Google Scholar 

  • Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Cote J, Simard MJ, Bonnet S (2011) Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 208:535–548

    Article  PubMed  CAS  Google Scholar 

  • Cracowski JL, Cracowski C, Bessard G, Pepin JL, Bessard J, Schwebel C, Stanke-Labesque F, Pison C (2001) Increased lipid peroxidation in patients with pulmonary hypertension. Am J Respir Crit Care Med 164:1038–1042

    Article  PubMed  CAS  Google Scholar 

  • Cracowski JL, Degano B, Chabot F, Labarere J, Schwedhelm E, Monneret D, Iuliano L, Schwebel C, Chaouat A, Reynaud-Gaubert M, Faure P, Maas R, Renversez JC, Cracowski C, Sitbon O, Yaici A, Simonneau G, Humbert M (2012) Independent association of urinary F2-isoprostanes with survival in pulmonary arterial hypertension. Chest DOI. doi:10.1378/chest.11-1267, prepublished online 8 Mar 2012

    Google Scholar 

  • Creemers EE, Tijsen AJ, Pinto YM (2012) Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 110:483–495

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Deboeck G, Coditti C, Uez S, Luc Vachiéry J, Amotte M, Harples L, Elot C, Naeije R (2012) Exercise to predict outcome in idiopathic vs associated pulmonary arterial hypertension. Eur Respir J. doi:10.1183/09031936.00217911, published on 22 Mar 2012

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Diller GP, van Eijl S, Okonko DO, Howard LS, Ali O, Thum T, Wort SJ, Bedard E, Gibbs JS, Bauersachs J, Hobbs AJ, Wilkins MR, Gatzoulis MA, Wharton J (2008) Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 117:3020–3030

    Article  PubMed  CAS  Google Scholar 

  • Diller GP, Thum T, Wilkins MR, Wharton J (2010) Endothelial progenitor cells in pulmonary arterial hypertension. Trends Cardiovasc Med 20:22–29

    Article  PubMed  CAS  Google Scholar 

  • Elias GJ, Ioannis M, Theodora P, Dimitrios PP, Despoina P, Kostantinos V, Charalampos K, Vassilios V, Petros SP (2008) Circulating tissue inhibitor of matrix metalloproteinase-4 (TIMP-4) in systemic sclerosis patients with elevated pulmonary arterial pressure. Mediators Inflamm 2008:164134

    PubMed  Google Scholar 

  • Ferrazza AM, Martolini D, Valli G, Palange P (2009) Cardiopulmonary exercise testing in the functional and prognostic evaluation of patients with pulmonary diseases. Respiration 77:3–17

    Article  PubMed  CAS  Google Scholar 

  • Fessel JP, Loyd JE, Austin ED (2011) The genetics of pulmonary arterial hypertension in the post-BMPR2 era. Pulm Circ 1:305–319

    Article  PubMed  Google Scholar 

  • Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, Szturmowicz M (2006) Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 129:1313–1321

    Article  PubMed  CAS  Google Scholar 

  • Filusch A, Zelniker T, Baumgartner C, Eschricht S, Frey N, Katus HA, Chorianopoulos E (2011) Soluble TWEAK predicts hemodynamic impairment and functional capacity in patients with pulmonary arterial hypertension. Clin Res Cardiol 100:879–885

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157

    Article  PubMed  CAS  Google Scholar 

  • Galië N, Rubin LJ, Hoeper MM, Jansa P, Al-Hiti H, Meyer GMB, Chiossi E, Kusic-Pajic A, Simonneau G (2008) Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371:2093–2100

    Article  PubMed  Google Scholar 

  • Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ, for the Ambrisentan in Pulmonary Arterial Hypertension RD-BP-CMESAG (2008) Ambrisentan for the treatment of pulmonary arterial hypertension. Circulation 117:3010–3019

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 34:1219–1263

    Article  PubMed  CAS  Google Scholar 

  • Ghofrani HA, Wiedemann R, Rose F, Weissmann N, Schermuly RT, Quanz K, Grimminger F, Seeger W, Olschewski H (2002) Lung cGMP release subsequent to NO inhalation in pulmonary hypertension: responders versus nonresponders. Eur Respir J 19:664–671

    Article  PubMed  CAS  Google Scholar 

  • Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X, Tregouet D, Reis A, Drouin-Garraud V, Fraisse A, Sitbon O, O’Callaghan DS, Simonneau G, Soubrier F, Humbert M (2010) Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 181:851–861

    Article  PubMed  CAS  Google Scholar 

  • Girgis RE, Champion HC, Diette GB, Johns RA, Permutt S, Sylvester JT (2005) Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am J Respir Crit Care Med 172:352–357

    Article  PubMed  Google Scholar 

  • Goetze JP, Rehfeld JF, Carlsen J, Videbaek R, Andersen CB, Boesgaard S, Friis-Hansen L (2006) Apelin: a new plasma marker of cardiopulmonary disease. Regul Pept 133:134–138

    Article  PubMed  CAS  Google Scholar 

  • Gorenflo M, Zheng C, Werle E, Fiehn W, Ulmer HE (2001) Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol 37:489–492

    Article  PubMed  CAS  Google Scholar 

  • Grapsa J, Gibbs JS, Cabrita IZ, Watson GF, Pavlopoulos H, Dawson D, Gin-Sing W, Howard LS, Nihoyannopoulos P (2012a) The association of clinical outcome with right atrial and ventricular remodelling in patients with pulmonary arterial hypertension: study with real-time three-dimensional echocardiography. Eur Heart J Cardiovasc Imaging 13(8):666–672

    Article  PubMed  Google Scholar 

  • Grapsa J, Gibbs JS, Dawson D, Watson G, Patni R, Athanasiou T, Punjabi PP, Howard LS, Nihoyannopoulos P (2012b) Morphologic and functional remodeling of the right ventricle in pulmonary hypertension by real time three dimensional echocardiography. Am J Cardiol 109:906–913

    Article  PubMed  Google Scholar 

  • Hagen M, Fagan K, Steudel W, Carr M, Lane K, Rodman DM, West J (2007) Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 292:L1473–L1479

    Article  PubMed  CAS  Google Scholar 

  • Hampole CV, Mehrotra AK, Thenappan T, Gomberg-Maitland M, Shah SJ (2009) Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension. Am J Cardiol 104:868–872

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M (2009) Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54:S10–S19

    Article  PubMed  CAS  Google Scholar 

  • Hayabuchi Y, Matsuoka S, Akita H, Kuroda Y (1993) Hyperuricaemia in cyanotic congenital heart disease. Eur J Pediatr 152:873–876

    Article  PubMed  CAS  Google Scholar 

  • Heger J, Schiegnitz E, von Waldthausen D, Anwar MM, Piper HM, Euler G (2010) Growth differentiation factor 15 acts anti-apoptotic and pro-hypertrophic in adult cardiomyocytes. J Cell Physiol 224:120–126

    PubMed  CAS  Google Scholar 

  • Heresi GA, Tang WH, Aytekin M, Hammel J, Hazen SL, Dweik RA (2012) Sensitive cardiac troponin I predicts poor outcomes in pulmonary arterial hypertension. Eur Respir J 39:939–944

    Article  PubMed  CAS  Google Scholar 

  • Hergenreider E, Heydt S, Treguer K, Boettger T, Horrevoets AJ, Zeiher AM, Scheffer MP, Frangakis AS, Yin X, Mayr M, Braun T, Urbich C, Boon RA, Dimmeler S (2012) Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 14:249–256

    Article  PubMed  CAS  Google Scholar 

  • Hiremath J, Thanikachalam S, Parikh K, Shanmugasundaram S, Bangera S, Shapiro L, Pott GB, Vnencak-Jones CL, Arneson C, Wade M, White RJ (2010) Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant 29:137–149

    Article  PubMed  Google Scholar 

  • Hlatky MA, Greenland P, Arnett DK, Ballantyne CM, Criqui MH, Elkind MSV, Go AS, Harrell FE, Hong Y, Howard BV, Howard VJ, Hsue PY, Kramer CM, McConnell JP, Normand SL, O’Donnell CJ, Smith SC, Wilson PWF, on behalf of the American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council (2009) Criteria for evaluation of novel markers of cardiovascular risk. Circulation 119:2408–2416

    Article  PubMed  Google Scholar 

  • Hoeper MM, Hohlfeld JM, Fabel H (1999) Hyperuricaemia in patients with right or left heart failure. Eur Respir J 13:682–685

    Article  PubMed  CAS  Google Scholar 

  • Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J (2005) Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 26:858–863

    Article  PubMed  CAS  Google Scholar 

  • Holmes SJ, Espiner EA, Richards AM, Yandle TG, Frampton C (1993) Renal, endocrine, and hemodynamic effects of human brain natriuretic peptide in normal man. J Clin Endocrinol Metab 76:91–96

    Article  PubMed  CAS  Google Scholar 

  • Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D (1995) Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151:1628–1631

    Article  PubMed  CAS  Google Scholar 

  • Humbert M, Deng Z, Simonneau G, Barst RJ, Sitbon O, Wolf M, Cuervo N, Moore KJ, Hodge SE, Knowles JA, Morse JH (2002) BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J 20:518–523

    Article  PubMed  CAS  Google Scholar 

  • Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jais X, Montani D, Souza R, Simonneau G (2010) Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122:156–163

    Article  PubMed  Google Scholar 

  • Jakobsen S, Kodahl GM, Olsen AK, Cumming P (2006) Synthesis, radiolabeling and in vivo evaluation of [11C]RAL-01, a potential phosphodiesterase 5 radioligand. Nucl Med Biol 33:593–597

    Article  PubMed  CAS  Google Scholar 

  • Jenkins M, Flynn A, Smart T, Harbron C, Sabin T, Ratnayake J, Delmar P, Herath A, Jarvis P, Matcham J (2011) A statistician’s perspective on biomarkers in drug development. Pharm Stat 10:494–507

    Article  PubMed  Google Scholar 

  • Kempf T, Wollert KC (2009) Growth differentiation factor-15: a new biomarker in cardiovascular disease. Herz 34:594–599

    Article  PubMed  Google Scholar 

  • Kereveur A, Callebert J, Humbert M, Herve P, Simonneau G, Launay JM, Drouet L (2000) High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy. Arterioscler Thromb Vasc Biol 20:2233–2239

    Article  PubMed  CAS  Google Scholar 

  • Khan SQ, Ng K, Dhillon O, Kelly D, Quinn P, Squire IB, Davies JE, Ng LL (2009) Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J 30:1057–1065

    Article  PubMed  CAS  Google Scholar 

  • Kielstein JT, Bode-Boger SM, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, Hoeper MM (2005) Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 25:1414–1418

    Article  PubMed  CAS  Google Scholar 

  • Kugathasan L, Ray JB, Deng Y, Rezaei E, Dumont DJ, Stewart DJ (2009) The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice. J Exp Med 206:2221–2234

    Article  PubMed  CAS  Google Scholar 

  • Kumpers P, Nickel N, Lukasz A, Golpon H, Westerkamp V, Olsson KM, Jonigk D, Maegel L, Bockmeyer CL, David S, Hoeper MM (2010) Circulating angiopoietins in idiopathic pulmonary arterial hypertension. Eur Heart J 31:2291–2300

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lankeit M, Dellas C, Panzenbock A, Skoro-Sajer N, Bonderman D, Olschewski M, Schafer K, Puls M, Konstantinides S, Lang IM (2008) Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension. Eur Respir J 31:1024–1029

    Article  PubMed  CAS  Google Scholar 

  • Lau EM, Manes A, Celermajer DS, Galie N (2011) Early detection of pulmonary vascular disease in pulmonary arterial hypertension: time to move forward. Eur Heart J 32:2489–2498

    Article  PubMed  Google Scholar 

  • Lawrie A, Waterman E, Southwood M, Evans D, Suntharalingam J, Francis S, Crossman D, Croucher P, Morrell N, Newman C (2008) Evidence of a role for osteoprotegerin in the pathogenesis of pulmonary arterial hypertension. Am J Pathol 172:256–264

    Article  PubMed  CAS  Google Scholar 

  • Lee WTN, Brown A, Peacock AJ, Johnson MK (2011) Use of non-invasive haemodynamic measurements to detect treatment response in precapillary pulmonary hypertension. Thorax 66:810–814

    Article  PubMed  Google Scholar 

  • Leuchte HH, Holzapfel M, Baumgartner RA, Neurohr C, Vogeser M, Behr J (2005) Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension. Chest 128:2368–2374

    Article  PubMed  CAS  Google Scholar 

  • Leuchte HH, El NM, Tuerpe JC, Hartmann B, Baumgartner RA, Vogeser M, Muehling O, Behr J (2007) N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension. Chest 131:402–409

    Article  PubMed  CAS  Google Scholar 

  • Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, Poole-Wilson PA, Coats AJ (1998) Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J 19:1814–1822

    Article  PubMed  CAS  Google Scholar 

  • Lopes AA, Barreto AC, Maeda NY, Cicero C, Soares RP, Bydlowski SP, Rich S (2011) Plasma von Willebrand factor as a predictor of survival in pulmonary arterial hypertension associated with congenital heart disease. Braz J Med Biol Res 44:1269–1275

    Article  PubMed  CAS  Google Scholar 

  • Lorenzen JM, Nickel N, Kramer R, Golpon H, Westerkamp V, Olsson KM, Haller H, Hoeper MM (2011) Osteopontin in patients with idiopathic pulmonary hypertension. Chest 139:1010–1017

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, Elliott CG, Glissmeyer E, Carlquist J, Kim M, Torbicki A, Fijalkowska A, Szewczyk G, Parma J, Abramowicz MJ, Galie N, Morisaki H, Kyotani S, Nakanishi N, Morisaki T, Humbert M, Simonneau G, Sitbon O, Soubrier F, Coulet F, Morrell NW, Trembath RC (2006) Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27:121–132

    Article  PubMed  CAS  Google Scholar 

  • Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E, Thenappan T, Bache-Wiig P, Piao L, Paul J, Chen CT, Archer SL (2012) Lung 18F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med 185:670–679

    Article  PubMed  CAS  Google Scholar 

  • McDonald RA, Hata A, MacLean MR, Morrell NW, Baker AH (2012) MicroRNA and vascular remodelling in acute vascular injury and pulmonary vascular remodelling. Cardiovasc Res 93:594–604

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin VV, Suissa S (2010) Prognosis of pulmonary arterial hypertension: the power of clinical registries of rare diseases. Circulation 122:106–108

    Article  PubMed  Google Scholar 

  • McLaughlin VV, Shillington A, Rich S (2002) Survival in primary pulmonary hypertension. Circulation 106:1477–1482

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K (2000) Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 161:487–492

    Article  PubMed  CAS  Google Scholar 

  • Montani D, Bergot E, Gunther S, Savale L, Bergeron A, Bourdin A, Bouvaist H, Canuet M, Pison C, Macro M, Poubeau P, Girerd B, Natali D, Guignabert C, Perros F, O’Callaghan DS, Jais X, Tubert-Bitter P, Zalcman G, Sitbon O, Simonneau G, Humbert M (2012) Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125:2128–2137

    Article  PubMed  CAS  Google Scholar 

  • Morisaki H, Nakanishi N, Kyotani S, Takashima A, Tomoike H, Morisaki T (2004) BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. Hum Mutat 23:632

    Article  PubMed  CAS  Google Scholar 

  • Nagaya N, Nishikimi T, Okano Y, Uematsu M, Satoh T, Kyotani S, Kuribayashi S, Hamada S, Kakishita M, Nakanishi N, Takamiya M, Kunieda T, Matsuo H, Kangawa K (1998) Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 31:202–208

    Article  PubMed  CAS  Google Scholar 

  • Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K (1999) Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 160:487–492

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Nakao K, Ogawa Y, Suga S, Imura H (1992) Molecular biology and biochemistry of the natriuretic peptide system. I: Natriuretic peptides. J Hypertens 10:907–912

    PubMed  CAS  Google Scholar 

  • Nasim MT, Ogo T, Ahmed M, Randall R, Chowdhury HM, Snape KM, Bradshaw TY, Southgate L, Lee GJ, Jackson I, Lord GM, Gibbs JS, Wilkins MR, Ohta-Ogo K, Nakamura K, Girerd B, Coulet F, Soubrier F, Humbert M, Morrell NW, Trembath RC, Machado RD (2011) Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 32:1385–1389

    Article  PubMed  CAS  Google Scholar 

  • Newman JH, Phillips JA III, Loyd JE (2008) Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med 148:278–283

    Article  PubMed  Google Scholar 

  • Nickel N, Kempf T, Tapken H, Tongers J, Laenger F, Lehmann U, Golpon H, Olsson K, Wilkins MR, Gibbs JS, Hoeper MM, Wollert KC (2008) Growth differentiation factor-15 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 178:534–541

    Article  PubMed  CAS  Google Scholar 

  • Nickel N, Golpon H, Greer M, Knudsen L, Olsson K, Westerkamp V, Welte T, Hoeper MM (2011a) The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 39:589–596

    Article  PubMed  CAS  Google Scholar 

  • Nickel N, Jonigk D, Kempf T, Bockmeyer CL, Maegel L, Rische J, Laenger F, Lehmann U, Sauer C, Greer M, Welte T, Hoeper MM, Golpon HA (2011b) GDF-15 is abundantly expressed in plexiform lesions in patients with pulmonary arterial hypertension and affects proliferation and apoptosis of pulmonary endothelial cells. Respir Res 12:62

    Article  PubMed  CAS  Google Scholar 

  • Nootens M, Kaufmann E, Rector T, Toher C, Judd D, Francis GS, Rich S (1995) Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic variables and endothelin levels. J Am Coll Cardiol 26:1581–1585

    Article  PubMed  CAS  Google Scholar 

  • Parikh VN, Jin RC, Rabello S, Gulbahce N, White K, Hale A, Cottrill KA, Shaik RS, Waxman AB, Zhang YY, Maron BA, Hartner JC, Fujiwara Y, Orkin SH, Haley KJ, Barabasi AL, Loscalzo J, Chan SY (2012) MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation 125:1520–1532

    Article  PubMed  CAS  Google Scholar 

  • Phillips JA III, Poling JS, Phillips CA, Stanton KC, Austin ED, Cogan JD, Wheeler L, Yu C, Newman JH, Dietz HC, Loyd JE (2008) Synergistic heterozygosity for TGFbeta1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genet Med 10:359–365

    Article  PubMed  CAS  Google Scholar 

  • Pletcher MJ, Pignone M (2011) Evaluating the clinical utility of a biomarker: a review of methods for estimating health impact. Circulation 123:1116–1124

    Article  PubMed  Google Scholar 

  • Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, Ghofrani HA, Weissmann N, Grimminger F, Bonauer A, Seeger W, Zeiher AM, Dimmeler S, Schermuly RT (2012) Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med 185:409–419

    Article  PubMed  CAS  Google Scholar 

  • Puls M, Dellas C, Lankeit M, Olschewski M, Binder L, Geibel A, Reiner C, Schafer K, Hasenfuss G, Konstantinides S (2007) Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism. Eur Heart J 28:224–229

    Article  PubMed  CAS  Google Scholar 

  • Quarck R, Nawrot T, Meyns B, Delcroix M (2009) C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol 53:1211–1218

    Article  PubMed  CAS  Google Scholar 

  • Rhodes CJ, Wharton J, Howard LS, Gibbs JS, Wilkins MR (2011a) Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart 97:1054–1060

    Article  PubMed  CAS  Google Scholar 

  • Rhodes CJ, Wharton J, Howard L, Gibbs JS, Vonk-Noordegraaf A, Wilkins MR (2011b) Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target. Eur Respir J 38:1453–1460

    Article  PubMed  CAS  Google Scholar 

  • Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs JS, Wharton J, Wilkins MR (2011c) Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol 58:300–309

    Article  PubMed  CAS  Google Scholar 

  • Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L (2000) Anorexigens and pulmonary hypertension in the United States. Chest 117:870–874

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, Hoeffken G (2001) Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 120:1562–1569

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sargent DJ, Conley BA, Allegra C, Collette L (2005) Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol 23:2020–2027

    Article  PubMed  Google Scholar 

  • Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S (2009) Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 10:6

    Article  PubMed  Google Scholar 

  • Schumann C, Lepper PM, Frank H, Schneiderbauer R, Wibmer T, Kropf C, Stoiber KM, Rudiger S, Kruska L, Krahn T, Kramer F (2010) Circulating biomarkers of tissue remodelling in pulmonary hypertension. Biomarkers 15:523–532

    Article  PubMed  CAS  Google Scholar 

  • Shah SJ, Thenappan T, Rich S, Tian L, Archer SL, Gomberg-Maitland M (2008) Association of serum creatinine with abnormal hemodynamics and mortality in pulmonary arterial hypertension. Circulation 117:2475–2483

    Article  PubMed  CAS  Google Scholar 

  • Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R (2009) A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 46:331–337

    Article  PubMed  CAS  Google Scholar 

  • Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, Rainisio M, Simonneau G (2002) Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 40:780–788

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Skoro-Sajer N, Mittermayer F, Panzenboeck A, Bonderman D, Sadushi R, Hitsch R, Jakowitsch J, Klepetko W, Kneussl MP, Wolzt M, Lang IM (2007) Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 176:1154–1160

    Article  PubMed  CAS  Google Scholar 

  • Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW (2010) Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122:920–927

    Article  PubMed  CAS  Google Scholar 

  • Souza R, Bogossian HB, Humbert M, Jardim C, Rabelo R, Amato MB, Carvalho CR (2005) N-terminal-pro-brain natriuretic peptide as a haemodynamic marker in idiopathic pulmonary arterial hypertension. Eur Respir J 25:509–513

    Article  PubMed  CAS  Google Scholar 

  • Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB (2009) Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 104:236–244

    Article  PubMed  CAS  Google Scholar 

  • Stewart DJ, Levy RD, Cernacek P, Langleben D (1991) Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 114:464–469

    Article  PubMed  CAS  Google Scholar 

  • Sztrymf B, Coulet F, Girerd B, Yaici A, Jais X, Sitbon O, Montani D, Souza R, Simonneau G, Soubrier F, Humbert M (2008) Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 177:1377–1383

    Article  PubMed  CAS  Google Scholar 

  • Sztrymf B, Souza R, Bertoletti L, Jais X, Sitbon O, Price LC, Simonneau G, Humbert M (2010) Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension. Eur Respir J 35:1286–1293

    Article  PubMed  CAS  Google Scholar 

  • Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M (2010) Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 35:1079–1087

    Article  PubMed  CAS  Google Scholar 

  • Thenappan T, Glassner C, Gomberg-Maitland M (2012) Validation of the pulmonary hypertension connection equation for survival prediction in pulmonary arterial hypertension. Chest 141:642–650

    Article  PubMed  Google Scholar 

  • Tonelli AR, Alnuaimat H, Mubarak K (2010) Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med 104:481–496

    Article  PubMed  Google Scholar 

  • Torbicki A, Kurzyna M, Kuca P, Fijalkowska A, Sikora J, Florczyk M, Pruszczyk P, Burakowski J, Wawrzynska L (2003) Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 108:844–848

    Article  PubMed  CAS  Google Scholar 

  • Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Howard LS, Marchesan D, Yang J, Suntharalingam J, Soon E, Exley A, Stewart S, Hecker M, Zhu Z, Gehling U, Seeger W, Pepke-Zaba J, Morrell NW (2009) Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med 180:780–787

    Article  PubMed  Google Scholar 

  • van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KMJ, Westerhof N, Vonk-Noordegraaf A (2011) Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58:2511–2519

    Article  PubMed  Google Scholar 

  • van Wolferen SA, Marcus JT, Boonstra A, Marques KMJ, Bronzwaer JGF, Spreeuwenberg MD, Postmus PE, Vonk-Noordegraaf A (2007) Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J 28:1250–1257

    Article  PubMed  Google Scholar 

  • Voelkel MA, Wynne KM, Badesch DB, Groves BM, Voelkel NF (2000) Hyperuricemia in severe pulmonary hypertension. Chest 117:19–24

    Article  PubMed  CAS  Google Scholar 

  • Vonk Noordegraaf A, Galie N (2011) The role of the right ventricle in pulmonary arterial hypertension. Eur Respir Rev 20:243–253

    Article  PubMed  CAS  Google Scholar 

  • Wang TJ (2011) Assessing the role of circulating, genetic, and imaging biomarkers in cardiovascular risk prediction. Circulation 123:551–565

    Article  PubMed  Google Scholar 

  • Wiedemann R, Ghofrani HA, Weissmann N, Schermuly R, Quanz K, Grimminger F, Seeger W, Olschewski H (2001) Atrial natriuretic peptide in severe primary and nonprimary pulmonary hypertension: response to iloprost inhalation. J Am Coll Cardiol 38:1130–1136

    Article  PubMed  CAS  Google Scholar 

  • Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA, Westwood MA, Stefanidis A, Ng LL, Pennell DJ, Mohiaddin RH, Nihoyannopoulos P, Gibbs JS (2005) Sildenafil versus Endothelin Receptor Antagonist For Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med 171:1292–1297

    Article  PubMed  Google Scholar 

  • Wilkins MR, Ali O, Bradlow W, Wharton J, Taegtmeyer A, Rhodes CJ, Ghofrani HA, Howard L, Nihoyannopoulos P, Mohiaddin RH, Gibbs JS, for the Simvastatin Pulmonary Hypertension Trial (SiPHT) Study Group (2010) Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med 181:1106–1113

    PubMed  CAS  Google Scholar 

  • Xu J, Kimball TR, Lorenz JN, Brown DA, Bauskin AR, Klevitsky R, Hewett TE, Breit SN, Molkentin JD (2006) GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res 98:342–350

    Article  PubMed  CAS  Google Scholar 

  • Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C, Dweik RA, Tuder RM, Stuehr DJ, Erzurum SC (2007) Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA 104:1342–1347

    Article  PubMed  CAS  Google Scholar 

  • Yandle TG, Richards AM, Gilbert A, Fisher S, Holmes S, Espiner EA (1993) Assay of brain natriuretic peptide (BNP) in human plasma: evidence for high molecular weight BNP as a major plasma component in heart failure. J Clin Endocrinol Metab 76:832–838

    Article  PubMed  CAS  Google Scholar 

  • Yoshimura M, Yasue H, Morita E, Sakaino N, Jougasaki M, Kurose M, Mukoyama M, Saito Y, Nakao K, Imura H (1991) Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 84:1581–1588

    Article  PubMed  CAS  Google Scholar 

  • Zamanian RT, Hansmann G, Snook S, Lilienfeld D, Rappaport KM, Reaven GM, Rabinovitch M, Doyle RL (2009) Insulin resistance in pulmonary arterial hypertension. Eur Respir J 33:318–324

    Article  PubMed  CAS  Google Scholar 

  • Zampetaki A, Willeit P, Drozdov I, Kiechl S, Mayr M (2012) Profiling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovasc Res 93:555–562

    Article  PubMed  CAS  Google Scholar 

  • Zhai Z, Murphy K, Tighe H, Wang C, Wilkins MR, Gibbs JS, Howard LS (2011) Differences in ventilatory inefficiency between pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Chest 140:1284–1291

    Article  PubMed  Google Scholar 

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Rhodes, C.J., Wharton, J., Wilkins, M.R. (2013). Pulmonary Hypertension: Biomarkers. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_4

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