Serial transthyretin monitoring captures disease trajectory and predicts survival in cardiac amyloidosis

Background Circulating transthyretin (TTR) reflects both disease biology and systemic status in cardiac amyloidosis. While baseline TTR levels may carry prognostic information, the determinants and clinical implications of longitudinal TTR variation remain unclear. Objectives To investigate (1) the prognostic value of baseline TTR levels, (2) the association between longitudinal TTR changes and survival, and (3) predictors of TTR decline in cardiac amyloidosis. Methods We analyzed 492 patients with transthyretin cardiac amyloidosis (ATTR) enrolled in the French national HEAR registry. Baseline TTR was evaluated as a continuous variable and using an outcome-derived cut-off. TTR variation was assessed between baseline and follow-up and analyzed continuously (per 10 mg/dL and per 1 standard deviation increase) and categorically (tertiles of relative change). Multivariable Cox regression models were adjusted for log-transformed NT-proBNP and sex. Determinants of TTR decline were assessed using multivariable logistic regression. Results Baseline TTR below the optimal prognostic cut-off was associated with increased mortality risk independent of NT-proBNP. Each 10 mg/dL increase in TTR over time was independently associated with a 5% reduction in mortality risk (HR 0.95, 95% CI 0.92–0.98; p=0.002). Expressed per 1 standard deviation increase, TTR change was associated with a 29% lower hazard of death (HR 0.71, 95% CI 0.56–0.88; p=0.002). Higher NT-proBNP levels remained strongly associated with mortality (HR 2.10, 95% CI 1.64–2.68; p<0.001). Determinants of TTR decline included markers of disease severity and systemic inflammation, suggesting that worsening cardiac and systemic status contribute to TTR reduction. Adjusted survival curves demonstrated a graded improvement in 48-month survival across tertiles of relative TTR increase. Model discrimination was good (C-index 0.74). Conclusions Both baseline TTR levels and longitudinal changes provide independent prognostic information beyond NT-proBNP in cardiac amyloidosis. Declines in circulating TTR appear to reflect disease severity and systemic burden, whereas increases are associated with improved survival, supporting the role of TTR as a dynamic biomarker of disease activity and potential treatment response.