The Role of Cardiac Fibrosis and Fibroblast Activation in Amyloid Light Chain (AL) Amyloidosis.

Recent studies suggest that interactions between collagen and amyloid fibril may influence amyloid formation, matrix remodeling, and disease progression in cardiac amyloid light chain (AL) amyloidosis. However, the precise pathophysiological mechanisms underlying fibrosis remain largely unexplored. Here, we performed transcriptome analysis of myocardial samples from patients with AL amyloidosis and identified upregulation of fibroblast activation genes, such as collagen type I/III and periostin. Histology showed predominantly type III collagen fibrosis, accompanied by cardiac fibroblasts present within the interstitial myocardium, including areas with amyloidogenic light chain (AL-LC). We further demonstrated a partial fibroblast-to-myofibroblast transition (FMT) in vitro by stimulating cardiac fibroblasts with AL-LC. This indicates that pathogenic AL-LC directly induces fibroblast activation and that matrix remodeling accelerates during amyloid fibril deposition. This extensive cellular and molecular characterization provides novel insights into the essential role of fibrotic pathology in AL cardiomyopathy and may enable the discovery of biomarkers and therapeutic targets.