Sepsis-induced Myocardial Dysfunction Research Articles

VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis.

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent and severe form of organ dysfunction with elusive underlying mechanisms and limited treatment options. In this study, the cecal ligation and puncture and lipopolysaccharide (LPS) were used to reproduce sepsis model in vitro and vivo. The level of voltage-dependent anion channel 2 (VDAC2) malonylation and myocardial malonyl-CoA were detected by mass spectrometry and LC-MS-based metabolomics. Role of VDAC2 malonylation on cardiomyocytes ferroptosis and treatment effect of mitochondrial targeting nano material TPP-AAV were observed. The results showed that VDAC2 lysine malonylation was significantly elevated after sepsis. In addition, the regulation of VDAC2 lysine 46 (K46) malonylation by K46E and K46Q mutation affected mitochondrial-related ferroptosis and myocardial injury. The molecular dynamic simulation and circular dichroism further demonstrated that VDAC2 malonylation altered the N-terminus structure of the VDAC2 channel, causing mitochondrial dysfunction, increasing mitochondrial ROS levels, and leading to ferroptosis. Malonyl-CoA was identified as the primary inducer of VDAC2 malonylation. Furthermore, the inhibition of malonyl-CoA using ND-630 or ACC2 knock-down significantly reduced the malonylation of VDAC2, decreased the occurrence of ferroptosis in cardiomyocytes, and alleviated SIMD. The study also found that the inhibition of VDAC2 malonylation by synthesizing mitochondria targeting nano material TPP-AAV could further alleviate ferroptosis and myocardial dysfunction following sepsis. In summary, our findings indicated that VDAC2 malonylation plays a crucial role in SIMD and that targeting VDAC2 malonylation could be a potential treatment strategy for SIMD.

Protective effect of Apelin/APJ system on lipopolysaccharide-related cardiac dysfunction.

At present, the pathogenesis of sepsis-induced myocardial dysfunction (SIMD) is not completely clear and effective treatment measures are lacking. Apelin is an endogenous ligand of the angiotensin like G protein coupled receptor APJ and a cardiovascular peptide with multiple functions. Our aim is to analyze the protective effect and mechanism of Apelin/APJ system on lipopolysaccharide (LPS)-induced myocardial dysfunction. One hour before LPS treatment, apelin-13 or an APJ antagonist [Ala]-apelin-13 (F13A) was given for pre-intervention to observe the effect of apelin-13 on cardiac ultrasound, pathological changes and inflammatory factors in LPS-treated mice. Another part of the mice was treated with apelin-13 or apelin-13 combined with F13A one hour after LPS treatment. The results showed that apelin-13 injection significantly reversed the decrease of ejection fraction and the increase of inflammatory factors induced by LPS in mice. Endogenous apelin may have protective effect on SIMD induced by LPS. Exogenous administration of apelin may inhibit LPS-induced inflammation, apoptosis and increase autophagy through TLR4/ERK1/2/NF-κB pathway.

Research progress of traditional Chinese and western medicine on myocardial dysfunction in sepsis

Sepsis is a dangerous disease with high mortality, which brings a huge economic burden to patients and society and has attracted more and more attention from the society. Sepsis is a systemic infectious disease. The dysregulated host immune response caused by infection is easy to cause multiple organ damage, and the heart is one of the most vulnerable organs, which leads to septic myocardial dysfunction. Therefore, the treatment of sepsis-induced myocardial dysfunction is a difficult and important point. In recent years, traditional Chinese medicine has shown great advantages in the treatment of this disease. Through the combination of disease differentiation and syndrome differentiation, the overall treatment rate can be significantly improved. Therefore, it is a bright prospect for the treatment of sepsis myocardial dysfunction with integrated traditional Chinese and western medicine. In recent years, the combination of traditional Chinese medicine and western medicine has made some progress in the treatment of sepsis, which has significantly reduced the mortality of sepsis.

Mitochondrial transplantation protects against sepsis-induced myocardial dysfunction by modulating mitochondrial biogenesis and fission/fusion and inflammatory response.

Sepsis-induced myocardial dysfunction is associated with worse clinical outcomes and high mortality, but no effective therapeutic intervention has been explored, reinforcing the urgent need to develop innovative strategies. Mitochondrial dysfunction underlies the pathogenesis of sepsis-induced myocardial dysfunction. Herein, we assessed the effect of mitochondrial transplantation on sepsis-induced myocardial dysfunction in a rat model of cecal ligation and puncture (CLP)-induced sepsis. Male Wistar rats (n = 80, 12 weeks old, 250-300g) were divided into groups with/without CLP-induced sepsis receiving mitochondrial transplantation in single or two repetitive injections (1h or 1 and 7h post-CLP, respectively). Mitochondria were isolated from donor rats and injected intravenously (400µl of mitochondrial suspension containing 7.5 × 106 mitochondria/ml of respiration buffer) in recipient groups. Twenty-four hours post-operation, LDH and cTn-I levels, mitochondrial functional endpoints, expression of mitochondrial biogenesis (SIRT-1 and PGC-1α) and fission/fusion (Drp1/Mfn1 and Mfn2) genes, and inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels were evaluated. Survival was tested over 72h post-operation. Mitotherapy significantly improved 72-hours survival (P < .05) and decreased LDH and cTn-I levels (P < .01). It also restored mitochondrial function and expression of mitochondrial biogenesis and fusion genes, and decreased the expression of mitochondrial fission gene and the levels of inflammatory cytokines (P < .05 to P < .01). Mitotherapy with repetitive injections at 1 and 7h post-CLP provided noticeable mitoprotection in comparison with the group receiving mitotherapy at single injection. Mitotherapy improved mitochondrial function, biogenesis, and dynamic associated with SIRT-1/PGC-1α network and suppressed inflammatory response in CLP-induced sepsis model, therefore, offers a promising strategy to overcome life-threatening sepsis challenge.

TRIM31: A molecule with a dual role in cancer.

Tripartite motif (TRIM) 31 is a new member of the TRIM family and functions as an E3 ubiquitin ligase. Abnormal TRIM31 expression leads to a variety of pathological conditions, such as cancer, innate immunity diseases, sepsis-induced myocardial dysfunction, cerebral ischemic injury, nonalcoholic fatty liver disease and hypertensive nephropathy. In this review, we comprehensively overview the structure, expression and regulation of TRIM31 in cancer. Moreover, we discuss the dual role of TRIM31 in human cancer, and this dual role may be linked to its involvement in the selective regulation of several pivotal cellular signaling pathways: the p53 tumor suppressor, mTORC1, PI3K-AKT, NF-κB and Wnt/β-catenin pathways. In addition, we also discuss the emerging role of TRIM31 in innate immunity, autophagy and its growing sphere of influence across multiple human pathologies. Finally, a better understanding of the dual role of TRIM31 in cancer may provide new therapeutic strategies aimed at inhibiting the cancer-promoting effects of TRIM31 without affecting its tumor suppressor effects.

Vitamin C alleviates LPS-induced myocardial injury by inhibiting pyroptosis via the ROS-AKT/mTOR signalling pathway

BackgroundThe efficacy of vitamin C in sepsis remains controversial. Whether vitamin C can alleviate lipopolysaccharide (LPS)-induced myocardial injury by inhibiting pyroptosis has not been studied. This study aimed to evaluate the effects of vitamin C on LPS-induced myocardial injury in vitro.MethodsH9C2 cells were treated with indicated concentrations of LPS, and the cell viability was then assessed by CCK-8 assay. The levels of lactate dehydrogenase (LDH), CK-MB, IL-18 and IL-1β were examined by enzyme-linked immunosorbent assay (ELISA). The levels of intracellular reactive oxygen species (ROS) were measured using the fluorescent probe dichlorodihydrofluorescein diacetate (DCFH-DA). Western blot assays were conducted to determine the levels of the ROS-associated protein nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) and pyroptosis-associated proteins, such as NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3), caspase-1 and gasdermin D (GSDMD). The AKT inhibitor MK-2206 was then applied to explore the signalling pathway. Finally, H9C2 cells were divided into the control group, LPS group, vitamin C + LPS group, and N-acetyl-l-cysteine (NAC) + LPS group. The intracellular ROS, levels of associated proteins, cell viability, and release of LDH, CK-MB, IL-18 and IL-1β were examined.ResultsLPS decreased cell viability and induced ROS and pyroptosis in H9C2 cells in a dose-dependent manner. Moreover, LPS activated the AKT/mTOR pathway in H9C2 cells. The AKT inhibitor MK-2206 protected H9C2 cells from LPS-induced death by suppressing pyroptosis, without changing intracellular ROS level. Vitamin C significantly inhibited intracellular ROS and cell pyroptosis in LPS-treated H9C2 cells. Moreover, vitamin C suppressed the activation of the AKT/mTOR pathway.ConclusionsOur data suggest that vitamin C alleviates LPS-induced myocardial injury by inhibiting pyroptosis via the ROS-AKT/mTOR signalling pathway and thus provide novel insights into the prevention of sepsis-induced myocardial dysfunction.

New insights of necroptosis and immune infiltration in sepsis-induced myocardial dysfunction from bioinformatics analysis through RNA-seq in mice.

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.

Mitochondria-endoplasmic reticulum contacts in sepsis-induced myocardial dysfunction.

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.

The E3 ubiquitin ligase CHIP protects against sepsis-induced myocardial dysfunction by inhibiting NF-κB-mediated inflammation via promoting ubiquitination and degradation of karyopherin-α 2

Cardiac dysfunction has been recognized as a major contributor to mortality in sepsis, which is closely associated with inflammatory reactions. The carboxy terminus of Hsc70-interacting protein (CHIP), a U-box E3 ubiquitin ligase, defends against cardiac injury caused by other factors, but its role in sepsis-induced cardiac dysfunction has yet to be determined. The present study was designed to investigate the effects of CHIP on cardiac dysfunction caused by sepsis and the molecular mechanisms underlying these processes. We discovered that the CHIP level decreased gradually in the heart at different time points after septic model construction. The decline in CHIP expression of lipopolysaccharide (LPS)-stimulated cardiomyocytes was related to c-Jun activation that inhibited the transcription of CHIP. Functional biology experiments indicated that CHIP bound directly to karyopherin-α 2 (KPNA2) and promoted its degradation through polyubiquitination in cardiomyocytes. CHIP overexpression in cardiomyocytes obviously inhibited LPS-initiated release of TNF-α and IL-6 by promoting KPNA2 degradation, reducing NF-κB translocation into the nucleus. Consistent with the in vitro results, data obtained from animal experiments indicated that septic transgenic mice with heart-specific CHIP overexpression showed a weaker proinflammatory response and reduced cardiac dysfunction than septic control mice. Furthermore, we found that the therapeutic effect of compound YL-109 on cardiac dysfunction in septic mice was due to the upregulation of myocardial CHIP expression. These findings demonstrated that sepsis-initiated the activation of c-Jun suppressed CHIP transcription. CHIP directly promoted ubiquitin-mediated degradation of KPNA2, which reduced the production of proinflammatory cytokines by inhibiting the translocation of NF-κB from the cytoplasm into the nucleus in myocardium, thereby attenuating sepsis-induced cardiac dysfunction.

Abstract 15505: Cardiac-Specific Jarid2 Deficiency, Results in Improved Survival and Myocardial Function Following Experimental Sepsis

Introduction: Myocardial depression and associated hemodynamic collapse are among the major causes of death in severe sepsis. Management of severe sepsis is largely supportive. Hypothesis: Emerging evidence suggests that the transcriptional repressor Jarid2 may play a regulatory role in sepsis; however, the functional role of Jarid2 in sepsis-induced myocardial dysfunction remains uninvestigated. Methods: Using both in in vivo (murine model of cecum ligation and puncture (CLP) in 12-week-old C57-wild type (WT) and cardiac specific Jarid2(knock-out, KO)) and in vitro (lipopolysaccharide, LPS) treatment of cultured murine cardiac myocytes) approaches we determined whether Jarid2 is a putative novel target for sepsis. Results: In response to CLP for 48hrs, WT displayed &gt;60% mortality, survivors developed bacterial peritonitis, a marked inflammatory response (3-5-fold increases in serum and left ventricular (LV) interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha), myocardial dysfunction (20-35% decreases in dp/dt and echo-derived % ejection fraction (EF) and % fractional shortening (FS)), and a 40-50% decrease in LV Jarid2mRNA and protein compared to WT-sham. Jarid2KO mice showed resistance to CLP-induced bacterial peritonitis resulting in improved cardiac function (10-15% decrease in %EF and %FS), and survival (&gt;90%) despite an exacerbated (10-15-fold increase in LV) inflammatory response compared to WT mice. In adult cultured cardiac myocytes derived from WT and Jarid2KO mice, treatment with the endotoxin LPS (1 microgram/mL) for 24 hrs, resulted in an 8-10-fold and 20-35-fold increase respectively, in the inflammatory cytokines TNF-alpha, IL-1beta and IL-6. Conclusions: These findings reveal that the loss of Jarid2 enhances bacterial clearance and despite an enhanced inflammatory response, resulted in improved myocardial function and survival following CLP-induced sepsis. As such, Jarid2 may be a novel therapeutic target in the treatment of sepsis-induced myocardial dysfunction.

Recombinant thrombomodulin may protect cardiac capillary endothelial glycocalyx through promoting Glypican-1 expression under experimental endotoxemia

IntroductionMyocardial dysfunction occurs in patients with sepsis due to vascular endothelial injury. Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries through endothelial glycocalyx (eGC) protection. HypothesisWe hypothesized that rhTM attenuates myocardial dysfunction via the inhibition of vascular endothelial injury during sepsis. MethodsTen-week-old male C57BL6 mice were injected intraperitoneally with 20 mg/kg of lipopolysaccharide (LPS). In rhTM-treated mice, rhTM was injected intraperitoneally at 3 and 24 h after LPS injection. Saline was injected intraperitoneally as control. To assess for eGC injury, intensity score was measured 48 h after the LPS injection. To confirm vascular endothelial injuries, ultrastructural analysis was performed using scanning (SEM) and transmission electron microscopy (TEM). ResultsThe survival rate of the rhTM group at 48 h after LPS injection was significantly higher than that of the control group (68% vs. 17%, p < 0.05). The serum level of troponin I in the rhTM group was lower than that in the control (2.2 ± 0.4 ng/dL vs 9.4 ± 1.1 ng/dL, p < 0.05). The expression of interleukin-6 (IL-6) was attenuated in the rhTM-treated group than in the control (65.3 ± 15.3 ng/mL vs 226.3 ± 19.4 ng/mL, p < 0.05). The serum concentration of syndecan-1, a marker of glycocalyx damage, was significantly decreased 48 h post-administration of LPS in the rhTM-treated group than in the control group. In ultrastructural analysis using SEM and TEM, eGC peeled off from the surface of the capillary lumen in the control. Conversely, the eGC injury was attenuated in the rhTM group. Gene set enrichment analysis revealed that osteomodulin, osteoglycin proline/arginine-rich end leucine-rich repeat protein, and glypican-1, which are proteoglycans, were preserved by rhTM treatment. Their protein expression was retained in endothelial cells. ConclusionrhTM attenuates sepsis-induced myocardial dysfunction via eGC protection.

Astragaloside IV ameliorates sepsis-induced myocardial dysfunction by regulating NOX4/JNK/BAX pathway

AimsSepsis can induce multiple organ dysfunction, and sepsis-induced myocardial dysfunction (SIMD) is relatively common. The current dilemma might ascribe partly to SIMD's lack of unified molecular mechanisms. Our study aims to assess the function of Astragaloside IV (ASI) in cecal ligation and puncture (CLP)-induced cardiac dysfunction and explore its underlying mechanisms. Main methodsIn vivo, ASI (30 mg/kg/day), NADPH oxidase 4 (NOX4) inhibitor 4-hydroxy-3-methoxyacetophenone (APO, 30 mg/kg/day), reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC, 150 mg/kg/day) and c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125, 15 mg/kg/day) were severally administered to Sprague Dawley rats following the CLP surgery. The cardiac function, cardiac enzyme markers, proinflammatory cytokine, and cell apoptosis-associated proteins were detected. In vitro, cardiomyocyte H9C2 cells were treated with lipopolysaccharide (LPS, 40 μg/ml) after the presence of ASI (100 μmol/ml), SP600125 (10 μmol/ml), APO (10 μmol/ml). A series of experiments verified the relationship among NOX4, JNK, and BAX. Key findingsThe results indicated that CLP-induced sepsis increased the secretion of creatine kinase isoenzymes (CKMB), brain natriuretic peptide (BNP), cardiac troponin T (c-TnI), interleukin-1β (IL-1β) and interleukin-18 (IL-18), as well as the protein expression of NOX4 and Caspase-3 in vivo. LPS increased the protein level of NOX4 and Caspase-3, upregulated the rate of p-JNK/JNK, and downregulated the rate of Bcl2/BAX in vitro. ASI can reverse these changes in vivo and has a synergistic effect with APO and SP600125 in vitro. SignificanceThis study suggested that ASI may ameliorate SIMD, through regulating NOX4/JNK/BAX signaling pathway, which may be a feasible therapeutic strategy.

Platelet-rich plasma ameliorates lipopolysaccharide-induced cardiac injury by inflammation and ferroptosis regulation.

Sepsis-induced myocardial dysfunction (SIMD) is a fatal disease with no specific treatment worldwide to this day. As a biological product, platelet-rich plasma (PRP) has attracted much attention due to its diverse and potential biological effects. However, its role in lipopolysaccharide (LPS)-induced cardiac injury has not been fully investigated. This study aimed to explore the mechanism of PRP in SIMD. PRP (30µL) was injected in situ into the heart, and LPS (10mg/kg) was injected intraperitoneally into mice. Neonatal rat cardiomyocytes were treated with LPS (1μg/ml) for 24h. The results showed that, compared with the LPS group, PRP significantly decreased the levels of Lactate dehydrogenase (LDH) and Creatine Kinase MB (CK-MB), and improved cardiac function. In addition, PRP markedly decreased the Malonic dialdehyde (MDA) content, and increased the Superoxide dismutase (SOD) activity and Glutathione (GSH) level, demonstrating that PRP alleviated LPS-induced oxidative stress. The Western blot and qPCR results showed that LPS-induced ferroptosis and inflammation effects in vivo and in vitro were ameliorated after PRP treatment. Moreover, PRP can alleviate erastin-induced ferroptosis and improve cell viability. Mechanistically, p-AKT and p-mTOR expressions were down-regulated after treatment with LPS, while PRP pretreatment could reverse this effect. In summary, our study demonstrated that PRP could play a unique role in reducing LPS-induced cardiac injury through regulation of AKT/mTOR signaling pathways. These findings provide a new therapeutic direction for treating SIMD.

Single-Cell Transcriptional Profiling Reveals Low-Level Tragus Stimulation Improves Sepsis-Induced Myocardial Dysfunction by Promoting M2 Macrophage Polarization.

Background Sepsis can lead to multiple organ damage, of which the heart is one of the most vulnerable organs. Vagal nerve stimulation can reduce myocardial injury in sepsis and improve survival rates. However, the potential impact of low-level tragus stimulation and disparate cell populations on sepsis-induced myocardial dysfunction remains undetermined. Methods A cardiac single-cell transcriptomic approach was used for characterizing cardiac cell populations that form the heart. Single-cell mRNA sequencing data were used for selecting all cardiac macrophages from CD45+ cells. Then, echocardiography, western blot, flow cytometry, immunofluorescence, and immunohistochemistry were performed to verify the single-cell mRNA sequencing results. Results Using single-cell mRNA sequencing data, we uncovered the multiple cell populations contributing to myocardial injury in sepsis under low-level tragus stimulation, thereby illustrating a comprehensive map of the cardiac cellular landscape. Pseudotiming analysis in single-cell sequencing showed that low-level vagal nerve stimulation played an anti-inflammatory role by promoting cardiac monocytes into M2 macrophages, which significantly increased α7nAChR expression in heart tissues. Echocardiography assessment indicated that low-level vagal nerve stimulation could also improve cardiac functions in mice with sepsis-induced myocardial dysfunction. In addition, the heart tissues of mice from the sepsis group with low-level tragus stimulation had significantly lower interleukin-1β expression levels than those from the sepsis group. Flow cytometry analysis showed that different acetylcholine concentrations promoted cardiac monocytes into M2 macrophages in in vitro experiments. Conclusion Low-level tragus stimulation could improve sepsis-induced myocardial dysfunction by promoting cardiac monocytes to M2 macrophages.

Long Noncoding RNA and mRNA Expression Profiles in Rats with LPS-induced Myocardial Dysfunction.

Sepsis is an uncontrolled systemic inflammatory response. Long noncoding RNAs (lncRNAs) are involved in the pathogenesis of sepsis. However, little is known about the roles of lncRNAs in sepsis-induced myocardial dysfunction. We aimed to determine the regulatory mechanism of lncRNAs in sepsis-induced myocardial dysfunction. In this study, we analysed the lncRNA and mRNA expression profiles using microarray analysis. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein-protein interaction network, and gene set enrichment analysis were used to evaluate the data. We also constructed coding and noncoding coexpression and competing endogenous RNA networks to investigate the mechanisms. In vivo lipopolysaccharide -induced sepsis rat model was established. A total of 387 lncRNAs and 1,952 mRNAs were identified as significantly changed in the left ventricle. Kyoto Encyclopedia of Genes and Genomes analysis of mRNAs showed that the upregulated genes were mainly enriched in the "complement and coagulation cascade pathway" and "immune-related biological processes" terms. Eight significantly changed lncRNAs detected by RT-qPCR may be responsible for these processes. A competing endogenous RNA network was generated, and the results indicated that eight lncRNAs were related to the "calcium ion binding" process. These results demonstrate that crosstalk between lncRNAs and mRNAs may play important roles in the development of sepsis-induced myocardial dysfunction.

Analysis of metabolic disturbances attributable to sepsis-induced myocardial dysfunction using metabolomics and transcriptomics techniques.

Background: Sepsis-induced myocardial dysfunction (SIMD) is the most common and severe sepsis-related organ dysfunction. We aimed to investigate the metabolic changes occurring in the hearts of patients suffering from SIMD. Methods: An animal SIMD model was constructed by injecting lipopolysaccharide (LPS) into mice intraperitoneally. Metabolites and transcripts present in the cardiac tissues of mice in the experimental and control groups were extracted, and the samples were studied following the untargeted metabolomics–transcriptomics high-throughput sequencing method. SIMD-related metabolites were screened following univariate and multi-dimensional analyses methods. Additionally, differential analysis of gene expression was performed using the DESeq package. Finally, metabolites and their associated transcripts were mapped to the relevant metabolic pathways after extracting transcripts corresponding to relevant enzymes. The process was conducted based on the metabolite information present in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: One hundred and eighteen significant differentially expressed metabolites (DEMs) (58 under the cationic mode and 60 under the anionic mode) were identified by studying the SIMD and control groups. Additionally, 3,081 significantly differentially expressed genes (DEGs) (1,364 were down-regulated and 1717 were up-regulated DEGs) were identified in the transcriptomes. The comparison was made between the two groups. The metabolomics–transcriptomics combination analysis of metabolites and their associated transcripts helped identify five metabolites (d-mannose, d-glucosamine 6-phosphate, maltose, alpha-linolenic acid, and adenosine 5′-diphosphate). Moreover, irregular and unusual events were observed during the processes of mannose metabolism, amino sugar metabolism, starch metabolism, unsaturated fatty acid biosynthesis, platelet activation, and purine metabolism. The AMP-activated protein kinase (AMPK) signaling pathways were also accompanied by aberrant events. Conclusion: Severe metabolic disturbances occur in the cardiac tissues of model mice with SIMD. This can potentially help in developing the SIMD treatment methods.

N-Terminal B Natriuretic Peptide as a Prognostic Marker in Sepsis Induced Myocardial Dysfunction

BACKGROUND: Sepsis-induced myocardial dysfunction (SIMD) is an increasingly recognized form of transient cardiac dysfunction in sepsis patients. AIM: The aim of the study was to evaluation of N-terminal pro brain natriuretic peptide (NT-pro BNP) as a predictor of SIMD and poor outcome in patients with sepsis or septic shock. METHODS: Forty patients were enrolled and divided into: Group 1 with sepsis; Group 2 with septic shock. Each group was subdivided according to the presence or absence of cardiomyopathy. Echocardiography, NT-pro BNP - assay on the 1st and 2nd days of admission - were performed. RESULTS: NT-pro BNP level was significant predictor for cardiomyopathy in all case group with 75% sensitivity, 70% specificity (cutoff level &gt;334 pg/ml) on 1st day of admission and 65% sensitivity, and 80% specificity (cutoff level &gt;325 pg/ml) on 2nd day. On subgroup analysis, pro-BNP had 70% sensitivity, 90% specificity; cutoff level &gt;334 pg/ml for prediction of cardiomyopathy in sepsis group and 70% sensitivity and 80% specificity; cutoff level &gt;357pg/ml in septic shock group. Pro-BNP on 2nd day was excellent predictor of mortality in septic shock group with 100% sensitivity and specificity; cutoff level &gt;350 pg/ml. CONCLUSION: N terminal pro-BNP is a good diagnostic and prognostic indicator for cardiomyopathy and mortality in septic patients.

Clinical features of patients with septic shock-triggered Takotsubo syndrome: a single-center 7 case series

BackgroundMyocardial 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 presentationAmong 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.ConclusionsTakotsubo 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.

Міокардіальна дисфункція як складова поліорганної невідповідності при неонатальному сепсисі

The formation of myocardial dysfunction in neonatal sepsis remains a topical issue in current neonatal practice. Myocardial dysfunction with neonatal sepsis is found to promote a double increase of neonatal loss rate, and maintenance of an adequate cardiac output is very important predictor for survival of patients with neonatal sepsis. Purpose - to study clinico-paraclinical markers of myocardial dysfunction in case of an alternative term of neonatal sepsis debut for timely verification and rational correction of cardiovascular disorders. Materials and methods. Considering various terms of neonatal sepsis manifestation with its early and late variants, a comparative analysis of clinical-paraclinical markers of generalized infectious-inflammatory process was made in 26 neonates at the stage of obstetrical aid (retrospective analysis) and in the intensive care departments for neonates and their resuscitation (prospective follow-up). According to the results of the analysis of medical records of newborns, the diagnosis of early neonatal sepsis was established in 14 (53.8%) newborns who were included in the clinical group I of the study, and the diagnosis of late neonatal sepsis was established in 12 (46.2%) newborns who were included in the clinical group II. Results. After birth general condition of patients from the group I was assessed as of moderate severity - in 1 (7.1%) and severe - in 13 (92.9%) neonates; in the group II the 2 neonates (16.7%) were in the condition of moderate severity (р&gt;0.05) and 10 (83.3%) neonates were in severe condition (р&gt;0.05). Assessment of cardiovascular constituent in the neonatal groups of comparison according to the constellation scale nSOFA in the means values did not differ reliably, though it was indicative of a tendency to deeper disorders in case of late neonatal sepsis. Conclusions. Sepsis-induced myocardial dysfunction is manifested by increase in the content of cardio-specific markers (creatine phosphokinase, МВ fraction, troponin I). An increased content of troponin I in the blood higher than that of the norm in case of late neonatal sepsis possesses a high inclination (83.3%) to the formation of myocardial dysfunction. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Keywords: neonates, neonatal sepsis, myocardial dysfunction.

Sepsis-related cardiomyopathy: Not an easy task for ICU physicians

Sepsis-induced myocardial dysfunction is common. In addition to acute coronary syndrome, at least two types of left ventricular dysfunction can occur in septic patients: typical septic cardiomyopathy (SC) and sepsis-related takotsubo cardiomyopathy (ST). Although the definition of septic cardiomyopathy is based on left ventricular (LV) systolic dysfunction, both ventricles can be affected. In this context, it has been increasingly recognized that right ventricular (RV) systolic dysfunction is associated with long-term prognosis in septic patients. Unlike typical SC, ST patients usually displayed LV apical and circumferential mid-ventricular hypokinesia and basal hypercontractility. Timely and precise evaluation of heart dysfunction in sepsis patients is not easy but obviously mandatory. Further studies are still warranted regarding the mechanism, evaluation, and management of septic cardiomyopathy.