Mathematical Modeling of Late-Stage LC Aggregation and Cardiac Injury Following Establishment of a Pathogenic Plasma-Cell Clone
Kuznetsov, A. V. · biophysics · 2026-09-06 · 原文
DOI：10.1101/2025.10.30.685705
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 olig
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1. 人话版
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.
2. 领域脉络
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3. 机制拆解
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.
4. 证据与数字
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.
5. 反例与边界
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