Sepsis-induced Myocardial Dysfunction Research Articles

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.

The Effect of Sepsis on Myocardial Function: A Review of Pathophysiology, Diagnostic Criteria, and Treatment.

Sepsis remains a worldwide challenge for physicians with many patients admitted to ICUs with septic shock. Septic shock management involves targeted treatment to control infections, reduce end-organ damage, and reverse the injury. Sepsis-induced myocardial dysfunction or septic cardiomyopathy remains an avenue to be explored with regard to underlying pathophysiology and definite treatment guidelines. This article has compiled various studies to explain the possible mechanisms involved in the development of septic cardiomyopathy and the existing diagnostic criteria including radiological and laboratory tests to assess septic cardiomyopathy. Furthermore, the article highlights management options currently available for physicians dealing with myocardial dysfunction secondary to sepsis.

LncRNA MALAT1 Regulates USP22 Expression Through EZH2-Mediated H3K27me3 Modification to Accentuate Sepsis-Induced Myocardial Dysfunction

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

Heart-targeted amelioration of sepsis-induced myocardial dysfunction by microenvironment responsive nitric oxide nanogenerators in situ

BackgroundA balanced endogenous level of bioavailable nitric oxide (NO) plays a key role in maintaining cardiovascular homeostasis. The bioactive NO level in the cardiomyocytes was much reduced during sepsis. However, it is clinically challenging for the NO gas therapy due to the lack of spatial and temporal release system with precise control. The purpose of this study is to design a NO-releasing biomaterial with heart-targeted capability responsive to the infectious microenvironment, thus ameliorating lipopolysaccharide (LPS)-induced cardiac dysfunction.ResultsThe heart-targeted NO delivery and in situ releasing system, PCM-MSN@LA, was synthesized using hollow mesoporous silica nanoparticles (MSN) as the carrier, and L-arginine (LA) as the NO donor. The myocardial delivery was successfully directed to heart by specific peptide (PCM) combined with low-intensity focused ultrasound (LIFU) guidance. The myocardial system synthesized NO from the LA released from PCM-MSN@LA in the presence of increased endogenous nitric oxide synthase (NOS) activity induced by LPS. This targeted NO release in situ achieved extraordinary protective effects against LPS-challenged myocardial injury by reducing the recruitment of inflammatory cells, inhibiting oxidative stress and maintaining the mitochondria integrity. In particular, this protection was not compromised by simultaneous circulation collapse as an adverse event in the context.ConclusionsPCM-MSN@LA + LIFU exhibited extraordinary cardioprotective effects against severe sepsis in the hearts of LPS-treated animals without the side effect of NO diffusion. This technology has great potential to be served as a novel therapeutic strategy for sepsis-induced myocardial injury.

Tp-Te Interval and Tp-Te/QT Ratio Are Valuable Tools in Predicting Poor Outcome in Sepsis Patients.

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

Carnosol Attenuates LPS-Induced Inflammation of Cardiomyoblasts by Inhibiting NF-κB: A Mechanistic in Vitro and in Silico Study.

Carnosol possesses several beneficial pharmacological properties. However, its role in lipopolysaccharide (LPS) induced inflammation and cardiomyocyte cell line (H9C2) has never been investigated. Therefore, the effect of carnosol and an NF-κB inhibitor BAY 11-7082 was examined, and the underlying role of the NF-κB-dependent inflammatory pathway was analyzed as the target enzyme. Cell viability, inflammatory cytokines levels (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and prostaglandin E2 (PGE2)), and related gene expression (TNF-α, IL-1β, IL-6, and cyclooxygenase-2 (COX-2)) were analyzed by ELISA and real-time PCR. In addition, docking studies analyzed carnosol's molecular interactions and binding modes to NF-κB and IKK. We report that LPS caused the reduction of cell viability while enhancing both cytokines protein and mRNA levels (P < 0.001, for all cases). However, the BAY 11-7082 pretreatment of the cells and carnosol increased cell viability and reduced cytokine protein and mRNA levels (P < 0.001 vs. LPS, for all cases). Furthermore, our in silico analyses also supported the modulation of NF-κB and IKK by carnosol. This evidence highlights the defensive effects of carnosol against sepsis-induced myocardial dysfunction and, contextually, paved the rationale for the next in vitro and in vivo studies aimed to precisely describe its mechanism(s) of action.

Role of stress granule activation in cardiomyocyte function in sepsis

Sepsis is a life‐threatening organ dysfunction caused by a dysregulated host response to infection. It is the leading cause of mortality in Intensive Care Unit (ICU). Sepsis‐induced myocardial dysfunction (SIMD) is a major complication of the sepsis that contributes to high mortality of patients with sepsis. Stress granule (SG) is a cytoplasmic membraneless platform that is formed in response to cellular stresses. The role of SG in SIMD is unknown. The aim of present study is to understand whether activation of SG in cardiomyocytes (CM) plays a role in CM function in sepsis.MethodsCMs were treated with lipopolysaccharide (LPS). CM SG activation (eIF2α phosphorylation) and TNFα production were assessed with Western blot and ELISA, respectively. CM function was evaluated with intracellular cAMP. ISRIB or over‐expression of G3BP1 was employed interfering SG.ResultsChallenging CMs with LPS results in eIF2α phosphorylation, an increase in TNFα production, and a decrease in intracellular cAMP in response to dobutamine. Pharmacologically (ISRIB) or genetically inhibition (G3BP1 knock down) of SG leads to an exaggerated increase in TNFα expression. Further, SG inhibition results in enhanced decrease in CM function (decreased intracellular cAMP) in CM with LPS. Over‐expression of G3BP1 in CMs prevents LPS‐induced CM TNFα production and improves CM contractility.ConclusionOur results indicate that the cardiomyocyte stress granule activation plays a protective role of myocardial function in sepsis.

Abstract 229: Burden And Predictors Of Sepsis-associated Cardiac Arrest: A National Inpatient Sample Analysis, 2018

Background: Sepsis-induced myocardial dysfunction with the resultant cardiomyopathy carries a high risk of mortality. We aimed to study the risk factors of cardiac arrest (CA) in Sepsis-related hospitalizations (SRH). Methods: We identified SRHs using the National Inpatient Sample (2018) and ICD10 codes to categorized them into with vs without CA. We then compared baseline characteristics and performed multivariate analysis adjusting for confounders to identify predictors of sepsis-associated CA. Results: Of SRH (1,345,595) in 2018, 0.8% (11,365) had a CA (Table1) . SRH with CA often had elderly (median age 70 vs 66 years), males (55.3% vs 48.8%), blacks (19.6% vs 13.3%), Hispanics (12.3 vs 11.7%), Medicare enrollees (69.9 vs 59.1%), and had patients from lower-income households (LIH, 36.9% vs 30.7%) than non-CA cohort. Statistically significant predictors for CA in SRH were age (5% increased risk every 5 years), male sex (aOR 1.28, 95CI 1.16-1.4), black (aOR 1.49, 95CI 1.3-1.7) &amp; Hispanic (aOR 1.26, 95CI 1.09-1.45) race, LIH (aOR 1.31, 95CI 1.13-1.52), CHF (aOR 2.4, 95CI 2.16-2.68), pulmonary circulation disorder (aOR 2.14, 95CI 1.72-2.66), prior cardiac arrest (aOR 1.95, 95CI 1.16-3.27), coagulopathy (aOR 1.69, 95CI 1.5-1.9), alcohol abuse (aOR 1.42 95CI 1.17-1.74), PVD (aOR 1.36, 95CI 1.17-1.58), CKD (aOR 1.26, 95CI 1.14-1.39), cancer without metastasis (aOR 1.49, 95CI 1.24-1.8) and with metastasis (aOR 1.24, 95CI 1.01-1.52). Urban non-teaching vs rural (aOR 1.32, 95CI 1.1-1.57) and Southern vs Northeast hospitals (aOR 1.26, 95CI 1.09-1.46) showed higher odds of CA. Conclusion: SRH associated CA had high mortality with prevalent demographic and regional disparities, evident from black and Hispanic, males, patients from LHI and Southern hospitals revealing a higher risk of sepsis-associated CA. Congestive heart failure, pulmonary disease, prior cardiac arrest, coagulopathy, alcohol abuse, PVD, CKD, and cancers were the strongest predictors of CA in SRH.

Shenfu injection attenuates cardiac dysfunction and inhibits apoptosis in septic mice.

BackgroundCardiac dysfunction frequently occurs after sepsis and septic shock and contributes to multiple organ failure. Shenfu injection, a well-known Chinese medicine formulation, has recently been demonstrated to possess potential cardio-protective effects, although its effect and mechanism in sepsis-induced myocardial dysfunction remains unclear.MethodsTo investigate whether Shenfu injection could alleviate myocardial injury and improve cardiac function, a model of sepsis was induced by cecal ligation and puncture (CLP) surgery in C57BL/6 mice. Cardiac function, inflammatory factors, and apoptosis were evaluated in the myocardium.ResultsOur results showed that the survival and left ventricular function markedly declined when exposed to CLP compared with the sham procedure. In contrast, Shenfu injection lowered mortality and prevented CLP from triggering left ventricular dysfunction. Moreover, mice treated with Shenfu injection exhibited noticeably decreased myocardial inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocytechemoattractantprotein-1 (MCP-1)] and reduced apoptotic myocardiocytes death compared with mice that had CLP. The activation of myocardial NF-кB detected in septic mice was suppressed by the presence of Shenfu injection, as evidenced by decreased nuclear translocation of the NF-кB p65 subunit. Moreover, Shenfu injection also prevented sepsis-caused decreases in myocardial phospho-Akt and phospho-GSK-3β in septic mice.ConclusionsThese data suggest that administration of Shenfu injection attenuates cardiac dysfunction, protects against inflammatory injury, and reduces apoptosis of myocardiocytes during sepsis by activating the AKT/GSK-3β pathway.

Pterostilbene Interferes With Lipopolysaccharide-Induced Myocardial Injury Through Oxidative Stress and Inflammasome Pathways.

Myocardial contractile dysfunction caused by sepsis is a serious threat to human health, and its pathogenesis is not completely clear. It is generally believed that excessive inflammation and oxidative stress are the main causes of myocardial damage caused by sepsis. Pterostilbene (PTS) has a variety of biological activities, including anti-oxidant, anti-inflammatory, and anti-aging. Whether PTS protect myocardial function in rats with sepsis through anti-inflammatory and anti-oxidant effects has not been reported. In this study, we investigated the role of PTS in septic mice induced by lipopolysaccharide (LPS). Mice were injected intraperitoneally with LPS (20 mg/kg) to simulate sepsis. Use Echocardiography, Masson, DHE, H&E, IHC, IF and other experimental methods to explore the effects of PTS on LPS. The results showed that PTS was indicated to significantly increase the cardiac function of mice with sepsis. PTS treatment also reduced the mRNA expression of IL-1α, IL-6, MCP-1, and IL-1β and the protein expression of NLRP3 in vivo and in vitro, and inhibited the migration of inflammatory cells. PTS treatment also reduced the mRNA expression of collagen I, collagen III and α-SMA, and inhibited fibrosis. PTS treatment reduced the mRNA expression of NOX1, NOX2, and NOX4 and inhibited DHE levels in vivo and in vitro. In summary, our data indicated that PTS played a crucial role in LPS-induced myocardial injured and might be a key target for the prevention and treatment of sepsis-induced myocardial dysfunction.

Assessing the Role of Lipopolysaccharide (LPS) Receptor (CD14) in Septic Cardiomyopathy: The Value of Immunohistochemical Diagnostics.

Sepsis-induced myocardial dysfunction (SIMD) is one of the major predictors of morbidity and mortality of sepsis. A high percentage of patients with SIMD develop a status similar to cardiogenic shock. A high level of bacterial lipopolysaccharide (LPS) associated with an overexpression of CD14 acts as the trigger for the release of a broad spectrum of cytokines. Our study aimed to understand the correlation between septic cardiomyopathy and CD14 immunohistochemical expression. The study included 29 patients who died of septic shock. Increased values of membranous CD14 and soluble CD14 in the heart tissue were correlated with adverse patient evolution. A high cellular expression of CD14 was noted in the study group vs. the control group (p = 0.0013). Therefore, a close positive association between the amount of LPS related to sCD14 and the cellular expression of mCD14 is probable. By extrapolation, we suggest that a large amount of sCD14 detected in the cardiac tissue will activate the mCD14–TRL4–LBP–LPS complex, which in turn will induce an inadequate immune response, resulting in heart damage proportional to the amount of LPS. CD14 could represent a valuable marker for septic cardiomyopathy; thus, apoptosis of cardiomyocytes could be foreseen by its high value.

MiR-501-5p alleviates cardiac dysfunction in septic patients through targeting NR4A3 to prevent its binding with Bcl-2

ABSTRACT Sepsis-induced myocardial dysfunction is a common complication in septic patients. To date, a limited number of biomarkers that could predict cardiomyocyte apoptosis have been explored. In this study, we successfully established a cecal ligation and puncture (CLP)-induced septic model, and it was found that miR-501-5p expression was down-regulated in peripheral blood samples of septic patients with cardiac dysfunction, lipopolysaccharide (LPS)-induced cardiomyocytes, and the myocardium and peripheral blood in the septic model. Moreover, it was revealed that miR-501-5p overexpression could increase left ventricular diastolic pressure (LVDP), fractional shortening (FS), ejection fraction (EF), and maximum rate of the rise of left ventricular pressure (+dp/dt) in vivo, while it decreased the levels of myocardial injury-related indicators. In addition, LPS induction accelerated apoptosis and elevated the inflammation in HL-1 and HCM cells, which could be reversed by miR-501-5p overexpression. Mechanistically, we considered nuclear receptor subfamily 4 group A member 3 (NR4A3) as the target of miR-501-5p, and it was found that miR-501-5p prevented the binding between NR4A3 and Bcl-2. It was found that miR-501-5p exerted an inhibitory effect on cardiomyocyte apoptosis and inflammation in a NR4A3-dependent manner. Overall, our results may provide evidence for consideration of miR-501-5p in the therapy of sepsis.

Clemastine protects against sepsis-induced myocardial injury in vivo and in vitro

ABSTRACT Sepsis-induced myocardial dysfunction (SIMD) is associated with high morbidity and mortality rates; however, it lacks targeted therapies. Modulating cardiomyocyte autophagy maintains intracellular homeostasis during SIMD. Clemastine, a histamine receptor inhibitor, promotes autophagy and other effective biological functions. Nevertheless, the effect of clemastine on SIMD remains unclear. This study aimed to explore the underlying mechanism of clemastine in cardiomyocyte injury in cecum ligation and perforation (CLP)-induced rats and lipopolysaccharide (LPS)-stimulated H9c2 cells. Clemastine (10 mg/kg, 30 mg/kg, and 50 mg/kg) was intraperitoneally injected after 30 min of CLP surgery. Serum cTnI levels and the 7-day survival rate were evaluated. Echocardiograms and H&E staining were used to evaluate cardiac function and structure. TEM was used to detect the mitochondrial ultrastructure and autophagosomes. Clemastine significantly improved the survival rate and reduced cTnI production in serum. Clemastine ameliorated cellular apoptosis, improved mitochondrial ultrastructure both in vivo and in vitro, increased ATP content, decreased dynamin-related protein 1 (DRP1) expression, and decreased mitochondrial ROS levels. Additionally, clemastine treatment increased autophagosome concentration, LC3II/LC3I rate, and Beclin 1 expression. However, 3-methyladenine (3-MA), an autophagy inhibitor, could abolish the effect of clemastine on alleviating myocardial apoptosis. In conclusion, clemastine protected against cardiac structure destruction and function dysfunction, mitochondrial damage, apoptosis, and autophagy in vivo and in vitro. Moreover, clemastine attenuated myocardial apoptosis by promoting autophagy. This study provides a novel favorable perspective for SIMD therapy.

IL-6/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice.

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

HSP70 alleviates sepsis-induced cardiomyopathy by attenuating mitochondrial dysfunction-initiated NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes.

Sepsis-induced cardiomyopathy (SIC) is an identified serious complication of sepsis that is associated with adverse outcomes and high mortality. Heat shock proteins (HSPs) have been implicated in suppressing septic inflammation. The aim of this study was to investigate whether HSP70 can attenuate cellular mitochondrial dysfunction, exuberated inflammation and inflammasome-mediated pyroptosis for SIC intervention. Mice with cecal ligation plus perforation (CLP) and lipopolysaccharide (LPS)-treated H9C2 cardiomyocytes were used as models of SIC. The mouse survival rate, gross profile, cardiac function, pathological changes and mitochondrial function were observed by photography, echocardiography, hematoxylin-eosin staining and transmission electron microscopy. In addition, cell proliferation and the levels of cardiac troponin I (cTnI), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were determined by Cell Counting Kit-8, crystal violet staining and enzyme-linked immunosorbent assay. Moreover, mitochondrial membrane potential was assessed by immunofluorescence staining, and dynamin-related protein 1 and pyroptosis-related molecules [nucleotide-binding domain, leucine-rich-repeat containing family pyrin domain-containing 3 (NLRP3), caspase-1, gasdermin-D (GSDMD), gasdermin-D N-terminal (GSDMD-N)] were measured by western blotting, immunoprecipitation and immunoblotting. Finally, hsp70.1 knockout mice with CLP were used to verify the effects of HSP70 on SIC and the underlying mechanism. Models of SIC were successfully established, as reduced consciousness and activity with liparotrichia in CLP mice were observed, and the survival rate and cardiac ejection fraction (EF) were decreased; conversely, the levels of cTnI, TNF-α and IL-1β and myocardial tissue damage were increased in CLP mice. In addition, LPS stimulation resulted in a reduction in cell viability, mitochondrial destabilization and activation of NLRP3-mediated pyroptosis molecules in vitro. HSP70 treatment improved myocardial tissue damage, survival rate and cardiac dysfunction caused by CLP. Additionally, HSP70 intervention reversed LPS-induced mitochondrial destabilization, inhibited activation of the NLRP3 inflammasome, caspase-1, GSDMD and GSDMD-N, and decreased pyroptosis. Finally, knockout of hsp70.1 mice with CLP aggravated cardiac dysfunction and upregulated NLRP3 inflammasome activity, and exogenous HSP70 significantly rescued these changes. It was further confirmed that HSP70 plays a protective role in SIC by attenuating mitochondrial dysfunction and inactivating pyroptotic molecules. Our study demonstrated that mitochondrial destabilization and NLRP3 inflammasome activation-mediated pyroptosis are attributed to SIC. Interestingly, HSP70 ameliorates sepsis-induced myocardial dysfunction by improving mitochondrial dysfunction and inhibiting the activation of NLRP3 inflammasome-mediated pyroptosis, and such a result may provide approaches for novel therapies for SIC.

Hsp22 ameliorates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidative stress, and apoptosis

ABSTRACT Sepsis-induced myocardial dysfunction (SIMD) is ubiquitous in septic shock patients and is associated with high morbidity and mortality rates. Heat shock protein 22 (Hsp22), which belongs to the small HSP family of proteins, is involved in several biological functions. However, the function of Hsp22 in lipopolysaccharide (LPS)-induced myocardial injury is not yet established. This study was aimed at investigating the underlying mechanistic aspects of Hsp22 in myocardial injury induced by LPS. In this study, following the random assignment of male C57BL/6 mice into control, LPS-treated, and LPS + Hsp22 treated groups, relevant echocardiograms and staining were performed to scrutinize the cardiac pathology. Plausible mechanisms were proposed based on the findings of the enzyme-linked immunosorbent assay and Western blotting assay. A protective role of Hsp22 against LPS-induced myocardial injury emerged, as evidenced from decreased levels of creatinine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and enhanced cardiac function. The post-LPS administration-caused spike in inflammatory cytokines (IL-1β, IL-6, TNF-α and NLRP3) was attenuated by the Hsp22 pre-treatment. In addition, superoxide dismutase (SOD) activity and B-cell lymphoma-2 (Bcl2) levels were augmented by Hsp22 treatment resulting in lowering of LPS-induced oxidative stress and cardiomyocyte apoptosis. In summary, the suppression of LPS-induced myocardial injury by Hsp22 overexpression via targeting of inflammation, oxidative stress, and apoptosis in cardiomyocytes paves the way for this protein to be employed in the therapy of SIMD.

Sepsis-Induced Myocardial Dysfunction in Pediatric Septic Shock: Prevalence, Predictors, and Outcome—A Prospective Observational Study

AbstractThere is a paucity of literature on the prevalence, predictors, prognostic markers, and outcomes of sepsis-induced myocardial dysfunction (SMD) in pediatric septic shock. The objectives of our study were to estimate the prevalence of SMD in pediatric septic shock by point-of-care functional echocardiography (POCFE) and to study the association of SMD with severity of illness, organ dysfunctions, and outcomes. This prospective, observational study was conducted over a period of 1 year (from July 2018 to July 2019) in a 12-bed, tertiary pediatric intensive care unit (PICU) of an academic and referral hospital in South India. Children presenting with septic shock were enrolled in the study. POCFE was done within 6 hours of PICU admission and patients were categorized as having SMD based on POCFE findings. The prevalence of SMD (left ventricle ± right ventricle) was 32% (32/100). More than half of the children (54.5%) died in SMD group, whereas only 7.5% died in non-SMD group (p &lt; 0.001). SMD was associated with higher organ dysfunctions, worse patient outcomes, and was found to be an independent predictor of mortality. The median lactate levels were higher in SMD group (3.15 [2.7, 5] vs. 2 [1.3, 2.7], p &lt; 0.001) as compared with non-SMD group. We observed significantly lower median lactate clearance at 6 hours in SMD than non-SMD (30.0% [−14.44, 44.22] vs. 59.8% [45.83, 71.43], p &lt; 0.001). Lactate levels at 6 hours with a threshold of 2.4 mmol/L was a good predictor of SMD with sensitivity and specificity of 73 and 80%, respectively. SMD is not an uncommon entity in children with septic shock. SMD was associated with worse patient outcomes, organ dysfunction, and mortality. Serum lactate trends may predict SMD and can be used as prognosticate markers as well.

Effect of Glucose-Insulin-Potassium Infusion on Hemodynamics in Patients with Septic Shock

BACKGROUND: Glucose-insulin-potassium (GIK) demonstrates a cardioprotective effect by providing metabolic support and anti-inflammatory action, and may be useful in septic myocardial depression. AIM: The aim of this study was to assess role of GIK infusion in improving hemodynamics in patients with septic shock in addition to its role in myocardial protection and preventing occurrence of sepsis-induced myocardial dysfunction and sepsis-induced arrhythmias. METHODS: This study was conducted on 75 patients admitted to the Critical Care Department in Cairo University Hospital with the diagnosis of septic shock during the period from January 2019 to December 2019. Patients were divided into two groups; first group was managed according to the last guidelines of surviving sepsis campaign and was subjected to the GIK infusion protocol while second group was managed following the last guidelines of surviving sepsis campaign only without adding GIK infusion. RESULTS: Patients in the GIK group showed better lactate clearance (50% vs. 46.7%) and less time needed for successful weaning of vasopressors than the control group (3.57±1.16 vs. 3.6±1.45 days) thought not reaching statistical significance. There was no statistically significant difference between both groups regarding development of septic-induced cardiomyopathy (16.7% in the control group vs. 13.3% in the GIK group); however, patients with hypodynamic septic shock showed better improvement in hemodynamic profile in the GIK group. Sepsis-induced arrhythmias occurred more in patients of the control group than in patients of the GIK group with no statistically significant difference between both groups (33.3% vs. 20%, p = 0.243). Few side effects were developed as a result of using GIK infusion protocol. CONCLUSIONS: GIK may help in improving hemodynamics and weaning of vasopressors in patients with refractory septic shock and those with septic induced cardiomyopathy. The use of GIK was well tolerated with minimal adverse reactions.

GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation.

Myocardial dysfunction is a serious consequence of sepsis and contributes to high mortality. Currently, the molecular mechanism of myocardial dysfunction induced by sepsis remains unclear. In the present study, we investigated the role of gasdermin D (GSDMD) in cardiac dysfunction in septic mice and the underlying mechanism. C57BL/6 wild-type (WT) mice and age-matched Gsdmd-knockout (Gsdmd -/-) mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg) to mimic sepsis. The results showed that GSDMD-NT, the functional fragment of GSDMD, was upregulated in the heart tissue of septic WT mice induced by LPS, which was accompanied by decreased cardiac function and myocardial injury, as shown by decreased ejection fraction (EF) and fractional shortening (FS) and increased cardiac troponin I (cTnI), creatine kinase isoenzymes MB (CK-MB), and lactate dehydrogenase (LDH). Gsdmd -/- mice exhibited protection against LPS-induced myocardial dysfunction and had a higher survival rate. Gsdmd deficiency attenuated LPS-induced myocardial injury and cell death. Gsdmd deficiency prevented LPS-induced the increase of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum, as well as IL-1β and TNF-α mRNA levels in myocardium. In addition, LPS-mediated inflammatory cell infiltration into the myocardium was ameliorated and activation of NF-κB signaling pathway and the NOD-like receptor protein 3 (NLPR3) inflammasome were suppressed in Gsdmd -/- mice. Further research showed that in the myocardium of LPS-induced septic mice, GSDMD-NT enrichment in mitochondria led to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which further regulated the activation of the NLRP3 inflammasome. In summary, our data suggest that GSDMD plays a vital role in the pathophysiology of LPS-induced myocardial dysfunction and may be a crucial target for the prevention and treatment of sepsis-induced myocardial dysfunction.

Predictive value and regulatory mechanism of serum miR-499a-5p on myocardial dysfunction in sepsis

BackgroundThis study sought to investigate the predictive value and regulatory mechanism of serum miR-499a-5p in sepsis-induced myocardial dysfunction (SIMD).MethodsA total of 60 patients with sepsis and 60 healthy volunteers were enrolled in this study. The serum levels of miRNAs (miR-451, miR-378 and miR-499a-5p) were detected. Receiver operating characteristic curve and logistic regression analysis were used to evaluate the diagnostic and prognostic value of miR-499a-5p in SIMD patients. AC16 cells were used to establish SIMD model in vitro using lipopolysaccharide (LPS). An analysis was conducted for miR-499a-5p expression, cell viability, and the concentration of creatine kinase-MB isoform (CK-MB), brain natriuretic peptide (BNP), superoxide dismutase (SOD) and cytochrome C oxidase IV (COX IV). The downstream target of miR-499a-5p was verified.ResultsOur results revealed a poor expression of miR-499a-5p in the serum of SIMD patients, while no significant difference was evident for miR-451 and miR-378. The level of miR-499a-5p in the survival group was higher than the non-survival group. miR-499a-5p elicited good diagnostic and prognostic value for SIMD. Our findings revealed that miR-499a-5p was decreased significantly in LPS-treated cardiomyocytes. After overexpression of miR-499a-5p, the cell viability increased, and the concentrations of CK-MB and BNP were decreased, while the concentrations of SOD and COX IV were increased. EIF4E was validated as the target of miR-499a-5p. After overexpression of EIF4E, the cell viability was decreased and the concentrations of CK-MB and BNP were increased while the concentrations of SOD and COX IV were decreased.ConclusionThe level of miR-499a-5p is weak in SIMD patients. miR-499a-5p has a good diagnostic and prognostic value for SIMD by inhibiting EIF4E transcription.