Mathematical modeling of light chain aggregation and cardiac damage in AL amyloidosis

AL amyloidosis is a rapidly progressive disorder characterized by clonal plasma cell expansion, excessive production of light chains (LCs), and their misfolding into aggregation-prone monomers. These monomers assemble into oligomers and ultimately deposit as amyloid fibrils, particularly within cardiac tissue, where they contribute to myocardial stiffening and direct cardiotoxicity. A mechanistic model was developed to quantify the interplay between these two pathogenic processes and to examine the kinetics of LC aggregation in different compartments. Simulations reveal that LC aggregation exhibits pronounced nonlinearity: oligomer concentrations remain low during early disease stages, followed by exponential growth driven by autocatalytic conversion. When aggregation is assumed to occur within cardiac tissue, fibril deposition is approximately 25 times greater, and oligomer-induced cardiotoxicity is about five times higher, compared with aggregation occurring in the blood plasma. These differences stem from the smaller cardiac volume, which accelerates autocatalytic oligomer formation. A combined cardiac damage criterion, integrating both oligomer-induced cardiotoxicity and fibril-associated myocardial stiffening, was introduced and found to reach values approximately tenfold higher when LC aggregation occurs within cardiac tissue compared with aggregation in the blood plasma. This parameter may serve as a quantitative measure of cardiac aging or disease severity. The model also predicts that therapeutic intervention markedly reduces, but does not eliminate cardiac injury, highlighting the importance of early treatment initiation in AL amyloidosis.