Sepsis-induced Cardiac Dysfunction Research Articles

Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis

AimsSepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular disease. The ketone β-hydroxybutyrate is reported to be cardioprotective in cardiovascular disease and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce the enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis. Methods and resultsTo assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism. ConclusionThese data show that the use of an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.

Cardiomyocyte death in sepsis:Mechanisms and regulation (Review).

Sepsis-induced cardiac dysfunction is one of the most common types of organ dysfunction in sepsis; its pathogenesis is highly complex and not yet fully understood. Cardiomyocytes serve a key role in the pathophysiology of cardiac function; due to the limited ability of cardiomyocytes to regenerate, their loss contributes to decreased cardiac function. The activation of inflammatory signalling pathways affects cardiomyocyte function and modes of cardiomyocyte death in sepsis. Prevention of cardiomyocyte death is an important therapeutic strategy for sepsis-induced cardiac dysfunction. Thus, understanding the signalling pathways that activate cardiomyocyte death and cross-regulation between death modes are key to finding therapeutic targets. The present review focused on advances in understanding of sepsis-induced cardiomyocyte death pathways, including apoptosis, necroptosis, mitochondria-mediated necrosis, pyroptosis, ferroptosis and autophagy. The present review summarizes the effect of inflammatory activation on cardiomyocyte death mechanisms, the diversity of regulatory mechanisms and cross-regulation between death modes and the effect on cardiac function in sepsis to provide a theoretical basis for treatment of sepsis-induced cardiac dysfunction.

Abstract 330: Kinin B1r Inhibitor Prevents Sepsis-induced Cardiac Dysfunction And Promotes Survival In Mice

Introduction: Hyperpermeability of the microvascular barrier and the resulting capillary leakage are hallmarks of sepsis. B1R has been proposed to be a therapeutic target for sepsis-induced microvascular hyperpermeability and multiorgan failure. However, its direct role in regulating of cardiac function during severe sepsis remains poorly characterized. Hypothesis: We hypothesized that B1R inhibition can protect against sepsis-induced cardiac dysfunction and improve survival. Methods and Results: To address the hypothesis, we pre-treated mice with either vehicle (control) or a specific B1R antagonist B6929via subcutaneous injection then subjected them to 40% cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Serum levels of IL-6 and TNFα increased significantly within 4 hours post-CLP in the controls. However, B1R antagonist treatment abolished CLP-induced expressions of IL-6 and TNFα by 70% and 30%, respectively. B1R antagonist also protected mice from sepsis-induced organ failure—as highlighted by the lowered increase in MSS score over the 24-h post-CLP—resulting in significant improvement in survival rate (P<0.05). In-vivo cardiac vascular permeability assessed using the Miles assay further demonstrated that B1R inhibition prevented sepsis-induced cardiac microvascular leakage and edema. Similar improvements were also observed in the liver and kidney. Further study revealed an early cardioprotective effect of B1R inhibitor, as evidenced by the improvement of EF%, FS%, and cardiac output in mice treated with B1R antagonist + CLP vs. CLP alone (p<0.01) from the echocardiogram analyses at 4-6 hours following CLP. Furthermore, mitochondrial H 2 O 2 measurement of the freshly isolated cardiac mitochondria from septic mice also showed that B1R inhibition partially abolished the production of H 2 O 2 . The opening of mPTP was also reduced with B1Ri treatment. Taken together, these findings indicated improvement in cardiac mitochondrial function following B1R inhibitor treatment. Conclusions: Our findings provide novel insights into the pathogenesis of sepsis-induced cardiac mitochondrial dysfunction and heart failure. Inhibition of B1R may be a novel therapeutic strategy for sepsis-associated cardiovascular disease.

Berberine attenuates sepsis-induced cardiac dysfunction by upregulating the Akt/eNOS pathway in mice.

The present study aimed to investigate the cardioprotective role of berberine in sepsis-induced cardiac dysfunction and consider the underlying mechanisms. C57BL/6J mice were randomized into four groups, namely, Control, lipopolysaccharide (LPS), LPS + berberine and LPS + Nω-nitro-L-arginine methyl ester (L-NAME) + berberine. A single dose (10 mg/kg body weight) of LPS was intraperitoneally administered to mice to induce cardiac dysfunction, whereas the Control group was administered with an equivalent volume of saline. In the LPS + berberine and LPS + L-NAME + berberine group, berberine (10 mg/kg body weight) dissolved in hot water was intraperitoneally administered 30 min after the LPS treatment. In the LPS + L-NAME + berberine group, L-NAME (100 mg/kg body weight) dissolved in saline was intraperitoneally administered 30 min before the LPS treatment. Then, ~6 h after the LPS treatment, a significant decrease was observed in the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). Meanwhile, the plasma myocardial injury markers, inflammatory factors and oxidative stress levels were significantly increased in the LPS group compared with the Control group. The administration of berberine improved the ventricular function and decreased the plasma myocardial injury markers, inflammatory factors and oxidative stress levels. In addition, it increased the heart total nitric oxide synthase (NOS) activity and upregulated the protein expressions of p-Akt and phosphorylated endothelial (e)NOS, which indicated that the Akt/eNOS pathway was activated by berberine. However, the cardioprotective effects of berberine were counteracted by L-NAME, an NOS inhibitor, which inhibited the eNOS activity. In conclusion, berberine attenuated sepsis-induced cardiac dysfunction by upregulating the Akt/eNOS pathway in mice.

Female hormones prevent sepsis-induced cardiac dysfunction: an experimental randomized study

Although epidemiologic research has demonstrated significant differences in incidence and outcomes of sepsis according to sex, their underlying biological mechanisms are poorly understood. Here, we studied the influence of hormonal status by comparing in vivo cardiac performances measured by MRI in non-ovariectomized and ovariectomized septic female rats. Control and ovariectomized rats were randomly allocated to the following groups: sham, sepsis and sepsis plus landiolol. Sepsis was induced by caecum ligation and punction (CLP). Landiolol, a short-acting selective β1-adrenergic blocker improving the in vivo cardiac performance of septic male rats was perfused continuously after sepsis induction. Cardiac MRI was carried out 18 h after induction of sepsis to assess in vivo cardiac function. Capillary permeability was evaluated by Evans Blue administration and measurement of its tissue extravasation. Variation in myocardial gene and protein expression was also assessed by qPCR and western-blot in the left ventricular tissue. Sepsis reduced indexed stroke volume, cardiac index and indexed end-diastolic volume compared to sham group in ovariectomized females whereas it had no effect in control females. This was associated with an overexpression of JAK2 expression and STAT3 phosphorylation on Ser727 site, and an inhibition of the adrenergic pathways in OVR females. Landiolol increased the indexed stroke volume by reversing the indexed end-diastolic volume reduction after sepsis in ovariectomized females, while it decreased indexed stroke volume and cardiac index in control. This was supported by an overexpression of genes involved in calcium influx in OVR females while an inactivation of the β-adrenergic and a calcium efflux pathway was observed in control females. Sepsis decreased in vivo cardiac performances in ovariectomized females but not in control females, presumably associated with a more pronounced inflammation, inhibition of the adrenergic pathway and calcium efflux defects. Administration of landiolol prevents this cardiac dysfunction in ovariectomized females with a probable activation of calcium influx, while it has deleterious effects in control females in which calcium efflux pathways were down-regulated.

Comparison of dobutamine and levosimendan for treatment of sepsis-induced cardiac dysfunction: A protocol for systematic review and meta-analysis.

Levosimendan and dobutamine are extensively used to treat sepsis-induced cardiomyopathy. Previous studies on whether levosimendan is superior to dobutamine are still controversial. We performed a protocol for systematic review and metaanalysis to compare the efficacy and safety of levosimendan versus dobutamine for the treatment of sepsis-induced cardiomyopathy. This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol statement. We will search the following databases: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Weipu Journal Database, and Chinese Biomedical Literature Database. The search time will be set from database establishment to February 2022. After literature screening, 2 reviewers will extract data from the respects of general information, methodology, and results. Risk of bias is assessed using the Cochrane Risk of Bias Tool for randomized controlled trials. We will apply RevMan 5.4 software for statistical analysis. The results will be submitted to a peer-reviewed journal once completed. Septic patients with myocardial dysfunction may partly benefit from levosimendan than dobutamine, mainly embodied in cardiac function improvement.

MicroRNA-124-3p attenuates myocardial injury in sepsis via modulating SP1/HDAC4/HIF-1\u03b1 axis

Sepsis-induced cardiac dysfunction can lead to death in sepsis. In this case, we targeted to explore in detail the relative mechanism of microRNA (miR)-124-3p in sepsis-induced myocardial injury via the specific protein 1/histone deacetylase 4/hypoxia-inducing factor 1α (SP1/HDAC4/HIF-1α) axis. Septic rats were modeled by cecal ligation puncture while in vitro septic cardiomyocyte H9C2 were induced by lipopolysaccharide (LPS). miR-124-3p/SP1/HDAC4/HIF-1α expression levels in myocardial tissues of septic rats and LPS-treated H9C2 cells were measured. miR-124-3p overexpression and SP1 silencing assays were implemented on LPS-treated H9C2 cells to explore theirs actions in inflammation, oxidative stress and cell apoptosis. The interactions of miR-124-3p, SP1, and HDAC4 were testified. miR-124-3p was lowly expressed while SP1, HDAC4, and HIF-1α were highly expressed in sepsis. Upregulation of miR-124-3p ameliorated inflammation, oxidative stress, and apoptosis of LPS-treated H9C2 cells. Silencing SP1 improved LPS-induced damage to cardiomyocytes. miR-124-3p targeted SP1 and HDAC4 interacted with SP1. SP1 overexpression antagonized miR-124-3p upregulation-induced improvements in LPS-induced cardiomyocyte damage. This study illustrates that miR-124-3p improves myocardial injury in septic rats through targeted regulation of SP1 to mediate HDAC4/HIF-1α.

Harmine Alleviated Sepsis-Induced Cardiac Dysfunction by Modulating Macrophage Polarization via the STAT/MAPK/NF-κB Pathway.

Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which is termed sepsis-induced cardiomyopathy (SIC). Harmine, a natural β-carboline alkaloid compound, has been shown to exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, the expression of the M1 phenotype markers iNOS and COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect was reversed by the harmine intervention. Furthermore, LPS-induced increases in the levels of inflammatory cytokines, including IL-1β, IL-6, TNF-α, iNOS, COX-2, PGE2 and TXB2, generated by macrophages were suppressed when the cells were pretreated with harmine. Meanwhile, our findings showed that harmine administration effectively attenuated inflammation and apoptosis in H9c2 cells in the proinflammatory environment produced by macrophages, as evidenced by reductions in NLRP3 and cleaved caspase 3 levels and the p-NF-κB/NF-κB ratio. The western blot results indicated that the mechanisms underlying harmine-mediated inhibition of M1 polarization might be associated with suppression of STAT1/3, NF-κB and MAPK activation. Furthermore, an LPS injection induced cardiac dysfunction and decreased the survival rate of mice, which were alleviated by harmine treatment, and the relevant mechanism was possibly attributed to a drug-induced attenuation of the inflammatory and apoptotic processes in cardiomyocytes. Collectively, these results implied that harmine treatment protected against SIC by suppressing M1 phenotypic polarization and inflammation in macrophages.

Sulfur Dioxide: Endogenous Generation, Biological Effects, Detection, and Therapeutic Potential.

Significance: Previously, sulfur dioxide (SO2) was recognized as an air pollutant. However, it is found to be endogenously produced in mammalian tissues. As a new gasotransmitter, SO2 is involved in regulating the structure and function of blood vessels, heart, lung, gastrointestinal tract, nervous system, etc.Recent Advances: Increasing evidence showed that endogenous SO2 regulates cardiovascular physiological processes, such as blood pressure control, vasodilation, maintenance of the normal vascular structure, and cardiac negative inotropy. Under pathological conditions including hypertension, atherosclerosis, vascular calcification, aging endothelial dysfunction, myocardial injury, myocardial hypertrophy, diabetic myocardial fibrosis, sepsis-induced cardiac dysfunction, pulmonary hypertension, acute lung injury, colitis, epilepsy-related brain injury, depression and anxiety, and addictive drug reward memory consolidation, endogenous SO2 protects against the pathological changes via different molecular mechanisms and the disturbed SO2/aspartate aminotransferase pathway is likely involved in the mechanisms for the earlier mentioned pathologic processes. Critical Issues: A comprehensive understanding of the biological effects of endogenous SO2 is extremely important for the development of novel SO2 therapy. In this review, we summarized the biological effects, mechanism of action, SO2 detection methods, and its related prodrugs. Future Directions: Further studies should be conducted to understand the effects of endogenous SO2 in various physiological and pathophysiological processes and clarify its underlying mechanisms. More efficient and accurate SO2 detection methods, as well as specific and effective SO2-releasing systems should be designed for the treatment and prevention of clinical related diseases. The translation from SO2 basic medical research to its clinical application is also worthy of further study. Antioxid. Redox Signal. 36, 256-274.

RETRACTED ARTICLE: Yin Yang 1 (YY1)-induced long intergenic non-protein coding RNA 472 (LINC00472) aggravates sepsis-associated cardiac dysfunction via the micro-RNA-335-3p (miR-335-3p)/Monoamine oxidase A (MAOA) cascade

Statement of Retraction Guixi Mo, Jian Mo, Xiujuan Tan, Jingjing Wang, Zhenyi Yan & Yijun Liu (2022) Yin Yang 1 (YY1)-induced long intergenic non-protein coding RNA 472 (LINC00472) aggravates sepsis-associated cardiac dysfunction via the micro-RNA-335-3p (miR-335-3p)/Monoamine oxidase A (MAOA) cascade, Bioengineered, 13:1, 1049-1061, DOI: 10.1080/21655979.2021.2017589 Since publication, significant concerns have been raised about the integrity of the data and reported results in the article. When approached for an explanation, the authors did not provide their original data or any necessary supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. All authors listed in this publication have been informed. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Cardiac Metabolism in Sepsis

The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of ATP, essential for myocardial energy metabolism, resulting in cardiac dysfunction. This review focuses on the metabolic changes in sepsis, particularly in the heart. In addition to managing inflammation, interventions focusing on metabolism may be a new therapeutic strategy for cardiac dysfunction due to sepsis.

Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3β signaling pathway.

Ginsenoside-Rg1 (G-Rg1), a saponin that is a primary component of ginseng, is effective against inflammatory diseases. The P2X purinoceptor 7 (P2X7) receptor is an ATP-gated ion channel that is predominantly expressed in immune cells and plays a key role in inflammatory processes. We investigated the role of G-Rg1 in sepsis-related cardiac dysfunction and the underlying mechanism involving the regulation of the P2X7 receptor. We detected cell viability, cytotoxicity, cellular reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP) with or without G-Rg1 in lipopolysaccharide (LPS)- or hypoxia/reoxygenation (H/R)-induced H9c2 cell models of ischemia/reperfusion injury. We applied cecal ligation and puncture (CLP) to induce a mouse model of sepsis and measured the survival duration and cardiac function of CLP mice. Next, we quantified the ROS level, MMP, respiratory chain complex I-IV enzymatic activity, and mitochondrial fusion in CLP mouse heart tissues. We then investigated the role of G-Rg1 in repairing LPS-induced cell mitochondrial damage, including mitochondrial superoxidation products. The results showed that G-Rg1 inhibited LPS- or H/R-induced cardiomyocyte apoptosis, cytotoxicity, ROS levels, and mitochondrial damage. In addition, G-Rg1 prolonged the survival time of CLP mice. G-Rg1 attenuated LPS-induced superoxide production in the mitochondria of cardiomyocytes and the excessive release of cytochrome c from mitochondria into the cytoplasm. Most importantly, G-Rg1 suppressed LPS-mediated induction of proapoptotic Bax, activated Akt, induced GSK-3β phosphorylation, and balanced mitochondrial calcium levels. Overall, G-Rg1 activates the Akt/GSK-3β pathway through P2X7 receptors to inhibit sepsis-induced cardiac dysfunction and mitochondrial dysfunction.

Ferrostatin-1 alleviates lipopolysaccharide-induced cardiac dysfunction

ABSTRACT Cardiac dysfunction is a common complication of sepsis, and is attributed to severe inflammatory responses. Ferroptosis is reported to be involved in sepsis-induced cardiac inflammation. Therefore, we speculated that ferrostatin-1 (Fer-1), a ferroptosis inhibitor, improves cardiac dysfunction caused by sepsis. An intraperitoneal injection of lipopolysaccharide (LPS) was performed to induce a rat cardiac dysfunction model. Echocardiography, cardiac histopathology, biochemical and western blot results were analyzed. Twelve hours after the LPS injection, LPS-treated rats exhibited deteriorating cardiac systolic function, increased levels of cardiac injury markers and levels of ferroptosis markers prostaglandin endoperoxide synthase 2 (PTGS2). Additionally, LPS increased iron deposition in the myocardium, with downregulating ferroportin (FPN, SLC40A1) and transferrin receptor (TfR)expression, and upregulating ferritin light chain (FTL) and ferritin heavy chain (FTH1) expression. Meanwhile, LPS also increased lipid peroxidation in the rat heart by decreasing the expression of glutathione peroxidase 4 (GPX4). Moreover, the expression of inflammatory cytokines, such as tumor necrosis-alpha (TNF-α), interleukin-1 (IL-1β), and interleukin-6 (IL-6), and inflammatory cell infiltration were also increased following LPS challenge. Finally, the abovementioned adverse effects of LPS were relieved by Fer-1 except for TfR expression. Mechanistically, Fer-1 significantly reduced the levels of toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (NF-κB), and phospho-inhibitor of kappa Bα (IκBα) in LPS-treated rats. In summary, these findings imply that Fer-1 improved sepsis-induced cardiac dysfunction at least partially via the TLR4/NF-κB signaling pathway.

Syringaresinol attenuates sepsis-induced cardiac dysfunction by inhibiting inflammation and pyroptosis in mice

The mortality of sepsis-induced cardiac dysfunction (SICD) is very high due to the complex pathophysiological mechanism. Syringaresinol (SYR) is a natural abstract which possesses anti-inflammatory property. The present study aims was to identify the protective impact of SYR on sepsis-induced cardiac dysfunction and investigate the specific mechanisms. We found that SYR improved the cardiac function and alleviated myocardial injury in mice that subjected to cecal ligation and puncture, in addition, SIRT1 expression was significantly elevated after SYR treatment compared to sepsis group both in vivo and in vitro, along with suppression of NLRP3 activation and proinflammatory cytokines release. However, SIRT1 inhibitor EX427 abolished the impact of SYR on LPS-induced pyroptosis in cardiomyocytes. Furthermore, molecular docking analysis predicted that there is high affinity between SYR and estrogen receptor (ER), ER inhibitor ICI182780, the specific ERβ inhibitor PHTP and the specific ERαinhibitor AZD9496 were used to examine the role of ER in the protective effect of SYR against SICD, and the results suggested that ER activation was essential for the cardioprotective function of SYR. In conclusion, SYR ameliorates SICD via the ER/SIRT1/NLRP3/GSDMD pathway.

Abstract 12470: miR-187 Mimic Targets Pro-Inflammatory Cytokynes in Cardiomyocytes Treated With Bacterial Endotoxin

Introduction: 1 in 18 Canadians dies from sepsis, a life-threatening dysfunction caused by a dysregulated host response to infection which can lead to sepsis-induced Cardiac dysfunction. In the past, we have shown that administration of mesenchymal stem cells (MSCs) in the cecal ligation and puncture (CLP) model of polybacterial sepsis leads to the mitigation of sepsis-induced cardiac dysfunction by modulating microRNAs in the septic heart. Differential expression of miRNAs alters mRNA expression profile leading to a change in cellular response. In our CLP model, we identified miR-187 as a host-derived MSC-regulated miRNA. Hypothesis: Here we investigate the broader immunoregulatory of miR-187. Therefore, we tested the hypothesis that miRNA-187 inversely regulates sepsis-induced cardiac dysfunction by attenuating pro-inflammatory gene expression. Methods: Primary cardiomyocytes were isolated from 1-2 days old CD1 neonates. Cultured cells were transfected with miR-187 mimic (25 nM/mL) for 24 hours. Transfected cells were then subsequentially exposed to lipopolysaccharide (LPS, 1 μg/mL) for an additional 24 hours post-transfection. We chose to measure the expression of pro and anti-inflammatory cytokines and some cardiac injury markers via Real-Time Polymerase Chain Reaction (RT-qPCR). Results: Cardiomyocytes treated with bacterial LPS showed a significant decline in expression of miR-187 (n=4, p<0.05) and a significant surge (n=4, p<0.05) in the expression of pro-inflammatory cytokines such as IL-1β, IL-6, TNFα and IL-12 in comparison to untreated cells. Conversely, LPS-stimulated cardiomyocytes transfected with exogenous miR-187 mimic versus non-transfected LPS-stimulated cardiomyocytes demonstrated reduced expression of IL-1β, IL-6, and IL-12 (n=3, p<0.05) and Fasl, S100A4 and S100A9 (n=3, p<0.05). Conclusions: Transfecting neonatal cardiomyocytes with mimic miR-187 in the presence of LPS decreases the production of key inflammatory genes involved in sepsis-induced cardiac dysfunction. Our findings show miR-187 to be a potential therapeutic target to improve cardiac function in a pre-clinical model of sepsis by reducing pro-inflammatory cytokine expression.

Abstract 14038: Deficiency of Arachidonate 5-Lipoxygenase Intensifies Sepsis-Induced Cardiac Dysfunction in Aging

Introduction: Age-related cardiac dysfunction is a prime component of sepsis-induced multi-organ failure in the clinical setting. Arachidonate 5-lipoxygenase (5LOX) pathway and 5LOX-derived lipid mediators are critical in early inflammation and immune response signaling. In addition, 5LOX derived mediators activate macrophages and other cells to counter infection via surface receptors. However, the role of 5LOX in sepsis-induced cardiac dysfunction superimposed on aging is still under-investigated. Hypothesis: Given that the inflammatory role of 5LOX, we tested the hypothesis that deletion of 5LOX in aging would be deleterious to cardiac function in sepsis. Methods: To induce sepsis, lipopolysaccharide (LPS; E. coli O55:B5) was injected into aging male C57BL/6J (WT) and 5LOX -/- mice (18-20 months). To study heart function, molecular, and cellular mechanisms, mice were challenged with a single subcutaneous dose of LPS (20mg/kg) for 4 hours. Survival was monitored for 7 days post-LPS challenge to testify therapeutic application of outcome. Results: Lack of 5LOX increased mortality (~70%) in aging mice with severe depression in cardiac function post-LPS compared with age-matched WT controls. LPS challenge in 5LOX -/- aging mice decreased resolution mediators (RvD1) and inflammation mediators (LTB 4 ) in the spleen with robust recruitment of leukocytes in a spleno-cardiac manner indicative of non-resolving inflammation. The spleen monocytes (CD11b + ), macrophages (F4/80 + ), and neutrophils (Ly6G + ) were significantly decreased in 5LOX -/- mice post-LPS with the consistent increase in the heart. The absence of 5LOX blunted physiological inflammatory response in aging by attenuating TLR4 and CD169 in both the heart and spleen as a sign of immunosuppression. Conclusion: Our results suggest that 5LOX -/- aging mice fail to initiate physiological inflammation-resolution signaling in response to LPS-induced septic shock, leading to cardiac dysfunction and immunosuppression. Our study highlights the role of 5LOX and 5LOX-derived mediators as targets for the inflammation-resolution response and therapeutics potential in aging-related sepsis.

Assessment of Sepsis in the ICU by Linear and Complex Characterization of Cardiovascular Dynamics.

Sepsis is one of the pathological conditions with the highest incidence in intensive care units. Sepsis-induced cardiac and autonomic dysfunction are well-known effects, among others, caused by a dysregulated host response to infection. In this context, we investigate the role of complex cardiovascular dynamics quantified through sample entropy indices from the inter-beat interval, systolic and diastolic blood pressure time series as well as the cross-entropy between heartbeat and systolic blood pressure in patients with sepsis in the first hour of intensive care when compared with non-septic subjects. Results show a significant (p<0.05) reduction in the probability of being septic for a unitary increase in entropy for systolic and diastolic time series (odds equal to 0.038 and 0.264, respectively) when adjusting for confounding factors. A significant (p<0.001) odds ratio (0.248) is observed also in cross-entropy, showing a reduced probability of being septic for an increase in heartbeat and systolic pressure asynchrony. The inclusion of our measures of complexity also determines an increase in the predictive ability (+0.03) of a logistic regression model reaching an area under the receiving operating and precision recall curves both equal to 0.95.Clinical relevance The study demonstrates the ability of information theory in catching a reduction of complex cardiovascular dynamics from vital signs commonly recorded in ICU. The considered complexity measures contribute to characterize sepsis development by showing a general loss of the interaction between heartbeat and pressure regulation. The extracted measures also improve the ability to identify sepsis in the first hour of intensive care.

Levosimendan versus dobutamine for sepsis-induced cardiac dysfunction: a systematic review and meta-analysis

Levosimendan and dobutamine are extensively used to treat sepsis-associated cardiovascular failure in ICU. Nevertheless, the role and mechanism of levosimendan in patients with sepsis-induced cardiomyopathy remains unclear. Moreover, previous studies on whether levosimendan is superior to dobutamine are still controversial. More importantly, these studies did not take changes (before-after comparison to the baseline) in quantitative parameters such as ejection fraction into account with the baseline level. Here, we aimed to determine the pros and cons of the two medicines by assessing the changes in cardiac function and blood lactate, mortality, with the standardized mean difference used as a summary statistic. Relevant studies were obtained by a thorough and disciplined literature search in several notable academic databases, including Google Scholar, PubMed, Cochrane Library and Embase until November 2020. Outcomes included changes in cardiac function, lactic acid, mortality and length of hospital stay. A total of 6 randomized controlled trials were included in this study, including 192 patients. Compared with dobutamine, patients treated with levosimendan had a greater improvement of cardiac index (ΔCI) (random effects, SMD = 0.90 [0.20,1.60]; I2 = 76%, P < 0.01) and left ventricular stroke work index (ΔLVSWI) (random effects, SMD = 1.56 [0.90,2.21]; I2 = 65%, P = 0.04), a significant decrease of blood lactate (Δblood lactate) (random effects, MD = − 0.79 [− 1.33, − 0.25]; I2 = 68%, P < 0.01) at 24-h after drug intervention, respectively. There was no significant difference between levosimendan and dobutamine on all-cause mortality in ICU (fixed effect, OR = 0.72 [0.39,1.33]; I2 = 0%, P = 0.99). We combine effect sizes related to different measurement parameters to evaluate cardiac function, which implied that septic patients with myocardial dysfunction might have a better improvement of cardiac function by levosimendan than dobutamine (random effects, SMD = 1.05 [0.69,1.41]; I2 = 67%, P < 0.01). This study suggested a significant improvement of CI, LVSWI, and decrease of blood lactate in septic patients with myocardial dysfunction in ICU after 24-h administration of levosimendan than dobutamine. However, the administration of levosimendan has neither an impact on mortality nor LVEF. Septic patients with myocardial dysfunction may partly benefit from levosimendan than dobutamine, mainly embodied in cardiac function improvement.

Circadian disruption on the susceptibility to sepsis-induced cardiac dysfunction: a prospective multi-modal imaging study

Abstract Background Sepsis is a significant cause of mortality, and cardiac dysfunction is one of the vital predictors for mortality of sepsis. However, the factors associated with the susceptibility to sepsis-induced cardiac dysfunction remain unclear. Disruption of circadian rhythms can profoundly influence cardiac health; however, to the knowledge of the authors, the relationship of circadian disruption to cardiac involvement in patients with sepsis is unknown. Purpose We aim to investigate the impact of circadian disruption on the susceptibility to sepsis-induced cardiac dysfunction. Methods Study patient data were obtained from the image database of EARLY-MYO-SEPSIS (EARLY assessment of MYOcardial tissue characteristics by multi-modal imaging in SEPSIS) registry, which was a prospective, multi-center registry of sepsis patients who have undergone cardiac magnetic resonance imaging (MRI) and echocardiography from 8 sites (clinical trial number NCT04513795). Cardiac involvement was evaluated using a comprehensive assessment comprising of echocardiography (with global longitudinal strain calculation), cardiac MRI and cardiac biomarker evaluation. Logistic regression was performed to identify independent predictors of left ventricular systolic dysfunction in sepsis. Results A total of 216 intensive care unit patients with sepsis was enrolled in the present analysis. Septic patients with a history of circadian disruption (i.e., sleep insufficiency &amp;lt;6 hours) presented more cardiac involvements (as indicated by edema on the cardiac MRI along with cardiac deformation and increased cardiac biomarkers) compared with those without circadian disruption history. Moreover, septic patients with a history of circadian disruption had increased mortality and incidence of heart failure. A history of circadian disruption was identified as an independent predictor of left ventricular systolic dysfunction in sepsis. Conclusions Our data from EARLY-MYO-SEPSIS registry demonstrated a previously unappreciated circadian sensitivity to sepsis-induced cardiac dysfunction. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by grants from the National Science Fund for Distinguished Young Scholars (81625002) and National Natural Science Foundation of China (81930007)

Ganoderma lucidum polysaccharides protect against sepsis-induced cardiac dysfunction by activating SIRT1.

To investigate whether the silent information regulator 1 (SIRT1) was involved in the protective effects of Ganoderma lucidum polysaccharides (GLP) against sepsis-induced cardiac dysfunction. Lipopolysaccharide (LPS)-induced sepsis model was constructed in C57/BL6J mice. Mice were randomly divided into LPS + GLP + EX-527, LPS + EX-527, LPS + GLP, LPS or control group). The levels of serum inflammatory factor markers were examined by ELISA. H&E staining was performed to assess the inflammation. TUNEL staining and bromodeoxyuridine staining were used to observe cell apoptosis and proliferation, respectively. Expression of apoptosis and proliferation-related proteins was detected by western blot. GLP treatment could significantly increase the expression of SIRT1, reduce levels of serum inflammatory factors (TNF-α, IL-1α and IL-6) and inflammatory cells in mice heart tissue of sepsis models (all Ps < 0.01). Compared with LPS group, GLP treatment inhibited apoptosis and promoted proliferation of myocardial tissues (all Ps < 0.01). Besides, EX-527 (SIRT1 inhibitor) treatment could partially reverse the protective effects of GLP against sepsis-induced cardiac dysfunction (all Ps < 0.01). GLP might play a protective role in sepsis-induced cardiac dysfunction through regulating inflammatory response, apoptosis and proliferation via activating SIRT1. Therefore, GLP is expected to be a probable novel strategy for treatment of sepsis.