When imaging is not enough: diagnostic performance of endomyocardial biopsy in cardiac amyloidosis

Introduction

The diagnosis of cardiac amyloidosis (CA) has increased in recent years, driven by growing clinical awareness and the recognition of clinical, echocardiographic and electrocardiographic red flags. Non-invasive diagnostic tools, such as bone scintigraphy, have become pivotal in the diagnostic algorithm; however, they can yield inconclusive or false-negative results in a relevant subset of patients. In these cases, endomyocardial biopsy (EMB) remains the gold standard, yet real-world data on its diagnostic yield, safety, and predictors of positivity are limited.

Aim

To evaluate the diagnostic performance and safety of EMB in CA and to identify clinical and imaging predictors of biopsy positivity.

Results

A total of 46 patients underwent endomyocardial biopsy for suspected CA (mean age 64 ± 2 years; 46% male). Among them, 41% were referred due to negative 99mTC-DPD scintigraphy and 59% due to abnormal immunofixation. Amyloid was histologically confirmed in 34 patients (74%): 59% TTR, 21% AL, 15% mixed TTR+AL, and 5% with non-characterizable/nonspecific amyloid.

Compared with biopsy-negative patients, those with positive biopsies showed a trend toward more advanced heart failure symptoms (NYHA III/IV: 15% vs 0%, p=0.10) and significantly higher NT-proBNP levels (3694 [IQR 1051–12826] vs 872 pg/mL [IQR 155–3065], p=0.02). ECG findings showed a non-significant trend toward longer PR intervals (181 [172–196] vs 150 ms [148–209], p=0.10). Biopsy-positive patients exhibited more pronounced structural remodeling, with greater myocardial wall thickening with higher prevalence of interventricular septum thickness ≥13 mm (80% vs 42%, p=0.02), increased posterior wall thickness (14.5 ± 0.7 vs 11.6 ± 1 mm, p=0.03) and higher indexed LV mass (166 ± 14 vs 119 ± 15 g/m², p=0.03). In logistic regression analysis, posterior wall thickness emerged as an independent predictor of biopsy positivity, with each 1-mm increase significantly increasing the odds of biopsy positivity (OR 1.28, 95% CI 1.00–1.63, p=0.046).

No significant association was found between 99mTC-DPD scintigraphy grade and biopsy results. No biopsy-related complications occurred. During a mean follow-up of 24 ± 3 months, one of the 12 biopsy-negative patients was subsequently diagnosed with AL amyloidosis on extracardiac biopsy. EMB demonstrated 97% sensitivity and 100% specificity, with no false positives and one false negative.

Conclusion

Non-invasive imaging plays an essential role in the diagnostic workup of cardiac amyloidosis and is sufficient in many cases. However, our findings highlight that in patients with high clinical suspicion, particularly those with elevated NT-proBNP and increased myocardial wall thickness, EMB provides excellent diagnostic accuracy and can be safely performed. Therefore, EMB should be considered an integral and safe diagnostic approach when non-invasive methods are inconclusive despite strong clinical suspicion.For image description, please refer to the figure legend and surrounding text.