Determinants and Clinical Interpretation of Circulating Transthyretin in ATTR Amyloidosis.

BACKGROUND: Transthyretin (TTR) amyloidosis (ATTR) ranges from localized to systemic disease, but the clinical interpretation of circulating TTR remains uncertain. OBJECTIVES: The objective of the study was to characterize serum TTR in ATTR and identify longitudinal determinants, including disease-modifying therapies. METHODS: In a single-center cohort, 134 patients with ATTR were enrolled. Serum TTR was measured at baseline (91 treatment-naive patients) and longitudinally during follow-up (347 measurements). Linear mixed-effects models were used to identify clinical and therapeutic determinants of circulating TTR. RESULTS: Baseline TTR levels declined across clinical stages, from isolated carpal tunnel syndrome to symptomatic heart failure (27 vs 20 mg/dL). In longitudinal mixed-effects analyses, older age (β = -0.310, P < 0.001), inflammation (log10[C-reactive protein+0.1], β = -6.011, P < 0.001), and cardiac stress (log10BNP, β = -1.460, P = 0.033) were independently associated with lower TTR levels, whereas albumin was positively associated (β = 3.041; P < 0.001). Wild-type ATTR showed higher TTR levels than variant ATTR (β = 6.766; P < 0.001). Tetramer stabilizers increased TTR (β = 8.095; P < 0.001), whereas small-interfering RNA therapy reduced TTR levels (β = -13.456; P < 0.001). Following stabilizer initiation, median TTR increased from 21.5 mg/dL to 32.2 mg/dL after >730 days of therapy. CONCLUSIONS: Circulating TTR reflects the integrated effects of systemic status and therapeutic interventions and should not be interpreted as a simple surrogate of ATTR disease severity.