Does human transthyretin aggregate in blood plasma or in cardiac tissue? A mathematical modeling study

Transthyretin (TTR) amyloidosis is a progressive disease characterized by the destabilization of TTR tetramers, leading to monomer dissociation, oligomer formation, and fibril deposition in cardiac tissue. This study presents a mathematical model that captures the kinetics of TTR aggregation and deposition, integrating clinically relevant parameters to distinguish between scenarios of TTR aggregation in blood plasma and cardiac tissue. The governing equations are derived by applying conservation principles to the number of TTR tetramers, monomers, and oligomers within defined control volumes, such as the blood plasma or heart. The model predicts that the scenario with fibril accumulation within cardiac tissue better reflects the clinical progression of wild-type TTR amyloidosis, aligning with observed patient survival times and measured tetramer concentrations. In this scenario, the model successfully recapitulates published physiological data, accurately predicting a total plasma TTR concentration of approximately 25 mg/dL. Sensitivity analyses reveal that the rate of tetramer dissociation and the half-deposition time of TTR oligomers are key regulators of disease progression. Lower tetramer dissociation rates, mimicking the stabilizing effect of tafamidis, reduce fibril accumulation and biological aging. Conversely, faster oligomer deposition into fibrils leads to reduced oligomer concentrations but accelerated tissue fibril accumulation. The model predicts that, after five years of disease progression, the volumetric ratio of deposited TTR fibrils to baseline myocardial volume may reach 58% in the tissue aggregation scenario, compared to 10% when aggregation occurs in plasma. These predictions are consistent with clinical observations that link higher amyloid burden to increased mortality. Overall, the findings support a pathogenic mechanism in which TTR aggregation predominantly occurs in cardiac tissue, highlighting potential therapeutic targets to modulate disease progression. A correlation is proposed for estimating biological age in humans, which incorporates both calendar age and the volumetric ratio of deposited TTR fibrils to baseline myocardial volume.