Circulating biomarkers in pulmonary arterial hypertension: Update and future direction
Section snippets
Biomarker: Definition
The National Institutes of Health Biomarker Definition Working Group stated in 2001 that a biomarker could be defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention,”5 whereas a more recent and practical definition describes a biomarker as a disease-associated molecular change in body tissue and fluids.6
An ideal biomarker should be also a valid surrogate
Circulating biomarker in PAH
The plasmatic biomarkers currently used or proposed in PAH could be summarized as follows: biomarkers of
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dysfunction/neurohormonal activation (natriuretic peptides, endothelin [ET]-1, adrenomedullin, copeptin);
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myocardial injury (troponins);
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inflammation/oxidative stress (interleukins [IL], C-reactive protein [CRP], isoprostans);
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vascular damage/remodelling (von Willebrand factor [vWF], angiopoietin [Ang], microparticles, growth differentiation factor-15 [GDF-15]);
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end-organ failure (creatinine,
Natriuretic peptides
Natriuretic peptides (Table 1) are a family of genetically distinct hormones that share a similar molecular structure and are involved in regulation of blood volume and pressure, thanks to their activity: diuretic, natriuretic, vasodilation functions, and inhibition of the renin-angiotensin-aldosterone system.7 Atrial natriuretic peptide (ANP) and BNP represent the major hormones of the natriuretic peptide system, and their plasmatic levels are elevated in pulmonary hypertension (PH), likely as
Biomarkers of myocardial injury
Cardiac troponins constitute a complex of 3 regulatory proteins—troponin C (TnC), TnI (cTnI), and TnT (cTnT)—in the context of the thin actin filaments of cardiac muscle (Table 4). The detection by highly sensitive assays of increased troponin plasma levels is associated with cardiac myocyte damage; therefore, cTnT and cTnI measurement plays a crucial role in the diagnostic and prognostic evaluation of patients with acute coronary syndromes,54 but elevated cardiac troponins have been also found
Comparison among biomarkers
In a recent study, Silva Marques et al53 determined baseline concentrations of NT-proBNP, COOH-terminal pro-ET-1 (CT-proET-1), midregional pro-ADM (MR-proADM), MR pro-ANP (MR-proANP), copeptin, and TnI in a cohort of 28 consecutive PAH patients, clinically monitored for 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation, or all-cause mortality. CT-proET-1, MR-proADM, and MR-proANP are precursors of ET-1, ADM, and ANP,
Biomarkers of inflammation/oxidative stress
The presence of inflammation in pulmonary hypertension has long been known (Table 5), because inflammatory cell infiltrates in absence of vasculitis have been described in the plexiform lesions of 7 patients with idiopathic PAH.60 Further studies have confirmed the presence of immune cells (B- and T-lymphocytes, macrophages, and mast cells) surrounding plexiform lesions.61, 62
The possible pathogenetic role of the immune system and inflammation in IPAH is also supported by the close association
Biomarkers of vascular remodelling and damage
Biomarkers of vascular remodelling and damage are summarized in Table 6.
Biomarkers of end-organ failure
Biomarkers of end-organ failure are summarized in Table 7.
Renal dysfunction is associated with hemodynamic impairment and presents as an independent predictor of death in PAH.158, 159 Thus, renal function, assessed measuring serum creatinine levels or creatinine clearance, represents a prognostic biomarker and must be considered in the evaluation of biomarkers undergoing renal clearance, such as NT-proBNP.23, 159
Hyponatremia in PAH was strongly associated with advanced RV dysfunction, WHO
High-density lipoprotein
Reduced circulating levels of high-density lipoprotein have recently been associated with higher mortality and clinical worsening in PAH patients168 independently from other cardiovascular risk factors, but there is still a need of further confirmation before introducing its measure as routine test in clinical practice.
Transcriptional regulators and oncogenes expression
Transcriptional regulators and oncogenes expression are summarized in Table 8
Future direction: Genomics and proteomics?
Because the histologic lesions in PAH are quite well characterized, another approach would be oriented to the identification of structural proteins that are specifically expressed in the diseased tissue, which could spillover into the blood stream in case of disease activity, such as an oncologic biomarker or troponins in myocardial injury (Table 9).
In this view, genomic or proteomic studies could represent the new frontier in the research for biomarkers in PAH, because they may allow us to
Current clinical use of circulating biomarkers
Table 10 summarizes the main features of the circulating biomarkers reviewed in this report. As already stated, BNP and NT-proBNP are to date the only circulating biomarkers that are currently used in clinical practice because of their availability, easy access, fast determination, cost, and prognostic effect. For these characteristics, they are included as prognostic indicators in PH guidelines186: BNP and NT-proBNP plasma levels are recommended for initial risk stratification and are
Disclosure statement
None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
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