by Dr Roopa Rao and Arden Shen

The incidence of heart failure (HF) is increasing globally. Biomarkers in HF play a key role in diagnosis and prognostication. Ideal biomarkers should be easily measurable with distinct values in normal physiology, disease state and be a marker of therapeutic intervention. Several biomarkers have emerged that are potentially useful for diagnosing HF; however, only a few are used clinically. Presently, key biomarkers used for HF include natriuretic peptides (NPs), cardiac troponins, soluble ST2, galectin-3, and high-sensitivity C-reactive protein. Among these, B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) stand out as the gold standard for both diagnosis and prognosis of HF.

Origin of natriuretic peptides

The heart functions like an endocrine organ and releases biologically active natriuretic peptides (NPs) when the myocardium is stretched. Atrial natriuretic peptide (ANP) is released by the atrium, B-type natriuretic peptide (BNP) released by the ventricle, and C-type natriuretic peptide (CNP) by vascular endothelium. The NPs counteract renin-angiotensin effects, reducing fibrosis, hypertrophy, and promoting natriuresis and diuresis. ANP, with a half-life of 1 minute, is quickly cleared and less consistent as a heart failure (HF) biomarker compared to BNP. BNP undergoes conversion into pre-proBNP, then proBNP, and is finally cleaved into bioactive BNP and inert NT-proBNP. Neprilysin, which is an endopeptidase, swiftly clears BNP from circulation. This results in a half-life of approximately 20 minutes, whereas NT-proBNP has a longer half-life of about 120 minutes. The impact of neprilysin on BNP clearance and fragmentation suggests that NT-proBNP might offer a more stable measurement.

There are multiple commercially available automated and point-of-care assays for both BNP and NT-proBNP. For healthy individuals, both BNP and NT-proBNP levels should be close to zero; however, various comorbidities or other stressors could increase BNP and NT-proBNP in the absence of HF. Current American Heart Association guidelines suggests BNP ≥35 pg/mL and NT-proBNP ≥125 pg/mL as thresholds for HF. However, recent advances have identified an age-stratified model for improved diagnostic performance HF. The International Collaborative of NT-proBNP Study found that NT-proBNP levels ≥450, ≥900, and ≥1800 pg/mL for ages less than 50, between 50 and 75, and greater than 75 years respectively provided the best predictive values for excluding HF diagnosis in an acute setting (Table 1). A multiple cut-point has also been suggested to help with the exclusion and identification of those in HF. The results of the Breathing Not Properly Multinational Study identified BNP values <100 pg/mL for ruling out acute exacerbation of HF, values >400 pg/mL for diagnosis of HF, and values between 100–400 pg/mL as a ‘grey zone’. Comorbidities can also lead to unexpectedly low NPs (Table 2). Obesity has been shown to suppress the BNP gene, thus decreasing BNP levels.

NPs in prognostication

BNP serves as an early indicator of wall stress before structural changes are detectable on echocardiogram. The redefined Stage B Heart Failure definition encompasses those with structural heart disease or congestion, evidenced by elevated filling pressures or abnormal NP or high-sensitivity troponin. This revised HF definition reclassifies many individuals, particularly women, Hispanics, and Black individuals, from Stage A to Stage B HF. Early identification in the pre-HF stage offers potential for timely intervention.

Serial NP level trends during hospitalization may signal prognosis in acute HF exacerbation. A 30% drop from presentation to discharge suggests a more favourable prognosis, whereas persistently elevated levels may indicate significant ventricular remodelling and worsening HF. Predischarge NT-proBNP > 1000 pg/mL poses a risk of readmission and an overall poor prognosis. NP levels are standard in HF clinical trials for inclusion and treatment response monitoring.

Table 1. N-terminal pro-B-type natriuretic peptide (NT-proBNP) age-stratified cut-off values in acute and outpatient settings

Table 2. Comorbidities that may affect NP values AHA, American Heart Association; COPD, chronic obstructive pulmonary disease; HF, heart failure.

Cardiac troponins

Troponin levels, primarily a marker of cardiac injury, are noted to be elevated in HF. The mechanism is thought to be due to elevated end diastolic pressure, decreased perfusion of the endocardium, myocardial stretch, infiltrative disease states, and inflammation. Troponin values are higher in men than women, one of the proposed mechanisms being higher ventricular mass in men. Troponin levels in HF typically show mild elevation and tend to decline more slowly than NPs once an acute exacerbation resolves.

Soluble ST2

Soluble ST2 (suppression of tumorigenicity 2 protein) is a member of the interleukin 1 family and is expressed by myocardial cells under stress. This is a marker of ventricular remodelling and fibrosis. In the PRIDE study, the ST2 levels were higher in the acute HF patients (0.50 ng/mL). This is a powerful marker of mortality with the higher values significantly correlating with risk of 1-year mortality. Unlike NP, ST2 is not confounded by age, renal failure, and obesity. Despite the promising results, the utility of ST2 is limited to research studies and has not entered day-to-day clinical decision making.

Galectin-3 and insulin-like growth factor binding protein

Galectin-3 is a biomarker of inflammation and fibrosis and is primarily located in the cytoplasm and widely expressed by various cell types. Galectin-3 has been a marker of prognosis in both acute and chronic HF, higher values indicative of mortality, hospital readmission and is a marker of incident HF.

Biomarkers in diastolic HF

In diastolic HF, myocardial stretch and increased end diastolic pressure triggers NP release, yet NT-proBNP levels are lower than in HF with reduced ejection fraction (HFrEF). Comorbidities linked to HF with preserved ejection fraction (HFpEF), such as obesity and renal failure, can influence overall levels of NPs. The severity of NP elevation aligns with diastolic dysfunction, especially in restrictive patterns. Diastolic HF exhibits increased cardiac troponins, fibrosis, and inflammation markers, mirroring findings in HFrEF.

Future directions

Clustering of different biomarkers and phenotyping HF with the use of artificial intelligence is evolving. Woolley et al. (2021) employed >300 biomarkers, categorizing diastolic HF into four phenotypes with diverse pathophysiological and clinical outcomes. MicroRNA expression is altered in cardiomyopathy and several microRNAs have been identified as dysregulated or upregulated in HF. Identifying these RNAs could serve as early markers, enhancing prognosis and pointing towards future gene therapy possibilities.

 Bibliography
1. Nadar SK, Shaikh MM. Biomarkers in routine heart failure clinical care. Card Fail Rev 2019;5(1):50–56 (https://www.cfrjournal.com/articles/biomarkers-routine-heart-failure-clinical-care).
2. Januzzi J. Natriuretic peptides as biomarkers in heart failure. J Investig Med 2013;61(6):950–955 (https://journals.sagepub.com/doi/10.2310/JIM.0b013e3182946b69).
3. Mehra MR, Uber PA, Park MH et al. Obesity and suppressed B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol 2004;43(9):1590–1595 (https://www.sciencedirect.com/science/article/pii/S0735109704003547?via%3Dihub).
4. Writing Committee Members; ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Card Fail 2022;28(5):e1–e167 ( https://bitly.ws/3f97I ).
5. Woolley RJ, Ceelen D, Ouwerkerk W et al. Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction. Eur J Heart Fail 2021;23(6):983–991 (https://pubmed.ncbi.nlm.nih.gov/33651430/).
6. Januzzi JL Jr, Peacock WF, Maisel AS et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50(7):607–613 ( https://www.sciencedirect.com/science/article/pii/S0735109707016993?via%3Dihub ).

The authors

Roopa Rao1* MD and Arden Shen2
1 Department of Internal Medicine/Cardiology,
Indiana University, Indianapolis,
Indiana 46032, USA
2 Indiana University, Indianapolis,
Indiana 46032, USA

* Corresponding author
Email: rrao@iuhealth.org