Circulating biomarkers in pulmonary arterial hypertension: Update and future direction

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Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. In recent years, great advances have occurred in our understanding of the pathophysiologic mechanisms underlying the characteristic vascular proliferative lesions, thus allowing the development of several specific drugs. Nevertheless, PAH still presents a high mortality; therefore, early diagnosis and prognostic stratification seem to be of paramount importance in order to choose the best therapeutic strategies. Circulating biomarkers have been proposed as potentially noninvasive and objective parameters for diagnosis, prognosis, and response to therapy. The molecules evaluated to date, including markers of dysfunction and neurohormonal activation, myocardial injury, inflammation and oxidative stress, vascular damage and remodelling, end-organ failure, and gene expression, reflect the complex pathophysiology of PAH. However, not one of these shows all the characteristics of the ideal biomarker; thus, a multiparameter approach is probably desirable. Moreover, future direction could be research of structural proteins specifically expressed in the pathologic tissue that act as disease-specific markers. This report presents an extensive review of circulating biomarkers in PAH and some consideration about potential future direction in this area.

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

  • dysfunction/neurohormonal activation (natriuretic peptides, endothelin [ET]-1, adrenomedullin, copeptin);

  • myocardial injury (troponins);

  • inflammation/oxidative stress (interleukins [IL], C-reactive protein [CRP], isoprostans);

  • vascular damage/remodelling (von Willebrand factor [vWF], angiopoietin [Ang], microparticles, growth differentiation factor-15 [GDF-15]);

  • 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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