Our study provides the first evidence that the pericardial space might represent a special compartment, in which functional forms of miRNAs that are released from the heart are enriched in comparison with the peripheral circulation. Because of their resilience to degradation in the extracellular space, miRNAs have been widely considered as new potential clinical biomarkers. Pioneer miRNA-oriented biomarker discovery studies have been developed by measuring miRNAs in the peripheral circulation. However, the emerging evidence for the multi-cellular and multi-tissue expression of virtually any of the known miRNAs, together with the understanding that several processes (release from different cells and organs, potential uptake from the circulation into other tissues, urinary excretion, etc.) dictate the miRNA concentration in the peripheral blood, diminish the potential value of miRNAs as peripheral blood circulating biomarkers. We propose that miRNA expression in the PF is more indicative of cardiac miRNA expression and secretion. In defense of our hypothesis, we have shown increased cardiovascular miRNA expression in the total PF and in PF-derived exosomes in comparison with the corresponding plasma counterparts. Exosomes have been already suggested as “liquid biopsies.”34 Our study stimulates the original hypothesis that obtaining such liquid biopsies out of the PF (when accessible) rather than from the peripheral blood could increase the diagnostic and prognostic power of exosomal biomarkers. Specifically designed clinical studies are necessary to validate the biomarker value of PF miRNAs.