Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.

The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.

The role of TREM-1 in septic myocardial pyroptosis and septic cardiomyopathy in vitro and in vivo.

Septic cardiomyopathy (SCM) is an acute cardiac dysfunction involving myocardial cell pyroptosis. TREM-1 is a known receptor on cell membrane that can amplify the inflammatory response. Our previous studies have shown that TREM-1 in cardiomyocytes is involved in the activation of NLRP3 through the SMC4/NEMO pathway. Here, we aimed to use Trem-1 and Nlrp3 knockout mice to verify the effect of TREM-1 through NLRP3 on cardiac function in septic mice. The results showed that TREM-1 knockout resulted in a decrease in the release of downstream cell signals, including SMC4 and NLRP3, resulting in a decrease in cytokine release and improvement of cardiac dysfunction. Knockout of NLRP3 also reduced cardiomyocyte pyroptosis and increased survival rate. The therapeutic targeting of TREM-1 activation of NLRP3 and its pathway may contribute to the treatment or prevention of SCM.

Integrated multi-omics analysis and machine learning developed diagnostic markers and prognostic model based on Efferocytosis-associated signatures for septic cardiomyopathy.

Septic cardiomyopathy (SCM) is characterized by an abnormal inflammatory response and increased mortality. The role of efferocytosis in SCM is not well understood. We used integrated multi-omics analysis to explore the clinical and genetic roles of efferocytosis in SCM. We identified six module genes (ATP11C, CD36, CEBPB, MAPK3, MAPKAPK2, PECAM1) strongly associated with SCM, leading to an accurate predictive model. Subgroups defined by EFFscore exhibited distinct clinical features and immune infiltration levels. Survival analysis showed that the C1 subtype with a lower EFFscore had better survival outcomes. scRNA-seq analysis of peripheral blood mononuclear cells (PBMCs) from sepsis patients identified four genes (CEBPB, CD36, PECAM1, MAPKAPK2) associated with high EFFscores, highlighting their role in SCM. Molecular docking confirmed interactions between diagnostic genes and tamibarotene. Experimental validation supported our computational results. In conclusion, our study identifies a novel efferocytosis-related SCM subtype and diagnostic biomarkers, offering new insights for clinical diagnosis and therapy.

m6A methylation in myocardial tissue of septic mice analyzed using MeRIP/m6A-sequencing and RNA-sequencing.

Septic cardiomyopathy is a secondary myocardial injury caused by sepsis. N6-methyl-adenosine (m6A) modification is involved in the pathological progression of septic cardiomyopathy; however, the pathological mechanism remains unclear. In this study, we identified the overall m6A modification pattern in septic myocardial injury and determined its potential interactions with differentially expressed genes (DEGs). A sepsis mouse model exhibiting septic symptoms and myocardial tissue damage was induced by lipopolysaccharide (LPS). LPS-induced septic myocardial tissues and control myocardial tissues were subjected to methylated RNA immunoprecipitation sequencing and RNA sequencing to screen for differentially expressed m6A peaks and DEGs. We identified 859 significantly m6A-modified genes in septic myocardial tissues, including 432 upregulated and 427 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore the biological importance of differentially expressed m6A methylated genes and DEGs. Differentially expressed m6A methylated genes were enriched in immune- and inflammation-related pathways. Conjoint analysis revealed co-expression of differentially expressed m6A genes and DEGs, including genes that were upregulated or downregulated and those showing opposite trends. High expression of m6A-related genes (WTAP and IGF2BP2), interleukin-17, and interleukin-17 pathway-related genes (MAPK11 and TRAF3IP2) was verified using reverse transcription-quantitative PCR. We confirmed the presence of m6A modification of the transcriptome and m6A-mediated gene expression in septic myocardial tissues.

MMP-8 causes leftward shift in end-diastolic pressure-volume relationship and may explain the development of diastolic dysfunction in septic cardiomyopathy.

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% (P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.

COX-2 optimizes cardiac mitochondrial biogenesis and exerts a cardioprotective effect during sepsis.

BACKGROUND: Septic cardiomyopathy is a component of multiple organ dysfunction in sepsis. Mitochondrial dysfunction plays an important role in septic cardiomyopathy. Studies have shown that cyclooxygenase-2 (COX-2) had a protective effect on the heart, and prostaglandin E2 (PGE2), the downstream product of COX-2, was increasingly recognized to have a protective effect on mitochondrial function. OBJECTIVE: This study aims to demonstrate that COX-2/PGE2 can protect against septic cardiomyopathy by regulating mitochondrial function. METHODS: Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and RAW264.7 macrophages and H9C2 cells were used to simulate sepsis in vitro. The NS-398 and celecoxib were used to inhibit the activity of COX-2. ZLN005 and SR18292 were used to activate or inhibit the PGC-1α activity. The mitochondrial biogenesis was examined through the Mitotracker Red probe, mtDNA copy number, and ATP content detection. RESULTS: The experimental data suggested that COX-2 inhibition attenuated PGC-1α expression thus decreasing mitochondrial biogenesis, whereas increased PGE2 could promote mitochondrial biogenesis by activating PGC-1α. The results also showed that the effect of COX-2/PGE2 on PGC-1α was mediated by the activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Finally, the effect of COX-2/PGE2 on the heart was also verified in the septic mice. CONCLUSION: Collectively, these results suggested that COX-2/PGE2 pathway played a cardioprotective role in septic cardiomyopathy through improving mitochondrial biogenesis, which has changed the previous understanding that COX-2/PGE2 only acted as an inflammatory factor.

A novel speckle-tracking echocardiography parameter assessing left ventricular afterload.

BACKGROUND: Left ventricular stroke work index (LVSWI) and afterload-related cardiac performance (ACP) consider left ventricular (LV) afterload and could be better prognosticators in septic cardiomyopathy. However, their invasive nature prevents their routine clinical applications. This study aimed to investigate (1) whether a proposed speckle-tracking echocardiography parameter, Pressure-Strain Product (PSP), can non-invasively predict catheter-based LVSWI, ACP and serum lactate in an ovine model of septic cardiomyopathy; and (2) whether PSP can distinguish the sub-phenotypes of acute respiratory distress syndrome (ARDS) with or without sepsis-like conditions. METHODS: Sixteen sheep with ARDS were randomly assigned to either (1) sepsis-like (n = 8) or (2) non-sepsis-like (n = 8) group. Each ARDS and sepsis-like condition was induced by intravenous infusion of oleic acid and lipopolysaccharide, respectively. Pulmonary artery catheter-based LVSWI (the product of stroke work index, mean arterial pressure and .0136), ACP (the percentage of cardiac output measured to cardiac output predicted as normal) and serum lactate were measured simultaneously with transthoracic echocardiography. Two PSP indices were calculated by multiplying the mean arterial blood pressure and either global circumferential strain (PSPcirc) or radial strain (PSPrad). RESULTS: PSPcirc showed a significant correlation with LVSWI (r2 = .66, p < .001) and ACP (r2 = .82, p < .001) in the sepsis-like group. Although PSP could not distinguish subphenotypes, PSPcirc predicted LVSWI (AUC .86) and ACP (AUC .88), and PSPrad predicted serum lactate (AUC .75) better than LV ejection fraction, global circumferential and radial strain. CONCLUSIONS: A novel PSP has the potential to non-invasively predict catheter-based LVSWI and ACP, and was associated with serum lactate in septic cardiomyopathy.

Salvianolic acid B improves mitochondrial dysfunction of septic cardiomyopathy via enhancing ATF5-mediated mitochondrial unfolded protein response.

AIMS: Septic cardiomyopathy is characterized by impaired contractile function and mitochondrial activity dysregulation. Salvianolic acid B (Sal B) is a potent therapeutic compound derived from the traditional Chinese medicine Salvia miltiorrhiza. This study explored the protective effects of Sal B on septic heart injury, emphasizing the mitochondrial unfolded protein response (UPRmt). MATERIALS AND METHODS: An in vivo mouse model of lipopolysaccharide (LPS)-induced heart injury was utilized to assess Sal B's protective role in septic cardiomyopathy. Additionally, cell models stimulated by LPS were developed to investigate the mechanisms of Sal B on UPRmt. Quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence were employed for molecular analysis. RESULTS: Sal B, administered at doses of 10, 30, and 60 mg/kg, demonstrated protective effects on cardiac contractile function, reduced heart inflammation, and mitigated cardiac injury in LPS-exposed mice. In cardiomyocytes, LPS induced apoptosis, elevated mitochondrial ROS levels, promoted mitochondrial fission, and decreased mitochondrial membrane potential, all of which were alleviated by Sal B. Mechanistically, Sal B was found to induce UPRmt both in vivo and in vitro. ATF5, identified as a UPRmt activator, was modulated by LPS and Sal B, resulting in increased ATF5 expression and its translocation from the cytosol to the nucleus. ATF5-siRNA delivery reversed UPRmt upregulation, exacerbating mitochondrial dysfunction in LPS-stimulated cardiomyocytes and counteracting the mitochondrial function enhancement in Sal B-treated cardiomyocytes. CONCLUSIONS: This study provides evidence that Sal B confers cardiac protection by enhancing UPRmt, highlighting its potential as a therapeutic approach for mitigating mitochondrial dysfunction in septic cardiomyopathy.

Septic Cardiomyopathy.

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.

miR-206 alleviates LPS-induced inflammatory injury in cardiomyocytes via directly targeting USP33 to inhibit the JAK2/STAT3 signaling pathway.

Previous reports have confirmed that miR-206 participates in inflammatory cardiomyopathy, but its definite mechanism remains elusive. This study aims to elucidate the potential mechanism of miR-206 in septic cardiomyopathy (SCM). The primary mouse cardiomyocytes were isolated and exposed to lipopolysaccharides (LPS) to construct a septic injury model in vitro. Then, the gene transcripts and protein levels were detected by RT-qPCR and/or Western blot assay. Cell proliferation, apoptosis, and inflammatory responses were evaluated by CCK-8/EdU, flow cytometry, and ELISA assays, respectively. Dual luciferase assay, Co-IP, and ubiquitination experiments were carried out to validate the molecular interactions among miR-206, USP33, and JAK2/STAT3 signaling. miR-206 was significantly downregulated, but USP33 was upregulated in LPS-induced cardiomyocytes. Gain-of-function of miR-206 elevated the proliferation but suppressed the inflammatory responses and apoptosis in LPS-induced cardiomyocytes. USP33, as a member of the USP protein family, was confirmed to be a direct target of miR-206 and could catalyze deubiquitination of JAK2 to activate JAK2/STAT3 signaling. Rescue experiments presented that neither upregulation of USP33 nor JAK2/STAT3 signaling activation considerably reversed the protective effects of miR-206 upregulation in LPS-induced cardiomyocytes. The above data showed that miR-206 protected cardiomyocytes from LPS-induced inflammatory injuries by targeting the USP33/JAK2/STAT3 signaling pathway, which might be a novel target for SCM treatment.

MiR-31-5p alleviates septic cardiomyopathy by targeting BAP1 to inhibit SLC7A11 deubiquitination and ferroptosis.

Septic cardiomyopathy is one of the most severe and common complications in patients with sepsis and poses a great threat to their prognosis. However, the potential mechanisms and effective therapeutic drugs need to be explored. The control of cardiac cell death by miRNAs has emerged as a prominent area of scientific interest in the diagnosis and treatment of heart disorders in recent times. In the present investigation, we discovered that overexpression of miR-31-5p prevented LPS-induced damage to H9C2 cells and that miR-31-5p could inhibit BAP1 production by binding to its 3'-UTR. BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase. BAP1 upregulation blocked effect of miR-31-5p on H9C2 cell injury. Moreover, BAP1 inhibited the expression of solute carrier family 7 member 11 (SLC7A11) by deubiquitinating histone 2 A (H2Aub) on the promoter of SLC7A11. Furthermore, overexpression of miR-31-5p and downregulation of BAP1 inhibited SLC7A11 mediated ferroptosis. In addition, the downregulation of SLC7A11 reversed the inhibitory effect of miR-31-5p on the expression of myocardial injury and inflammatory factors, and cell apoptosis was reversed. In conclusion, these results indicate that miR-31-5p alleviates malignant development of LPS-induced H9C2 cell injury by targeting BAP1 and regulating SLC7A11 deubiquitination-mediated ferroptosis, which confirmed the protective effect of miR-31-5p on H9C2 cell injury and revealed potential mechanisms that may provide new targets for treatment of septic cardiomyopathy.

Pyruvate kinase M2 sustains cardiac mitochondrial integrity in septic cardiomyopathy by regulating PHB2-dependent mitochondrial biogenesis.

Previous studies have highlighted the protective effects of pyruvate kinase M2 (PKM2) overexpression in septic cardiomyopathy. In our study, we utilized cardiomyocyte-specific PKM2 knockout mice to further investigate the role of PKM2 in attenuating LPS-induced myocardial dysfunction, focusing on mitochondrial biogenesis and prohibitin 2 (PHB2). Our findings confirmed that the deletion of PKM2 in cardiomyocytes significantly exacerbated LPS-induced myocardial dysfunction, as evidenced by impaired contractile function and relaxation. Additionally, the deletion of PKM2 intensified LPS-induced myocardial inflammation. At the molecular level, LPS triggered mitochondrial dysfunction, characterized by reduced ATP production, compromised mitochondrial respiratory complex I/III activities, and increased ROS production. Intriguingly, the absence of PKM2 further worsened LPS-induced mitochondrial damage. Our molecular investigations revealed that LPS disrupted mitochondrial biogenesis in cardiomyocytes, a disruption that was exacerbated by the absence of PKM2. Given that PHB2 is known as a downstream effector of PKM2, we employed PHB2 adenovirus to restore PHB2 levels. The overexpression of PHB2 normalized mitochondrial biogenesis, restored mitochondrial integrity, and promoted mitochondrial function. Overall, our results underscore the critical role of PKM2 in regulating the progression of septic cardiomyopathy. PKM2 deficiency impeded mitochondrial biogenesis, leading to compromised mitochondrial integrity, increased myocardial inflammation, and impaired cardiac function. The overexpression of PHB2 mitigated the deleterious effects of PKM2 deletion. This discovery offers a novel insight into the molecular mechanisms underlying septic cardiomyopathy and suggests potential therapeutic targets for intervention.

New insights into the role of mitochondrial metabolic dysregulation and immune infiltration in septic cardiomyopathy by integrated bioinformatics analysis and experimental validation.

BACKGROUND: Septic cardiomyopathy (SCM), a common cardiovascular comorbidity of sepsis, has emerged among the leading causes of death in patients with sepsis. SCM's pathogenesis is strongly affected by mitochondrial metabolic dysregulation and immune infiltration disorder. However, the specific mechanisms and their intricate interactions in SCM remain unclear. This study employed bioinformatics analysis and drug discovery approaches to identify the regulatory molecules, distinct functions, and underlying interactions of mitochondrial metabolism and immune microenvironment, along with potential interventional strategies in SCM. METHODS: GSE79962, GSE171546, and GSE167363 datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and module genes were identified using Limma and Weighted Correlation Network Analysis (WGCNA), followed by functional enrichment analysis. Machine learning algorithms, including support vector machine-recursive feature elimination (SVM-RFE), least absolute shrinkage and selection operator (LASSO) regression, and random forest, were used to screen mitochondria-related hub genes for early diagnosis of SCM. Subsequently, a nomogram was developed based on six hub genes. The immunological landscape was evaluated by single-sample gene set enrichment analysis (ssGSEA). We also explored the expression pattern of hub genes and distribution of mitochondria/inflammation-related pathways in UMAP plots of single-cell dataset. Potential drugs were explored using the Drug Signatures Database (DSigDB). In vivo and in vitro experiments were performed to validate the pathogenetic mechanism of SCM and the therapeutic efficacy of candidate drugs. RESULTS: Six hub mitochondria-related DEGs [MitoDEGs; translocase of inner mitochondrial membrane domain-containing 1 (TIMMDC1), mitochondrial ribosomal protein S31 (MRPS31), F-box only protein 7 (FBXO7), phosphatidylglycerophosphate synthase 1 (PGS1), LYR motif containing 7 (LYRM7), and mitochondrial chaperone BCS1 (BCS1L)] were identified. The diagnostic nomogram model based on the six hub genes demonstrated high reliability and validity in both the training and validation sets. The immunological microenvironment differed between SCM and control groups. The Spearman correlation analysis revealed that hub MitoDEGs were significantly associated with the infiltration of immune cells. Upregulated hub genes showed remarkably high expression in the naive/memory B cell, CD14+ monocyte, and plasma cell subgroup, evidenced by the feature plot. The distribution of mitochondria/inflammation-related pathways varied across subgroups among control and SCM individuals. Metformin was predicted to be the most promising drug with the highest combined score. Its efficacy in restoring mitochondrial function and suppressing inflammatory responses has also been validated. CONCLUSIONS: This study presents a comprehensive mitochondrial metabolism and immune infiltration landscape in SCM, providing a potential novel direction for the pathogenesis and medical intervention of SCM.

Exploration and validation of signature genes and immune associations in septic cardiomyopathy.

An early and accurate diagnosis of septic cardiomyopathy is vital for improving the overall prognosis of sepsis. In our research, we aimed to identify signature genes and their immune connections in septic cardiomyopathy. By analyzing the mouse myocardial transcriptome from sepsis induced by cecum ligation and puncture (CLP), we identified four distinct k-means clusters. Further analysis of human myocardial datasets using Weighted Gene Co-expression Network Analysis (WGCNA) revealed a strong correlation between the MEturquoise module and septic cardiomyopathy (cor = 0.79, p < .001). Through the application of Cytoscape plug-in MCODE and comprehensive analysis, we pinpointed two signature genes, THBS1 and TIMP1. These genes demonstrated significant involvement in immune cell infiltration, as detected by CIBERSORT, and displayed promising prognostic potential as validated by external datasets. Our experimental validation confirmed the up-regulation of both THBS1 and TIMP1 in septic murine hearts, underscoring their positive association with septic cardiomyopathy.

[Construction and Evaluation of a Risk Prediction Model for Septic Cardiomyopathy Based on MIMIC-â £ Database].

Objective To analyze the risk factors of septic cardiomyopathy (SC),and to construct and evaluate the risk prediction model of SC. Methods The clinical data of patients with sepsis were extracted from MIMIC-Ⅳ database and randomized into a training set and a validation set at a ratio of 7 to 3.According to the presence or absence of SC,the patients were assigned into SC and non-SC groups.The independent risk factors of SC were determined by univariate and multivariate Logistic regression analysis,and a risk prediction model and a nomogram were established.The area under the receiver operating characteristic curve (AUC),calibration curve,and decision curve analysis (DCA) were employed to evaluate the distinguishing degree,calibration,and clinical applicability of the model,respectively. Results A total of 2628 sepsis patients were enrolled in this study,including 1865 patients in the training set and 763 patients in the validation set.There was no significant difference in the incidence of SC between the training set and the validation set (58.98% vs. 62.25%,P=0.120).Except chronic obstructive pulmonary disease (P=0.015) and length of stay in intensive care unit (P=0.016),there was no significant difference in other clinical indicators between the two groups (all P>0.05).Logistic regression analysis showed that coronary heart disease (P=0.028),heart failure (P<0.001),increased neutrophil count (P=0.001),decreased lymphocyte count (P=0.036),increased creatine kinase isoenzyme (P<0.001),and increased blood urea nitrogen (P=0.042) were independent risk factors for SC.The AUC of the nomogram prediction model in the training set and validation set was 0.759 (95% CI=0.732-0.785) and 0.765 (95% CI=0.723-0.807),respectively.The established model showcased good fitting degrees in both data sets (training set:P=0.075;validation set:P=0.067).The DCA results showed that the nomogram prediction model had good clinical applicability. Conclusion The nomogram prediction model based on basic diseases and clinical biochemical indicators can effectively predict the risk of SC occurrence.

Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy.

BACKGROUND: Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury, including sepsis-induced myocardial dysfunction (SIMD). However, the mechanisms behind p53 localization to the mitochondria have not been well established. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization. Here we examined the role of Drp1/p53 interaction in SIMD using in vitro and murine models of sepsis. METHODS: H9c2 cardiomyoblasts and BALB/c mice were exposed to lipopolysaccharide (LPS) to model sepsis phenotype. Pharmacologic inhibitors of Drp1 activation (ψDrp1) and of p53 mitochondrial binding (pifithrin µ, PFTµ) were utilized to assess interaction between Drp1 and p53, and the subsequent downstream impact on mitochondrial morphology and function, cardiomyocyte function, and sepsis phenotype. RESULTS: Both in vitro and murine models demonstrated an increase in physical Drp1/p53 interaction following LPS treatment, which was associated with increased p53 mitochondrial localization, and mitochondrial dysfunction. This Drp1/p53 interaction was inhibited by ΨDrp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either ΨDrp1 or PFTµ inhibited the LPS mediated localization of Drp1/p53 to the mitochondria, decreased oxidative stress, improved cellular respiration and ATP production. Similarly, treatment of BALB/c mice with either ΨDrp1 or PFTµ decreased LPS-mediated mitochondrial localization of p53, mitochondrial ROS in cardiac tissue, and subsequently improved cardiomyocyte contractile function and survival. CONCLUSION: Drp1/p53 interaction and mitochondrial localization is a key prodrome to mitochondrial damage in SIMD and inhibiting this interaction may serve as a therapeutic target.

USF2 activates RhoB/ROCK pathway by transcriptional inhibition of miR-206 to promote pyroptosis in septic cardiomyocytes.

Septic cardiomyopathy (SCM) is one of the most serious complications of sepsis. The present study investigated the role and mechanism of upstream stimulatory factor 2 (USF2) in SCM. Serum samples were extracted from SCM patients and healthy individuals. A murine model of sepsis was induced by caecal ligation and puncture (CLP) surgery. Myocardial injury was examined by echocardiography and HE staining. ELISA assay evaluated myocardial markers (CK-MB, cTnI) and inflammatory cytokines (TNF-α, IL-1ß, IL-18). Primary mouse cardiomyocytes were treated with lipopolysaccharide (LPS) to simulate sepsis in vitro. RT-qPCR and Western blot were used for analyzing gene and protein levels. CCK-8 assay assessed cell viability. NLRP3 was detected by immunofluorescence. ChIP, RIP and dual luciferase reporter assays were conducted to validate the molecular associations. USF2 was increased in serum from SCM patients, septic mice and primary cardiomyocytes. USF2 silencing improved the survival of septic mice and attenuated sepsis-induced myocardial pyroptosis and inflammation in vitro and in vivo. Mechanistically, USF2 could directly bind to the promoter of miR-206 to transcriptionally inhibit its expression. Moreover, RhoB was confirmed as a target of miR-206 and could promote ROCK activation and NLRP3 inflammasome formation. Moreover, overexpression of RhoB remarkably reversed the protection against LPS-induced inflammation and pyroptosis mediated by USF2 deletion or miR-206 overexpression in cardiomyocytes. The above findings elucidated that USF2 knockdown exerted a cardioprotective effect on sepsis by decreasing pyroptosis and inflammation via miR-206/RhoB/ROCK pathway, suggesting that USF2 may be a novel drug target in SCM.

Prevalence and Prognosis of Sepsis-Induced Cardiomyopathy: A Systematic Review and Meta-Analysis.

Purpose: The prevalence and its impact on mortality of sepsis-induced cardiomyopathy (SICM) remain controversial. In this systematic review and meta-analysis, we investigated the prevalence and prognosis of SICM. Materials and Methods: We searched MEDLINE, Cochrane Central Register of Controlled Trials, and Embase. Titles and abstracts were evaluated based on the following criteria: (1) published in English, (2) randomized controlled trials, cohort studies, or cross-sectional studies, (3) ≥ 18 years with sepsis, (4) reporting the prevalence and/or comparison of short-term mortality between those with and without SICM, defined as the new-onset reduction in left ventricular ejection fraction (LVEF) within 72 h on admission or from the diagnosis of sepsis. The random-effect model was used for all analyses. This meta-analysis was registered at PROSPERO (CDR42022332896). Results: Sixteen studies reported the prevalence of SICM and the pooled prevalence of SICM was 20% (95% confidence interval [CI], 16-25%; I2 = 89.9%, P < 0.01). Eleven studies reported short-term mortality and SICM was associated with significantly higher short-term mortality (The pooled odds ratio: 2.30, 95% CI, 1.43-3.69; I2 = 0%, P = 0.001). Conclusion: The prevalence of SICM was 20% in patients with sepsis, and the occurrence of SICM was associated with significantly higher short-term mortality.

The Chronological Demographics of Ventricular-Arterial Decoupling in Patients with Sepsis and Septic Shock: A Prospective Observational Study.

BACKGROUND: Ventricular-arterial coupling (V-A coupling) recently gathers attention from clinicians to evaluate the interaction between afterload and left ventricular systolic function. We aimed to describe the chronological demographics of V-A decoupling in patients with sepsis and septic shock through the clinical course. METHOD: We conducted a single-center prospective observational study comprising adult patients with sepsis and septic shock admitted to the tertiary care hospital between 04/2017 and 03/2019. Patients' characteristics, lab data on admission, and echocardiographic parameters including Ea and Ees on the day- 1, 2, 3, 7, and 14-28 were collected. V-A decoupling was defined as Ea/Ees ≥ 1.36. RESULTS: Seventy-one patients with sepsis or septic shock were enrolled. The prevalence of V-A decoupling was as follows; day-1: 25.4%, day-2: 23.8%, day-3: 13.3%, day-7: 18.5%, day-14-28: 30.3%, respectively. Ea was higher in patients with V-A decoupling than those without throughout the clinical course (day1; 2.8 vs. 1.8, p < 0.01, day2; 2.7 vs. 1.9, p < 0.01, day3; 2.8 vs. 2.1, p = 0.06, day7; 2.7 vs. 1.9, p = 0.02, day14-28; 2.4 vs. 1.8, p = 0.08). This increase in Ea was mainly induced by reduced stroke volume (SV) as well as high systolic blood pressure (SBP) in the earlier course of sepsis but only by increased SBP in the later course of sepsis. Ees was lower in patients with V-A decoupling than those without throughout the clinical course (day1; 1.3 vs. 2.1, p < 0.01, day2; 1.5 vs. 2.3, p < 0.01, day3; 1.6 vs. 2.3, p = 0.02, day7; 1.8 vs. 2.3, p = 0.01, day14-28; 1.2 vs. 1.9, p = 0.07). CONCLUSION: We reported that V-A decoupling was commonly seen in patients with sepsis and septic shock. In patients with V-A decoupling, both Ea and Ees were significantly altered, but the causes of these alterations appeared to be changing over the clinical course of sepsis.

Efficacy of Levosimendan in the Treatment of Patients With Severe Septic Cardiomyopathy.

OBJECTIVE: This study was designed to compare the effects of levosimendan and dobutamine on hemodynamics and clinical efficacy in patients with severe septic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤35%). DESIGN: A prospective, single-blind, randomized controlled study. SETTING: In Baoding, China. PARTICIPANTS: Thirty patients with severe septic cardiomyopathy treated in the authors' hospital's Department of Critical Medicine from September 2018 to September 2021 were enrolled in this study. INTERVENTIONS: These patients were divided randomly into the levosimendan group and dobutamine group. The LVEF, cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index, heart rate, norepinephrine dose, and lactate at the time of enrollment and the 24th hour were compared, along with myocardial injury markers on the third day, C-reactive protein, mechanical ventilation time, length of intensive care unit (ICU) stay, cost, and 28-day mortality. The primary outcome was 28-day mortality. MEASUREMENTS AND MAIN RESULTS: At the 24th hour after treatment, CI, LVEF, SVI, and fluid volume were found to be higher in the levosimendan group than in the dobutamine group, whereas the dose of norepinephrine was lower in the former rather than the latter group. On the third day of treatment, cardiac troponin I in the levosimendan group was lower than that in the dobutamine group. Although the differences in 28-day mortality, ICU stay, and ICU treatment cost between the groups were not statistically significant, the ventilator application time of the levosimendan group was significantly shorter than that of the dobutamine group. CONCLUSIONS: Compared with dobutamine, levosimendan was more effective at improving cardiac function, reducing myocardial injury, and reducing mechanical ventilation time in patients with severe septic cardiomyopathy.