Our study aims to verify the potential effects and underlying mechanisms of IL-37 in Coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC). VMC model was established by intraperitoneal injection of CVB3 into 6-week-old male balb-c mice on day 0. Each mouse of the IL-37-control group and IL-37-VMC CVB3 groups was intraperitoneally injected with IL-37 on day 4 and day 7. The cardiac function was evaluated by transthoracic echocardiography including LVEF, LVFE, IVSs and IVSd. Myocardial injury was measured by Elisa for serum cTnI. The inflammation infiltration and fibrosis were evaluated by hematoxylin and eosin (HE) staining and Masson staining. The expression levels of NLRP3 inflammasome components in pyroptosis were determined by western blot, Elisa, and immunofluorescent analysis. We also detected the expression of IL-37-IL-1R8 in PBMCs by immunofluorescence after injection with CVB3 and IL-37. Compared with the VMC group, mice received CVB3 and IL-37 have improved cardiac function, reduced inflammation infiltration and fibrosis, and with lower expression of cTnI, IL-1β, IL-18 and NLRP3 inflammasome component. IL-37 weakened the upregulation of GSDMD and phosphorylation of NF-κB p65 induced by CVB3. Exogenous addition of IL-37 with CVB3 further increases the production of IL-37-IL-1R8 -IL-18RA complex in vitro. Our findings indicate that IL-37 alleviates CVB3-induced VMC, which may be produced by inhibiting NLRP3 inflammasome-mediated pyroptosis, NF-κB signaling pathway, and IL-37-IL-1R8 -IL-18RA complex.

The incidence of cardiovascular disease is increasing year by year and is showing a younger trend. At the same time, existing medical resources are tight. The automatic detection of ECG signals becomes increasingly necessary. This paper proposes an automatic classification of ECG signals based on a dilated causal convolutional neural network. To solve the problem that the recurrent neural network framework network cannot be accelerated by hardware equipment, the dilated causal convolutional neural network is adopted. Given the features of the same input and output time steps of the recurrent neural network and the nondisclosure of future information, the network is constructed with fully convolutional networks and causal convolution. To reduce the network depth and prevent gradient explosion or gradient disappearance, the dilated factor is introduced into the model, and the residual blocks are introduced into the model according to the shortcut connection idea. The effectiveness of the algorithm is verified in the MIT-BIH Atrial Fibrillation Database (MIT-BIH AFDB). In the experiment of the MIT-BIH AFDB database, the classification accuracy rate is 98.65.

—: Viral myocarditis (VMC), which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. Dapagliflozin, a kind of sodium glucose co-transporters 2(SGLT-2) inhibitor, exhibited protective effects on plenty of inflammatory diseases, while its effect on viral myocarditis has not been studied. Recently, we found the protective effect of dapagliflozin on VMC. After CVB3 infection, dapagliflozin and STATTIC (a kind of stat3 inhibitor) were given to Balb/c male mice for 8 days, and then the severity of myocarditis was assessed. Our results indicated that dapagliflozin significantly alleviated the severity of viral myocarditis, elevated the survival rate, and ameliorated cardiac function. Besides, dapagliflozin can decrease the level of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α. Furthermore, dapagliflozin can inhibit macrophages differentiate to classically activated macrophages (M1) in cardiac tissue and activate the Stat3 signal pathway which is reported to promote polarization of the alternatively activated macrophage (M2). And STATTIC can reverse these changes caused by dapagliflozin. In conclusion, we found that dapagliflozin treatment increased anti-inflammatory macrophage polarization and reduced cardiac injury following VMC via activating Stat3 signal pathway.

To investigate whether interleukin-37 (IL-37) could directly inhibit the formation of neutrophil extracellular traps (NETs) in the early stage of acute viral myocarditis (VMC) and its potential mechanisms of action. Acute VMC was induced by intraperitoneally injecting coxsackievirus B3 (CVB3)(10³ TCID50) in mice on day 0. Mice were injected with AAV9-IL-37 or AAV9-NC through the caudal vein 1 week before intraperitoneal administration of CVB3. DNASE1 (50ug per mouse) was administered on days 0 to 7 to investigate the role of NETs formation during acute VMC. The severity of myocardial inflammation was evaluated by observing the general condition of mice and detecting cardiac histopathology. Moreover, neutrophils isolated from healthy human peripheral blood were stimulated by phorbol myristate acetate (PMA 100 nM) and treated with IL-37 (0.1 ng/ml) or BAY11-7082(2.5uM) in vitro. The production of NETs was detected by immunofluorescence labeled MPO and DNA. The expression of related proteins (IκBα, P-IκBα, NFκb, P-NFκb) was detected by Western blot. The results showed that, like DNASE1, IL-37 alleviates the symptoms in acute VMC induced by CVB3, reduces inflammatory cell infiltration, improves cardiac function, and inhibits the formation of NETs in the myocardium. Besides, both IL-37 and DNASE1 could effectively inhibit the activation of NFκb /IκBα. In the isolated peripheral blood neutrophils, the inhibitory effect of IL-37 on the formation of NETs and the activation of NFκb /IκBα was further confirmed. IL-37 has a protective effect on VMC by reducing the infiltration of inflammatory cells and inhibiting the formation of NETs at an early phase.