Aims: The aims of this study were to evaluate the effects of sodium tanshinone IIA sulfonate (STS) on left ventricular (LV) remodelling after for ST‐elevated myocardial infarction (STEMI).Methods and results: In this prospective, randomized clinical trial, 101 patients with the ST‐elevated MI (STEMI) and a successful reperfusion were immediately randomized to receive STS (80 mg qd for 7 days) or saline control, along with standard therapy. The primary effectiveness endpoint is the % change in LV end diastolic volumes index (%∆ LVEDVi) as measured by echocardiography from baseline to 6 months. Secondary effectiveness endpoints include 6‐month period for major adverse cardiac events (MACE), including the occurrence of recurrent myocardial infarction, death, hospitalization for heart failure and malignant arrhythmia. The 6‐month changes in %∆ LVEDVi were significantly smaller in the STS group than in the control group [−5.05% vs 3.32%; P < 0.001]. With respect to MACE, there was a significant difference between those who received STS (8.16%) and those patients on control (26.00%) (P = 0.019). Meaningfully, results of parallel tests aimed at mechanistic explanation of the reported clinical effects, revealed a significantly reduced levels of neutrophils‐derived granule components in the blood of STS treated patients.Conclusion: We found that short‐term treatment with STS reduced progressive left ventricular remodelling and subsequent better clinical outcome that could be mechanistically linked to the inhibition of the ultimate damage of infarcted myocardium by infiltrating neutrophils.

Increasing evidence indicates that patients or experimental animals exposure to endotoxin (lipopolysaccharides, LPS) exert deleterious cardiac functions that greatly contribute to morbidity and mortality. The pathophysiologic processes, including NLRP3 inflammasome overactivation and cardiac inflammatory injury, are complicated. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, is a naturally occurring compound extracted from Salvia miltiorrhiza and has anti-inflammatory and cardioprotective properties. In this study we examined the effect of STS on endotoxin-induced cardiomyopathy and investigated the underlying mechanisms. An endotoxemic mouse model was established by injecting LPS (10 mg/kg). Different doses of STS were administered intraperitoneally (5, 10, or 50 mg/kg) at different time points (2/12 h, 4/12 h, and 8/12 h) after LPS challenge to assess its effect on survival of mice with endotoxemia. In parallel, cardiac function, myocardial inflammatory cytokines, cardiomyocyte pyroptosis and autophagy were evaluated to determine the extent of myocardial damage due to sepsis in the presence and absence of STS at the optimal dose (10 mg/kg) and time-point (2/12 h). The results demonstrated that STS increased the survival rates, improved the compromised cardiac function and reduced myocardial inflammatory injury associated with enhanced autophagy and mitigated NLRP3 inflammasome activation. Moreover, inhibiting of autophagy or blocking the AMPK pathway reversed STS-elicited prevention of cardiomyopathy and activated the NLRP3 inflammasome in endotoxemic mice. Collectively, our study demonstrates that STS attenuates endotoxemia-induced mortality and cardiomyopathy, which may be associated with promotion of autophagy and inhibition of NLRP3 inflammasome overactivation.

Background Diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher mortality due to the more frequent development of subsequent pathological myocardial remodelling and concomitant functional deterioration. This study investigates the molecular pathways underlying accelerated cardiac remodelling in a well-established mouse model of diabetes exposed to MI. Methods and results Myocardial infarction in DM mice was established by ligating the left anterior descending coronary artery. Cardiac function was assessed by echocardiography. Myocardial hypertrophy and cardiac fibrosis were determined histologically 6 weeks post-MI or sham operation. Autophagy, the NLRP3 inflammasome, and caspase-1 were evaluated by western blotting or immunofluorescence. Echocardiographic imaging revealed significantly increased left ventricular dilation in parallel with increased mortality after MI in DM mice (53.33%) compared with control mice (26.67%, P < 0.05). Immunoblotting, electron microscopy, and immunofluorescence staining for LC3 and p62 indicated impaired autophagy in DM + MI mice compared with control mice (P < 0.05). Furthermore, defective autophagy was associated with increased NLRP3 inflammasome and caspase-1 hyperactivation in DM + MI mouse cardiomyocytes (P < 0.05). Consistent with NLRP3 inflammasome and caspase-I hyperactivation, cardiomyocyte death and IL-1β and IL-18 secretion were increased in DM + MI mice (P < 0.05). Importantly, the autophagy inducer and the NLRP3 inhibitor attenuated the cardiac remodelling of DM mice after MI. Conclusion In summary, our results indicate that DM aggravates cardiac remodelling after MI through defective autophagy and associated exaggerated NLRP3 inflammasome activation, proinflammatory cytokine secretion, suggesting that restoring autophagy and inhibiting NLRP3 inflammasome activation may serve as novel targets for the prevention and treatment of post-infarct remodelling in DM.

Aims Cardiac malfunctions developing in result of sepsis are hard to treat so they eventually contribute to the increased mortality. Previous reports indicated for therapeutic potential of exogenous ω‐3 polyunsaturated fatty acids (PUFA) in sepsis, but potential benefits of this compound on the malfunctional heart have not been explored yet. In the present study, we investigated whether the constantly elevated levels of endogenous ω‐3 PUFA in transgenic fat‐1 mice would alleviate the lipopolysaccharide (LPS)‐induced cardiac failure and death. Methods and results After both wild type (WT) and transgenic fat‐1 mice were challenged with LPS, a Kaplan–Meier curve and echocardiography were performed to evaluate the survival rates and cardiac function. Proteomics analysis, RT‐PCR, western blotting, immune‐histochemistry, and transmission electron microscopy were further performed to investigate the underlying mechanisms. Results showed that transgenic fat‐1 mice exhibited the significantly lower mortality after LPS challenge as compared with their WT counterparts (30% vs. 42.5%, P < 0.05). LPS injection consistently impaired the left ventricular contractile function and caused the cardiac injury in the wild type mice, but not significantly affected the fat‐1 mice (P < 0.05). Proteomic analyses, ELISA, and immunohistochemistry further revealed that myocardium of the LPS‐challenged fat‐1 mice demonstrated the significantly lower levels of pro‐inflammatory markers and ROS than WT mice. Meaningfully, the LPS‐treated fat‐1 mice also demonstrated a significantly higher levels of LC3 II/I and Atg7 expressions than the LPS‐treated WT mice (P < 0.05), as well as displayed a selectively increased levels of peroxisome proliferator‐activated receptor (PPAR) γ and sirtuin (Sirt)‐1 expression, associated with a parallel decrease in NFκB activation. Conclusions The fat‐1 mice were protected from the detrimental LPS‐induced inflammation and oxidative stress, and exhibited enhancement of the autophagic flux activities, associating with the increased Sirt‐1 and PPARγ signals.

Background:Septic shock has increasingly become a cause of death threatening human survival. Shenfu Injection (SFI), a patented Chinese medicine, has been widely used in the treatment of patients with sepsis and cardiovascular diseases domestically. We sought to examine whether combination therapy with SFI can improve clinical outcomes in critically ill patients undergoing mechanical ventilation (MV).Methods:This real-world, multicenter retrospective trial enrolled consecutive adult patients with sepsis requiring MV from four medical/surgical intensive care units (ICUs) in China between August 2016 and September 2021. Patients were identified from the medical information department database of each center and assigned to either of two groups (SFI or control) on the basis of the initial treatment received. The primary outcome was 28-day all-cause mortality, and the durations of vasopressor therapy and MV, the ICU length of stay, and costs were assessed as secondary outcomes. Subsequently, we performed a meta-analysis of randomized controlled trials (RCTs) on SFI published before July 2021 to verify our conclusions.Results:2311 mechanically ventilated patients with septic shock (1128 patients in the SFI group and 1183 in the control group) were analyzed. The survival probability during the first 28 days after admission in the SFI group was greater than that in the control group [p< 0.01 by log-rank test; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.39–0.72]. Patients in the SFI group also experienced a significantly reduced duration of vasopressor therapy [7.28 (95% CI, 6.14–8.42)vs.12.06 (95% CI, 10.71–13.41) days,p< 0.001], more ventilator-free days [6.49 (95% CI, 5.42–7.55)vs.10.84 (95% CI, 9.59–12.09) days,p< 0.001], a shorter ICU length of stay [18.48 (95% CI, 17.59–19.38)vs.23.77 (95% CI, 22.47–25.07) days,p< 0.001], and more time free from organ failure [14.23 (95% CI, 12.94–15.52)vs.19.07 (95% CI, 16.09–22.05) days,p< 0.001]. No major adverse effects were reported in either group.Conclusion:Among critically ill patients requiring MV, combination therapy with SFI can improve the survival probability without any obvious adverse reactions.

Emerging studies indicate that extracellular vesicles (EVs) and their inner circular RNAs (circRNAs), play key roles in the gene regulatory network and cardiovascular repair. However, our understanding of EV-derived circRNAs in cardiac remodeling after myocardial infarction (MI) remains limited. Here we show that the level of circCEBPZOS is downregulated in serum EVs of patients with the adverse cardiac remodeling compared with those without post-MI remodeling or normal subjects. Loss-of-function approaches in vitro establish that circCEBPZOS robustly promote angiogenesis. Overexpression of circCEBPZOS in mice attenuates MI-induced left ventricular dysfunction, accompanied by a larger functional capillary network at the border zone. Further exploration of the downstream target gene indicates that circCEBPZOS acts as a competing endogenous RNA by directly binding to miR-1178-3p and thereby inducing transcription of its target gene phosphoinositide-dependent kinase-1 (PDPK1). Together, our results reveal that circCEBPZOS attenuates detrimental post-MI remodeling via the miR-1178-3p/PDPK1 axis, which facilitates revascularization, ultimately improving the cardiac function.