Background: Transthyretin (TTR) amyloidosis results from extracellular deposition of amyloid fibrils derived from misfolded TTR, leading to progressive cardiac dysfunction. TTR is a homotetrameric transport protein for thyroxine and retinol-binding protein. Amyloid formation begins with tetramer dissociation, monomer unfolding, and β-sheet aggregation. Post-translational deamidation and oxidation promote tetramer destabilization and are facilitated by oxidative stress, inflammation, and age-related proteostatic decline. This pilot study aimed to characterize the serum proteomic signature of cardiac ATTR amyloidosis and to identify molecular and pathway-level features distinguishing it from biopsy-proven cardiac AL amyloidosis. Methods: Serum samples from patients with cardiac ATTR amyloidosis (n = 18) and cardiac AL amyloidosis (n = 16) were analyzed by label-free data-independent acquisition (DIA) LC–MS/MS proteomics. Differential protein abundance was evaluated using linear modeling (limma), followed by Gene Ontology–based functional enrichment analysis to delineate biological processes and molecular networks. Results: Compared with cardiac AL amyloidosis, ATTR sera showed higher levels of TTR and multiple acute-phase and transport proteins (APOA1, APOA2, APOA4, APCS, SAA4, ORM1, ORM2, VTN), consistent with hepatic activation and proteostatic stress adaptation. Functional enrichment indicated overrepresentation of acute and antibacterial inflammatory responses, lipoprotein remodeling, and wound-healing regulation. Upregulated proteins such as CTSG, TF, and HPX were linked to neutrophil-associated and antibacterial pathways. In contrast, classical neutrophil and myeloid markers (LYZ, MPO, CD14) as well as complement- and coagulation-related proteins (MASP1/2, C1QB, C4BPA, VWF, F9, F12) were less abundant in ATTR than in cardiac AL amyloidosis. In a subgroup analysis of ATTR patients stratified by Perugini score, higher cardiac amyloid burden (score 3 vs 2) was associated with increased levels of acute-phase and complement proteins (HP, CRP, APCS, C4B, VSIG4) and endothelial or ECM regulators (ICAM1, SPARCL1, DPP4), while proteins related to proteostasis, oxidative-stress defense, and matrix maintenance (HSP90AA1, TXN, SPARC, TIMP2, THBS1) were reduced. Conclusions: Serum proteomics differentiates cardiac ATTR from cardiac AL amyloidosis based on distinct circulating protein signatures. In ATTR, higher amyloid burden may be associated with enhanced acute-phase and complement activity and reduced proteostatic capacity. These data support the presence of divergent systemic and myocardial pathophysiological mechanisms in TTR- versus light chain–mediated amyloid cardiomyopathy and may inform future marker-driven diagnostic strategies.
