Abstract Background Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disorder characterized by the deposition of transthyretin (TTR) amyloid fibrils in the myocardium. Tafamidis, a TTR stabilizer, has been shown to reduce mortality and hospitalizations in ATTR-CA patients. However, its biochemical effects on circulating TTR species have not been assessed in vivo. Purpose To evaluate longitudinal changes in TTR and retinol-binding protein 4 (RBP4) levels in ATTR-CA patients undergoing tafamidis therapy using native electrophoresis and Western blotting. Methods Forty-eight ATTR-CA patients and 41 age- and sex-matched controls were enrolled. Plasma TTR and RBP4 levels were measured at baseline and at 14, 30, 90, and 180 days following tafamidis initiation in ATTR-CA patients. Native electrophoresis and mass spectrometry-based proteomic analysis were used to characterize TTR isoforms and TTR-RBP4 complexes. Results A significant increase in plasma TTR concentration and a slight decrease in RBP4 levels were observed at all time points during the 180-day follow-up compared to baseline. However, tafamidis treatment did not result in significant changes in clinical parameters, functional capacity, echocardiographic findings, or cardiac, renal, and liver biomarkers over six months. Electrophoretic analysis revealed distinct circulating TTR isoforms in ATTR-CA patients and controls. Tafamidis significantly reduced low-molecular-weight (MW) TTR species, including dimers and trimers. Proteomic analysis confirmed the presence of TTR-RBP4 complexes and identified changes in TTR isoform distribution post-treatment. Conclusions Tafamidis reduces circulating low-MW TTR species, an effect that may contribute to its clinical benefits. The increase in total TTR concentration suggests its potential utility as a pharmacodynamic biomarker.
Castiglione et al. (Sat,) studied this question.