Dr. Sundeep Mishra details on new biomarkers in heart failure that can serve as essential indicators for diagnosis, prognosis, risk stratification, therapeutic targeting, and therapeutic guidance.

Heart failure (HF) is the end-stage of a wide range of cardiovascular diseases that result in the decompensation of the heart's ability to act as a pump (contract/relax), producing typical signs and symptoms of fluid overload and insufficient blood supply to organs. While essentially a mechanical problem, its pathophysiology involves release of a series of factors, hormones, and proteins into the bloodstream, which could be utilised as diagnostic biomarkers.

Natriuretic peptides (NPs) are the biomarkers classically associated with heart failure and therefore their estimation plays an important role in routine clinical practice. Natriuretic peptides (NPs) are composed of three structurally similar peptides, i.e. atrial natriuretic peptide (ANP), B-type (or brain) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They are essentially released in response to stretch; increased wall stretching due to volume or load stress in HF.

In reality BNPs play a critical role in maintaining homeostasis in the cardiovascular system, serving as counter-regulatory hormones for volume and pressure overload. Indeed, the levels of blood BNP and the N-terminal pro-B-type natriuretic peptide (NT-proBNP) are widely measured in clinical applications for the diagnosis, risk stratification, and management of patients with HF, as they are the closest to optimal biomarker standards for clinical outcomes in HF. Furthermore, they can even be used in the diagnosis of HF; higher levels suggesting that the aetiology of dyspnoea in a random patient could be because of HF.

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BNP or NT-proBNP

As discussed BNP is synthesised and released by cardiac ventricular cells in response to volume or pressure overload. Both active BNP and inactive NT-proBNP are generated from the cleavage of proBNP and therefore they are secreted into the bloodstream in equal concentrations. While ANP is stored as the preform in the intracellular granules, BNP is predominantly synthesised when triggered by extracellular stimuli, thus, BNP is more useful in context of HF.

BNP once secreted activates the intracellular cGMP signaling cascades to reduce the volume or pressure overload thus benefitting patients with HF. BNP and NT-proBNP are the two most commonly used natriuretic peptides and play a diagnostic role in the assessment of any pathology of HF; systolic and/or diastolic dysfunction, left ventricular hypertrophy, valvular heart disease, ischaemia, or a combination of these factors. Moreover, the measurement of BNP is also highly predictive of congestive heart failure (OR 29.60). Thus, BNP appears to be the single best predictor of a final diagnosis of HF, far over and above individual history, physical examination, chest X-ray, and other laboratory findings. Finally, the BNP level in the bloodstream could also serve as a therapeutic target for HF.

The value of NPs is so robust that current guidelines recommend the use of BNP/NT-proBNP in the diagnostic algorithm for HF, especially for the patients whose echocardiography was not found to reveal any significant cardiac abnormality, higher levels indicating a higher likelihood for decompensated HF as a cause of acute dyspnoea. Practically, these tests help clinicians to rule out heart failure quickly and identify those who would benefit from additional confirmatory tests, typically echocardiography.

In addition to their utility in HF diagnosis, the levels of BNP/NT-proBNP are remarkably useful for risk stratification and management of patients with suspected HF. In HF management, the trend of decreasing levels of natriuretic peptide indicates effective management strategies.

As a matter of fact, NP-guided treatment can decrease the all-cause mortality and readmission rate compared with clinically guided therapy in select HF patients. Moreover, levels of BNP and NT-proBNP also have prognostic value. Furthermore, NT-proBNP can improve the prediction of HF in patients with type 2 diabetes. Finally, assessment of risk stratification is particularly important in planning end-of-life care for patients and when making the decision to undergo cardiac surgery (including transplantation) and non-cardiac surgery.

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Galectin-3 (Gal-3)

Gal-3 is a member of the inflammation mediators and is related to the extent of myocardial inflammation and fibrosis, which is also negatively correlated with ventricular ejection fraction. Serum Gal-3 is related to left ventricular dilation and is a contributory factor in predicting the outcome and guiding the monitoring of patients with both acute heart failure and chronic heart failure.

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Suppression of Tumorigenicity 2 (ST2)

ST2 is a member of IL-1 receptor family with two forms, namely, transmembrane (ST2L) and soluble (sST2) isoforms. The 2017 ACCF/AHA guidelines for the management of heart failure have specified ST2 receptors and galectin-3 as prognostic biomarkers for the prediction of hospitalisation and death and to provide additional prognostic value in patients with HF. Moreover, sST2 have a beneficial role in diagnosing heart failure, especially for patients with high IL-33 levels.

The sST2-assist score enables the prediction of left ventricular reverse remodeling in systolic heart failure patients, and the sST2 concentration is highly related to cardiac death and readmission for worsening heart failure. sST2 estimation also contributes to the risk stratification for long-term HF and is superior to Gal-3, whose contribution to clinical risk factors is trivial. However, it should be noted that compared with NT-proBNP, the prognostic information of baseline sST2 is much less.

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Cystatin C (cys-C)

cys-C is generated in almost all human nucleated cells and serves as a biomarker for early renal impairment. An elevated cys-C level is associated with higher readmission rates and all-cause mortality in HF patients.

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Long Noncoding RNAs (lncRNAs)

lncRNAs could predict future death in patients with heart failure.

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Sirtuin (SIRT)

The SIRT family, comprising seven proteins (SIRT1–SIRT7), attracted attention as stress adaptors and epigenetic enzymes involved in the cellular events controlling aging-related disorders and cardiovascular disease, endogenous SIRT1 playing a pivotal role in mediating the cell death/survival process and has been implicated in the pathogenesis of cardiovascular diseases. Among sirtuins, SIRT1 is the best characterised protein for its protective roles in heart disease, its mRNA expression significantly down-regulated in the failing heart.

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Thus, biomarkers are useful in a variety of situations in heart failure; diagnostic, prognostic, risk stratification, therapeutic targeting and therapeutic guidance. The role of various biomarkers in heart failure is discussed in the table.

Biomarker	Patho-physiology	Clinical usefulness
BNP/NT-proBNP		Diagnostic Prognostic Risk stratification Therapeutic target
Gal-3	Myocyte stretch	Therapeutic guidance Prognostic
ST-2	Hypertrophy/fibrosis	Therapeutic guidance Risk stratification Prognostic
cys-C	Myocardial injury	Therapeutic guidance Prognostic
lncRNA	-	Potential prognostic value
SIRT	Oxidative stress	Potential prognostic value

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To read other articles by Dr. Mishra, click here.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Sundeep Mishra is a Professor of Cardiology.