Orthopaedic red flags at time of diagnosis and disease severity in patients with cardiac amyloidosis

Background

Cardiac amyloidosis (CA) is frequently preceded by soft tissue infiltration, manifesting as orthopaedic "red flags" such as carpal tunnel syndrome (CTS), spontaneous rupture of the distal biceps tendon, and lumbar spinal stenosis. While these signs are recognised as early diagnostic clues, their relationship with the severity of cardiac involvement at the time of diagnosis warrants further investigation.

Purpose

This study aimed to evaluate whether patients with or without orthopaedic red flags at time of diagnosis have different disease severity.

Methods

We retrospectively analysed data from patients referred to our tertiary Center for the diagnostic work-up and management of CA from January 2018 to September 2025. Medical history regarding CTS, spinal stenosis, and biceps rupture was systematically collected.

We compared N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity Troponin T (hs-TnT), and New York Heart Association (NYHA) class using the Wilcoxon rank-sum test.

Results

We enrolled 551 patients (80% male, mean age 77 years) with confirmed cardiac amyloidosis: wild-type ATTR (n=409), variant ATTR (n=16), AL (n=122), ATTR+AL (n=2), and AA amyloidosis (n=2). CTS was present in 31% patients (160 ATTR, 9 AL), distal biceps tendon rupture in 5% (24 ATTR, 1 AL), and spinal canal stenosis in 7% (37 ATTR).

In patients with at least one red flag, median NT-proBNP was 1,764 ng/L (IQR 2,388) compared to 3,335 ng/L (IQR 6,469) in those without red flags (p < 0.0001). Similarly, median hs-TnT was lower in the red flag group (47.5 ng/L vs 61.0 ng/L; p < 0.0001). Symptoms were also milder in the red flag group (p = 0.011), with no patients in NYHA class IV vs 3.3% in the no-red-flag group.

Patients with CTS presented with lower median NT-proBNP (1,764 ng/L vs 3,329 ng/L; p < 0.0001) and lower median hs-TnT (45.0 ng/L vs 61.3 ng/L; p < 0.0001). CTS patients also showed a more favourable NYHA class distribution (p = 0.012), with no patients in class IV (Figure 1).

Conclusions

In this large real-world cohort, patients presenting with orthopaedic red flags had significantly lower markers of haemodynamic stress and myocardial injury, alongside preserved functional capacity. These findings suggest that orthopaedic prodromes facilitate intercepting the heart disease at a distinctively earlier stage of the natural history compared to patients without these musculoskeletal warning signs (Figure 2).Figure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.