Small Extracellular Vesicles Isolated from Cardiac Tissue Matrix or Plasma Display Distinct Aging-Related Changes in Cargo Contributing to Chronic Cardiovascular Disease.

Aging is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and numerous other diseases, but the mechanisms of these aging-related effects remain elusive. Chronic changes in the microenvironment and paracrine signaling behaviors have been implicated, but remain understudied. Here, for the first time, we directly compare extracellular vesicles obtained from young and aged patients to identify therapeutic or disease-associated agents, and directly compare vesicles isolated from heart tissue matrix (TEVs) or plasma (PEVs). While young EVs showed notable overlap of miRNA cargo, aged EVs differed substantially, indicating differential age-related changes between TEVs and PEVs. TEVs overall were uniquely enriched in miRNAs which directly or indirectly demonstrate cardioprotective effects, with 45 potential therapeutic agents implicated in our analysis. Both populations also showed increased predisposition to disease with aging, though through different mechanisms. PEVs were largely correlated with chronic systemic inflammation, while TEVs were more related to cardiac homeostasis and local inflammation. From this, 17 protein targets unique to TEVs were implicated as aging-related changes which likely contribute to the development of cardiovascular disease.