Natriuretic Peptides

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Summary

Natriuretic Peptides

Based on the results of studies such as the Breathing Not Properly Multinational Study,¹⁹ ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE),^20,21 Rapid Emergency Department Heart failure Outpatient Trial (REDHOT),²² Valsartan Heart Failure Trial (Val-HeFT),²³ Groenning et al.²⁴ or the International Collaborative of NT-proBNP Study,²⁵ among others, international guidelines on both acute and chronic HF (AHF/CHF) describe a role for BNP and NT-proBNP in the diagnosis and prognostic assessment of HF^{.7,12,15,26–29} Additionally, increasing evidence is emerging about a possible role for natriuretic peptides (NP) to guide therapy.^12,30 However, despite their usefulness and increasing use in clinical practice, some limitations must still be acknowledged. For instance, the optimal cut-off points are still not well-established and different thresholds have been proposed;^{18,27,31–33} additionally, there is a range of values (a ‘grey zone’) where they are less helpful in decision-making;^27,31,32 furthermore, while low NP concentrations make the diagnosis of HF unlikely (high negative predictive value), increased levels can be also a consequence of several cardiac and non-cardiac conditions^.7,12,27 Levels of NP can also be affected by factors such as age, obesity, anaemia and renal function.¹² In addition, NP are released as a result of myocyte stress caused by pressure or volume overload;^16,34,35 therefore, they may not completely reflect other mechanisms within the complex pathophysiology of HF (e.g. renin–angiotensin–aldosteron system; autonomic nervous sytem). Finally, more evidence is needed in relation to the use of NP to guide therapy. This aspect has been approached in different trials comparing a strategy based on BNP or NT-proBNP-guided therapy versus the usual or standard care;³⁶ however, many of these studies were small, lacked power to assess major end-points and their results were not always consistent.^12,30,36 More recently, several meta-analyses have suggested that NP-guided therapy strategies could be associated with a reduction in all-cause mortality and HF-related hospitalisations in CHF;^30,36–42 this is of interest, but the findings seemed to be influenced by age as it was mainly observed in individuals aged <70–75 years.^{30,36,39–42}

Better understanding of the role of NPs in clinical practice and their contribution to the diagnosis and management of HF in recent years^16,18 has stimulated research into newer biomarkers. As an example,Table 1 shows a classification of established and novel biomarkers.^15,16,34,35 A multi-marker strategy, covering different and complementary aspects of HF in an integrated algorithm, has been proposed and may improve both diagnostic and prognostic assessment strategies.^43–45 The incorporation of newer biomarkers may however potentially increase the complexity of the assessment and costs, a matter that will need to be explored in due course.

Soluble ST2 – An Emerging Biomarker

The interleukin-1 receptor-like 1 (IL1RL1) protein, commonly referred to as ST2 (growth stimulation expressed gene 2), has emerged as a promising novel biomarker for AHF and CHF46–49 and other related conditions, such as CAD50,51 and hypertension.⁵² While soluble ST2 (sST2) lacks disease specificity, which may limit its role in the diagnosis of HF,⁵³ it may have a role regarding prognosis assessment in HF. The recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines on HF management state that ST2 can provide additive value regarding risk stratification, particularly in patients with acutely decompensated HF (Class IIb, level of evidence A) and those with CHF (Class IIb, level of evidence B).¹² sST2 was first described in 1989 by Klemenz et al.^54,55 and Tominaga.⁵⁶ It was independently identified and subsequently designated as T1,^{54,55 ST,2,56,57} delayed early response gene 4 (DER-4)⁵⁸ and Fit-1 (the homologue of mouse ST2/T1 protein).⁵⁹ The expression of the IL1RL1 gene generates three different messenger RNA (mRNA) isoforms by alternative 3’ splicing: a membrane-bound (ST2L), a secreted (sST2) and a variant (ST2V) protein.^57,59–63 ST2L is a transmembrane receptor expressed in the cell surface, having an intracellular domain, a single transmembrane domain and an extracellular domain formed by three immunoglobulin (Ig)- like repeats.^57,59,61,64 Like the rest of the members of the IL-1 receptor/tolllike receptor (IL-1R/TLR) superfamily, it has a cytosolic toll/IL-1 receptor (TIR) domain responsible for signalling after receptor activation;^64–66 and as part of the type I IL-1 receptor (IL-1RI)-like subfamily, it has extracellular Ig-like domains responsible for ligand binding.⁶⁴ The sST2 form can be measured in circulating blood and consists of the extracellular domain only, lacking the transmembrane and intracellular ones; it is considered to act as a decoy receptor, competitively binding IL-33, hence preventing its effect through the ST2L receptor.^{57,59,61,67–70} The third ST2 form (ST2V) is the result of an inserted nucleotide sequence in the middle of ST2 DNA, leading to the absence of the third Ig-like domain;⁶² it seemed to have a different expression pattern from sST2 and ST2L,⁶³ and the importance and physiological role of this variant remain unknown.