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

Abstract

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 reduced-order mechanistic model is developed to describe LC secretion by a pathogenic plasma-cell clone, LC unfolding and aggregation, cardiac deposition, and the resulting myocardial injury during advanced cardiac AL amyloidosis. Simulations reveal pronounced nonlinear LC aggregation kinetics: oligomer concentrations remain low during the early part of the modeled terminal cardiac-progression interval and subsequently increase rapidly as autocatalytic conversion becomes dominant. When aggregation is assumed to occur within cardiac tissue, fibril deposition is approximately 30 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 provide a candidate model-based 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.