QUANTITATIVE PROTEOMICS OF PLASMA EXTRACELLULAR VESICLES REVEALS A TTR-PLASMINOGEN NETWORK IN ATTR CARDIAC AMYLOIDOSIS

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ABSTRACT Background Despite recent progress, the prognosis of patients with transthyretin (TTR) cardiac amyloidosis remains poor; this is primarily due to late diagnosis, when irreversible damage has already occurred. Today’s diagnostic work-up still relies on peripheral tissue or a cardiac biopsy, while circulating levels of TTR or other plasma markers have little diagnostic value. Although extracellular vesicles (EVs, as key mediators of intercellular communication) may reflect disease-specific molecular changes, their protein cargo has not yet been explored in the context of TTR amyloidosis (ATTR) cardiomyopathy. Objectives To characterize the plasma EV proteome in ATTR cardiomyopathy and identify potential biomarkers for pathophysiological pathways, diagnosis, or prognosis. Methods We performed mass-spectrometry-based, label-free, proteomic profiling of plasma EVs from 65 patients with hypertrophic cardiomyopathy due to TTR amyloidosis (the ATTR+ group, n=41) or non-amyloid cardiac disease (the ATTR- group, n=24). The groups were matched by age and sex. Results A distinct protein signature comprising 117 deregulated proteins was identified in EVs from ATTR+ patients. The ATTR+ EVs were enriched in proteins associated with vascular homeostasis, coagulation, and inflammation. At least 18 of these proteins formed an interconnected network centered on plasmin/plasminogen. Notably, EV levels of TTR and plasminogen levels were elevated, while the level of alpha2-antiplasmin (plasmin’s primary inhibitor) was low. This imbalance is particularly relevant because plasmin is known to promote amyloidogenesis via TTR cleavage. Conclusions Our findings provide new insights into the molecular mechanisms underlying ATTR cardiomyopathy and suggest that plasma EV proteins are potential diagnostic or prognostic biomarkers and/or therapeutic targets. CONDENSED ABSTRACT TTR amyloidosis (ATTR) causes severe cardiac damage, which is often diagnosed late. Through a comparative proteomic analysis of plasma extracellular vesicles (EVs) in patients with ATTR cardiomyopathy vs. patients with other cardiomyopathies, we identified several proteins of relevance to the pathophysiology of ATTR. Our analysis is the first to have highlighted an enrichment of plasmin/plasminogen (known to initiate the amyloidogenic process) and TTR in circulating EVs. Our results might foster the development of (i) diagnostic and prognostic markers for ATTR cardiomyopathy that do not require invasive procedures, and (ii) new therapeutic strategies. CENTRAL ILLUSTRATION - GRAPHICAL ABSTRACT ETHICAL APPROVAL The present analysis was based on blood samples collected as part of a research project entitled "Study of the myocardial microenvironment and toxicity of amyloid proteins in patients with cardiac amyloidosis", which was approved by an institutional review board (CPP Sud- Méditerranée II, Marseille, France; approval references: 2021T2-12/2021-A00950-41 and 2022-A02416-37).

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