Serum transthyretin decline: an early warning signal for heart failure in hATTR-CM

Introduction

Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive infiltrative cardiomyopathy that arises from the misfolding of the transthyretin protein leading to amyloid deposition. Nowadays, a few biomarker-based prognostic models for ATTR-CM have been proposed. Serum transthyretin levels (sTTR) may serve as a surrogate marker of disease burden and amyloid deposition. Despite its potential, the prognostic value of sTTR and its association with clinical outcomes remains uncertain.

Aims

To evaluate the prognostic value of sTTR in patients with hereditary transthyretin cardiac amyloidosis (hATTR-CM).

Methods

We conducted a single-center retrospective observational study including patients diagnosed with hATTR-CM between 2022-2025. Diagnosis was established according to international criteria, including genetic testing. Clinical, laboratory, 99mTC-DPD scintigraphy and echocardiographic data were collected at baseline and during follow-up. sTTR levels (measured as pre-albumin) were collected at baseline and serially during follow-up and were correlated with disease severity and prognostic events.

Results

A total of 51 patients with hATTR-CM were included (median age at diagnosis 57 years [IQR 47–67]; 40 [78%] male). The majority carried the Val30Met variant (44 [86%]), followed by V122I (6 [12%]) and G89L (1 [2%]). Hypertension was present in 40 (78%) and atrial fibrillation in 11 (22%). Forty patients were treated with tafamidis 61mg and 9 with vutrisiran. Median sTTR at diagnosis was 20 mg/dL (IQR 12–24).

Lower sTTR levels were observed in patients with greater functional impairment requiring diuretics, (23 [IQR 16–26] vs 27 [IQR 22–33]; p=0.047) and in those with interventricular septum thickness >15 mm (21 ± 3 vs 26 ± 1 mm; p=0.049). A non-significant trend towards lower sTTR levels was seen in patients with a Perugini score 3 on 99mTC-DPD bone scintigraphy (22.5 ± 2 vs 26 ± 2 mg/dL; p=0.20).

During a mean follow-up of 35 months, 11 heart-failure (HF) decompensations requiring diuretic uptitration occurred. Patients who experienced HF events had significantly lower sTTR at diagnosis (17.7 ± 3 vs 26 ± 1 mg/dL; p=0.010). A decline in sTTR from baseline was also strongly associated with cardiovascular events (−1.3 ± 0.6 vs +6 ± 1 mg/dL in those without events; p=0.010).

Patients with sTTR <25 mg/dL had shorter event-free survival compared with those ≥25 mg/dL (log-rank χ²=4.48; p=0.034). In Cox regression analysis, low sTTR was associated with a seven-fold higher risk of events (HR 7.06; 95% CI 0.85–58.7; p=0.071).

Conclusion

Lower serum transthyretin levels at diagnosis were associated with more advanced cardiac involvement, impaired functional status and a higher risk of subsequent heart failure decompensation. sTTR may represent a practical and clinically relevant biomarker for disease severity and short-term prognosis in hATTR-CM, serving as a complementary tool alongside established markers such as NT-proBNP.For image description, please refer to the figure legend and surrounding text.