Quantitative Proteomics of Plasma-Derived Extracellular Vesicles Reveals a Plasminogen-Centered Protein Network in Transthyretin Cardiac Amyloidosis

Abstract

BACKGROUND: The prognosis of patients with transthyretin cardiac amyloidosis (ATTR) remains poor; this is primarily due to late diagnosis, when irreversible damage has already occurred. Circulating levels of transthyretin or other plasma markers have little value for diagnosis. Although extracellular vesicles (EVs) (key mediators of intercellular communication) may reflect disease-specific molecular changes, their protein cargo has not yet been explored in the context of ATTR cardiomyopathy (ATTR-CM). OBJECTIVES: We evaluated whether cardiac amyloidosis alters the proteome of circulating EVs and assessed whether these changes define signature of ATTR. METHODS: Plasma EVs were prospectively isolated by ultracentrifugation from 41 patients with confirmed ATTR-CM (ATTR+ group; wild-type ATTR and variant ATTR) and 24 frequency-matched patients with nonamyloid cardiomyopathy (ATTR- group), all referred to the Referral Center for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil, France). EVs were characterized by flow cytometry and analyzed by quantitative liquid chromatography mass spectrometry/mass spectrometry proteomics. RESULTS: ATTR+ patients had a distinct signature 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 transthyretin and plasminogen were elevated, whereas the level of alpha2-antiplasmin (plasmin's primary inhibitor) was low. This imbalance is particularly relevant because plasmin is known to promote amyloidogenesis via transthyretin cleavage. CONCLUSIONS: These exploratory findings highlight a plasmin/plasminogen-centered protein network linking fibrinolysis, complement activation, and vascular inflammation to ATTR pathophysiology, and suggest that plasma EV proteomics warrant further evaluation as a minimally invasive approach for disease monitoring and biomarker discovery in ATTR-CM.

The authors' abstract, as published at the source. JACC Advances, 2026 · DOI ↗