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Yujie Hao, Runmin Liu, Hao Wang, Tao Rui, Junfang Guo Division of Cardiology, Department of Medicine, the Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of ChinaCorrespondence: Junfang Guo, Email zjyyxngjf@163.comAbstract: Sepsis is a syndrome of organ dysfunction caused by a dysregulated immune response to infection, with high morbidity and mortality. At present, there have been many advances in the study of its pathogenesis, especially the cardiac dysfunction caused by sepsis, namely sepsis-induced myocardial dysfunction, SIMD, which has received widespread attention. The mechanisms of SIMD mainly include excessive release of inflammatory mediators, impaired mitochondrial function, autophagy, apoptosis and myocardial dysfunction. This article reviews the pathogenesis of SIMD and elaborates on the progress in its treatment, aiming to improve the prognosis of patients with SIMD and sepsis.Keywords: sepsis, sepsis-induced myocardial dysfunction, pathogenesis, treatment

Introduction: This study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms. Methods: Male mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice. Results: SO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid β-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80. Conclusion: Our study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD.

Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.

Abstract Background Sepsis not only causes inflammation, but also damages the heart and increases the risk of death. The glycolytic pathway plays a crucial role in the pathogenesis of sepsis-induced cardiac injury. This study aims to investigate the value of bisphosphoglycerate mutase (BPGM), an intermediate in the glycolytic pathway, in evaluating cardiac injury in septic patients and predicting poor prognosis in sepsis. Methods This prospective study included 85 patients with sepsis. Serum BPGM was measured at the time of enrollment, and the patients were divided into a BPGM-positive group (n = 35) and a BPGM-negative group (n = 50) according to their serum BPGM levels. Baseline clinical and echocardiographic parameters, and clinical outcomes were analyzed and compared between the two groups. Kaplan–Meier analysis was used to compare the 28-day survival rate between BPGM-negative and BPGM-positive patients. Multivariate logistic regression analysis was conducted to explore the independent risk factors for 28-day mortality in septic patients. The predictive value of serum BPGM for sepsis-induced myocardial injury and poor prognosis in sepsis was evaluated using receiver operating characteristic (ROC)curve analysis. Result The serum level of BPGM was significantly higher in patients who died within 28 days compared to survivors (p

Background: Sepsis not only causes inflammation, but also damages the heart and increases the risk of death. The glycolytic pathway plays a crucial role in the pathogenesis of sepsis-induced cardiac injury. This study aims to investigate the value of bisphosphoglycerate mutase (BPGM), an intermediate in the glycolytic pathway, in evaluating cardiac injury in septic patients and predicting poor prognosis in sepsis. Methods: This prospective study included 85 patients with sepsis. Serum BPGM was measured at the time of enrollment, and the patients were divided into a BPGM-positive group (n = 35) and a BPGM-negative group (n = 50) according to their serum BPGM levels. Baseline clinical and echocardiographic parameters, and clinical outcomes were analyzed and compared between the two groups. Kaplan–Meier analysis was used to compare the 28-day survival rate between BPGM-negative and BPGM-positive patients. Multivariate logistic regression analysis was conducted to explore the independent risk factors for 28-day mortality in septic patients. The predictive value of serum BPGM for sepsis-induced myocardial injury and poor prognosis in sepsis was evaluated using receiver operating characteristic (ROC)curve analysis. Result: The serum level of BPGM was significantly higher in patients who died within 28 days compared to survivors (p < 0.001). Kaplan–Meier analysis showed that serum BPGM-positive sepsis patients had a significantly shorter 28-day survival time (p < 0.001). Multivariate logistic regression analysis showed that serum BPGM (OR = 9.853, 95%CI 1.844–52.655, p = 0.007) and left ventricular ejection fraction-simpson(LVEF-S) (OR = 0.032, 95% CI 0.002–0.43, p = 0.009) were independent risk factors for 28-day mortality in sepsis patients. Furthermore, BPGM levels was negatively correlated with LVEF-S (p = 0.005) and positively correlated with the myocardial performance (Tei) index (p < 0.001) in sepsis patients. ROC curve analysis showed that serum BPGM was a good predictor of septic myocardial injury and 28-day mortality in sepsis patients. Conclusion: The level of BPGM in the serum of sepsis patients can serve as a monitoring indicator for myocardial injury, with its high level indicating the occurrence of secondary myocardial injury events and adverse outcomes in sepsis patients. [ABSTRACT FROM AUTHOR]

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced myocardial dysfunction represents reversible myocardial dysfunction which ultimately results in left ventricular dilatation or both, with consequent loss of contractility. Studies on septic cardiomyopathy report a wide range of prevalence ranging from 10% to 70%. Myocardial damage occurs as a result of weakened myocardial circulation, direct myocardial depression, and mitochondrial dysfunction. Mitochondrial dysfunction is the leading problem in the development of septic cardiomyopathy and includes oxidative phosphorylation, production of reactive oxygen radicals, reprogramming of energy metabolism, and mitophagy. Echocardiography provides several possibilities for the diagnosis of septic cardiomyopathy. Systolic and diastolic dysfunction of left ventricular is present in 50-60% of patients with sepsis. Right ventricular dysfunction is present in 50-55% of cases, while isolated right ventricular dysfunction is present in 47% of cases. Left ventricle (LV) diastolic dysfunction is very common in septic shock, and it represents an early biomarker, it has prognostic significance. Right ventricular dysfunction associated with sepsis patients with worse early prognosis. Global longitudinal stress and magnetic resonance imaging (MRI) of the heart are sufficiently sensitive methods, but at the same time MRI of the heart is difficult to access in intensive care units, especially when dealing with critically ill patients. Previous research has identified two biomarkers as a result of the integrated mitochondrial response to stress, and these are fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15). Both of the mentioned biomarkers can be easily quantified in serum or plasma, but they are difficult to be specific in patients with multiple comorbidities. Mitochondrial dysfunction is also associated with reduced levels of miRNA (microRNA), some research showed significance of miRNA in sepsis-induced myocardial dysfunction, but further research is needed to determine the clinical significance of these molecules in septic cardiomyopathy. Therapeutic options in the treatment of septic cardiomyopathy are not specific, and include the optimization of hemodynamic parameters and the use of antibiotic thera-pies with targeted action. Future research aims to find mechanisms of targeted action on the initial mechanisms of the development of septic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Abstract Objective Xinyang Tablet (XYT) has emerged as a potential intervention to counter sepsis-induced myocardial dysfunction (SMID) by influencing macrophage autophagy and M2 polarization. This study aimed to unravel the underlying mechanism of XYT in sepsis-induced myocardial dysfunction (SIMD). Methods A microarray analysis was employed to explore sepsis-related changes, and bioinformatics analysis was used to predict lncRNAs binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). This studio utilized SIMD mouse models induced by lipopolysaccharide (LPS) injection, followed by treatments involving varied doses of XYT, digoxin (positive control), or si-LncSICRNT1. After seven days, evaluations encompassing mouse hair/mental state/diet/weight were measured, and cardiac function via echocardiography were conducted. Myocardial tissue changes were observed using hematoxylin–eosin staining. Additionally, bone marrow-derived macrophages (BMDMs) subjected to LPS for M1 polarization were treated with oe-LncSICRNT1, si-TRAF6 and their negative control, XYT, or autophagy inhibitor 3-Methyladenine (3-MA) (positive control). RT-qPCR and Western blot analyses were employed to assess LncSICRNT1, TRAF6, Beclin-1, LC3II/LC3I, and p62 levels. Immunohistochemistry and flow cytometry were used for M1/M2 polarization markers, while enzyme-linked immunosorbent assay (ELISA) gauged inflammatory factor levels. Interaction between TRAF6 and LncSICRNT1 was probed using RNA pull-down and RNA immunoprecipitation (RIP) assays. Results Chip analysis obtained 1463 differentially expressed lncRNAs, including LINC01550 (LncSICRNT1). Further prediction indicated that LncSICRNT1 was highly likely to directly bind to TRAF6. XYT treatment in LPS-induced SIMD mice led to notable enhancements in sleep/hair/diet/activity, increased weight/left ventricular end-diastolic diameter (LVEDd)/LV ejection fraction (LVEF)/LV fraction shortening (LVFS). These improvements were associated with elevated LncSICRNT1 expression and decreased TRAF6 protein levels, culminating in reduced myocardial inflammatory responses and improved cardiac function. Notably, XYT was found to suppress macrophage M1 polarization, while enhancing M2 polarization, ultimately benefitting cardiac function via LncSICRNT1 modulation. Furthermore, the study revealed LncSICRNT1 modulated Beclin-1 ubiquitination and restrained macrophage autophagy by targeting TRAF6 expression. Conclusion The study highlights XYT’s potential to ameliorate LPS-induced SIMD by elevating LncSICRNT1 expression, influencing TRAF6 expression, and regulating Beclin-1 ubiquitination. These actions collectively inhibit macrophage autophagy and foster M1/M2 polarization, contributing to cardiac function improvement.

Abstract Background and Aims The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity. Conclusion Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. Graphical Abstract

Myocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SMD) is often associated with gastrointestinal dysfunction, but its pathophysiological significance remains unclear. The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD. In mice, knockdown of the gastrin receptor, cholecystokinin B receptor (Cckbr), aggravated lipopolysaccharide (LPS)-induced cardiac dysfunction and increased inflammation in the heart, whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury. Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes, 48 h prior to LPS administration, alleviated LPS-induced cardiac injury in Cckbr-deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing Cckbr reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 (TLR4) expression through the peroxisome proliferator-activated receptor α (PPAR-α) signaling pathway in BMMs. Thus, our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD, which could be used to develop new treatment modalities for SMD.

Cardiomyopathy is a common complication and significantly increases the risk of death in septic patients. Our previous study demonstrated that post-treatment with dexmedetomidine (DEX) aggravates septic cardiomyopathy. However, the mechanisms for the side effect of DEX post-treatment on septic cardiomyopathy are not well-defined. Here we employed a cecal ligation and puncture (CLP) model and α2A-adrenoceptor deficient (Adra2a-/-) mice to observe the effects of DEX post-treatment on myocardial metabolic disturbances in sepsis. CLP mice displayed significant cardiac dysfunction, altered mitochondrial dynamics, reduced cardiac lipid and glucose uptake, impaired fatty acid and glucose oxidation, enhanced glycolysis and decreased ATP production in the myocardium, almost all of which were dramatically enhanced by DEX post-treatment in septic mice. In Adra2a-/- mice, DEX post-treatment did not affect cardiac dysfunction and metabolic disruptions in CLP-induced sepsis. Additionally, Adra2a-/- mice exhibited impaired cardiac function, damaged myocardial mitochondrial structures, and disturbed fatty acid metabolism and glucose oxidation. In sum, DEX post-treatment exacerbates metabolic disturbances in septic cardiomyopathy in a α2A-adrenoceptor dependent manner.

Background and Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results: In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity. Conclusion: Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. [ABSTRACT FROM AUTHOR]

Myocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SMD) is often associated with gastrointestinal dysfunction, but its pathophysiological significance remains unclear. The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD. In mice, knockdown of the gastrin receptor, cholecystokinin B receptor (Cckbr), aggravated lipopolysaccharide (LPS)-induced cardiac dysfunction and increased inflammation in the heart, whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury. Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes, 48 h prior to LPS administration, alleviated LPS-induced cardiac injury in Cckbr -deficient mice. The intravenous injection of bone marrow macrophages (BMMs) overexpressing Cckbr reduced LPS-induced myocardial dysfunction. Furthermore, gastrin treatment inhibited toll-like receptor 4 (TLR4) expression through the peroxisome proliferator-activated receptor α (PPAR- α) signaling pathway in BMMs. Thus, our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD, which could be used to develop new treatment modalities for SMD. Gastrin/CCKBR inhibits the expression of TLR4 by stimulation of the transcription of PPAR- α , and thereby inhibits the activation of LPS/TLR4/NF- κ B axis, and eventually attenuates sepsis-induced myocardial dysfunction. [Display omitted] [ABSTRACT FROM AUTHOR]

Sepsis-induced myocardial dysfunction (SIMD) is one of the serious health-affecting problems worldwide. At present, the mechanisms of SIMD are still not clearly elucidated. The NOD-like receptor protein 3 (NLRP3) inflammasome has been assumed to be involved in the pathophysiology of SIMD by regulating multiple biological processes. NLRP3 inflammasome and its related signaling pathways might affect the regulation of inflammation, autophagy, apoptosis, and pyroptosis in SIMD. A few molecular specific inhibitors of NLRP3 inflammasome (e.g., Melatonin, Ulinastatin, Irisin, Nifuroxazide, and Ginsenoside Rg1, etc.) have been developed, which showed a promising anti-inflammatory effect in a cellular or animal model of SIMD. These experimental findings indicated that NLRP3 inflammasome could be a promising therapeutic target for SIMD treatment. However, the clinical translation of NLRP3 inhibitors for treating SIMD still requires robust in vivo and preclinical trials.

BACKGROUND: Studies have found that inflammasome and autophagy play important roles in the immune function of patients with sepsis. However, the current research is only limited to exploring the characteristics of changes in a certain autophagy signaling pathway in sepsis, and the specific mechanism of autophagy regulation in sepsis-induced myocardial dysfunction has not been elucidated. OBJECTIVE: To investigate the changes of NOD-like receptor family, pyrin domain-containing protein 4 (NLRC4) inflammasome and autophagy levels in a mouse model of sepsis-induced myocardial dysfunction, in order to provide a theoretical basis for the pathogenesis of sepsis-induced myocardial dysfunction. METHODS: Forty-eight clean and healthy Kunming male mice were randomly divided into six groups, sham operation group (6, 12, 24 hours) and cecal ligation and puncture group (6, 12, 24 hours) with three groups each. In the cecal ligation and puncture group, the distal half of the cecum of the mice was ligated, and a 22-gauge needle was used for puncturing twice to squeeze out a little intestinal content. Except for ligation and perforation, other operations in the sham operation group were the same as those in the cecal ligation and perforation group. The general condition of the mice after operation was observed. Mouse cardiac function was measured by VINNO 7 6LAB ultrasound. Levels of tumor necrosis factor α and troponin T were detected by enzyme-linked immunosorbent assay. Pathological changes of the myocardium were observed by hematoxylin-eosin staining. Changes in myocardial mitochondria and autophagosome were observed under transmission electron microscope. Real-time quantitative polymerase chain reaction was used to detect the expression of NLRC4 mRNA in myocardial tissue, and western blot was used to detect the expression of inflammatory factors, LC3, Beclin-1, and NLRC4 protein in mouse myocardial tissue. RESULTS AND CONCLUSION: Tumor necrosis factor α level, Beclin-1 level, and LC3-II/LC3-I ratio were significantly increased in mice at 6 hours after cecal ligation and puncture (P < 0.05). At 12 hours after cecal ligation and puncture, tumor necrosis factor α and troponin T levels in the peripheral blood of mice increased, left ventricular ejection fraction and left ventricular shortening rate decreased, and NLRC4 mRNA and protein levels, interleukin-1β level, interleukin-18 level, Beclin-1 level, and LC3-II/LC3-I ratio increased (P < 0.05). At 24 hours after cecal ligation and puncture, NLRC4 mRNA and protein levels increased progressively, interleukin-1β and interleukin-18 were highly expressed, and Beclin-1 level and LC3-II/LC3-I ratio significantly decreased (P < 0.05). Myocardial pathological changes detected by hematoxylin-eosin staining showed that the myocardial fibers were normal in the sham operation group and at 6 hours after cecal ligation and perforation, and there was no inflammatory cell infiltration. Myocardial fibroedema and inflammatory cell infiltration occurred at 12 hours after cecal ligation and perforation. With the prolongation of time, the arrangement of myocardial fibers was disordered, the infiltration of inflammatory cells was aggravated, and some myocardial fibers appeared to have degeneration and necrosis. Under the transmission electron microscope, in the cecal ligation and perforation group, myocardial mitochondria were swollen, and with the extension of time, the swelling was aggravated, vacuolar degeneration of mitochondria occurred, and the myofibrils were slightly dissolved. Autophagosomes appeared at 6 hours after cecal ligation and perforation and increased in number at 12 hours, but occasionally appeared at 24 hours. In conclusion, the mouse model of sepsis-induced myocardial dysfunction is successfully established at 12 hours after cecal ligation and perforation. Excessive activation of NLRC4 inflammasomes is involved in the pathogenesis of sepsisinduced myocardial dysfunction by down-regulating the expression of autophagy. BACKGROUND: Studies have found that inflammasome and autophagy play important roles in the immune function of patients with sepsis. However, the current research is only limited to exploring the characteristics of changes in a certain autophagy signaling pathway in sepsis, and the specific mechanism of autophagy regulation in sepsis-induced myocardial dysfunction has not been elucidated. OBJECTIVE: To investigate the changes of NOD-like receptor family, pyrin domain-containing protein 4 (NLRC4) inflammasome and autophagy levels in a mouse model of sepsis-induced myocardial dysfunction, in order to provide a theoretical basis for the pathogenesis of sepsis-induced myocardial dysfunction. METHODS: Forty-eight clean and healthy Kunming male mice were randomly divided into six groups, sham operation group (6, 12, 24 hours) and cecal ligation and puncture group (6, 12, 24 hours) with three groups each. In the cecal ligation and puncture group, the distal half of the cecum of the mice was ligated, and a 22-gauge needle was used for puncturing twice to squeeze out a little intestinal content. Except for ligation and perforation, other operations in the sham operation group were the same as those in the cecal ligation and perforation group. The general condition of the mice after operation was observed. Mouse cardiac function was measured by VINNO 7 6LAB ultrasound. Levels of tumor necrosis factor α and troponin T were detected by enzyme-linked immunosorbent assay. Pathological changes of the myocardium were observed by hematoxylin-eosin staining. Changes in myocardial mitochondria and autophagosome were observed under transmission electron microscope. Real-time quantitative polymerase chain reaction was used to detect the expression of NLRC4 mRNA in myocardial tissue, and western blot was used to detect the expression of inflammatory factors, LC3, Beclin-1, and NLRC4 protein in mouse myocardial tissue. RESULTS AND CONCLUSION: Tumor necrosis factor α level, Beclin-1 level, and LC3-II/LC3-I ratio were significantly increased in mice at 6 hours after cecal ligation and puncture (P < 0.05). At 12 hours after cecal ligation and puncture, tumor necrosis factor α and troponin T levels in the peripheral blood of mice increased, left ventricular ejection fraction and left ventricular shortening rate decreased, and NLRC4 mRNA and protein levels, interleukin-1β level, interleukin-18 level, Beclin-1 level, and LC3-II/LC3-I ratio increased (P < 0.05). At 24 hours after cecal ligation and puncture, NLRC4 mRNA and protein levels increased progressively, interleukin-1β and interleukin-18 were highly expressed, and Beclin-1 level and LC3-II/LC3-I ratio significantly decreased (P < 0.05). Myocardial pathological changes detected by hematoxylin-eosin staining showed that the myocardial fibers were normal in the sham operation group and at 6 hours after cecal ligation and perforation, and there was no inflammatory cell infiltration. Myocardial fibroedema and inflammatory cell infiltration occurred at 12 hours after cecal ligation and perforation. With the prolongation of time, the arrangement of myocardial fibers was disordered, the infiltration of inflammatory cells was aggravated, and some myocardial fibers appeared to have degeneration and necrosis. Under the transmission electron microscope, in the cecal ligation and perforation group, myocardial mitochondria were swollen, and with the extension of time, the swelling was aggravated, vacuolar degeneration of mitochondria occurred, and the myofibrils were slightly dissolved. Autophagosomes appeared at 6 hours after cecal ligation and perforation and increased in number at 12 hours, but occasionally appeared at 24 hours. In conclusion, the mouse model of sepsis-induced myocardial dysfunction is successfully established at 12 hours after cecal ligation and perforation. Excessive activation of NLRC4 inflammasomes is involved in the pathogenesis of sepsisinduced myocardial dysfunction by down-regulating the expression of autophagy. [ABSTRACT FROM AUTHOR]

Sepsis-induced myocardial dysfunction is primarily accompanied by severe sepsis, which is associated with high morbidity and mortality. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), encoded by Hsd11b1, is a reductase that can convert inactive cortisone into metabolically active cortisol, but the role of 11β-HSD1 in sepsisinduced myocardial dysfunction remains poorly understood. The current study aimed to investigate the effects of 11β-HSD1 on a lipopolysaccharide (LPS)-induced mouse model, in which LPS (10 mg/kg) was administered to wild-type C57BL/6J mice and 11β-HSD1 global knockout mice. We asscessed cardiac function by echocardiography, performed transmission electron microscopy and immunohistochemical staining to analyze myocardial mitochondrial injury and histological changes, and determined the levels of reactive oxygen species and biomarkers of oxidative stress. We also employed polymerase chain reaction analysis, Western blotting, and immunofluorescent staining to determine the expression of related genes and proteins. To investigate the role of 11β-HSD1 in sepsis-induced myocardial dysfunction, we used LPS to induce lentivirus-infected neonatal rat ventricular cardiomyocytes. We found that knockdown of 11β-HSD1 alleviated LPS-induced myocardial mitochondrial injury, oxidative stress, and inflammation, along with an improved myocardial function; furthermore, the depletion of 11β-HSD1 promoted the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and silent information regulator 1 (SIRT1) protein levels both in vivo and in vitro. Therefore, the suppression of 11β-HSD1 may be a viable strategy to improve cardiac function against endotoxemia challenges. [ABSTRACT FROM AUTHOR]

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced myocardial dysfunction represents reversible myocardial dysfunction which ultimately results in left ventricular dilatation or both, with consequent loss of contractility. Studies on septic cardiomyopathy report a wide range of prevalence ranging from 10% to 70%. Myocardial damage occurs as a result of weakened myocardial circulation, direct myocardial depression, and mitochondrial dysfunction. Mitochondrial dysfunction is the leading problem in the development of septic cardiomyopathy and includes oxidative phosphorylation, production of reactive oxygen radicals, reprogramming of energy metabolism, and mitophagy. Echocardiography provides several possibilities for the diagnosis of septic cardiomyopathy. Systolic and diastolic dysfunction of left ventricular is present in 50–60% of patients with sepsis. Right ventricular dysfunction is present in 50–55% of cases, while isolated right ventricular dysfunction is present in 47% of cases. Left ventricle (LV) diastolic dysfunction is very common in septic shock, and it represents an early biomarker, it has prognostic significance. Right ventricular dysfunction associated with sepsis patients with worse early prognosis. Global longitudinal stress and magnetic resonance imaging (MRI) of the heart are sufficiently sensitive methods, but at the same time MRI of the heart is difficult to access in intensive care units, especially when dealing with critically ill patients. Previous research has identified two biomarkers as a result of the integrated mitochondrial response to stress, and these are fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15). Both of the mentioned biomarkers can be easily quantified in serum or plasma, but they are difficult to be specific in patients with multiple comorbidities. Mitochondrial dysfunction is also associated with reduced levels of miRNA (microRNA), some research showed significance of miRNA in sepsis-induced myocardial dysfunction, but further research is needed to determine the clinical significance of these molecules in septic cardiomyopathy. Therapeutic options in the treatment of septic cardiomyopathy are not specific, and include the optimization of hemodynamic parameters and the use of antibiotic thera-pies with targeted action. Future research aims to find mechanisms of targeted action on the initial mechanisms of the development of septic cardiomyopathy.

Abstract Background Myocardial dysfunction is common in septic shock and has long been recognized. Takotsubo syndrome is an acute and usually reversible myocardial injury without evidence of an obstructive coronary artery disease, yet little is known about this syndrome in septic shock patients. Case presentation Among 84 septic shock patients admitted to the ICU over a period of 8 months, 7 patients (8.3%) were diagnosed with Takotsubo syndrome. The percentage of men was 71%, and the mean age was 58 (19–87) years. Sudden hemodynamic deterioration and/or dyspnea were the presenting symptoms in 6 patients. T-wave inversion was the major ECG anomaly in 5 patients. The mean left ventricular ejection fraction was 31.8% (20.0–53.0). Mild elevation of cardiac troponin disproportionate to the extent of regional wall motion abnormalities was present in all patients. Cardiac complications occurred in 6 patients. The mean time to recover the cardiac function was 6.5 (3–11) days. In-hospital death was observed in 2 patients. Conclusions Takotsubo syndrome is not uncommon in septic shock patients and may be the cause of some patients with sepsis-induced myocardial dysfunction. New-onset hemodynamic and respiratory worsening could arouse the suspicion of Takotsubo syndrome and prompt the screening for this syndrome using echocardiography in this clinical context.

Sepsis is a life-threatening organ dysfunction caused by dysregulated host immune response to infection. Sepsis-induced myocardial dysfunction (SIMD) is a common complication in patients with severe sepsis and is associated with increased mortality. The molecular mechanisms underlying SIMD are complex and not well characterized. Excessive inflammation due to impaired regulation of immune response is one of the major causes of SIMD. Necroptosis is a novel type of cell death that is closely related to tissue injury and inflammation. However, the role of necroptosis in SIMD is not known. Therefore, in this study, we performed an in-depth bioinformatics analysis to investigate the relationship between necroptosis and SIMD using a mouse model generated by intraperitoneal injection of lipopolysaccharide (LPS) and the underlying mechanisms. Myocardial function was assessed by echocardiography. Histopathological changes in SIMD were analyzed by hematoxylin and eosin (H&E) staining. Gene expression profiles of the heart tissues from the SIMD and control mice were analyzed by bioinformatics analysis. Transcriptome sequencing demonstrated significant differences in the expression levels of 3654 genes in the heart tissues of SIMD mice including 1810 up-regulated and 1844 down-regulated genes. The necroptosis pathway genes were significantly enriched in the heart tissues from the SIMD group mice. We identified 35 necroptosis-related differentially expressed genes (NRDEGs) including MLKL and RIPK3. Cardiomyocyte necroptosis was confirmed by qRT-PCR and western blot analysis. The expression levels of most NRDEGs showed positive correlation with the infiltration levels of mast cells, macrophages, and neutrophils, and negative correlation with the infiltration levels of B cells and plasma cells in the heart tissues of the SIMD group mice. In conclusion, this study demonstrated that necroptosis was associated with changes in the infiltration levels of several immune cell types in the heart tissues of the SIMD model mice. This suggested that necroptosis influenced SIMD development by modulating the immune microenvironment. This suggested that NRDEGs are potential diagnostic biomarkers and therapeutic targets for patients with SIMD. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms. Male mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice. SO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid β-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80. Our study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD. [Display omitted] ● Early administration of sodium octanoate (SO) following sepsis induction can enhance cardiac function, reduce myocardial damage and prolong survival in septic mice through both GPR84-dependent protective effects and GPR84-independent promotion of energy metabolism. ● This study demonstrates that, under the high-inflammatory state of sepsis, the activation of GPR84 by medium-chain fatty acids can inhibit the NF-κB and MAPK pathways, thereby modulating the inflammatory response and alleviating myocardial oxidative stress injury. ● Sodium octanoate improves myocardial cell energy and exerts its epigenetic modification capabilities through MCAD. [ABSTRACT FROM AUTHOR]

There is still a lack of effective treatment for sepsis-induced myocardial dysfunction (SIMD), while the pathogenesis of SIMD still remains largely unexplained. RNA sequencing results (GSE267388 and GSE79962) were used for cross-species integrative analysis. Bioinformatic analyses were used to delve into function, tissue- and cell- specificity, and interactions of genes. External datasets and qRT-PCR experiments were used for validation. L1000 FWD was used to predict targeted drugs, and 3D structure files were used for molecular docking. Based on bioinformatic analyses, ten differentially expressed genes were selected as genes of interest, seven of which were verified to be significantly differential expression. Bucladesine was considered as a potential targeted drug for SIMD, which banded to seven target proteins primarily by forming hydrogen bonds. It was considered that Cebpd , Timp1 , Pnp , Osmr , Tgm2 , Cp, and Asb2 were novel disease genes, while bucladesine was a potential therapeutic drug, of SIMD. • The pathogenesis of sepsis-induced myocardial dysfunction remains largely unexplained. • This study produced a new RNA sequencing dataset of heart tissue from mouse models. • Seven novel disease genes of sepsis-induced myocardial dysfunction were screened. • Bucladesine was considered as a potential targeted drug of these genes. [ABSTRACT FROM AUTHOR]

Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD. [Display omitted] • The JAK2-AKT-mTOR pathway limits cardiac mitophagy activation in septic mice. • Baricitinib improves cardiac function in septic mice by enhancing mitophagy. • Inhibiting mitophagy reverses Baricitinib's cardiac protection benefit. • Baricitinib treatment is a promising therapeutic strategy for SIMD. [ABSTRACT FROM AUTHOR]

BackgroundSepsis-induced myocardial dysfunction (SIMD) has a significant contribution to sepsis-caused death in critically ill patients. In recent years, the number of published articles related to SIMD has increased rapidly. However, there was no literature that systematically analyzed and evaluated these documents. Thus, we aimed to lay a foundation for researchers to quickly understand the research hotspots, evolution processes and development trends in the SIMD field via a bibliometric analysis.MethodsArticles related to SIMD were retrieved and extracted from the Web of Science Core Collection on July 19th, 2022. CiteSpace (version 6.1.R2) and VOSviewer (version 1.6.18) were used for performing visual analysis.ResultsA total of 1,076 articles were included. The number of SIMD-related articles published each year has increased significantly. These publications mainly came from 56 countries, led by China and the USA, and 461 institutions, but without stable and close cooperation. As authors, Li Chuanfu published the most articles, while Rudiger Alain had the most co-citations. Shock was the journal with the most studies, and Critical Care Medicine was the most commonly cited journal. All keywords were grouped into six clusters, some of which represented the current and developing research directions of SIMD as the molecular mechanisms.ConclusionResearch on SIMD is flourishing. It is necessary to strengthen cooperation and exchanges between countries and institutions. The molecular mechanisms of SIMD, especially oxidative stress and regulated cell death, will be critical subjects in the future.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA (lncRNA), has been confirmed to recruit enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) to regulate cardiomyocyte apoptosis in diabetic cardiomyopathy. However, whether the similar regulatory axis exists in sepsis-induced myocardial dysfunction (SIMD) has not been clearly established. The current study sought to define the mechanism governing MALAT1-mediated EZH2 in SIMD. MALAT1 was significantly upregulated in lipopolysaccharide-induced cardiomyocytes. Depletion of MALAT1 by caudal vein injection of small interfering RNA targeting MALAT1 alleviated myocardial injury in SIMD rats, restored cardiac function, reduced oxidative stress production and fibrosis, and inhibited inflammatory factors and apoptosis in myocardial tissues. Moreover, MALAT1 bound to EZH2 and promoted EZH2 activity in the nucleus of cardiomyocytes. EZH2 repressed ubiquitin-specific peptidase 22 (USP22) expression through H3K27me3 modification. EZH2 elevation aggravated the cardiac injury in SIMD rats, while USP22 upregulation inhibited the effect of EZH2, which reduced the cardiac injury in SIMD rats. Taken together, MALAT1 decreased USP22 expression by interacting with EZH2, thereby worsening SIMD, highlighting an attractive therapeutic strategy for SIMD. [ABSTRACT FROM AUTHOR]

Sepsis is a severe inflammatory syndrome with high mortality and morbidity. Sepsis-induced myocardial dysfunction (SIMD) is a common cause of death in sepsis. The female sex is less susceptible to sepsis-related organ dysfunction, although the underlying mechanism of this sex difference remains unclear. This study explored the role of estrogen receptor G protein-coupled estrogen receptor 30 (GPR30) in septic cardiac dysfunction. Results from the present study indicated that GPR30 activation by the G1 agonist protected female mouse hearts against SIMD exposed to lipopolysaccharides. However, this beneficial effect was absent in female ACE2-knockout mice, as demonstrated by poorer cardiac contractility, myocardial injury, and necroptosis. We also demonstrated that the Stat6 transcription factor induced ace2 transcription by enhancing its promoter activity under GPR30 activation in septic hearts. The adenovirus-mediated inhibition of ACE2 targeting c-FOS expression reversed the deterioration, restored cardiac function, and improved survival in female ACE2-knockout mice. These results demonstrate the essential role of GPR30/STAT6/ACE2/c-FOS-mediated necroptosis in G1-mediated protection and provide novel insight into the pathogenesis of sepsis-related organ damage.

The signaling pathway mediated by high mobility group protein B1 (HMGB1) plays a key role in myocardial injury during sepsis. Glyrrhizin (GL) is a natural product that inhibits HMGB1 biological activities through forming GL-HMGB1 complex; the research shows its aglycone (GA) is the main pharmacophore binding to HMGB1, while the glycosyl mainly altering its pharmacokinetic properties and enhances the stability of the complex. GL is often metabolized to GA in the gastrointestinal tract, which has a lower efficacy in the treatment of HMGB1-mediated diseases. To obtain the GL analogs with higher activity and better pharmacokinetic properties, 24 GL analogs were synthesized by simplification the glycosyl of GL. Among all the compounds, compound 11 with furanoylpiperazine was screened. The pharmacokinetics experiments showed that compound 11 is converted to 11a in vivo, and 11 serves as its prodrug. Compound 11a displayed a lower cytotoxicity to RAW264.7 cells and three types of cardiomyocyte lines, with IC 50  > 800 µM. In the anti-inflammatory assay, 11a not only strongly inhibited NO production (IC 50 5.73 µM), but also down-regulated the levels of HMGB1, IL-1β and TNF-α in a dose-dependent manner; in the anti-oxidative stress assay, compound 11a reduced the level of ROS and increased the MMP in H9c2 cells. More importantly, in the myocardial injury model of septic mice, compound 11a not only alleviated the symptom of myocardial injury by reducing inflammatory infiltration and oxidative stress, but also improved the myocardial blood supply by shrinking the inner diameter of the left ventricle and increasing the ejection fraction (EF) more dramatically (155.8 %); meanwhile, compound 11a adjusted myocardial enzymes in serum of septic mice. In addition, in molecular docking experiments, compound 11a showed stronger HMGB1 binding ability than GL. In summary, compound 11 is a prodrug, which can be converted to 11a in vivo. And compound 11a has a good activity against septic myocardial injury, as well as improving the myocardial blood supply function. This suggests compound 11 is a potential drug candidate for the treatment of septic myocardial injury and deserves further investigate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Jian-Biao Meng,1,2 Ma-Hong Hu,2 Ming Zhang,3 Gong-Pai Hu,4 Wei Zhang,5 Shen-Jiang Hu1 1Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, People’s Republic of China; 2Intensive Care Unit, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, People’s Republic of China; 3Intensive Care Unit, Hangzhou Cancer Hospital, Hangzhou, Zhejiang Province, 310002, People’s Republic of China; 4Department of Ultrasonography, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, People’s Republic of China; 5Department of Cardiology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, People’s Republic of ChinaCorrespondence: Shen-Jiang HuDepartment of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310003, People’s Republic of ChinaEmail hzhzl85519933@zju.edu.cnPurpose: This study aimed to explore relationships between whole blood copper (Cu), zinc (Zn) and Cu/Zn ratio and cardiac dysfunction in patients with septic shock.Subjects and Methods: Between April 2018 and March 2020, septic shock patients with sepsis-induced left ventricular systolic dysfunction (SILVSD, left ventricular ejection fraction, LVEF< 50%) and with no sepsis-induced myocardial dysfunction (non-SIMD, septic shock alone and LVEF> 50%) and controls were prospectively enrolled. Whole blood Cu and Zn levels were measured using flame atomic absorption spectrophotometry.Results: Eighty-six patients with septic shock including both 41 SILVSD and 45 non-SIMD and 25 controls were studied. Whole blood Cu levels and Cu/Zn ratio were significantly higher and Zn levels were lower in SILVSD compared with non-SIMD and controls (Cu, p=0.009, < 0.001; Zn, p=0.029, < 0.001; Cu/Zn ratio, p=0.003, < 0.001). Both increased whole blood Cu and Cu/Zn ratio and reduced Zn were associated with lower LVEF (all p< 0.001) and higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) (Cu, p=0.002; Zn, p< 0.001; Cu/Zn ratio, p< 0.001) and had predictive values for SILVSD (Cu, AUC=0.666, p=0.005; Zn, AUC=0.625, p=0.039; Cu/Zn ratio, AUC=0.674, p=0.029). Whole blood Cu levels and Cu/Zn ratio were increased but Zn levels were reduced in non-survivors compared with survivors (Cu, p< 0.001; Zn, p< 0.001; Cu/Zn ratio, p< 0.001). Whole blood Cu and Zn displayed the value of predicting 28-day mortality (Cu, AUC = 0.802, p< 0.001; Zn, AUC=0.869, p< 0.001; Cu/Zn ratio, AUC=0.902, p< 0.001).Conclusion: Findings of the study suggest that whole blood Cu levels and Cu/Zn ratio are increased in SILVSD patients and positively correlated with cardiac dysfunction, while whole blood Zn levels are reduced and negatively associated with cardiac dysfunction. Moreover, both whole blood Cu, Zn and Cu/Zn ratio might distinguish between SILVSD and non-SIMD in septic shock patients and predict 28-day mortality.Trial Registration: Registered at http://www.chictr.org.cn/ChiCTR1800015709.Keywords: copper, zinc, Cu/Zn ratio, septic shock, sepsis-induced left ventricular systolic dysfunction, sepsis-induced myocardial dysfunction, diagnosis, prognosis

Abstract Background Troponin levels can be elevated in various diseases other than acute myocardial infarction, including sepsis. In diseases without myocardial necrosis, the elevated troponin levels are relatively low and normalize quickly. Case presentation A 61-year-old Japanese man with impaired consciousness was transported to our hospital. He was diagnosed as having pneumonia and septic shock. His condition was severe, but his clinical course was good. However, his troponin level remained extremely high during admission; on the second day, it was higher than the measurable range. We consulted a cardiologist and performed echocardiography and myocardial perfusion scintigraphy but found no new ischemic changes. Conclusion In septic shock, troponin levels can be extremely high, which can persist even after recovery, as in very large myocardial infarctions.

Mitochondrial and endoplasmic reticulum (ER) are important intracellular organelles. The sites that mitochondrial and ER are closely related in structure and function are called Mitochondria-ER contacts (MERCs). MERCs are involved in a variety of biological processes, including calcium signaling, lipid synthesis and transport, autophagy, mitochondrial dynamics, ER stress, and inflammation. Sepsis-induced myocardial dysfunction (SIMD) is a vital organ damage caused by sepsis, which is closely associated with mitochondrial and ER dysfunction. Growing evidence strongly supports the role of MERCs in the pathogenesis of SIMD. In this review, we summarize the biological functions of MERCs and the roles of MERCs proteins in SIMD.

Background: Myocardial dysfunction is common in septic shock and has long been recognized. Takotsubo syndrome is an acute and usually reversible myocardial injury without evidence of an obstructive coronary artery disease, yet little is known about this syndrome in septic shock patients.Case Presentation: Among 84 septic shock patients admitted to the ICU over a period of 8 months, 7 patients (8.3%) were diagnosed with Takotsubo syndrome. The percentage of men was 71%, and the mean age was 58 (19-87) years. Sudden hemodynamic deterioration and/or dyspnea were the presenting symptoms in 6 patients. T-wave inversion was the major ECG anomaly in 5 patients. The mean left ventricular ejection fraction was 31.8% (20.0-53.0). Mild elevation of cardiac troponin disproportionate to the extent of regional wall motion abnormalities was present in all patients. Cardiac complications occurred in 6 patients. The mean time to recover the cardiac function was 6.5 (3-11) days. In-hospital death was observed in 2 patients.Conclusions: Takotsubo syndrome is not uncommon in septic shock patients and may be the cause of some patients with sepsis-induced myocardial dysfunction. New-onset hemodynamic and respiratory worsening could arouse the suspicion of Takotsubo syndrome and prompt the screening for this syndrome using echocardiography in this clinical context. [ABSTRACT FROM AUTHOR]

Objective: Sepsis-induced myocardial dysfunction (SIMD) seriously affects the evolution and prognosis of the sepsis patient. The gut microbiota has been confirmed to play an important role in sepsis or cardiovascular diseases, but the changes and roles of the gut microbiota in SIMD have not been reported yet. This study aims to assess the compositions of the gut microbiota in sepsis or septic patients with or without myocardial injury and to find the relationship between the gut microbiota and SIMD. Methods: The prospective, observational, and 1:1 matched case–control study was conducted to observe gut microbiota profiles from patients with SIMD (n = 18) and matched non-SIMD (NSIMD) patients (n = 18) by 16S rRNA gene sequencing. Then the relationship between the relative abundance of microbial taxa and clinical indicators and clinical outcomes related to SIMD was analyzed. The receiver operating characteristic (ROC) curves were used to evaluate the predictive efficiencies of the varied gut microbiota to SIMD. Results: SIMD was associated with poor outcomes in sepsis patients. The beta-diversity of the gut microbiota was significantly different between the SIMD patients and NSIMD subjects. The gut microbiota profiles in different levels significantly differed between the two groups. Additionally, the abundance of some microbes (Klebsiella variicola , Enterobacteriaceae, and Bacteroides vulgatus) was correlated with clinical indicators and clinical outcomes. Notably, ROC analysis indicated that K. variicola may be a potential biomarker of SIMD. Conclusion: Our study indicates that SIMD patients may have a particular gut microbiota signature and that the gut microbiota might be a potential diagnostic marker for evaluating the risk of developing SIMD. [ABSTRACT FROM AUTHOR]

ObjectiveAbout 50% of patients with sepsis have different degrees of myocardial inhibition, known as sepsis-induced myocardial dysfunction (SMD), which increases the mortality rate of sepsis. Tp-Te interval and Tp-Te/QT ratio reflect ventricular transmural dispersion repolarization (TDR), and have good predictive value for death in patients with heart disease. This study aimed to investigate the prognostic value of Tp-Te and Tp-Te/QT in patients with sepsis.MethodsThe current study included a total of 625 participants: 201 patients with sepsis, 213 patients with heart failure, and 211 healthy participants. According to the severity and outcome, the patients with sepsis were divided into the sepsis group and the septic shock group, and the death group and the survival group to explore the differences of indicators among subgroups of sepsis. The ROC curve was used to analyze the predictive value of the indicators for deaths of patients with sepsis and calculate the cutoff point. Then, we investigated the incidence of arrhythmia in patients with sepsis with different TDR. The correlation between Tp-Te/QT and the commonly used predictive indicators in ICU was also discussed.Results(1) Tp-Te and Tp-Te/QT in patients with sepsis and heart failure (HF) were significantly higher than the control group (p < 0.01). (2) Compared with patients with sepsis, the increase of Tp-Te and Tp-Te/QT is more prominent in patients with HF. Especially, the increase of the Tp-Te/QT was statistically significant (p < 0.001). (3) compared with patients with sepsis (no shock), the Tp-Te, Tp-Te/QT, and SOFA were increased in patients with septic shock (p < 0.05). (4) In the death group, Tp-Te /QT, SOFA, and Apache-II were higher; LVEF was lower than the survival group (p < 0.05). (5) ROC curves showed that Tp-Te/QT, SOFA, and LVEF have predictive values for death (p < 0.05; AUC = 0.808, 0.716, 0.412). The cutoff point of Tp-Te/QT was 0.32. (6) The incidence of arrhythmia is different in patients with sepsis with different TDR. (7) There is a significant correlation between Tp-Te/QT and SOFA (p < 0.001, r = 0.79).ConclusionTDR in patients with sepsis is significantly increased, which was between healthy population and patients with HF. Tp-Te and Tp-Te/QT are effective indicators to reflect the severity and poor outcome of patients with sepsis.

ObjectiveSepsis-induced myocardial dysfunction (SIMD) seriously affects the evolution and prognosis of the sepsis patient. The gut microbiota has been confirmed to play an important role in sepsis or cardiovascular diseases, but the changes and roles of the gut microbiota in SIMD have not been reported yet. This study aims to assess the compositions of the gut microbiota in sepsis or septic patients with or without myocardial injury and to find the relationship between the gut microbiota and SIMD.MethodsThe prospective, observational, and 1:1 matched case–control study was conducted to observe gut microbiota profiles from patients with SIMD (n = 18) and matched non-SIMD (NSIMD) patients (n = 18) by 16S rRNA gene sequencing. Then the relationship between the relative abundance of microbial taxa and clinical indicators and clinical outcomes related to SIMD was analyzed. The receiver operating characteristic (ROC) curves were used to evaluate the predictive efficiencies of the varied gut microbiota to SIMD.ResultsSIMD was associated with poor outcomes in sepsis patients. The beta-diversity of the gut microbiota was significantly different between the SIMD patients and NSIMD subjects. The gut microbiota profiles in different levels significantly differed between the two groups. Additionally, the abundance of some microbes (Klebsiella variicola, Enterobacteriaceae, and Bacteroides vulgatus) was correlated with clinical indicators and clinical outcomes. Notably, ROC analysis indicated that K. variicola may be a potential biomarker of SIMD.ConclusionOur study indicates that SIMD patients may have a particular gut microbiota signature and that the gut microbiota might be a potential diagnostic marker for evaluating the risk of developing SIMD.

AimsCytokine storm is closely related to the initiation and progression of sepsis, and the level of IL-6 is positively correlated with mortality and organ dysfunction. Sepsis-induced myocardial dysfunction (SIMD) is one of the major complications. However, the role of the IL-6/STAT3 signaling in the SIMD remains unclear.Methods and ResultsSeptic mice were induced by intraperitoneal injection of LPS (10 mg/kg). Echocardiography, cytokines detection, and histologic examination showed that sepsis mice developed cardiac systolic and diastolic dysfunction, increase of inflammatory cytokines in serum, activated STAT3 and TLR4/NFκB pathway in heart, and raised myocardial apoptosis, which were attenuated by IL-6/STAT3 inhibitor, Bazedoxifene. In vitro, we found that LPS decreased cell viability in a concentration-dependent manner and activated STAT3. Western blot and immunofluorescence results indicated that STAT3 phosphorylation induced by LPS was inhibited by Bazedoxifene. Bazedoxifene also suppressed LPS-induced IL-6 transcription. sIL-6R caused LPS-induced p-STAT3 firstly decreased and then significantly increased. More importantly, we found STAT3-knockdown suppressed LPS-induced expression of FUNDC1, a protein located in mitochondria-associated endoplasmic reticulum membranes (MAMs). Overexpression of STAT3 led to an increase in FUNDC1 expression. Dual-luciferase reporter assay was used to confirm that STAT3 was a potential transcription factor for FUNDC1. Moreover, we showed that LPS increased MAMs formation and intracellular Ca2+ levels, enhanced the expression of Cav1.2 and RyR2, decreased mitochondrial membrane potential and intracellular ATP levels, and promoted mitochondrial fragmentation, the expression of mitophagy proteins and ROS production in H9c2 cells, which were reversed by knockdown of FUNDC1 and IL-6/STAT3 inhibitor including Bazedoxifene and Stattic.ConclusionsIL-6/STAT3 pathway plays a key role in LPS-induced myocardial dysfunction, through regulating the FUNDC1-associated MAMs formation and interfering the function of ER and mitochondria. IL-6/STAT3/FUNDC1 signaling could be a new therapeutic target for SIMD.

Background: Troponin levels can be elevated in various diseases other than acute myocardial infarction, including sepsis. In diseases without myocardial necrosis, the elevated troponin levels are relatively low and normalize quickly.Case Presentation: A 61-year-old Japanese man with impaired consciousness was transported to our hospital. He was diagnosed as having pneumonia and septic shock. His condition was severe, but his clinical course was good. However, his troponin level remained extremely high during admission; on the second day, it was higher than the measurable range. We consulted a cardiologist and performed echocardiography and myocardial perfusion scintigraphy but found no new ischemic changes.Conclusion: In septic shock, troponin levels can be extremely high, which can persist even after recovery, as in very large myocardial infarctions. [ABSTRACT FROM AUTHOR]

Shenfu injection(SFI), as a famous classical Chinese patent medicine injection for the treatment of sepsis, has achieved good curative effects in clinical practice. However, its specific ingredients and molecular mechanisms is still unclear. To analyze the effective ingredients and molecular mechanisms of SFI in the treatment of sepsis via network pharmacology technology and experimental validation. A total of 198 mice were used in this experiment. Septic mice model was performed by cecal ligation and puncture (CLP). First, Survival rates were calculted to screen the dosage and the treatment time window of SFI. Cardiac function was evaluated by echocardiography. The potential targets and pathways of SFI in the treatment of sepsis were predicted by network pharmacology. Myocardial tissue samples were harvest from different groups after CLP surgery. Hematoxylin-eosin (H&E) and TUNEL staining were used to examine the injury of heart. Western-blot analysis was performed to determine the protein expression of apoptosis. Meanwhile, the structural changes and mitochondrial membrane potential in the mitochondria of cardiomyocytes were also observed by transmission electron microscopy. The Kaplan-Meier survival analysis showed that SFI significantly improved the 7-day survival rate as compared with that of CLP mice (P < 0.05). Echocardiography analysis found that LVEF and FS were significantly reduced in CLP mice compared with Sham mice, while SFI significantly increased LVEF (P < 001). Network pharmacology analysis indicated that the potential targets with higher degrees include IL2, BCL2, BAX, CASP7, BID, CASP8. Pathways with higher degrees include apoptosis, TNF signaling pathway, mitochondrial pathway apoptosis, PI3K-AKT signaling pathway. SFI treatment markedly attenuated the quantity of apoptotic cells as compared with the CLP group (P < 0.01). Western blot analysis indicated that CLP surgery decreased the expression of Bcl-2 (anti-apoptotic) but improved the protein expression of Bid, t-Bid, Cyc (pro-apoptotic) as compared with the Sham group (P < 0.01). While, SFI treatment markedly prevent the expression of Bid, t-Bid, Cyc and Caspase-9. The myocardial mitochondrial membrane potential of CLP group decreased after CLP surgery, while the mitochondrial membrane potential of SFI group increased significantly. Compared with the CLP group, in SFI group, the Z-line of the sarcomere was clear and distinguishable, and swollen mitochondria were significantly improved. The present study demonstrated that SFI improved survival rate and cardiac function of septic mice mainly by suppressing inflammation and apoptosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Sepsis-induced myocardial dysfunction is a major contributor to the poor outcomes of septic shock. As an add-on with conventional sepsis management for over 15 years, the effect of Xuebijing injection (XBJ) on the sepsis-induced myocardial dysfunction was not well understood. The material basis of Xuebijing injection (XBJ) in managing infections and infection-related complications remains to be defined. A murine cecal ligation and puncture (CLP) model and cardiomyocytes in vitro culture were adopted to study the influence of XBJ on infection-induced cardiac dysfunction. XBJ significantly improved the survival of septic-mice and rescued cardiac dysfunction in vivo. RNA-seq revealed XBJ attenuated the expression of proinflammatory cytokines and related signalings in the heart which was further confirmed on the mRNA and protein levels. Xuebijing also protected cardiomyocytes from LPS-induced mitochondrial calcium ion overload and reduced the LPS-induced ROS production in cardiomyocytes. The therapeutic effect of XBJ was mediated by the combination of paeoniflorin and hydroxysafflor yellow A (HSYA) (C0127-2). C0127-2 improved the survival of septic mice, protected their cardiac function and cardiomyocytes while balancing gene expression in cytokine-storm-related signalings, such as TNF-α and NF-κB. In summary, Paeoniflorin and HSYA are key active compounds in XBJ for managing sepsis, protecting cardiac function, and controlling inflammation in the cardiac tissue partially by limiting the production of IL-6, IL-1β, and CXCL2.

Introduction: Sepsis-induced myocardial dysfunction (SIMD) is a condition manifested by an intrinsic myocardial systolic and diastolic dysfunction during sepsis, which is associated with worse clinical outcomes and a higher mortality. Materials and methods: Several pathophysiological mechanisms including mitochondrial dysfunction, abnormal body immune reaction, metabolic reprogramming, excessive production of reactive oxygen species (ROS), and disorder of calcium regulation have been involved in SIMD. Mitophagy has potential role in protecting myocardial cells in sepsis, especially in survivors. Conclusion: In the current review, we focus on the role of mitochondrial dysfunction and other mitochondria-related mechanisms including immunologic imbalance, energetic reprogramming, mitophagy, and pyroptosis in the mechanisms of SIMD. [ABSTRACT FROM AUTHOR]

Purpose of Review: To briefly review epidemiology and pathophysiology of SICM and provide a more extensive review of the data on diagnostic and management strategies. Recent Findings: SICM is likely underdiagnosed and that has mortality implications. Current evidence supports speckle tracking echocardiography to identify decreased contractility irrespective of left ventricular ejection fraction for the diagnosis of SICM. There continues to be a dearth of large clinical trials evaluating the treatment of SICM and current consensus focuses on supportive measures such as vasopressors and inotropes. Summary: Sepsis is a significant cause of mortality, and sepsis-induced cardiomyopathy has both prognostic and management implications for these patients. Individualized work-up and management of these patients is crucial to improving outcomes. [ABSTRACT FROM AUTHOR]

• Sivelestat improved the viability and suppressed the apoptosis of LPS-stimulated H9c2 cells. • S ivelestat reduced serum cTnT, TNF-α, IL-1β levels, and cardiomyocyte apoptosis; ameliorated cardiac function and structure. • Sivelestat treatment substantially increased Bcl-2 expression and suppressed caspase-3 and Bax expression. • The PI3K/AKT/mTOR signaling pathway was activated both in vitro and in vivo. • The protective effect of sivelestat against SIMD was reversed by the PI3K inhibitor LY294002. The cardioprotective role of sivelestat, a neutrophil elastase inhibitor, has already been demonstrated, but the underlying molecular mechanism remains unclear. This study aimed to explore the mechanism underlying the role of sivelestat in sepsis-induced myocardial dysfunction (SIMD). We found that sivelestat treatment remarkably improved the viability and suppressed the apoptosis of lipopolysaccharide (LPS)-stimulated H9c2 cells. In vivo , sivelestat treatment was associated with an improved survival rate; reduced serum cTnT, TNF-α, IL-1β levels and myocardial TNF-α and IL-1β levels; ameliorated cardiac function and structure; and reduced cardiomyocyte apoptosis. Moreover, sivelestat treatment substantially increased Bcl-2 expression and suppressed caspase-3 and Bax expression in LPS-induced H9c2 cells and in the heart tissues of septic rats. Furthermore, the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway was activated both in vitro and in vivo. The protective effect of sivelestat against SIMD was reversed by the PI3K inhibitor LY294002. In summary, sivelestat can protect against SIMD by activating the PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is a common complication and significantly increases the risk of death in septic patients. Our previous study demonstrated that post-treatment with dexmedetomidine (DEX) aggravates septic cardiomyopathy. However, the mechanisms for the side effect of DEX post-treatment on septic cardiomyopathy are not well-defined. Here we employed a cecal ligation and puncture (CLP) model and α 2A -adrenoceptor deficient (Adra2a -/- ) mice to observe the effects of DEX post-treatment on myocardial metabolic disturbances in sepsis. CLP mice displayed significant cardiac dysfunction, altered mitochondrial dynamics, reduced cardiac lipid and glucose uptake, impaired fatty acid and glucose oxidation, enhanced glycolysis and decreased ATP production in the myocardium, almost all of which were dramatically enhanced by DEX post-treatment in septic mice. In Adra2a -/- mice, DEX post-treatment did not affect cardiac dysfunction and metabolic disruptions in CLP-induced sepsis. Additionally, Adra2a -/- mice exhibited impaired cardiac function, damaged myocardial mitochondrial structures, and disturbed fatty acid metabolism and glucose oxidation. In sum, DEX post-treatment exacerbates metabolic disturbances in septic cardiomyopathy in a α 2A -adrenoceptor dependent manner. [Display omitted] • Dexmedetomidine (DEX) post-treatment deteriorates cardiac dysfunction in septic mice. • DEX post-treatment worsens myocardial mitochondrial injury induced by sepsis. • DEX exacerbates disorders of fatty acids and glucose metabolism in septic myocardium. • DEX activates α 2A -adrenoceptor to aggravate metabolic disturbances in septic heart. [ABSTRACT FROM AUTHOR]

• The potential effect of Plk-1 in SIMD is investigated. • Plk-1 promotes SIMD by enhancing inflammation and cardiac injury by inflammatory responses. • Plk-1 promotes cardiac dysfunction in sepsis by activating NF-κB signal pathway. Sepsis-induced myocardial dysfunction (SIMD) is the main cause of mortality in sepsis. In this study, we identified Polo-like kinase 1 (Plk-1) is a promoter of SIMD. Plk-1 expression was increased in lipopolysaccharide (LPS)-treated mouse hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of Plk-1 either by heterozygous deletion of Plk-1 or Plk-1 inhibitor BI 6727 alleviated LPS-induced myocardial injury, inflammation, cardiac dysfunction, and thereby improved the survival of LPS-treated mice. Plk-1 was identified as a kinase of inhibitor of kappa B kinase alpha (IKKα). Plk-1 inhibition impeded NF-κB signal pathway activation in LPS-treated mouse hearts and NRCMs. Augmented Plk-1 is thus essential for the development of SIMD and is a druggable target for SIMD. [ABSTRACT FROM AUTHOR]

Abstract Background Recognition of cardiomyopathy in sepsis can be challenging due to the limitations of conventional measures such as ejection fraction (EF) and fractional shortening (FS) in the context of variable preload and afterload conditions. This study correlates myocardial function using strain echocardiography (SE) with cardiomyocyte oxidative stress in a murine model of sepsis. Methods C57BL/6J mice were randomized into control (n = 10), sham (n = 25), and a cecal ligation and puncture (CLP) (n = 33) model of sepsis. Echocardiography was performed pre-, 12, 24, and 48 h post-injury. Cardiac pro-inflammatory cytokines and mitochondrial redox scavenger expression were evaluated in a subset of each arm. To evaluate the influence of redox scavenger upregulation on oxidative injury and cardiac function, CLP was performed on mitochondrial catalase-upregulated C57BL/6J MCAT+/+ mice (n = 12) and wild-type (WT) animals for comparison. Results Septic C57BL/6J mice exhibited depressed longitudinal strain (LS) when compared to sham and control at 24 h (p

Sepsis-induced myocardial dysfunction (SIMD) is one of the serious health-affecting problems worldwide. At present, the mechanisms of SIMD are still not clearly elucidated. The NOD-like receptor protein 3 (NLRP3) inflammasome has been assumed to be involved in the pathophysiology of SIMD by regulating multiple biological processes. NLRP3 inflammasome and its related signaling pathways might affect the regulation of inflammation, autophagy, apoptosis, and pyroptosis in SIMD. A few molecular specific inhibitors of NLRP3 inflammasome (e.g., Melatonin, Ulinastatin, Irisin, Nifuroxazide, and Ginsenoside Rg1, etc.) have been developed, which showed a promising anti-inflammatory effect in a cellular or animal model of SIMD. These experimental findings indicated that NLRP3 inflammasome could be a promising therapeutic target for SIMD treatment. However, the clinical translation of NLRP3 inhibitors for treating SIMD still requires robust in vivo and preclinical trials. [Display omitted] • NLRP3 inflammasome, a pivotal mediator in the activation of the innate immune system in response to infection, has been found to play a key role in the pathophysiology of SIMD. • NLRP3 contributes to the development of SIMD by regulating its targeted genes and signal cascades, which function together on inflammation, autophagy, apoptosis, and pyroptosis. • NLRP3 inflammasome inhibitor exert potential anti-inflammatory effects in SIMD, indicating it may be a potential therapeutic target or preventive agent for SIMD treatment in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Recognition of cardiomyopathy in sepsis can be challenging due to the limitations of conventional measures such as ejection fraction (EF) and fractional shortening (FS) in the context of variable preload and afterload conditions. This study correlates myocardial function using strain echocardiography (SE) with cardiomyocyte oxidative stress in a murine model of sepsis. Methods: C57BL/6J mice were randomized into control ( n = 10), sham ( n = 25), and a cecal ligation and puncture (CLP) ( n = 33) model of sepsis. Echocardiography was performed pre-, 12, 24, and 48 h post-injury. Cardiac pro-inflammatory cytokines and mitochondrial redox scavenger expression were evaluated in a subset of each arm. To evaluate the influence of redox scavenger upregulation on oxidative injury and cardiac function, CLP was performed on mitochondrial catalase-upregulated C57BL/6J MCAT mice ( n = 12) and wild-type (WT) animals for comparison. Results: Septic C57BL/6J mice exhibited depressed longitudinal strain (LS) when compared to sham and control at 24 h ( p < 0.01) and 48 h ( p = 0.04) post-CLP despite having a preserved EF. Furthermore, there was a significant association between increased odds of mortality and depressed LS (OR = 1.23, p = 0.04). Septic C57BL/6J mice concomitantly demonstrated increased expression of cardiomyocyte pro-inflammatory cytokines and decreased expression of redox scavengers at 24 and 48 h. When comparing C57Bl/6 MCAT mice and C57BL/6J WT mice, a significant decrease in LS was identified in the WT mice at 24 h (MCAT = −23 ± 5% vs. WT = −15 ± 4% p < 0.01) and 48 h (MCAT = −23 ± 7% vs. WT = −15 ± 4.3% p = 0.04) post-CLP which correlated with significant increase in the level of cardiac oxidative stress following CLP. Conclusions: In this sepsis model, SE identified cardiomyopathy despite normal EF. SE depression temporally coincides with upregulation of inflammatory cytokines and decreases expression of key mitochondrial ROS scavengers. Upregulation of redox scavenger (CAT) abrogates oxidative stress and cardiac dysfunction in this sepsis model. [ABSTRACT FROM AUTHOR]

Introduction Interleukin (IL)-27 is an important cytokine involved in many human inflammatory diseases. In this study, we investigated its role in the pathogenesis of sepsis-induced myocardial dysfunction (SIMD). Methods Twenty patients with SIMD and 24 healthy donors were prospectively enrolled. Expression of IL-27 was detected in serum from SIMD patients by ELISA. Cardiac dysfunction was induced by administration of Escherichia coli lipopolysaccharide (LPS) to C57BL/6 (wild type) or IL-27R −/− mice. IL-27 mRNA in the myocardium was measured by RT-PCR. Cytokine levels in serum were determined by ELISA. Results Expression of IL-27 in the serum was markedly increased in patients with SIMD compared with that in controls. Serum IL-27 levels and cardiac IL-27 mRNA expression were significantly increased after LPS injection compared with control specimens. Compared with wild-type mice, IL-27R −/− mice had higher expression of brain natriuretic peptide, cardiac troponin I, IL-6, IL-12, tumor necrosis factor-α and transforming growth factor-β. Conclusions IL-27 is an important protective mediator of SIMD. [ABSTRACT FROM AUTHOR]