Role of Biomarkers in Heart Failure

Introduction

Heart failure (HF) is a progressive clinical syndrome characterized by impaired ability of the heart to pump or fill with blood, leading to symptoms such as dyspnea, fatigue, and fluid retention. It is one of the leading causes of morbidity and mortality worldwide, imposing a substantial economic and social burden.

A major challenge in HF management is the timely diagnosis and risk stratification of patients. Clinical evaluation alone may be insufficient due to overlapping symptoms with other conditions (e.g., COPD, renal disease). This is where biomarkers play an essential role.

Biomarkers in HF provide diagnostic, prognostic, and therapeutic information. They are measurable biological molecules that reflect underlying pathophysiological processes such as myocardial stress, injury, inflammation, remodeling, and neurohormonal activation.

Among these, natriuretic peptides (BNP and NT-proBNP) and cardiac troponins are the most established, while a wide range of novel biomarkers continue to emerge from research.

This article provides a detailed overview of the role of biomarkers in heart failure, focusing on BNP, NT-proBNP, troponins, and new candidates with clinical relevance.

1. Natriuretic Peptides (BNP and NT-proBNP)

1.1 Background and Physiology

Brain natriuretic peptide (BNP) and its inactive fragment N-terminal pro-BNP (NT-proBNP) are produced in the heart, primarily by ventricular myocytes, in response to increased wall stress, volume overload, and pressure overload.
BNP is secreted as pro-BNP, which is cleaved into active BNP (biologically functional) and inactive NT-proBNP.
Actions of BNP:
- Natriuresis (excretion of sodium).
- Vasodilation (reduces preload and afterload).
- Inhibition of renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system.

Thus, natriuretic peptides serve as natural counter-regulators in HF.

1.2 Diagnostic Role

BNP and NT-proBNP are first-line biomarkers for diagnosing HF in patients presenting with acute dyspnea.
Elevated levels strongly support HF, while low levels make it unlikely.
Cut-off values (approximate, may vary by guideline):
- BNP: >100 pg/mL suggests HF (higher specificity in acute settings).
- NT-proBNP: >300 pg/mL (acute), >125 pg/mL (chronic).
Advantages:
- High sensitivity in ruling out HF.
- Useful in distinguishing cardiac vs non-cardiac dyspnea.
Limitations:
- Levels influenced by age, sex, renal dysfunction, obesity, atrial fibrillation.
- Interpretation requires integration with clinical context.

1.3 Prognostic Role

BNP/NT-proBNP levels correlate with disease severity, hospitalization risk, and mortality.
Serial measurements can track treatment response (e.g., after diuretics, ACE inhibitors, ARNI therapy).
Persistently high levels indicate poor outcomes, while a decline suggests better prognosis.

1.4 Therapeutic Monitoring

Biomarker-guided therapy using natriuretic peptides has been investigated.
Some studies show benefit in adjusting treatment intensity based on NP levels, particularly in younger patients.
However, guideline recommendations are cautious, suggesting use as adjunctive information rather than the sole basis for therapy decisions.

2. Troponins in Acute Heart Failure

2.1 Background and Physiology

Cardiac troponins (cTnI, cTnT) are structural proteins unique to cardiac myocytes.
They regulate calcium-mediated contraction.
Troponins are released into circulation during myocyte injury or necrosis.

2.2 Role in Acute HF

Traditionally, troponins are used in diagnosing acute myocardial infarction (AMI).
In HF, elevated troponins indicate:
- Ongoing myocardial injury (ischemia, increased wall stress).
- Apoptosis and necrosis due to neurohormonal and hemodynamic stress.
High-sensitivity troponins (hs-cTnT, hs-cTnI) have improved detection of low-level myocardial injury.

2.3 Diagnostic and Prognostic Significance

Elevated troponins in HF patients are not always due to AMI but often reflect:
- Acute decompensated HF (ADHF).
- Chronic progressive HF with ongoing myocyte turnover.
Clinical utility:
- Helps identify acute HF exacerbations with underlying ischemia.
- Provides prognostic information: higher troponin levels predict higher risk of hospitalization and mortality.

2.4 Limitations

Troponin elevation in HF is not specific to ischemia—it may occur due to pressure overload, renal dysfunction, or myocarditis.
Interpretation must consider clinical presentation and ECG/imaging findings.

3. Novel Biomarkers in Heart Failure

Beyond natriuretic peptides and troponins, research has identified numerous novel biomarkers reflecting different aspects of HF pathophysiology.

3.1 Biomarkers of Myocardial Remodeling and Fibrosis

Galectin-3:
- A marker of inflammation and fibrosis.
- Elevated in HF patients with worse outcomes.
- FDA-approved as an adjunct biomarker.
ST2 (soluble suppression of tumorigenicity-2):
- Member of interleukin-1 receptor family.
- Reflects myocardial strain and fibrosis.
- Provides additive prognostic value beyond BNP.
- Less affected by age, sex, renal function.

3.2 Biomarkers of Inflammation and Oxidative Stress

C-reactive protein (CRP): Elevated in HF due to systemic inflammation.
Growth differentiation factor-15 (GDF-15): Linked with oxidative stress, remodeling, and poor outcomes.
Myeloperoxidase (MPO): Indicates oxidative stress, associated with worse prognosis.

3.3 Biomarkers of Renal Dysfunction

HF and kidney disease are closely linked (cardiorenal syndrome).
Cystatin C: Marker of renal function; superior to creatinine in detecting early impairment.
Neutrophil gelatinase-associated lipocalin (NGAL): Predicts acute kidney injury in HF patients.

3.4 Biomarkers of Neurohormonal Activation

Copeptin: Surrogate marker of vasopressin activity.
Adrenomedullin (ADM) and Mid-regional pro-adrenomedullin (MR-proADM): Reflect vascular tone regulation; high levels predict adverse outcomes.

3.5 Biomarkers of Metabolic Dysfunction

Adiponectin: Elevated in advanced HF, paradoxically associated with worse prognosis.
Ketone metabolism markers: Emerging area, as failing hearts rely on altered substrate metabolism.

3.6 Multi-Biomarker Strategies

Combining multiple biomarkers (BNP + troponin + ST2 + galectin-3) enhances risk stratification.
Personalized biomarker panels may allow precision medicine in HF.

4. Clinical Relevance of Biomarkers in HF

4.1 Advantages

Non-invasive and widely available.
Provide objective measures to support clinical decision-making.
Aid in diagnosis, prognosis, risk stratification, and therapy monitoring.

4.2 Limitations

No single biomarker is perfect.
Influenced by comorbidities (renal disease, obesity, inflammation).
High costs of novel assays limit routine use.

4.3 Current Guideline Perspective

BNP and NT-proBNP: Recommended for diagnosis and risk assessment (ESC, ACC/AHA guidelines).
Troponins: Recommended in suspected acute HF to evaluate for ischemia.
Galectin-3 and ST2: Considered for prognosis, but not universally adopted in guidelines.

5. Future Directions

Integration with AI and machine learning: Predictive models using biomarker panels + clinical data.
Point-of-care testing: Rapid bedside assays for early diagnosis.
Genomic and proteomic approaches: Discovery of patient-specific molecular signatures.
Therapeutic targeting: Some biomarkers (e.g., galectin-3, ST2) may become treatment targets.