Circulating Extracellular Vesicles in the Pathogenesis of Heart Failure in Patients With Chronic Kidney Disease

BACKGROUND: Cardiovascular disease causes >50% of deaths in patients with advanced chronic kidney disease (CKD). Clinical studies suggest that kidney-derived factors contribute to cardiovascular disease development in CKD, independently of comorbidities. However, to date, no kidney-specific humoral risk factor that triggers direct cardiotoxicity has been identified. In this cross-sectional study, we investigate how, in patients with CKD, circulating extracellular vesicles (EVs) facilitate pathological kidney-heart communication, thereby causing cardiotoxicity, impairing cardiac function, and contributing to heart failure progression. METHODS: We investigated the function of EVs from patients with CKD and adenine diet–induced CKD mice on cardiomyocyte and cardiac contractility. microRNA (miRNA) cargo of EVs was identified by small RNA sequencing and quantitative reverse transcription polymerase chain reaction, and their cardiotoxicity was tested by using miRNA mimics. Tissue and cellular origin of CKD-EV-miRNAs were determined from their corresponding primary miRNA expressions in mice. RESULTS: EVs from plasma of patients with CKD, but not from healthy controls, were cardiotoxic; they significantly induced apoptosis both in vitro and in vivo and impaired contractility of adult rat primary cardiomyocytes in vitro. Likewise, EVs from both plasma and kidneys of CKD mice were cardiotoxic. Pharmacologically depleting circulating EVs in CKD mice significantly recovered cardiac function and ameliorated heart failure, improvements that suggest CKD-EVs play a causal role in heart failure pathogenesis. Both human and mouse CKD-EVs were enriched in distinct miRNAs compared with control EVs. CKD-EV-miRNA mimics were cardiotoxic, impairing contractility and downregulating contractile gene expression in human induced pluripotent stem cell–derived cardiomyocytes. It is interesting that levels of endogenous primary miRNAs corresponding to circulating CKD-EV-miRNAs were significantly higher in CKD kidney tissues, specifically in CD45 -ve CD31 -ve renal cells, but not in CKD hearts, CKD livers, or CKD-peripheral blood mononuclear cells, a result that indicates CKD-EV-miRNAs originate renally. It is remarkable that CKD-EV-miRNA levels correlated with established markers of cardiac injury, thus uncovering the presence of subclinical heart disease and demonstrating heterogeneity in reno-cardiac disease. CONCLUSIONS: Collectively, our human subject and mouse studies show that circulating CKD-EVs, carrying distinct renal-derived miRNAs, mediate the molecular crosstalk that contributes to the pathogenesis of heart failure in CKD. Consequently, CKD-EVs hold promise as diagnostic and prognostic biomarkers for early disease detection and as targets for novel therapeutic interventions in chronic reno-cardiac disease.