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Atrial fibrillation (AF), the most common type of cardiac arrhythmia, is thought to be regulated by changes in microRNA (miRNA) expression. However, the evidence for this is inconsistent. The high stability and expression of circulating exosomal miRNAs may allow their use as candidate biomarkers. For the discovery phase, exosomes were isolated from the serum of patients with supraventricular tachycardia (SVT) as the controls (n = 5) and with paroxysmal AF (n = 4) and persistent AF (n = 5) for microarray analysis of miRNAs. Forty‐five miRNAs were expressed significantly higher (>1.5‐fold) in patients with persistent AF, but not in patients with paroxysmal AF, relative to the levels in patients with SVT control. Notably, expression of 5 miRNAs (miRNA‐103a, ‐107, ‐320d, ‐486, and let‐7b) was elevated by more than 4.5‐fold in patients with persistent AF. For the validation phase, miRNAs were analyzed using quantitative RT‐PCR analysis in exosomes from the serum of patients with SVT control (n = 20) and patients with persistent AF (n = 40). These miRNAs and their target genes were involved in atrial function and structure, oxidative stress, and fibrosis pathways. These findings suggest that serum exosomal miRNAs might be used as novel biomarkers to reflect the progression of AF.—Mun, D., Kim, H., Kang, J.‐Y., Park, H., Park, H., Lee, S.‐H., Yun, N., Joung, B. Expression of miRNAs in circulating exosomes derived from patients with persistent atrial fibrillation. FASEB J. 33, 5979–5989 (2019). http://www.fasebj.org

PurposeBioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotective effects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effects of EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs).Materials and MethodsEV solutions (0.4 µg/µL) derived from normoxia-preconditioned MSCs (EVNM) and hypoxia-preconditioned MSCs (EVHM) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26 staining in hearts from EV-treated rats.ResultsEVHM significantly reduced infarct size (24±2% vs. 8±1%, p<0.001), and diminished arrhythmias by recovering electrical conduction, INa current, and Cx43 expression. EVHM also reversed reductions in Wnt1 and β-catenin levels and increases in GSK3β induced after IR injury. miRNA-26a was significantly increased in EVHM, compared with EVNM, in real-time PCR. Finally, in in vitro experiments, hypoxia-induced increases in GSK3β expression were significantly reduced by the overexpression of miRNA-26a.ConclusionEVHM reduced IR injury by suppressing GSK3β expression via miRNA-26a and increased Cx43 expression. These findings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway.

Small extracellular vesicles (sEVs) are nanometer-sized membranous vesicles secreted by cells, with important roles in physiological and pathological processes. Recent research has established the application of sEVs as therapeutic vehicles in various conditions, including heart disease. However, the high risk of off-target effects is a major barrier for their introduction into the clinic. This study evaluated the use of modified sEVs expressing high levels of cardiac-targeting peptide (CTP) for therapeutic small interfering RNA (siRNA) delivery in myocarditis, an inflammatory disease of heart. sEVs were extracted from the cell culture medium of HEK293 cells stably expressing CTP-LAMP2b (referred to as C-sEVs). The cardiac targeting ability of C-sEVs with the highest CTP-LAMP2b expression was >2-fold greater than that of normal sEVs (N-sEVs). An siRNA targeting the receptor for advanced glycation end products (RAGE) (siRAGE) was selected as a therapeutic siRNA and loaded into C-sEVs. The efficiency of cardiac-specific siRNA delivery via C-sEVs was >2-fold higher than that via N-sEVs. Furthermore, siRAGE-loaded C-sEVs attenuated inflammation in both cell culture and an in vivo model of myocarditis. Taken together, C-sEVs may be a useful drug delivery vehicle for the treatment of heart disease.

PurposeBridge anticoagulation therapy is mostly utilized in patients with mechanical heart valves (MHV) receiving warfarin therapy during invasive dental procedures because of the risk of excessive bleeding related to highly vascular supporting dental structures. Bridge therapy using low molecular weight heparin may be an attractive option for invasive dental procedures; however, its safety and cost-effectiveness compared with unfractionated heparin (UFH) is uncertain.Materials and MethodsThis study investigated the safety and cost-effectiveness of enoxaparin in comparison to UFH for bridge therapy in 165 consecutive patients (57±11 years, 35% men) with MHV who underwent invasive dental procedures.ResultsThis study included 75 patients treated with UFH-based bridge therapy (45%) and 90 patients treated with enoxaparin-based bridge therapy (55%). The bleeding risk of dental procedures and the incidence of clinical adverse outcomes were not significantly different between the UFH group and the enoxaparin group. However, total medical costs were significantly lower in the enoxaparin group than in the UFH group (p<0.001). After multivariate adjustment, old age (≥65 years) was significantly associated with an increased risk of total bleeding independent of bridging methods (odds ratio, 2.51; 95% confidence interval, 1.15-5.48; p=0.022). Enoxaparin-based bridge therapy (β=-0.694, p<0.001) and major bleeding (β=0.296, p=0.045) were significantly associated with the medical costs within 30 days after dental procedures.ConclusionConsidering the benefit of enoxaparin in cost-effectiveness, enoxaparin may be more efficient than UFH for bridge therapy in patients with MHV who required invasive dental procedures.