• Brian C Netzel, M Cristine Charlesworth, Kenneth L Johnson, Amy J French, Angela Dispenzieri, Joseph J Maleszewski, Ellen D McPhail, Martha Grogan, Margaret M Redfield, Megan Weivoda, Eli Muchtar, Morie A Gertz, Shaji K Kumar, Pinaki Misra, Julie Vrana, Jason Theis, Suzanne R Hayman, Marina Ramirez-Alvarado, Surendra Dasari, and Taxiarchis Kourelis.
• Bioinformatics and Computational Biology Graduate Program, University of Minnesota, Minneapolis, MN, USA.
• Amyloid. 2025 Mar 1; 32 (1): 728072-80.

BackgroundCardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations.ObjectivesTo evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach.MethodsWe performed proteomics analysis on 76 ATTR and 27 AL diagnostic endomyocardial biopsies.ResultsStage-3 AL patients exhibited increased coagulation, extracellular matrix remodelling (ECM), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia, and clathrin-mediated endocytosis pathways vs. stages-1/2, with decreased healthy cardiac metabolism. In stages-2 and 3 ATTR, immunoglobulin proteins, complement, and keratinisation pathways were increased compared to stage-1. Unsupervised analyses identified an ATTR group with worse survival characterised by upregulated complement and downregulated metabolic pathways. Compared to ATTR, AL had higher clathrin-mediated endocytosis, mRNA splicing, and ribosomal proteins, while ATTR had higher complement levels.ConclusionsThis study identifies known processes dysregulated in heart failure with preserved ejection fraction as well as novel pathways responsible for tissue damage. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis, especially among patients with worse outcomes.

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