Harriette Van Spall:
I'm Harriette Van Spall, a clinical trialist from Canada, and I'm delighted to be joined by Professor James Januzzi, Professor of Medicine at Harvard Medical School and a leading expert in cardiovascular biomarkers. Welcome, Professor Januzzi.

James Januzzi:
Thank you very much, Dr Van Spall. I appreciate the invitation.

Harriette Van Spall:
Let's start with a fundamental question. What is a biomarker, and what makes a good biomarker?

James Januzzi:
A biomarker is a measurable biological indicator. That can include imaging findings, circulating proteins, genetic information, transcriptomic markers and many other measurable signals. Clinicians often think of biomarkers as blood tests, but even routine laboratory measurements such as sodium are biomarkers. A good biomarker is one that answers the clinical question for which it is being used. Its value depends heavily on the setting in which it is measured and interpreted.

Harriette Van Spall:
NT-proBNP is one of the most widely used biomarkers in heart failure. How can it be used in people at risk of heart failure and in those with established disease?

James Januzzi:
Clinical practice has evolved considerably in this area. Elevated natriuretic peptide concentrations in patients without a diagnosis of heart failure should not be dismissed as false positives. In many cases, they identify patients who are at increased risk of developing heart failure or who may already have undiagnosed disease.

Patients with diabetes, hypertension and chronic kidney disease are particularly important populations in whom elevated NT-proBNP identifies increased risk. Values above approximately 125 pg/mL are associated with a substantially greater likelihood of future heart failure events.

Harriette Van Spall:
How should NT-proBNP be used in the diagnosis of heart failure, and how should clinicians interpret values across the ejection fraction spectrum?

James Januzzi:
We generally use the same diagnostic thresholds regardless of ejection fraction because ejection fraction is often unknown at the time of initial assessment. We do, however, adjust thresholds according to age.

Patients with heart failure with preserved ejection fraction tend to have lower natriuretic peptide concentrations than those with reduced ejection fraction. This is partly because obesity is more common in HFpEF and partly because ventricular wall stress is lower in smaller ventricular chambers. As a result, clinicians need to interpret natriuretic peptide levels within the broader clinical context.

Harriette Van Spall:
Chronic kidney disease is common in heart failure. What challenges does it create when interpreting biomarkers?

James Januzzi:
Chronic kidney disease influences biomarker concentrations through two mechanisms. First, it increases cardiovascular risk and cardiac injury. Second, it reduces the clearance of many biomarkers.

For natriuretic peptides, it can therefore be difficult to distinguish between elevated values caused by cardiac disease and those partly related to impaired renal function. We still do not know whether universal diagnostic threshold adjustments are required for patients with chronic kidney disease.

Harriette Van Spall:
What additional biomarkers might be useful in these patients?

James Januzzi:
Cystatin C is an important marker because it provides a complementary assessment of kidney function and cardiorenal risk. Urinary albumin-to-creatinine ratio (UACR) is also highly valuable. Although NT-proBNP remains the strongest heart failure biomarker, albuminuria provides important prognostic information and can identify patients at increased cardiovascular and renal risk.

Harriette Van Spall:
When do you use cystatin C in clinical practice?

James Januzzi:
Cystatin C is particularly useful in patients with mild chronic kidney disease, reduced muscle mass, amputations or conditions where creatinine-based assessments may be less reliable. It often provides a more accurate estimate of kidney function in these groups.

Harriette Van Spall:
Albuminuria remains under-recognised despite being a powerful predictor of adverse cardiovascular outcomes. Who should undergo UACR testing?

James Januzzi:
People with diabetes should routinely have UACR measured, given their increased risk of chronic kidney disease. Many patients with heart failure would also benefit from regular assessment.

UACR not only identifies risk but can also help guide treatment decisions because therapies that reduce albuminuria, including SGLT2 inhibitors, GLP-1 receptor agonists, mineralocorticoid receptor antagonists and renin–angiotensin system inhibitors, are associated with improved cardiovascular and renal outcomes.

Current guidelines recommend confirming an abnormal UACR result with repeat testing. A value above 30 mg/g is considered abnormal, while values above 100 mg/g and 300 mg/g indicate progressively higher levels of risk.

Harriette Van Spall:
Professor Januzzi, thank you for this excellent overview of biomarkers and their role in heart failure.

James Januzzi:
Thank you very much, Harriette. It's been a pleasure to join you.

Harriette Van Spall:
Thank you for sharing your expertise with us.

James Januzzi:
Thank you for having me.