Chest
Volume 139, Issue 5, May 2011, Pages 1010-1017
Journal home page for Chest

Original Research
Pulmonary Vascular Disease
Osteopontin in Patients With Idiopathic Pulmonary Hypertension

https://doi.org/10.1378/chest.10-1146Get rights and content

Background

Osteopontin (OPN) is a pleiotropic cytokine that has been postulated to play a role in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). OPN plasma levels may be related to disease severity and mortality in patients with PAH.

Methods

OPN plasma levels obtained during right-sided heart catheterization were assessed by a commercially available enzyme-linked immunosorbent assay and related to hemodynamics, exercise capacity, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, uric acid level, C-reactive protein level, and survival in two cohorts of patients with IPAH: a 4-year retrospective cohort (n = 70) and a prospective cohort (n = 25) followed for 3 months after initiation of therapy. Forty apparently healthy individuals served as control subjects.

Results

Baseline OPN levels were elevated in patients with IPAH compared with healthy control subjects (50.2 ± 35.9 vs 23.7 ± 2.8 ng/mL, P < .0001). In the retrospective as well as in the prospective cohort, OPN levels correlated with mean right atrial pressure and NT-BNP. In the retrospective cohort, OPN levels also correlated with age (r = 0.3, P = .02), 6-min walking distance (r=−0.4, P = .05), and New York Heart Association class (r = 0.4, P = .001). Multivariate Cox analysis demonstrated that baseline OPN levels were independent predictors of mortality (P = .02). When patients were divided according to their baseline OPN values, being normal or elevated at baseline (below or above 34.5 ng/mL), proportional survival rates were 100% vs 80% after 1 year and 77% vs 51% after 3 years, respectively.

Conclusion

Circulating OPN predicts survival in patients with IPAH and is associated with a higher New York Heart Association class. OPN, thus, may be useful as a biomarker in IPAH.

Section snippets

Patients and Study Design

The study was carried out in accordance with the Declaration of Helsinki and approved by the institutional review board (No. 3558). Written informed consent was obtained. This study consisted of the following two patient groups: a retrospective treatment-naive cohort (n = 70) and a prospective cohort (n = 25). Patients in the retrospective cohort were referred to Hannover Medical School (Hannover, Germany) between 2004 and 2008. The median surveillance time of the retrospective cohort was 24

OPN Levels in Patients With IPAH Are Elevated Compared With Control Subjects

Patient characteristics of the retrospective cohort are shown in Table 1. Baseline OPN levels in patients with pulmonary hypertension (n = 70, 50.2 ± 35.9 ng/mL) were significantly elevated compared with healthy control subjects (n = 40, 23.7 ± 2.8 ng/mL, P < .001) (Fig 1A). Healthy control subjects (n = 40) were matched for age (median, 52 years; IQR, 42–60 years) and sex (24 women, 16 men).

OPN and Clinical Characteristics at Baseline

In the retrospective cohort, baseline OPN levels correlated with age (r = 0.3, P = .02), 6-min walking

OPN and Outcome in IPAH

The present study showed that OPN plasma levels were significantly elevated in patients with IPAH compared with healthy control subjects. About two-thirds of the present study population presented with elevated OPN levels. These individuals had a poorer clinical status and an inferior prognosis compared with those with OPN levels below the upper reference limit. An OPN cutoff value of 34.5 ng/mL separated survivors from nonsurvivors with a sensitivity of 88% and a specificity of 63%. In

Acknowledgments

Author contributions: Dr Lorenzen: contributed the initial idea, performed the experiments, and wrote the manuscript.

Dr Nickel: contributed to the performance of the statistical analysis and wrote the manuscript.

Dr Krämer: contributed to the performance of the experiments.

Dr Golpon: contributed patient clinical data and to the performance of the statistical analysis.

Dr Westerkamp: contributed patient clinical data and to the performance of the statistical analysis.

Dr Olsson: contributed patient

References (44)

  • J Dupuis

    Endothelin-receptor antagonists in pulmonary hypertension

    Lancet

    (2001)
  • R Souza et al.

    NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension

    Respir Med

    (2007)
  • T Kempf et al.

    Growth-differentiation factor-15 in heart failure

    Heart Fail Clin

    (2009)
  • HH Leuchte et al.

    Clinical significance of brain natriuretic peptide in primary pulmonary hypertension

    J Am Coll Cardiol

    (2004)
  • KH Yoo et al.

    Osteopontin regulates renal apoptosis and interstitial fibrosis in neonatal chronic unilateral ureteral obstruction

    Kidney Int

    (2006)
  • H Milting et al.

    Plasma biomarkers of myocardial fibrosis and remodeling in terminal heart failure patients supported by mechanical circulatory support devices

    J Heart Lung Transplant

    (2008)
  • LJ Rubin

    Primary pulmonary hypertension

    N Engl J Med

    (1997)
  • A O'Regan et al.

    Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation

    Int J Exp Pathol

    (2000)
  • DT Denhardt et al.

    Osteopontin: a protein with diverse functions

    FASEB J

    (1993)
  • R Patarca et al.

    Molecular and cellular basis of genetic resistance to bacterial infection: the role of the early T-lymphocyte activation-1/osteopontin gene

    Crit Rev Immunol

    (1993)
  • SD Ricardo et al.

    Angiotensinogen and AT(1) antisense inhibition of osteopontin translation in rat proximal tubular cells

    Am J Physiol Renal Physiol

    (2000)
  • N Ashizawa et al.

    Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction

    J Clin Invest

    (1996)
  • Cited by (77)

    • Cell senescence in pulmonary hypertension

      2022, Cellular Senescence in Disease
    • Cerebrovascular damage after midlife transient hypertension in non-transgenic and Alzheimer's disease rats

      2021, Brain Research
      Citation Excerpt :

      To gain a fuller understanding of the mechanisms underlying hypertensive remodeling in both NTg and TgAD rats, we isolated cortical blood vessels from all treatment groups and examined the expression of signaling proteins implicated in clinical and experimental hypertension. Osteopontin (OPN) is a secreted protein synthesized by smooth muscle and endothelial cells; modulation of OPN expression has been associated with hypertension as well as with post-insult vascular remodeling (Caesar et al., 2017; deBlois et al., 1996; Lorenzen et al., 2011). Here, we found that transient hypertension (p = 0.01) but not AD (p = 0.18) contributed to decreased OPN levels (Fig. 6A, B).

    • Biomarkers in Pulmonary Hypertension

      2021, Encyclopedia of Respiratory Medicine, Second Edition
    View all citing articles on Scopus

    Drs Lorenzen and Nickel contributed equally to the study.

    Funding/Support: This work was supported by the Deutsche Forschungsgemeinschaft [DFG LO 1736/1-1 to J. M. L. and SFB Transregio 37/project B4] and the European Commission under the 6th Framework Program [contract No. LSHM-CT-2005-018725, PULMOTENSION].

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

    View full text