**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Brian Netzel, Christine Charlesworth, Kenneth Johnson, Amy French, Angela Dispenzieri, Ellen McPhail, Joseph Maleszewski, Martha Grogan, Margaret Redfield, Megan Weivoda, Eli Muchtar, Morie Gertz,Julie Vrana, Jason Theis, Suzanne Hayman, Surendra Dasari *, Taxiarchis Kourelis *.

**Main Body of the Abstract**
Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction, mostly because these remain unknown. Our prior work has focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations. In this study, we used a whole biopsy proteomics approach to evaluate mechanisms of tissue dysfunction in cardiac AL/ATTR. We included 76 ATTR cases and 27 AL cases. In stage 3 AL patients, pathways involved in coagulation, extracellular matrix remodeling (ECM-R), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia and clathrin-mediated endocytosis were increased compared to stage 1/2,whereas pathways involved in healthy cardiac metabolism and proteostasis were decreased. In Mayo stage 2/3 ATTR, immunoglobulin proteins, complement and keratin pathways were increased compared to stage 1. Principal component analyses identified an ATTR group with worse survival independent of existing staging systems that also showed upregulation of complement and downregulation of oxidative phosphorylation pathways. Finally, when comparing AL with ATTR, complement proteins were increased in ATTR whereas clathrin-mediated endocytosis , mRNA splicing, spliceosome pathways and ribosomal proteins were increased in AL. Clathrin-mediated endocytosis has been implicated in Aβ amyloid clearance by non-immune cells in the setting of Alzheimer’s disease and could represent a proteostatic mechanism of cardiomyocytes in response to AL fibrils. Impaired spliceosome and translation machinery has been associated with cardiac ECM-R in other cardiomyopathies. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis including activation of the complement cascade, especially among ATTR patients with worse outcomes.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Brian Netzel, Christine Charlesworth, Kenneth Johnson, Amy French, Angela Dispenzieri, Ellen McPhail, Joseph Maleszewski, Martha Grogan, Margaret Redfield, Megan Weivoda, Eli Muchtar, Morie Gertz,Julie Vrana, Jason Theis, Suzanne Hayman, **Surendra Dasari *, Taxiarchis Kourelis *.**

**Main Body of the Abstract**
Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction, mostly because these remain unknown. Our prior work has focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations. In this study, we used a whole biopsy proteomics approach to evaluate mechanisms of tissue dysfunction in cardiac AL/ATTR. We included 76 ATTR cases and 27 AL cases. In stage 3 AL patients, pathways involved in coagulation, extracellular matrix remodeling (ECM-R), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia and clathrin-mediated endocytosis were increased compared to stage 1/2,whereas pathways involved in healthy cardiac metabolism and proteostasis were decreased. In Mayo stage 2/3 ATTR, immunoglobulin proteins, complement and keratin pathways were increased compared to stage 1. Principal component analyses identified an ATTR group with worse survival independent of existing staging systems that also showed upregulation of complement and downregulation of oxidative phosphorylation pathways. Finally, when comparing AL with ATTR, complement proteins were increased in ATTR whereas clathrin-mediated endocytosis , mRNA splicing, spliceosome pathways and ribosomal proteins were increased in AL. Clathrin-mediated endocytosis has been implicated in Aβ amyloid clearance by non-immune cells in the setting of Alzheimer’s disease and could represent a proteostatic mechanism of cardiomyocytes in response to AL fibrils. Impaired spliceosome and translation machinery has been associated with cardiac ECM-R in other cardiomyopathies. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis including activation of the complement cascade, especially among ATTR patients with worse outcomes.



Whole tissue proteomic analyses of cardiac ATTR and AL unveil mechanisms of tissue damage. OB15 (#270)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.