Sepsis-induced Myocardial Dysfunction Research Articles

The Correlation Between Whole Blood Copper (Cu), Zinc (Zn) Levels and Cu/Zn Ratio and Sepsis-Induced Left Ventricular Systolic Dysfunction (SILVSD) in Patients with Septic Shock: A Single-Center Prospective Observational Study.

PurposeThis 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 MethodsBetween 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.ResultsEighty-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).ConclusionFindings 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 RegistrationRegistered at http://www.chictr.org.cn/ChiCTR1800015709.

New Onset of Atrial Fibrillation" as an Outcome Predictor in Critically Ill Patients with Sepsis: A Systemic Review

Abstract Background Evidence of various cardiac arrhythmias in septic patients has been demonstrated by multiple clinical reports and observations .Most cardiac arrhythmias in sepsis are new-onset and may be related to sepsis-induced myocardial dysfunction, autonomic dysfunction and, most likely also, by impairment and involvement of the cardiac conduction system. Aim of the Work to describe the incidence of NOAF and to determine the risk factors associated with its development, as well as its clinical course and its effect on the outcome of patients with sepsis admitted to the ICU. Patients and Methods A systematic search was conducted to retrieve articles that investigated the association of NOAF in patients diagnosed with sepsis. We identified potential Englishlanguage sources from the PubMed, Medline, and EMBASE databases. Keywords used were “atrial fibrillation” and (“sepsis” or “septic shock”). In addition, reference lists of any studies meeting inclusion criteria were reviewed manually to identify additional relevant publications. Results In our meta-analysis, we found that NOAF is a common occurrence in critically ill patients with sepsis, and its incidence rises with increasing severity of disease. Also, we found that NOAF in sepsis patients is significantly associated with increased risk of ICU. In hospital, and After hospital discharge mortality, as well as, increased risk of developing ischemic stroke. Conclusion NOAF is a common occurrence in critically ill patients with sepsis, and its incidence rises with increasing severity of disease. Our Meta-analysis suggests that it is independently associated with poor outcome. In view of these findings there is a need for better quality observational studies, because reliable identification of patients with sepsis who are prone for the development of AF may allow for early pharmacological interventions to prevent this complication.

Butorphanol alleviates lipopolysaccharide-induced inflammation and apoptosis of cardiomyocytes via activation of the κ-opioid receptor.

Sepsis-induced myocardial dysfunction is a leading cause of the high mortality rates associated with sepsis. The aim of the present study was to investigate the effect of butorphanol on sepsis-induced cardiomyocyte dysfunction. Lipopolysaccharide (LPS) was used to induce H9C2 cardiomyocytes to establish an in vitro sepsis model. The effect of butorphanol on the viability of LPS-induced H9C2 cells was analyzed using a Cell Counting Kit-8 assay. The levels of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 were detected using ELISA. Western blotting was used to analyze the expression levels of inflammation-and apoptosis-related proteins. Cell apoptosis was measured using a TUNEL assay. The expression levels of κ-opioid receptor (KOR) were analyzed using reverse transcription-quantitative PCR analysis and western blotting. Following LPS induction, the levels of inflammatory cytokines and proapoptotic proteins were found to be upregulated in H9C2 cells, while butorphanol treatment downregulated these levels. The expression levels of KOR were also upregulated following butorphanol treatment in LPS-induced H9C2 cells. Addition of the KOR inhibitor, nor-binaltorphimine, alleviated the inhibitory effects of butorphanol on inflammation and apoptosis in LPS-induced H9C2 cells. In conclusion, the findings of the present study provided evidence indicating that butorphanol may alleviate LPS-induced inflammation and apoptosis in cardiomyocytes by upregulating KOR expression, which may provide a novel insight into the potential therapeutic effects of butorphanol and its underlying mechanism of action.

MiR-940 Serves as a Diagnostic Biomarker in Patients with Sepsis and Regulates Sepsis-Induced Inflammation and Myocardial Dysfunction.

IntroductionSepsis is a heterogeneous syndrome with a life-long threat caused by infection. This study aimed to investigate the clinical function of miR-940 and its influence on cardiomyocyte models.MethodsThe relative expression of miR-940 was assessed by qRT-PCR and the roles in the clinical diagnosis of miR-940 were revealed by the ROC curve. The relationship between miR-940 and clinical parameters was validated by Pearson analysis. The sepsis rat models were established by treatment with cecal ligation and perforation (CLP) and clinical items including left ventricular systolic pressure (LVSP), left ventricular and end-diastolic pressure (LVEDP), maximum rate of increase/decrease in left ventricular blood pressure (± dp/dtmax) as well as troponin (cTnl), creatine kinase isoenzyme (CK-MB), TNF-α, IL-1β, and IL-6 were detected.ResultsThe finding of qRT-PCR accentuated that the relative expression of miR-940 was significantly decreased in sepsis patients and CLP-stimulated models. The ROC curve proposed that miR-940 could be a satisfactory diagnostic biomarker for sepsis patients. Pearson analysis reinforced the expression of miR-940 was negatively associated with the PCT, WBC, CRP, Scr, SOFA score, and APACHE II score. The outcome of CLP-steered rat verified that overexpression of miR-940 inhibited the detrimental effects of CLP on myocardial dysfunction and inflammation reactions.ConclusionThe downregulation of miR-940 was reported and it might be an underlying diagnostic marker in sepsis patients. Overexpression of miR-940 protected myocardial function from damage and inflammation induced by CLP.

A Retrospective Observational Study of the Association Between Plasma Levels of Interleukin 8 in 42 Patients with Sepsis-Induced Myocardial Dysfunction at a Single Center Between 2017 and 2020.

BackgroundThis retrospective, observational study from a single center aimed to evaluate the association between complement (C)3 and C4, lymphocytes markers CD4 and CD8, and the interleukins IL-1β, IL-2R, IL-6, IL-10, and IL-8 in patients with sepsis-induced myocardial dysfunction (SIMD) and a reduced left ventricular ejection fraction (LVEF) of < 50%.Material/MethodsPatients with sepsis from July 2017 to December 2020 were divided into a SIMD group (42 patients) and NO-SIMD group (214 patients). Diagnostic criteria of sepsis were based on SEPSIS 3.0 guidelines. SIMD was defined as LVEF <50% by echocardiography and global ejection fraction <25% by transpulmonary thermodilution during hospitalization. The lymphocyte markers and interleukins were detected by flow fluorescence immunomicrobead assay, and C3 and C4 were detected by enzyme-linked immunosorbent assay.ResultsPlasma levels of IL-8 in the SIMD group were significantly higher than those in the NO-SIMD group, 133.90 (80.20, 402.79) vs 46.35 (16.80, 125.00) pg/mL (P<0.001). Logistic regression showed that N terminal pro B type natriuretic peptide (NT-proBNP; 95%CI 1.000–1.000, P<0.001) and IL-8 (95%CI 1.000–1.002, P=0.019) were independent risk factors for SIMD. Receiver operating characteristic curve analysis showed NT-proBNP, IL-8, and cardiac troponin T (cTnT) had different predictive values for SIMD: AUCNT-proBNP (0.810) >AUCIL-8 (0.748) >AUCcTnT (0.710). The cut-off value of IL-8 was 67.55 pg/mL; using this cut-off value, IL-8 predicted SIMD in sepsis with a sensitivity of 83.3% and specificity of 59.3%.ConclusionsIncreased plasma levels of IL-8 were significantly associated with cardiac dysfunction in patients with SIMD.

Lipopolysaccharide Alters the m6A Epitranscriptomic Tagging of RNAs in Cardiac Tissue.

N6-methyladenosine (m6A) modification plays important roles in the pathology of a variety of diseases. However, the roles of m6A modification in sepsis-induced myocardial dysfunction are not well defined. Rats were divided into control and lipopolysaccharide (LPS)-induced sepsis group. Global m6A levels of left ventricle tissue were measured by LC-MS/MS, and transcriptome-wide m6A modifications were profiled using epitranscriptomic microarrays (mRNAs and lncRNAs). Bioinformatics analysis was conducted to understand the functional implications of m6A modifications during sepsis. Methylated lncRNAs and mRNAs were measured by m6A single-base site qPCR. The global m6A levels in left ventricle tissue were significantly decreased in the LPS group. While 27 transcripts (23 mRNAs and four lncRNAs) were hypermethylated, 46 transcripts (39 mRNAs and 7 lncRNAs) were hypomethylated in the LPS group. The mRNA expression of writers and readers was significantly decreased in the LPS group. The m6A modification of Clec1b, Stk38l and Tnfrsf26 was associated with platelet activation and apoptotic pathways. Moreover, the decrease in m6A modification of lncRNA XR_346,771 may be related to cation import in cardiac tissue. Our data provide novel information regarding changes to m6A modifications in cardiac tissue during sepsis, and m6A modifications might be promising therapeutic targets.

Neferine Ameliorates Sepsis-Induced Myocardial Dysfunction Through Anti-Apoptotic and Antioxidative Effects by Regulating the PI3K/AKT/mTOR Signaling Pathway.

Septic cardiomyopathy is a common complication of severe sepsis, which is one of the leading causes of death in intensive care units. Therefore, finding an effective therapy target is urgent. Neferine is an alkaloid extracted from the green embryos of mature seeds of Nelumbo nucifera Gaertn., which has been reported to exhibit various biological activities and pharmacological properties. This study aims to explore the protective effects of neferine against lipopolysaccharide (LPS)-induced myocardial dysfunction and its mechanisms. The LPS-induced cardiac dysfunction mouse model was employed to investigate the protective effects of neferine. In this study, we demonstrated that neferine remarkably improved cardiac function and survival rate and ameliorated morphological damage to heart tissue in LPS-induced mice. Neferine also improved cell viability and mitochondrial function and reduced cell apoptosis and the production of reactive oxygen species in LPS-treated H9c2 cells. In addition, neferine significantly upregulated Bcl-2 expression and suppressed cleaved caspase 3 activity in LPS-induced mouse heart tissue and H9c2 cells. Furthermore, neferine also upregulated the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway in vivo and in vitro. Conversely, LY294002 (a PI3K inhibitor) reversed the protective effect of neferine in LPS-induced H9c2 cells. Our findings thus demonstrate that neferine ameliorates LPS-induced cardiac dysfunction by activating the PI3K/AKT/mTOR signaling pathway and presents a promising therapeutic agent for the treatment of LPS-induced cardiac dysfunction.

Angiotensin-(1-7) protects against sepsis-associated left ventricular dysfunction induced by lipopolysaccharide

Sepsis-induced myocardial dysfunction is a major cause of death. The present study explored whether angiotensin (Ang)-(1-7), an important biologically active peptide of the renin-angiotensin system, could improve cardiac dysfunction and attenuate inflammation and apoptosis. Experiments were carried out in mice and in neonatal rat cardiomyocytes (NRCMs) treated with lipopolysaccharide (LPS) or Ang-(1-7). Angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and Mas receptor (MasR) expressions were reduced in the mouse left ventricular and NRCM treated with LPS. Ang-(1-7) increased the ejection fraction and fractional shortening of left ventricular, which were reduced upon LPS injection in mice. Ang-(1-7) pre-treatment reversed LPS-induced decreases of α-myosin heavy chain (MHC) and β-MHC, and increases of S100 calcium binding protein A8 (S100A8) and S100A9 in the mouse left ventricular. The LPS-induced increases of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the mouse left ventricular and NRCMs were inhibited by Ang-(1-7) administration. Ang-(1-7) treatment reversed the increases of cleaved-caspase 3, cleaved-caspase 8 and Bax, and the decrease of Bcl2 induced by LPS in the mouse left ventricular and NRCMs. The increases of MAPKs pathway induced by LPS in NRCMs were inhibited by Ang-(1-7). These results indicate that Ang-(1-7) protects against sepsis-associated left ventricular dysfunction induced by LPS, and increases cardiac contractility via attenuating inflammation and apoptosis.

Hydrogen Sulfide Attenuated Sepsis-Induced Myocardial Dysfunction Through TLR4 Pathway and Endoplasmic Reticulum Stress.

Aims: We examined the change in endogenous hydrogen sulfide (H2S) production and its role in sepsis-induced myocardial dysfunction (SIMD).Results: Significant elevations in plasma cardiac troponin I (cTnI), creatine kinase (CK), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were noted in SIMD patients, whereas left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and plasma H2S were significantly decreased relative to those in the controls. Plasma H2S was linearly related to LVEF and LVFS. Subsequently, an SIMD model was developed in mice by injecting lipopolysaccharide (LPS), and NaHS, an H2S donor, was used to elucidate the pathophysiological role of H2S. The mice showed decreased ventricular function and increased levels of TNF-α, IL-1β, cTnI, and CK after LPS injections. Toll-like receptor (TLR) 4 protein and endoplasmic reticulum stress (ERS) proteins were over expressed in the SIMD mice. All of the parameters above showed more noticeable variations in cystathionine γ-lyase knockout mice relative to those in wild type mice. The administration of NaHS could improve ventricular function and attenuate inflammation and ERS in the heart.Conclusion: Overall, these findings indicated that endogenous H2S deficiency contributed to SIMD and exogenous H2S ameliorated sepsis-induced myocardial dysfunction by suppressing inflammation and ERS via inhibition of the TLR4 pathway.

Silencing Cardiac Troponin I-Interacting Kinase Reduces Lipopolysaccharide-Induced Sepsis-Induced Myocardial Dysfunction in Rat by Regulating Apoptosis-Related Proteins.

The aim of this study was to investigate the effect of cardiac troponin I-interacting kinase (TNNI3K) on sepsis-induced myocardial dysfunction (SIMD) and further explore the underlying molecular mechanisms. In this study, a lipopolysaccharide- (LPS-) induced myocardial injury model was used. qRT-PCR was performed to detect the mRNA expression of TNNI3K. Western blot was conducted to quantitatively detect the expression of TNNI3K and apoptosis-related proteins (Bcl-2, Bax, and caspase-3). ELISA was performed to detect the content of lactate dehydrogenase (LDH) and creatine kinase (CK). TUNEL assay was used to detect the apoptosis of H9C2 cells. In LPS-induced H9C2 cells, TNNI3K was up regulated. Besides, the CK activity, the content of LDH, and the apoptosis of H9C2 cells were significantly increased after treatment with LPS. Silencing TNNI3K decreased the LDH release activity and CK activity and inhibited apoptosis of H9C2 cell. Further research illustrated that si-TNNI3K promoted the protein expression of Bcl-2 and decreased the protein expression of Bax and cleaved caspase-3. The study concluded that TNNI3K was upregulated in LPS-induced H9C2 cells. Importantly, functional research findings indicated that silencing TNNI3K alleviated LPS-induced H9C2 cell injury by regulating apoptosis-related proteins.

Piceatannol protects against sepsis-induced myocardial dysfunction via direct inhibition of JAK2

Sepsis-induced myocardial dysfunction (SIMD) represents one of the serious complications secondary to sepsis, which is a leading cause of the high mortality rate among septic cases. Subsequent cardiomyocyte apoptosis, together with the uncontrolled inflammatory response, has been suggested to be closely related to SIMD. Piceatannol (PIC) is verified with potent anti-apoptotic and anti‐inflammatory effects, but its function and molecular mechanism in SIMD remain unknown so far. This study aimed to explore the potential role and mechanism of action of PIC in resisting SIMD. The interaction of PIC with JAK2 proteins was evaluated by molecular docking, molecular dynamics (MD) simulation and surface plasmon resonance imaging (SPRi). The cecal ligation and puncture-induced septicemia mice and the LPS-stimulated H9C2 cardiomyocytes were prepared as the models in vivo and in vitro, separately. Molecular docking showed that JAK2-PIC complex had the −8.279 kcal/mol binding energy. MD simulations showed that JAK2-PIC binding was stable. SPRi analysis also showed that PIC has a strong binding affinity to JAK2. PIC treatment significantly ameliorated the cardiac function, attenuated the sepsis-induced myocardial loss, and suppressed the myocardial inflammatory responses both in vivo and in vitro. Further detection revealed that PIC inhibited the activation of the JAK2/STAT3 signaling, which was tightly associated with apoptosis and inflammation. Importantly, pre-incubation with a JAK2 inhibitor (AG490) partially blocked the cardioprotective effects of PIC. Collectively, the findings demonstrated that PIC restored the impaired cardiac function by attenuating the sepsis‐induced apoptosis and inflammation via suppressing the JAK2/STAT3 pathway both in septic mice and H9C2 cardiomyocytes.

Brain natriuretic peptide and cardiac troponin I for prediction of the prognosis in cancer patients with sepsis

BackgroundThis article aimed to study the value of brain natriuretic peptide (BNP) and cardiac troponin I(cTnI) for predicting the prognosis in cancer patients with sepsis.MethodsA cohort of 233 cancer patients with sepsis admitted to our ICU from January 2017 to October 2020 was included in this retrospective study. The data of BNP and cTnI on the first day (d1) and the third day(d3) after entering ICU, blood lactate (Lac), procalcitonin (PCT), Leucocyte and Sequential Organ failure assessment (SOFA) scores within 24 hr of entering ICU, the incidence of septic shock, acute kidney injury(AKI), acute respiratory failure (ARF) or sepsis-induced myocardial dysfunction(SIMD) in ICU, fluid balance in 24 hr and 72 hr after entering ICU, time of mechanical ventilation(MV), length of stay, emergency surgery were collected. According to 28-day mortality, patients were divided into survival group (190 cases) and death group (43 cases). All the above variables were compared.ResultsBNP was an independent predictor for the mortality in these patients (P < 0.05).While cTnI was not. BNP on d3 in 681.5 pg/ml predicted the mortality with a sensitivity of 91.5 % and a specificity of 88.7 %. All patients were divided into the new two groups following the cutoff value of BNP on d3(681.5pg/ml), and the survival curve showed a significant difference with Kaplan-Meier analysis (P < 0.05). BNP had statistical differences between four groups based on the comorbidities(septic shock, AKI, ARF or SIMD), but cTnI was not.ConclusionsBNP was a great predictor for the prognosis of cancer patients with sepsis, while cTnI was not.

Lipocalin 10 as a New Prognostic Biomarker in Sepsis-Induced Myocardial Dysfunction and Mortality: A Pilot Study.

Introduction Sepsis-induced myocardial dysfunction (SIMD) is the most common complications of sepsis and septic shock with extremely high incidence and mortality. Lipocalin 10 (Lcn10) has recently been identified as a potential biomarker for heart failure, yet its relation to sepsis has not been investigated. The purpose of this study was to explore whether circulating Lcn10 could be used as a prognostic tool in patients with SIMD. Methods In this single-center observational pilot study, seventy-five sepsis patients were enrolled after sepsis diagnosis or ICU admission (45.3% female, median age 60 years), and 35 patients (46.7%) developed myocardial dysfunction. Serum Lcn10 levels of septic patients were measured using the enzyme-linked immunosorbent assay (ELISA) at the time of admission. Other biomarkers of cardiac function and Lcn10 concentration were compared between SIMD and non-SIMD groups. Results We observed that the median Lcn10 levels were 2.780 ng/mL in patients with SIMD and 2.075 ng/mL in patients without SIMD (P < 0.05). The area under the receiver operating characteristic (ROC) curve for the diagnosis of SIMD was 0.797 (P < 0.05). In addition, elevated serum Lcn10 levels at the time of admission were positively associated with 28-day mortality in septic patients. Conclusions Our study indicates that circulating Lcn10 levels may serve as a novel biomarker for the diagnosis and prognosis of myocardial dysfunction induced by sepsis. An additional large multicenter study may be warranted to confirm the findings of this study.

MiR-210-3p Enhances Cardiomyocyte Apoptosis and Mitochondrial Dysfunction by Targeting the NDUFA4 Gene in Sepsis-Induced Myocardial Dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) is a common complication with high incidence rates in sepsis patients. This study aimed to investigate the roles of miR-210-3p in regulating cardiomyocyte apoptosis and mitochondrial dysfunction associated with SIMD pathogenesis.A rat sepsis model was established by cecal ligation and puncture. Serum inflammatory factors, myocardial tissue apoptosis, and expression of miR-210-3p were evaluated. In vitro, miR-210-3p expression in H9C2 cells was altered by transfection with its mimics or inhibitors. H9C2 viability was assessed via CCK-8 assay, and reactive oxygen species (ROS) production and apoptosis were detected through flow cytometry. The targeting regulatory relations between miR-210-3p and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4) were validated by dual luciferase reporter assay.The rat sepsis model showed increased serum TNF-α and IL-6 levels, significant myocardial tissue injuries and apoptosis with decreased Bcl-2 and increased Caspase-1 protein levels. In vitro, septic rat serum suppressed viability, promoted ROS production and apoptosis, impaired COX IV activities and increased cytochrome release in H9C2 cells. The expression of miR-210-3p was greatly increased in myocardial tissues of septic rats and septic serum-treated H9C2 cells. miR-210-3p directly binds to the 3' UTR of the NDUFA4 gene. Septic rat serum suppressed NDUFA4 and Iron-Sulfur Cluster Assembly Protein U gene expressions in H9C2 cells. The above cellular and molecular alterations in H9C2 cells induced by septic serum were enhanced by miR-210-3p mimics and abrogated by miR-210-3p inhibitors.miR-210-3p promoted SIMD pathogenesis by targeting NDUFA4 to enhance cardiomyocyte apoptosis and impair mitochondrial function.

Aldehyde Dehydrogenase 2 Protects Against Lipopolysaccharide-Induced Myocardial Injury by Suppressing Mitophagy.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced circulatory and cardiac dysfunction is associated with high mortality rates. Mitophagy, a specific form of autophagy, is excessively activated in lipopolysaccharide-induced myocardial injury. The present study investigated whether aldehyde dehydrogenase 2 (ALDH2) regulates mitophagy in sepsis-induced myocardial dysfunction. After lipopolysaccharide administration, cardiac dysfunction, inflammatory cell infiltration, biochemical indicators of myocardial cell injury, and cardiomyocyte apoptosis were ameliorated in mice by ALDH2 activation or overexpression. In contrast, cardiac dysfunction and cardiomyocyte apoptosis were exacerbated in mice followed ALDH2 inhibition. Moreover, ALDH2 activation or overexpression regulated mitophagy by suppressing the expression of phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin, by preventing the accumulation of 4-hydroxy-trans-nonenal. Conversely, ALDH2 inhibition promoted the expression of LC3B by increasing 4-hydroxy-trans-2-nonenal accumulation. Consequently, ALDH2 may protect the heart from lipopolysaccharide-induced injury by suppressing PINK1/Parkin-dependent mitophagy.

Paeoniflorin and Hydroxysafflor Yellow A in Xuebijing Injection Attenuate Sepsis-Induced Cardiac Dysfunction and Inhibit Proinflammatory Cytokine Production.

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.

Echocardiographic evaluation of sepsis induced myocardial dysfunction in patients with sepsis or septic shock: a prospective cohort study

Background: Sepsis-induced myocardial dysfunction (SIMD) occurs in 50% of septic patients and is characterized by reduced ejection fraction (EF), cardiac index, impaired contractility, and diastolic dysfunction (DD). In sepsis-induced cardiomyopathy (SICM), EF shows initial significant deterioration on the 1st day, then final improvement at the end of the study. This study evaluated the value of different parameters measured with trans-thoracic echocardiography (TTE) in the diagnosis and prognosis of SIMD in the surgical intensive care unit (SICU).&#x0D; Methodology: This prospective cohort study was conducted on 100 patients, aged from 18 to 50 years admitted to SICU being affected by sepsis or septic shock. TTE parameters [EF, tricuspid annular systolic excursion (TAPSE), inferior vena cava (IVC) diameter, E/A ratio and grading of DD and hemodynamic parameters [mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP)] on admission, three day post-admission and after one week.&#x0D; Results: The mortality rate was 45%. DD was found in 90%. The mortality group had higher DD, higher HR, and lower MAP than the surviving group, with an insignificant difference in LVEF, TAPSE, IVC, and CVP on the 3rd and 7th days. Sepsis-induced cardiomyopathy (SICM) was found in 31% of surviving patients. DD (grade III had the highest mortality followed by grade I then grade II), HR &gt;110 bpm, and MAP &lt; 65mmHg are independent factors that negatively affect the duration of survival significantly.&#x0D; Conclusion: TTE in patients with sepsis or septic shock is vital for diagnosis and prognosis. DD, tachycardia (HR &gt;110 bpm), and hypotension (MAP &lt; 65mmHg) are independent predictors of mortality in those patients. Patients with SICM (little reversible impairment of LV systolic function) had a good prognosis.&#x0D; Keywords: Sepsis Induced Myocardial Dysfunction, Diastolic dysfunction, Sepsis, Septic Shock&#x0D; Preregistration: The study was registered in the Ethical Committee of Faculty of Medicine, Tanta University, Tanta, Egypt (approval number: 31728/08/17)&#x0D; Abbreviations: SIMD–Sepsis-induced myocardial dysfunction; SICM–sepsis-induced cardiomyopathy; TTE– transthoracic echocardiogram. EF–Ejection fraction; DD–diastolic dysfunction; MD–Myocardial dysfunction; TAPSE–tricuspid annular systolic excursion; SICU–surgical intensive care unit&#x0D; Citation: El-Oraby MA, Shaban AES, El-Dada AA, El-Badawy AEH. Echocardiographic evaluation of sepsis induced myocardial dysfunction in patients with sepsis or septic shock: a prospective cohort study. Anaesth pain intensive care 2021;25(2):150-162. DOI: 10.35975/apic.v25i2.1463&#x0D; Received: 6 November 2020, Reviewed: 30 December 2020, Accepted: 3 February 2021

Sepsis-induced myocardial dysfunction: the role of mitochondrial dysfunction.

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. 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. In the current review, we focus on the role of mitochondrial dysfunction and other mitochondria-related mechanisms including immunologicimbalance, energetic reprogramming, mitophagy, and pyroptosis in the mechanisms of SIMD.

Melatonin alleviates lipopolysaccharide-induced myocardial injury by inhibiting inflammation and pyroptosis in cardiomyocytes.

BackgroundMelatonin (MT) has been shown to protect against various cardiovascular diseases. However, the effect of MT on lipopolysaccharide (LPS)-induced myocardial injury is poorly understood. This study aims to evaluate the effects of MT on LPS-induced myocardial injury in vitro.MethodsH9C2 cells were divided into a control group, MT group, LPS group, and MT + LPS group. The control group was treated with sterile saline solution, the LPS group received 8 µg/mL LPS for 24 h, MT + LPS cells were pretreated with 200 µmol/L MT for 2 h then with 8 µg/mL LPS for 24 h, and the MT group received only 200 µmol/L MT for 2 h. The CCK-8 assay and lactate dehydrogenase (LDH) activity assay were used to analyze cell viability and LDH release, respectively. Intracellular reactive oxygen species (ROS) and the rate of pyroptosis were measured using the fluorescent probe dichloro-dihydro-fluorescein diacetate (DCFH-DA) and propidium iodide (PI) staining, respectively. The cell supernatants were used to measure the levels of inflammatory cytokines, including IL-6, TNF-α, and IL-1β by enzyme-linked immunosorbent assay (ELISA). The protein levels of iNOS, COX-2, NF-κB, p-NF-κB, NLRP3, caspase-1, and GSDMD were detected by western blot.ResultsMT pretreatment significantly improved LPS-induced myocardial injury by inhibiting inflammation and pyroptosis in H9C2 cells. Moreover, MT inhibited the activation of the NF-κB pathway, and reduced the expression of inflammation-related proteins (iNOS and COX-2), and pyroptosis-related proteins (NLRP3, caspase-1, and GSDMD).ConclusionsOur data suggests that MT can alleviate LPS-induced myocardial injury, providing novel insights into the treatment of sepsis-induced myocardial dysfunction.

Protective effects of NLRP3 inhibitor MCC950 on sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD) leads to poor prognosis or even death in severe sepsis cases, therefore, exploring its pathogenesis and new therapeutic targets has become the focus of current research. Specifically, an SIMD rat model was constructed by cecal ligation and puncture (CLP) method. At 24 h after intraperitoneal injection of the NLRP3 selective inhibitor MCC950, the levels of serum cardiac troponin I (cTnI) and Lactate dehydrogenase (LDH) in serum were detected, and the cardiac function of rats was examined via echocardiography. In addition, the pathological changes of myocardial tissues were observed by histological method, and the expression changes of inflammatory factors were detected in the tissue and serum. At the same time, H9C2 cells were treated with lipopolysaccharide (LPS) to simulate the in vitro model, and the expressions of inflammation and pyroptosis-related factors were detected. The results manifested that in the CLP group, the levels of serum cTnI and LDH were obviously increased, the myocardial tissue structure was disordered, the cell edema was severe, and the cardiac function was markedly reduced. Meanwhile, the expressions of inflammatory factors IL-6, IL-8 and TNF-α rose remarkably. On the contrary, MCC950 effectively reversed the above situation. Moreover, MCC950 inhibited LPS-induced inflammation and pyroptosis of H9C2 cells. In conclusion, the NLRP3 inhibitor MCC950 can reduce the release of LDH and other cellular inflammatory factors in the cytoplasm, thereby improving the cardiac function and slowing down the apoptosis of cardiomyocytes, which may be related to the inhibition of NLRP3/Caspase-1/IL-1β pathway.