In vitro and in vivo disease models of cardiac amyloidosis: progress, pitfalls and potential

Abstract

Amyloid light chain (AL) and transthyretin amyloidosis (ATTR)-induced cardiomyopathy are life-threatening protein misfolding disorders characterized by amyloid fibril deposition in the heart, which significantly impairs cardiac function. The lack of representative disease models has impeded progress in understanding the underlying mechanisms and hindered the discovery and development of specific biomarkers and effective therapies. To address this, researchers have developed various cell and animal models to recapitulate these diseases. In AL amyloidosis, cell and mouse models have highlighted the toxic effects of both soluble light chains (LCs) and LC-derived amyloid fibrils, such as lysosomal dysfunction, endoplasmic reticulum stress, and oxidative stress. Transgenic mouse models, particularly those without the mouse heavy chain and with amyloid seeds addition, have successfully replicated systemic AL amyloidosis, with clear effects on the heart. For ATTR amyloidosis, acid-induced transthyretin (TTR) fibrils induce cellular dysfunction, such as increased intracellular reactive oxygen species (ROS) level, disorganized sarcomere, and prolonged calcium handling in 2D cell models. Transgenic mouse models expressing human WT or variant TTR have offered insights into the development of amyloid cardiomyopathy, but challenges persist in fully replicating the human phenotype. This review offers a comprehensive overview of the significant advancements, challenges, and future perspectives in the development of various cell and animal models for studying AL and ATTR amyloidosis-induced cardiomyopathy, thereby providing valuable insights into disease pathophysiology, early accurate biomarkers identification, and development of novel therapies.