Exosomes’ molecular cargo is variable and dependent on the parental cell type and the environment. It is therefore intuitive that the actions of exosomes are disparate. Within the cardiovascular area, exosomes were reported to exert direct actions on cultured cardiac myocytes, including promoting hypertrophy14 and survival.15 Some pioneering human studies on circulating exosomes have focused at finding new clinical biomarkers, particularly in the oncology area, in which the concept of exosomes as “liquid biopsies” enriched with cancer cell-derived factors is receiving attention.16 However, the characterization of the exosomes present in human biological fluids and their possible role as cell-to-cell communicators of cardiovascular relevance is still undeveloped. We have recently provided preliminary evidence that exosomes containing high levels of cardiovascular miRNAs are trafficked out of the heart to reach the peripheral blood in patients undergoing cardiac surgery using cardiopulmonary bypass.17 This is an acute scenario that is associated with ischemia/reperfusion stress to the myocardium.17 Indeed, we observed that the abundance of plasma circulating exosomes and their content of cardiovascular miRNAs were highly correlated with high sensitive cardiac troponin T, the gold-standard biomarker of myocardial injury.17 This suggests that the release of exosomes from the heart is regulated in vivo. We reasoned that exosomes released by the heart and large vessels could accumulate in the pericardial space, which could gain new interest as a niche for cardiac biomarker discovery. Moreover, PF exosomes could be involved in yet unreported EV-based crosstalk between cells exposed directly or indirectly to the PF.