Skip to main content

Advertisement

SpringerLink
Log in

Biomarkers in Pulmonary Arterial Hypertension

  • Biomarkers of Heart Failure (WHW Tang, Section Editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Pulmonary hypertension prevalence continues to rise and remains a clinical dilemma with regards to patient recognition and management. Despite advances in our understanding of the pathophysiology and pathogenesis behind pulmonary hypertension (PH), this heterogeneous cohort continues to demonstrate significant morbidity and mortality. Biomarkers serve as a dynamic, noninvasive tool in a physician’s clinical armamentarium. Their role is to impact clinical decision-making and to facilitate patient education with respect to diagnosis, prognosis, and therapeutic intervention. This review will elucidate the relationship between PH and serum biomarkers related to inflammation, myocardial dysfunction or stress, and endothelial dysfunction. Over the last two decades, the utilization and incorporation of biomarkers into the evaluation and management of pulmonary hypertension has exploded. Consequently, current guidelines and consensus documents have adopted their use. The additive roles of both established and innovative biomarkers in individuals with pulmonary arterial hypertension (PAH) will be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. McLaughlin VV et al. 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. 2009;119(16):2250–94.

    Article  PubMed  Google Scholar 

  2. Galie N et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219–63.

    Article  CAS  PubMed  Google Scholar 

  3. Hoeper MM et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D42–50.

    Article  PubMed  Google Scholar 

  4. Simonneau G et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(12):5S–12S.

    Article  PubMed  Google Scholar 

  5. Fishman AP. Clinical classification of pulmonary hypertension. Clin Chest Med. 2001;22(3):385–91. vii.

    Article  CAS  PubMed  Google Scholar 

  6. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114(13):1417–31.

    Article  PubMed  Google Scholar 

  7. Torbicki A, Kurzyna M. Pulmonary arterial hypertension: evaluation of the newly diagnosed patient. Semin Respir Crit Care Med. 2005;26(4):372–8.

    Article  PubMed  Google Scholar 

  8. McGoon MD et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol. 2013;62(25):D51–9. This is a historical overview of pulmonary hypertension.

    Article  PubMed  Google Scholar 

  9. McGoon MD et al. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc. 2008;83(8):923–31.

    Article  PubMed  Google Scholar 

  10. D’Alonzo GE et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343–9.

    Article  PubMed  Google Scholar 

  11. Benza RL et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142(2):448–56.

    Article  PubMed  Google Scholar 

  12. Strange G et al. Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: the delay study. Pulm Circ. 2013;3(1):89–94.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358(20):2148–59.

    Article  CAS  PubMed  Google Scholar 

  14. Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardiovascular biomarkers. Circulation. 2007;115(8):949–52.

    Article  PubMed  Google Scholar 

  15. Hochholzer W, Morrow DA, Giugliano RP. Novel biomarkers in cardiovascular disease: update 2010. Am Heart J. 2010;160(4):583–94.

    Article  CAS  PubMed  Google Scholar 

  16. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425–36.

    Article  CAS  PubMed  Google Scholar 

  17. Benza RL et al. Management of pulmonary arterial hypertension with a focus on combination therapies. J Heart Lung Transplant. 2007;26(5):437–46.

    Article  PubMed  Google Scholar 

  18. Currie PJ et al. Continuous wave Doppler determination of right ventricular pressure: a simultaneous Doppler-catheterization study in 127 patients. J Am Coll Cardiol. 1985;6(4):750–6.

    Article  CAS  PubMed  Google Scholar 

  19. Forfia PR et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006;174(9):1034–41.

    Article  PubMed  Google Scholar 

  20. Vonk MC et al. Right ventricle Tei-index: a tool to increase the accuracy of non-invasive detection of pulmonary arterial hypertension in connective tissue diseases. Eur J Echocardiogr. 2007;8(5):317–21.

    Article  CAS  PubMed  Google Scholar 

  21. Borgeson DD et al. Frequency of Doppler measurable pulmonary artery pressures. J Am Soc Echocardiogr. 1996;9(6):832–7.

    Article  CAS  PubMed  Google Scholar 

  22. Fisher MR et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med. 2009;179(7):615–21.

    Article  PubMed Central  PubMed  Google Scholar 

  23. McLaughlin VV et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25):D73–81. This article describes the goals of treatment in PH.

    Article  PubMed  Google Scholar 

  24. Vonk-Noordegraaf A et al. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62(25 Suppl):D22–33.

    Article  PubMed  Google Scholar 

  25. Mahadavan G, Nguyen TH, Horowitz JD. Brain natriuretic peptide: a biomarker for all cardiac disease? Curr Opin Cardiol. 2014;29(2):160–6.

    Article  PubMed  Google Scholar 

  26. Nagaya N et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102(8):865–70.

    Article  CAS  PubMed  Google Scholar 

  27. Hachulla E et al. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum. 2009;60(6):1831–9.

    Article  PubMed  Google Scholar 

  28. Simonneau G et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34–41.

    Article  PubMed  Google Scholar 

  29. Tyndall AJ et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTA R) database. Ann Rheum Dis. 2010;69(10):1809–15.

  30. Coghlan JG et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73:1340–9.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Mathai SC et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J. 2010;35(1):95–104.

    Article  CAS  PubMed  Google Scholar 

  32. Tuder RM et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25):D4–D12. This article describes the pathology and biology of pulmonary hypertension.

    Article  PubMed  Google Scholar 

  33. Bogaard HJ et al. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest. 2009;135(3):794–804.

    Article  CAS  PubMed  Google Scholar 

  34. Fijalkowska A et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest. 2006;129(5):1313–21.

    Article  CAS  PubMed  Google Scholar 

  35. Benza RL et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122(2):164–72.

    Article  PubMed  Google Scholar 

  36. Benza RL et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012;141(2):354–62.

    Article  PubMed  Google Scholar 

  37. Benza RL et al. Development of prognostic tools in pulmonary arterial hypertension: lessons from modern day registries. Thromb Haemost. 2012;108(6):1049–60.

    Article  PubMed  Google Scholar 

  38. Munagala VK, Burnett Jr JC, Redfield MM. The natriuretic peptides in cardiovascular medicine. Curr Probl Cardiol. 2004;29(12):707–69.

    Article  PubMed  Google Scholar 

  39. Cracowski JL, Leuchte HH. The potential of biomarkers in pulmonary arterial hypertension. Am J Cardiol. 2012;110(6 Suppl):32S–8S.

    Article  PubMed  Google Scholar 

  40. Torbicki A et al. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation. 2003;108(7):844–8.

    Article  CAS  PubMed  Google Scholar 

  41. Filusch A et al. High-sensitive troponin T: a novel biomarker for prognosis and disease severity in patients with pulmonary arterial hypertension. Clin Sci (Lond). 2010;119(5):207–13.

    Article  CAS  Google Scholar 

  42. Heresi GA et al. Sensitive cardiac troponin I predicts poor outcomes in pulmonary arterial hypertension. Eur Respir J. 2012;39(4):939–44.

    Article  CAS  PubMed  Google Scholar 

  43. Vélez-Martínez M et al. Association of cardiac troponin I with disease severity and outcomes in patients with pulmonary hypertension. Am J Cardiol. 2013;111(12):1812–7.

    Article  PubMed  Google Scholar 

  44. Mahajan VS, Jarolim P. How to interpret elevated cardiac troponin levels. Circulation. 2011;124(21):2350–4.

    Article  PubMed  Google Scholar 

  45. Hoeper MM, Hohlfeld JM, Fabel H. Hyperuricaemia in patients with right or left heart failure. Eur Respir J. 1999;13(3):682–5.

    Article  CAS  PubMed  Google Scholar 

  46. Leyva F et al. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J. 1997;18(5):858–65.

    Article  CAS  PubMed  Google Scholar 

  47. Voelkel MA et al. Hyperuricemia in severe pulmonary hypertension. Chest. 2000;117(1):19–24.

    Article  CAS  PubMed  Google Scholar 

  48. Nagaya N et al. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med. 1999;160(2):487–92.

    Article  CAS  PubMed  Google Scholar 

  49. Njaman W et al. Serum uric acid as a prognostic predictor in pulmonary arterial hypertension with connective tissue disease. Int Heart J. 2007;48(4):523–32.

    Article  CAS  PubMed  Google Scholar 

  50. Dawson J, Walters M. Uric acid and xanthine oxidase: future therapeutic targets in the prevention of cardiovascular disease? Br J Clin Pharmacol. 2006;62(6):633–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Foris V et al. Biomarkers in pulmonary hypertension: what do we know? Chest. 2013;144(1):274–83.

    Article  CAS  PubMed  Google Scholar 

  52. Ky B et al. High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail. 2011;4(2):180–7.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7(10):827–40. This is a review of IL-33/ST2 pathway which elucidates the biology of ST2 biomarker and potential role in PH.

    Article  CAS  PubMed  Google Scholar 

  54. Felker GM et al. Soluble ST2 in ambulatory patients with heart failure: association with functional capacity and long-term outcomes. Circulation: Heart Failure. 2013;6(6):1172–9.

    CAS  PubMed Central  Google Scholar 

  55. Zheng YG et al. Plasma soluble ST2 levels correlate with disease severity and predict clinical worsening in patients with pulmonary arterial hypertension. Clin Cardiol. 2014;37(6):365–70.

    Article  PubMed  Google Scholar 

  56. Rhodes CJ et al. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart. 2011;97(13):1054–60.

    Article  CAS  PubMed  Google Scholar 

  57. Warwick G, Thomas PS, Yates DH. Biomarkers in pulmonary hypertension. Eur Respir J. 2008;32(2):503–12.

    Article  CAS  PubMed  Google Scholar 

  58. Rosenberg M et al. Osteopontin, a new prognostic biomarker in patients with chronic heart failure. Circ Heart Fail. 2008;1(1):43–9.

    Article  CAS  PubMed  Google Scholar 

  59. Singh K et al. Myocardial osteopontin expression coincides with the development of heart failure. Hypertension. 1999;33(2):663–70.

    Article  CAS  PubMed  Google Scholar 

  60. Denhardt DT et al. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest. 2001;107(9):1055–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Rosenberg M et al. Osteopontin (OPN) improves risk stratification in pulmonary hypertension (PH). Int J Cardiol. 2012;155(3):504–5.

    Article  PubMed  Google Scholar 

  62. Rosenberg M et al. Osteopontin predicts adverse right ventricular remodelling and dysfunction in pulmonary hypertension. Eur J Clin Invest. 2012;42(9):933–42.

    Article  CAS  PubMed  Google Scholar 

  63. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis. 2002;40(2):221–6.

    Article  CAS  PubMed  Google Scholar 

  64. Shlipak MG et al. Cystatin-C and mortality in elderly persons with heart failure. J Am Coll Cardiol. 2005;45(2):268–71.

    Article  CAS  PubMed  Google Scholar 

  65. Fenster BE et al. Cystatin C: a potential biomarker for pulmonary arterial hypertension. Respirology. 2014;19:583–9.

    Article  PubMed  Google Scholar 

  66. Deftereos S et al. Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study. JACC Heart Fail. 2014;2(2):131–7.

    Article  PubMed  Google Scholar 

  67. Ghofrani H-AMD et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–40.

    Article  CAS  PubMed  Google Scholar 

  68. Barst RJ et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301.

    Article  CAS  PubMed  Google Scholar 

  69. Galie N et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Julie L. Rosenthal and Miriam S. Jacob declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Cleveland Clinic, 9500 Euclid Avenue, J3-4, Cleveland, OH, 44195, USA

    Julie L. Rosenthal & Miriam S. Jacob

Authors
  1. Julie L. Rosenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miriam S. Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miriam S. Jacob.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rosenthal, J.L., Jacob, M.S. Biomarkers in Pulmonary Arterial Hypertension. Curr Heart Fail Rep 11, 477–484 (2014). https://doi.org/10.1007/s11897-014-0225-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-014-0225-5

Keywords

Search

Navigation