Deciphering the Pathogenic Landscape of Amyloid Light-Chain Cardiomyopathy

Amyloid light-chain cardiomyopathy (ALCA) is an infiltrative disorder marked by misfolded immunoglobulin light-chain deposition in the myocardium, ultimately leading to cardiac dysfunction. Despite its clinical severity, the underlying mechanisms remain poorly understood. Here, we integrated multi-omics analyses of human cardiac samples to construct a comprehensive cellular and spatial atlas of the ALCA heart.

We observed a marked expansion of PTX3 ⁺ fibroblasts (FB), which undergo a distinct phenotypic transition into pro-fibrotic POSTN ⁺ FB regulated by EGR1.Concurrently, SPP1 ⁺ macrophages (Mac) emerged as major drivers of fibrosis, interacting robustly with PTX3 ⁺ FB via APP–CD74, GAS6–MERTK, and TGF-β1–TGF-β1/2 pathways. Endothelial cell (EC) profiling revealed substantial vascular remodeling characterized by the emergence of specialized capillary-like immune endothelial cells expressing chemokines CXCL1, CXCL3, and CCL2, alongside depletion of functional capillary EC. Immunologically, elevated cytotoxic CD8 ⁺ T cells and reduced NK cells contributed to an imbalanced inflammatory milieu, with NFκB2 orchestrating both fibrotic and immune pathways across multiple cell types.

These findings highlight the pivotal role of fibroblast–immune crosstalk, particularly the SPP1 ⁺ Mac–PTX3 ⁺ FB axis, in driving ALCA pathogenesis. Targeting these pathological cellular interactions may offer a promising therapeutic avenue to mitigate fibrosis, restore immune homeostasis, and improve cardiac function in ALCA.