Circulating transthyretin as an independent systemic vulnerability signal in transthyretin amyloidosis: insights from the French HEAR Registry

Background In transthyretin amyloidosis (ATTR), prognosis is primarily stratified using cardiac biomarkers reflecting myocardial injury and wall stress. Circulating transthyretin (TTR), beyond its role as the amyloid precursor protein, may reflect systemic biological reserve and metabolic integrity independently of cardiac injury pathways. Objectives To determine whether circulating TTR constitutes an independent systemic prognostic axis in ATTR, distinct from established cardiac biomarkers. Methods We analyzed 1,924 consecutive patients with ATTR enrolled in the French national HEAR registry and managed according to contemporary standards, with 172 patients with non-amyloid cardiomyopathy included as a reference group. Multivariable Cox regression adjusted for age, sex, CRP, creatinine, high-sensitivity troponin T (hsTnT), and NT-proBNP assessed the independent association of TTR with all-cause mortality. Restricted cubic splines evaluated dose-response relationships, and principal component analysis (PCA) explored the biological structure of circulating biomarkers. Results Circulating TTR was significantly lower in ATTR than in non-amyloid cardiomyopathy (230 [187–274] vs. 259 [222–304] mg/L; p<0.001), indicating disease-specific systemic alteration. Within the ATTR cohort (median age 81 years, 79% male, 12% hereditary), 165 deaths occurred over a median follow-up of 23 months. TTR showed modest correlations with cardiac biomarkers (NT-proBNP ρ=−0.19; hsTnT ρ=−0.15) but a stronger association with albumin (ρ=0.34), supporting biological independence from myocardial injury pathways. Four-year mortality increased progressively across decreasing TTR quartiles (Q1: 47% vs. Q4: 23%; log-rank p=0.0023). After full adjustment, each 10 mg/L increment in TTR was independently associated with reduced mortality (HR 0.97, 95% CI 0.94–0.99; p=0.01), with patients in the highest quartile carrying a 42% lower risk of death (HR 0.58, 95% CI 0.36–0.95). Spline modeling confirmed a linear dose-response without threshold effect. PCA identified two orthogonal biological dimensions: a cardiac severity axis (NT-proBNP, hsTnT) and a systemic nutritional-biological axis (TTR, albumin), establishing their biological independence. Conclusions Lower circulating TTR identifies a systemic vulnerability phenotype in ATTR that is biologically and prognostically distinct from myocardial injury. The near-doubling of 4-year mortality across TTR quartiles, independent of established cardiac biomarkers, supports TTR as an autonomous risk dimension. These findings suggest that circulating TTR reflects global metabolic and inflammatory reserve, providing incremental prognostic stratification beyond conventional cardiac staging — and positioning TTR as both a complementary risk biomarker and a potential systemic therapeutic target in ATTR.Impact of TTR on survival