The Potential of Biomarkers in Pulmonary Arterial Hypertension
Section snippets
Defining Suitable Biomarkers
The most reliable way to assess the clinical impact of a therapeutic intervention is through its effect on well-defined clinical endpoints such as mortality. However, this standard is often impractical because long periods of time and large numbers of patients are required to reach these clinical endpoints. Biomarkers can be reliable substitutes for clinical endpoints, and are termed “surrogate endpoints” when they meet such requirements. According to the National Institutes of Health (NIH)
Biomarkers in Pulmonary Arterial Hypertension
The pathophysiologic process of PAH is characterized by endothelial dysfunction of the pulmonary arteries, associated with inflammation, imbalance of vasoactive mediators, in situ thrombosis, and oxidative stress.9 The resulting vascular remodeling and proliferation of small pulmonary arteries leads to a chronic elevation of pulmonary vascular resistance (PVR), and right heart insufficiency and failure with the development of second organ dysfunction and, eventually, death. Therefore, an
Integrative Biomarkers
Hyponatremia is an established biomarker of advanced left heart failure. Forfia and colleagues showed that hyponatremia (serum sodium ≤136 mEq/L) is strongly associated with right heart failure and poor survival in PAH, and suggested that hyponatremia in PAH results from neurohormonal activation in response to advanced RV.59 Similarly, serum sodium at time of admission has been shown to correlate with survival in patients with PAH suffering from acute right heart failure.60 Such an association
Biomarkers With Future Potential in Pulmonary Arterial Hypertension
Several other parameters should be considered when assessing the potential of biomarkers for determining the prognosis of PAH. The metabolism and excretion of biomarkers must be taken into consideration, because plasma and serum levels may increase in parallel with renal failure for those biomarkers undergoing renal clearance.
When considering other markers, there was initial interest in norepinephrine levels; however, they were not identified as prognostic in a multivariate analysis.48 Heresi
Conclusion
In conclusion, BNP or NT-proBNP, serum sodium, creatinine clearance, and troponin T are biomarkers that can be used routinely to assess PAH prognosis. Moreover, the potential of combining markers is currently of considerable interest. Future studies are required to determine whether biomarkers of inflammation can be used in a clinical setting.
Author Disclosures
The authors who contributed to this article have disclosed the following industry relationships:
Jean-Luc Cracowski, MD, PhD, has worked as a consultant to Actelion Pharmaceuticals, Ltd; and has received research/grant support from Actelion Pharmaceuticals, Ltd, Boiron Laboratories, and Pfizer Inc.
Hanno H. Leuchte, MD, is a member of the Speakers' Bureau of Actelion Pharmaceuticals, Ltd, Bayer Corporation, Eli Lilly and Company, GlaxoSmithKline, and Pfizer Inc; has served on the Advisory Boards
Acknowledgment
Editorial support was provided by Liesje Quine, PhD, Elements Communications Ltd, Westerham, Kent, UK and funded by Actelion Pharmaceuticals Ltd. Allschwil, Switzerland.
References (70)
- et al.
Exhaled nitric oxide during exercise in primary pulmonary hypertension and pulmonary fibrosis
Chest
(1997) - et al.
Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension
Chest
(2001) - et al.
Endothelin-1/endothelin-3 ratio: a potential prognostic factor of pulmonary arterial hypertension
Chest
(2007) - et al.
von Willebrand factor independently predicts long-term survival in patients with pulmonary arterial hypertension
Chest
(2005) - et al.
Circulating von Willebrand factor antigen as a predictor of short-term prognosis in pulmonary hypertension
Chest
(1998) - et al.
Osteopontin in patients with idiopathic pulmonary hypertension
Chest
(2011) - et al.
C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension
J Am Coll Cardiol
(2009) - et al.
Oxidant stress but not thromboxane decreases with epoprostenol therapy
Free Radic Biol Med
(2005) - et al.
Pulmonary hypertension and inflammation
J Lab Clin Med
(1998) - et al.
Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction
Am Heart J
(1998)
Treatment of heart failure guided by plasma aminoterminal BNP (N-) concentration
Lancet
Atrial natriuretic peptide in severe primary and nonprimary pulmonary hypertension: response to iloprost inhalation
J Am Coll Cardiol
Clinical significance of brain natriuretic peptide in primary pulmonary hypertension
J Am Coll Cardiol
Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension
J Am Coll Cardiol
Characterization of brain natriuretic peptide in long-term follow-up of pulmonary arterial hypertension
Chest
Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension
Chest
N-terminal pro-brain natriuretic peptide and renal insufficiency as predictors of mortality in pulmonary hypertension
Chest
Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial
Lancet
Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial
J Am Coll Cardiol
Plasma brain natriuretic peptide concentration: impact of age and gender
J Am Coll Cardiol
Sensitive and high sensitivity next generation cardiac troponin assays: more than just a name
Pathology
The SELDI-TOF MS approach to proteomics: protein profiling and biomarker identification
Biochem Biophys Res Commun
Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)
Eur Heart J
Goal-oriented treatment and combination therapy for pulmonary arterial hypertension
Eur Respir J
Biomarkers and surrogate endpoints: preferred definitions and conceptual framework
Clin Pharmacol Ther
Bring on the biomarkers
Nature
Novel risk markers and clinical practice
N Engl J Med
The limitations of risk factors as prognostic tools
N Engl J Med
The utility of troponin measurement to detect myocardial infarction: review of the current findings
Vasc Health Risk Manag
Pulmonary arterial hypertension
N Engl J Med
Biomarkers in pulmonary hypertension
Eur Respir J
Biomarkers in pulmonary arterial hypertension
Int J Clin Pract Suppl
Clinical perspective: biomarkers in pulmonary arterial hypertension
Int J Clin Pract Suppl
An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension
N Engl J Med
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Biomarkers for pediatric pulmonary arterial hypertension: Challenges and recommendations
2015, Paediatric Respiratory ReviewsCitation Excerpt :For this review, we have arbitrarily divided biomarkers for pediatric PAH into two classes: biochemical and imaging. Over the past several years excellent reviews on biomarkers and their application in PAH have been published [23–25]. However, these reviews have focused on adult PAH.
Publication of this supplement was supported by Actelion Pharmaceuticals Ltd.
Statement of author disclosure: Please see the Author Disclosures section at the end of this article.