Cardiac amyloidosis is a progressive stiffening of the heart muscle that leads to heart failure. There are two main types of disease and treatment differs accordingly. Several cardiac biomarkers are useful for disease diagnosis, staging and therapeutic decision making. CLI chatted to Dr Andreea Foghis (Washington University in Saint Louis, MO, USA) to discover more about how high-sensitivity cardiac troponin I assays can be usefully added to the mix of existing biomarkers.

Can you give us some background about cardiac amyloidosis, please?

Cardiac amyloidosis is an underrecognized but increasingly diagnosed cause of heart failure, driven by the deposition of misfolded proteins within the myocardium. This process leads to progressive stiffening of the heart muscle and a restrictive cardiomyopathy. The two main subtypes are light-chain (AL) amyloidosis, resulting from a plasma cell disorder, and transthyretin (ATTR) amyloidosis, which may be hereditary or age-related and is now more frequently identified in older adults.

Advances in diagnostic tools have revealed that the condition is more common than previously thought, particularly among patients with heart failure with preserved ejection fraction. Prognosis is closely linked to the degree of cardiac involvement and is typically assessed using biomarkers such as cardiac troponins, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and, in AL amyloidosis, serum free light chains (FLCs). These markers form the basis of established staging systems that help guide clinical decision-making.

Treatment strategies differ by subtype but have evolved significantly in recent years. In AL amyloidosis, therapy targets the underlying plasma cell clone, while in ATTR amyloidosis, disease-modifying treatments aim to stabilize or reduce transthyretin production. Together with optimized supportive care, these advances are reshaping outcomes and highlight the importance of early recognition and precise diagnosis.

What biomarkers are usually used for determining cardiac amyloidosis staging and prognosis?

Cardiac amyloidosis staging and prognosis are guided by a small set of well-validated circulating biomarkers that reflect myocardial injury, hemodynamic stress and underlying disease burden. In clinical practice, the most widely used markers are cardiac troponins [particularly cardiac troponin T (cTnT)], NT-proBNP and serum FLCs.

cTnT serves as a sensitive indicator of ongoing myocardial injury caused by amyloid infiltration, with levels ≥0.025 ng/mL (or ~40 ng/L using high-sensitivity assays) associated with worse outcomes. NT-proBNP, a marker of cardiac wall stress, is often markedly elevated in these patients; a threshold of ≥1800 pg/mL is commonly used in staging systems and carries significant prognostic weight. In AL amyloidosis, the difference between involved and uninvolved serum FLCs (dFLC) reflects clonal disease activity, with levels ≥18 mg/dL (≥180 µg/mL) indicating higher disease burden. These biomarkers are integrated into the Mayo Clinic staging system, where the number of abnormal values directly correlates with survival. This biomarker-driven approach has become central to risk stratification, enabling clinicians to more accurately predict outcomes and tailor management strategies.

Can other cardiac biomarkers be used also?

Yes – beyond the established biomarkers such as cTnT, NT-proBNP, and serum FLCs, there is growing interest in the role of cardiac troponin I (cTnI) as an alternative marker of myocardial injury in cardiac amyloidosis.

This interest is driven by both practical and clinical considerations. Although cTnT measurement is embedded in widely used staging systems assay availability varies across institutions and high-sensitivity cTnI assays are often routinely used in clinical practice as well. As evidence of this, the Boston University staging system for amyloidosis uses cTnI. However, data supporting prognostic equivalence between cTnI and cTnT in staging cardiac amyloidosis – particularly in AL disease – have historically been limited.

In this context, a study that we recently presented at the Association for Diagnostics and Labroatory Medicine Annual meeting sought to directly compare the prognostic utility of high-sensitivity cTnI assays with cTnT measurement in patients with AL cardiac amyloidosis.
We conducted a prospective observational analysis including 117 patients, with 347 remnant specimens analysed over a two-year follow-up period. Samples initially tested for cTnT were subsequently assessed by high-sensitivity cTnI assay using a Abbott Alinity platform, and outcomes were determined through chart review, focusing on 24-month mortality.

Using the established Mayo Clinic staging framework – based on thresholds for troponin, NT-proBNP (≥1800 pg/mL) and FLC – we evaluated how cTnI performed relative to cTnT in risk stratification. Receiver operating characteristic curve analysis was used to define optimal, including sex-specific, cTnI thresholds, and predictive performance was assessed through measures such as positive
and negative predictive values.

Our findings demonstrated that high-sensitivity cTnI provides robust prognostic information, with strong discrimination for mortality comparable to cTnT. These results suggest that cTnI may serve as a reliable alternative biomarker for staging and risk assessment in AL cardiac amyloidosis, particularly in settings where cTnT is not readily available.

Overall, incorporating cTnI into clinical practice could enhance flexibility in biomarker-based prognostication while maintaining the accuracy needed for guiding therapeutic decisions.

Are there any advantages of the different biomarkers?

Each of the key biomarkers (troponin, natriuretic peptides, and sFLC)used in prognosticating cardiac amyloidosis reflectdifferent aspects of disease biology and help refine both diagnosis and prognosis.

Cardiac troponins – whether cTnT or cTnI – are markers of myocardial injury and are central to staging systems. Our findings reinforce that both provide comparable prognostic performance in patients with AL cardiac amyloidosis, supporting the use of either marker in clinical practice. However, there are important nuances. The conventional cTnT threshold used in established staging systems is highly sensitive and therefore maximizes the negative predictive value (NPV) – making it particularly useful for identifying lower-risk patients. At the same time, this comes at the expense of a relatively low positive predictive value (PPV) for mortality, limiting its ability to discriminate among higher-risk groups.

In contrast, high-sensitivity cTnI measurement appears to offer improved granularity at higher risk levels. In our analysis, a threshold of 35 ng/L for cTnI provided prognostic performance comparable to cTnT for overall staging while offering better separation between intermediate and advanced stages, particularly between stage II and stages IIIa/IIIb. This suggests that cTnI may be especially useful in identifying patients with more advanced cardiac involvement, where risk stratification becomes most clinically relevant.

NT-proBNP, by comparison, reflects cardiac wall stress and hemodynamic burden and remains the most sensitive biomarker for detecting cardiac involvement. It is particularly valuable for monitoring disease progression and response to therapy, although it can be influenced by renal function. Serum FLCs, meanwhile, are specific to AL amyloidosis and provide insight into the underlying plasma cell disorder, complementing cardiac biomarkers by capturing systemic disease activity.

Taken together, these biomarkers are not interchangeable but, rather, complementary. Whereas cTnT remains the historical standard, cTnI offers a practical and potentially more discriminative alternative in certain contexts, and its integration into staging frameworks may enhance risk stratification – particularly in patients at the more advanced end of the disease spectrum.

What further developments are on the horizon in this field?

One of the most important developments on the horizon is the refinement of biomarker-based staging systems. As our findings suggest, integrating alternative markers such as high-sensitivity assays for cTnI – alongside established tools such as NT-proBNP and FLCs – may improve risk discrimination, particularly in patients with more advanced disease. Future models are likely to incorporate multi-marker strategies, dynamic (serial) measurements, and potentially renal-adjusted thresholds to enhance prognostic precision. This may be particularly important for distinguishing cardiac involvement in patients with plasma cell dyscrasias.

At the same time, earlier and less invasive diagnosis is becoming a major focus. Advances in cardiac imaging – particularly with cardiac bone scintigraphy and cardiac MRI – are enabling detection of transthyretin amyloidosis without the need for biopsy in many cases. There is also growing interest in screening high-risk populations, such as older patients with heart failure with preserved ejection fraction or aortic stenosis, where cardiac amyloidosis is increasingly recognized.

On the therapeutic front, the landscape is also changing. In transthyretin (ATTR) amyloidosis, disease-modifying therapies that stabilize the transthyretin protein or silence its production at the RNA level are already improving survival and quality of life. Next-generation agents – including more potent gene silencers and even gene-editing approaches – are under active investigation and hold the potential for long-term disease control with infrequent dosing. In AL amyloidosis, ongoing advances in plasma-cell-directed therapies, including monoclonal antibodies and combination regimens, are leading to deeper and more rapid hematologic responses.

Another promising area is the development of amyloid-targeting therapies designed to directly clear deposited fibrils from the myocardium. While still investigational, these approaches aim not just to halt disease progression but to reverse organ dysfunction – an outcome that has historically been difficult to achieve. Finally, there is increasing emphasis on personalized medicine, integrating biomarkers, imaging, genetic data and clinical features to guide treatment selection and monitor response. As awareness continues to grow and diagnostic tools become more accessible, the shift toward earlier detection and more effective, targeted therapies is expected to significantly improve outcomes in what was once considered a uniformly progressive and fatal disease.

The interviewee

Dr Andreea Foghis MD, MS Postdoctoral Research Associate

Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, MO, USA
E-mail: foghis@wustl.edu

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