A journey through the molecular networks of endomyocardial biopsies to explore ATTR and ALλ cardiac amyloidosis

Immunoglobulin light chains (AL) and transthyretin (ATTR) characterize most cardiac amyloidosis cases. Several proteomic studies have analyzed microdissected amyloid plaques. However, they did not capture the molecular dysfunctions triggered in surrounding tissue. We, therefore, holistically investigated the protein profiles of endomyocardial biopsies from patients with AL λ and ATTR conditions. Both conditions showed extracellular matrix remodeling and downregulation of proteostasis, signaling, and mitochondrial energetics. The results also suggested vesicle-mediated transport and complement activation as hallmarks of patients with AL λ and ATTR conditions, respectively. These findings corroborate previously proposed pathological mechanisms, namely, direct mitochondrial toxicity of light chain fibrils internalized via macropinocytosis and massive extracellular deposition of ATTR. Notably, protein quantification and network topology enabled the identification of potential disease markers. Although the selection criteria were robust, validation in larger cohorts is needed. Nevertheless, given the challenging accessibility of the analyzed samples, the proposed landscape of results provides a valuable resource to encourage further studies on cardiac amyloidosis.