Inflammation and oxidative damage play critical roles in the pathogenesis of sepsis-induced cardiac dysfunction. Multiple EGF-like domains 9 (MEGF9) is essential for cell homeostasis; however, its role and mechanism in sepsis-induced cardiac injury and impairment remain unclear.

Adenoviral and adeno-associated viral vectors were applied to overexpress or knock down the expression of MEGF9 in vivo and in vitro. To stimulate septic injury, cardiomyocytes and mice were treated lipopolysaccharide (LPS). To clarify the necessity of AMP-activated protein kinase (AMPK), global AMPK knockout mice were used.

We found that MEGF9 expressions were reduced in cardiomyocytes and mice by LPS stimulation. Compared with negative controls, plasma MEGF9 levels were also decreased in septic patients, and negatively correlated with LPS-induced cardiac dysfunction. In addition, MEGF9 overexpression attenuated, while MEGF9 knockdown aggravated LPS-induced inflammation and oxidative damage in vivo and in vitro, thereby regulating LPS-induced cardiac injury and impairment. Mechanistic studies revealed that MEGF9 overexpression alleviated LPS-induced cardiac dysfunction through activating AMPK pathway.

We for the first time demonstrate that MEGF9 prevents LPS-related inflammation, oxidative damage and cardiac injury through activating AMPK pathway, and provide a proof-of-concept for the treatment of LPS-induced cardiac dysfunction by targeting MEGF9.

This article describes how takotsubo syndrome was misdiagnosed as other diagnoses prior to its being named in 1990.

Given our present understanding of the clinical, echocardiographic, and angiographic features of takotsubo, the modern literature from about 1970 to the present was reviewed to find other cardiac conditions consistent with the takotsubo diagnosis. Nine conditions were recognized, including 6 that have been previously reported. These include some patients with either STEMI, NSTEMI, MINOCA, cerebral T-waves, sepsis-related LV dysfunction, or stress-related cardiomyopathy. Three other conditions have not previous been reported and include some patients with either non-obstructive or angiographically normal coronary arteries following IV thrombolytic therapy, myocarditis mimicking acute myocardial infarction, or myocardial stunning.

Takotsubo syndrome has been a great pretender, mimicking or misdiagnosed as several other cardiac conditions. Some of these conditions have been previously reported, while others are newly described. It is intriguing to speculate what signs or symptoms of a present-day illness/ailment may, in the future, represent other conditions currently unclassified or misdiagnosed.

Septic myocardial injury, a severe sepsis complication linked to high morbidity and mortality, remains a major global clinical challenge. Interleukin-33 (IL-33), a damage-associated pro-inflammatory factor, has been implicated in regulating immune responses and inflammation, but its specific role in septic myocardial injury has not been fully elucidated. This study examined IL-33's role in septic myocardial injury using Gene Expression Omnibus (GEO) database datasets, alongside in vitro and in vivo experiments. Our results indicated a significant upregulation of IL-33 in septic myocardial injury, as demonstrated in both clinical and experimental settings. Blocking IL-33 significantly enhanced cardiac function and alleviated cardiomyocyte damage. Mechanistic investigations revealed that neutralizing IL-33 mitigates inflammation, oxidative stress, and apoptosis in cardiomyocytes by regulating the nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 3 (STAT3)/suppressors of cytokine signaling 3 (SOCS3) signaling pathway. Peritoneal macrophages are recognized as a potential origin of IL-33, and targeting IL-33 derived from these cells further reduced cardiomyocyte injury. The study underscores IL-33's crucial involvement in septic myocardial injury pathogenesis, indicating that IL-33 may serve as a promising therapeutic target.

Endotoxemic shock is a severe complication characterized by multiple organ failure, hypotension, and impaired tissue perfusion, all contributing to high morbidity and mortality. Recent studies have highlighted the anti-inflammatory and antioxidant properties of tomentosin. This study investigates the protective effects of tomentosin against lipopolysaccharide (LPS)-induced cardiac injury and elucidates its underlying mechanisms. Mice were pre-treated with tomentosin before the LPS administration. Subsequently, cardiac injury markers, oxidative stress parameters, inflammatory mediators, and Nrf-2/NF-κB protein expression levels were analysed. The results demonstrated that tomentosin significantly reduced Troponin and CK-MB levels, alleviated oxidative stress, and suppressed inflammatory responses. Furthermore, tomentosin inhibited NF-κB activation while enhancing Nrf-2 expression. In conclusion, our findings suggest that tomentosin exerts cardioprotective effects by modulating the Nrf-2/NF-κB pathway, positioning it as a potential therapeutic candidate for preventing LPS-induced cardiac dysfunction.

Lipopolysaccharide (LPS), a bacterial endotoxin prevalent in Gram-negative pathogens (e.g., Escherichia coli), induces severe immune responses linked to endotoxemia and hepatitis. Despite its clinical significance, conventional LPS detection methods (e.g., limulus amebocyte lysate assays) face challenges including operational complexity, high cost, and limited sensitivity. Addressing these limitations necessitates the development of innovative strategies for ultrasensitive LPS quantification.

We present an electrochemical biosensor integrating dual-signal amplification: (1) affinity amplification via phenylboronic acid-cis-diol covalent binding on LPS polysaccharide chains, and (2) photocatalytic amplification using perylene diimide (PDI)-mediated atom transfer radical polymerization (Photo-ATRP) under red light (615-650 nm). Thiol-functionalized DNA aptamers enable specific LPS capture, while PDI catalyzes rapid ferrocene monomer polymerization, achieving exponential signal enhancement. The sensor demonstrates exceptional performance: (1) Ultrahigh sensitivity: Detection limit of 0.25 fg/mL. (2) Wide dynamic range: Linear response from 1.0 fg/mL to 0.1 pg/mL. (3) Robust specificity: Minimal interference in human serum matrices.

This work establishes a paradigm for LPS detection through three key advances: (1) Operational simplicity: Eliminates enzymatic/nanomaterial dependencies via metal-free PDI photocatalysis. (2) Translational utility: Serum compatibility supports clinical diagnostics and point-of-care applications. (3) Catalytic innovation: Validates PDI as a high-efficiency photocatalyst for controlled polymer synthesis. The sensor's low-cost fabrication, rapid response (<4.5 h), and femtomolar sensitivity position it as a transformative tool for sepsis monitoring and biomedical research.

Sepsis, a medical emergency with high mortality rates, demands comprehensive care spanning from early identification to patient rehabilitation. The sepsis survival chain encompasses early recognition, severity assessment, activation of emergency services, initial antimicrobial therapy, hemodynamic stabilization, and integrated rehabilitation. These interconnected steps are critical to reducing morbidity and mortality. Despite advancements in international guidelines, adherence remains limited, contributing to a significant disease burden. Beyond its acute phase, post-sepsis syndrome (PSS) is characterized by long-term immune dysregulation, chronic inflammation, and metabolic dysfunction, predisposing survivors to recurrent infections, cardiovascular disease, and neurocognitive decline. Mitochondrial dysfunction and epigenetic modifications play a central role in prolonged immunosuppression, impairing adaptive and innate immune responses. Sepsis-induced organ dysfunction impacts multiple systems, including the brain, heart, and kidneys. In the brain, it is associated with neuroinflammation, blood-brain barrier dysfunction, and the accumulation of neurotoxic proteins, leading to acute and chronic cognitive impairment. Myocardial dysfunction involves inflammatory mediators such as TNF-α and IL-6, while sepsis-associated acute kidney injury (SA-AKI) arises from hypoperfusion and inflammation, heightening the risk of progression to chronic kidney disease. Additionally, immune alterations such as neutrophil dysfunction, continuous platelet activation, and suppressed antitumoral responses contribute to increased infection risk and long-term complications. Timely and targeted interventions, including antimicrobial therapy, cytokine modulation, immune restoration, metabolic support, and structured rehabilitation strategies, are pivotal for improving outcomes. However, financial and infrastructural limitations in low-resource settings pose significant barriers to effective sepsis management. Precision medicine, AI-driven early warning systems, and optimized referral networks can enhance early detection and personalized treatments. Promoting public and professional awareness of sepsis, strengthening multidisciplinary post-sepsis care, and integrating long-term follow-up programs are imperative priorities for reducing mortality and improving the quality of life in sepsis survivors.

We investigated inflammation-induced changes in femoral hematopoietic bone marrow using advanced magnetic resonance imaging (MRI) techniques, including T2-weighted imaging, scalar T2 mapping, and machine learning-enhanced T2 distribution analysis to improve the detection of bone marrow microstructural alterations. Findings were correlated with histological markers and systemic inflammation.

Using a 9.4-T magnet, T2-weighted and multislice multiecho sequences were applied to evaluate bone marrow in female C57BL/6J mice divided into three groups: (1) controls; (2) lipopolysaccharide-induced acute inflammation (LPS); and (3) streptozotocin (STZ)- and LPS-induced diabetic inflammation (STZ + LPS). T2 relaxation times and their distributions with scalar mapping and model-informed machine learning (MIML) were analyzed. Correlations with histological iron levels and blood neutrophil counts were assessed.

T2-weighted imaging showed a reduced signal-to-noise ratio in inflamed bone marrow (p = 0.034). Scalar T2 mapping identified decreased T2 relaxation times (p = 0.042), moderately correlating with neutrophil counts (ρ = 0.027) and iron levels (ρ = 0.016). MIML-enhanced T2 distribution analysis exhibited superior sensitivity than scalar T2 mapping, revealing significant reductions in the first T2 distribution peak (p = 0.0025), which strongly correlated with neutrophil counts (ρ = 0.0016) and iron sequestration (ρ = 0.0002). Histology confirmed elevated iron deposits in inflamed marrow, aligning with systemic inflammation.

Combining T2-weighted imaging, scalar T2 mapping, and MIML-enhanced T2 distribution analysis offers complementary insights into inflammation-induced bone marrow remodeling. T2 distribution analysis emerged as a more sensitive tool for detecting microstructural changes, such as iron sequestration, supporting its potential as a noninvasive biomarker for diagnosing and monitoring inflammatory diseases.

This study highlights the potential of advanced MRI T2 analysis and machine learning methods for noninvasive detection of inflammation-induced microstructural changes in bone marrow, offering promising diagnostic tools for inflammatory diseases.

This study investigated inflammation-induced changes in bone marrow with T2 MRI and MIML. MIML outperformed quantitative scalar T2 analysis, increasingly detecting inflammation and iron sequestration in the hematopoietic bone marrow. T2 MRI with MIML analysis could aid in the early diagnosis and management of inflammatory diseases.

Septic cardiac dysfunction (SCD) is the most common complication of sepsis, which has become the primary cause of death in intensive care units. The muscle-specific protein mitsugumin-53 (MG53) has been identified to protect cell integrity as a "Molecular Band-Aid".

The recombinant human MG53 (rhMG53) pretreatment has been reported to prevent cardiac function damage caused by cecal ligation and puncture (CLP). However, whether or not MG53 protects against SCD remains to be further clarified.

C57BL/6J mice were intraperitoneally injected with lipopolysaccharide (LPS) to generate the SCD model. MG53 was overexpressed by intravenously injected adeno-associated virus, and the rhMG53 was administrated intraperitoneally. The cardiac function was evaluated by echocardiography, and the cardiac inflammation was assessed through ELISA and Western blot. The mechanisms of MG53 were studied by quantitative real-time PCR (qPCR) and co-immunoprecipitation (co-IP).

Our present study found that MG53 expression was lower in hearts from SCD mice than controls. Overexpression or exogenous MG53 treatment alleviated cardiac dysfunction, improved survival rate in SCD mice, accompanied with improved pathological changes, reduced cardiomyocyte apoptosis, and lowered inflammatory factor levels in serum or hearts. Mechanistically, MG53 inhibited TLR4 transcriptional activity by ubiquitinating ATF2, an essential transcriptional factor for TLR4, which ultimately reduced the expression of TLR4.

MG53 protect the cardiac function against sepsis by down-regulation of TLR4 expression, via ubiquitination of ATF2, a TLR4 transcriptional factor, which might be a promising therapeutic approach for septic cardiac dysfunction.

Sepsis, a life-threatening condition arising from an uncontrolled immune response to infection, can lead to organ dysfunction, with severe inflammation potentially causing multiple organ failures. Sepsis-induced cardiac dysfunction (SIMD) is a common and severe complication of sepsis, significantly increasing patient mortality. Understanding the pathogenesis of SIMD is crucial for improving treatment, and microRNAs (miRNAs) have emerged as important regulators in this process.

A comprehensive literature search was conducted in PubMed, Science Direct, and Embase databases up to September 2024. The search terms included ["miRNA" or "microRNA"] and ["Cardiac" or "Heart"] and ["Sepsis" or "Septic"], with the language limited to English. After initial filtering by the database search engine, Excel software was used to further screen references. Duplicate articles, those without abstracts or full texts, and review/meta-analyses or non-English articles were excluded. Finally, 106 relevant research articles were included for data extraction and analysis.

The pathogenesis of SIMD is complex and involves mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis and pyroptosis, dysregulation of myocardial calcium homeostasis, myocardial inhibitory factors, autonomic nervous regulation disorders, hemodynamic changes, and myocardial structural alterations. miRNAs play diverse roles in SIMD. They are involved in regulating the above-mentioned pathological processes.

Although significant progress has been made in understanding the role of miRNAs in SIMD, there are still challenges. Some studies on the pathogenesis of SIMD have limitations such as small sample sizes and failure to account for confounding factors. Research on miRNAs also faces issues like inconsistent measurement techniques and unclear miRNA-target gene relationships. Moreover, the translation of miRNA-based research into clinical applications is hindered by problems related to miRNA stability, delivery mechanisms, off-target effects, and long-term safety. In conclusion, miRNAs play a significant role in the pathogenesis of SIMD and have potential as diagnostic biomarkers. Further research is needed to overcome existing challenges and fully exploit the potential of miRNAs in the diagnosis and treatment of SIMD.

Sepsis is a life-threatening form of organ dysfunction resulting from a dysregulated response to infection. The complex pathogenesis of sepsis poses challenges because of the lack of reliable biomarkers for early identification and effective treatments. As sepsis progresses to severe forms, cardiac dysfunction becomes a major concern, often manifesting as ventricular dilation, a reduced ejection fraction, and a diminished contractile capacity, known as sepsis-induced cardiomyopathy (SIC). The absence of standardized diagnostic and treatment protocols for SIC leads to varied criteria being used across medical institutions and studies, resulting in significant outcome disparities. Despite the high prevalence of SIC, accurate statistical data are lacking. To understand how SIC affects sepsis prognosis, a thorough exploration of its pathophysiological mechanisms, including systemic factors and complex signalling within myocardial and immune cells, is required. Identifying the factors influencing SIC occurrence and progression is crucial and must be conducted within specific clinical contexts. In this review, the clinical manifestations, pathophysiological mechanisms, and treatment strategies for SIC are discussed, along with the clinical background. We aim to connect current practices with future research challenges, providing clear guidance for clinicians and researchers.

Atrial fibrillation (AF) is a common arrhythmia in critically ill patients. The objective of this narrative review is to evaluate the characteristics of patients who develop new-onset atrial fibrillation (NOAF) because of sepsis, current management of NOAF in sepsis patients, special consideration in different populations that developed NOAF, health economic and quality of life of patients. We conducted a literature search on PubMed to find research related to NOAF, sepsis and critical illness. Nineteen studies were analyzed for risk factors and outcomes. The incidence rate ranges from 0.53% to 43.9% among these studies. There were numerous risk factors that had been reported from these articles. The most reported risk factors included advanced age, male sex, White race, and cardiovascular comorbidities. The management of septic patients is significantly challenging because of the unfavorable cardiovascular consequences and thromboembolic hazards associated with NOAF. There are comprehensive guidelines available for managing AF, but the effectiveness and safety of therapies in patients with sepsis are still uncertain. Various approaches for managing newly diagnosed AF have been explored. Sinus rhythm can be restored through either pharmacological or non-pharmacological intervention or combination of both. In addition, thromboembolism is a complication that can occur in patients with AF and can have a negative impact on the prognosis of sepsis patients. The use of anticoagulation to prevent stroke after NOAF in sepsis patients is still controversial. Extensive prospective investigations are required to have a deeper understanding of the necessity for anticoagulation following NOAF in sepsis. Beside the treatment of NOAF, early detection of NOAF in sepsis plays a critical role. The prompt initiation of rhythm control medication following a clinical diagnosis of AF can enhance cardiovascular outcomes and reduce mortality in patients with AF and cardiovascular risk factors. Additionally, NOAF in the intensive care unit can prolong hospital stays, increasing hospitalization costs and burdening the hospital. Therefore, preventing and managing NOAF effectively not only benefit the patients but also the hospital in financial aspect. Lastly, to address the existing gaps in knowledge, future research should focus on developing machine learning models that can accurately anticipate risks, establish long-term follow-up protocols, and create complete monitoring systems. The focus is on early intervention and personalized approaches to improve outcomes and quality of life.

Sepsis is a life-threatening condition resulting from pathogen infection and characterized by organ dysfunction. Programmed cell death (PCD) during sepsis has been associated with the development of multiple organ dysfunction syndrome (MODS), impacting various physiological systems including respiratory, cardiovascular, renal, neurological, hematological, hepatic, and intestinal systems. It is well-established that pathogen infections lead to immune dysregulation, which subsequently contributes to MODS in sepsis. However, recent evidence suggests that sepsis-related opportunistic pathogens can directly induce organ failure by promoting PCD in parenchymal cells of each affected organ. This study provides an overview of PCD in damaged organ and the induction of PCD in host parenchymal cells by opportunistic pathogens, proposing innovative strategies for preventing organ failure in sepsis.

Hyponatremia is one of the complicating findings in acute decompensated heart failure. Decrease in cardiac output and systemic blood pressure triggers activation of renin-angiotensin-aldosterone system, antidiuretic hormone, and norepinephrine due to the perceived hypovolemia. Fluid-overloaded heart failure patients are commonly treated with loop diuretics, acutely decompensated heart failure patients tend to be less responsive to conventional oral doses of a loop diuretic, while other different diuretics could work in different part of nephron circulation system. In this study, we aim to further examine the role of tolvaptan, a vasopressin receptor antagonist, in the treatment of hyponatremia secondary to acutely decompensated heart failure.

A total of 71 patients with hyponatremia secondary to ADHF were included, and all patients were given tolvaptan. 37 patients were administered tolvaptan early (up until 5 th day of admission). 34 patients received tolvaptan after 5 th day of admission mean administration as 6.86 th day, and median administration was 5 th day. Analysis showed lower length of stay in patients receiving early administration of tolvaptan compared to late administration (8.86 ± 5.06 vs 18.5 ± 9.05 p0.001, respectively). Patients with early initiation of tolvaptan also achieved a larger net increase in sodium levels at discharge compared to admission (6.46 ± 6.69 vs 3.68 ± 4.70 p0.048, respectively).

Early administration of tolvaptan in treating hyponatremia in acutely decompensated heart failure patients is associated with a lower length of hospitalization and a higher increase in serum sodium of patients in hyponatremic ADHF patients.

Septic cardiomyopathy (SCM) is a severe cardiac complication of sepsis, characterized by cardiac dysfunction with limited effective treatments. This study aimed to identify repurposable drugs for SCM by integrated multi-omics and network analyses.

We generated a mouse model of SCM induced by lipopolysaccharide (LPS) and then obtained comprehensive metabolic and genetic data from SCM mouse hearts using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and RNA sequencing (RNA-seq). Using network proximity analysis, we screened for FDA-approved drugs that interact with SCM-associated pathways. Additionally, we tested the cardioprotective effects of two drug candidates in the SCM mouse model and explored their mechanism-of-action in H9c2 cells.

Network analysis identified 129 drugs associated with SCM, which were refined to 14 drug candidates based on strong network predictions, proven anti-infective effects, suitability for ICU use, and minimal side effects. Among them, acetaminophen and pyridoxal phosphate significantly improved cardiac function in SCM moues, as demonstrated by the increased ejection fraction (EF) and fractional shortening (FS), and the reduced levels of cardiac injury biomarkers: B-type natriuretic peptide (BNP) and cardiac troponin I (cTn-I). In vitro assays revealed that acetaminophen inhibited prostaglandin synthesis, reducing inflammation, while pyridoxal phosphate restored amino acid balance, supporting cellular function. These findings suggest that both drugs possess protective effects against SCM.

This study provides a robust platform for drug repurposing in SCM, identifying acetaminophen and pyridoxal phosphate as promising candidates for clinical translation, with the potential to improve treatment outcomes in septic patients with cardiac complications.

Cancer patients who are exposed to sepsis and had previous chemotherapy may have increased severity. Among chemotherapeutic agents, anthracyclines have been associated with cardiac toxicity. Like other chemotherapeutic agents, they may cause endothelial toxicity. The aim of this study was to evaluate the effect of anthracycline treatment on the outcome of cancer patients with sepsis.

Data from cancer patients admitted to intensive care units (ICUs) for sepsis or septic shock were extracted from the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique database (1994-2015). Comparison between patients who received anthracycline and those who did not was performed using a propensity score, including confounding variables (age and underlying diseases). A competing risk adjusted for severity of illness (Sequential Organ Failure Assessment [SOFA] score) was used to analyze the duration of vasopressor requirement.

Among 2046 patients, 1070 (52.3%) patients who received anthracycline were compared with 976 (47.7%) who did not. The underlying disease was mostly acute hematological malignancy (49.2%). Sepsis, mostly pneumonia (47.7%), had developed 2 days (interquartile range [IQR]:1-4 days) prior to ICU admission. Most patients (n=1156/1980,58.4%) required vasopressors for 3 days (IQR: 2-6 days). Factors associated with the need for vasopressors were aplasia (hazard ratio [HR]=1.72, 95% confidence interval [CI]: 1.21 to 2.47, P=0.002) and day 1 respiratory SOFA score (HR=7.07, 95% CI: 2.75 to 22.1, P <0.001). Previous anthracycline treatment was not associated with an increased risk of vasopressor use. The duration of vasopressors was not different between patients who received anthracycline and those who did not (P=0.79). Anthracycline was not associated with ICU mortality.

Previous anthracycline treatment did not alter the course of sepsis in a cohort of cancer patients admitted to intensive care with sepsis.

Decades of mainstream SIDS research based on the Triple Risk Model and neuropathological findings have failed to provide convincing evidence for a primary CNS-based mechanism behind putative secondary dyshomeostasis (respiratory or cardiac) or impaired arousal. Newly revealed data indicate that severe metabolic acidosis (and severe hyperkalemia) is a common accompaniment in SIDS. This supports the direct effect of sepsis on vital-organ function and occurrence of secondary CNS changes accompanied by the dyshomeostasis leading to SIDS.

Using PubMed and Google Scholar literature searches, this paper examines how metabolic acidosis and sepsis might contribute to the underlying pathophysiologic mechanisms in SIDS.

The discovery of a series of non-peer-reviewed publications provided the basis for a serious examination of the role of metabolic acidosis and sepsis in SIDS. Most SIDS risk factors relate directly or indirectly to infection. This consequently elevated the position of septic or superantigenic shock and viremia in causing secondary organ failure leading to SIDS. The latter could include diaphragmatic failure, as evidenced by peripheral respiratory (muscle) arrests in experimental septic shock, as well as infectious myositis and diaphragm myopathy in sudden unexpected deaths, including SIDS. In addition, just as acidosis lowers the threshold for ventricular fibrillation and sudden cardiac arrest, it could also contribute to similarly unstable diaphragm excitation states leading to respiratory failure.

This paper uniquely reveals compelling evidence for a connection between metabolic acidosis, sepsis, viral infections, and sudden unexpected child deaths and provides a solid basis for further work to define which pathway (or pathways) lead to the tragedy of SIDS. It is recommended that all autopsies in sudden unexpected deaths should include pH, bicarbonate, lactate, and electrolyte measurements, as well as diaphragm histology.

Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.

Cardiovascular disease (CVD) is the leading cause of death in the United States, and sepsis significantly contributes to hospitalization and mortality. This study aims to assess the trends of sepsis-associated CVD mortality rates and variations in mortality based on demographics and regions in the US.

The Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database was used to identify CVD and sepsis-related deaths from 1999 to 2022. Data on gender, race and ethnicity, age groups, region, and state classification were statistically analyzed to obtain crude and age-adjusted mortality rates (AAMR). The Joinpoint Regression Program was used to determine trends in mortality within the study period.

During the study period, there were a total of 1,842,641 deaths with both CVD and sepsis listed as a cause of death. Sepsis-associated CVD mortality decreased between 1999 and 2013, from AAMR of 65.7 in 1999 to 58.8 in 2013 (APC -1.06*%, 95% CI: -2.12% to -0.26%), then rose to 74.3 in 2022 (APC 3.23*%, 95% CI: 2.18%-5.40%). Throughout the study period, mortality rates were highest in men, NH Black adults, and elderly adults (65+ years old). The Northeast region, which had the highest mortality rate in the initial part of the study period, was the only region to see a decline in mortality, while the Northwest, Midwest, and Southern regions experienced significant increases in mortality rates.

Sepsis-associated CVD mortality has increased in the US over the past decade, and both this general trend and the demographic disparities have worsened since the onset of the COVID-19 pandemic.

Sepsis is a severe inflammatory syndrome with high mortality and morbidity. Sepsis-induced myocardial dysfunction (SIMD) is a common cause of death in sepsis. The female sex is less susceptible to sepsis-related organ dysfunction, although the underlying mechanism of this sex difference remains unclear. This study explored the role of estrogen receptor G protein-coupled estrogen receptor 30 (GPR30) in septic cardiac dysfunction. Results from the present study indicated that GPR30 activation by the G1 agonist protected female mouse hearts against SIMD exposed to lipopolysaccharides. However, this beneficial effect was absent in female ACE2-knockout mice, as demonstrated by poorer cardiac contractility, myocardial injury, and necroptosis. We also demonstrated that the Stat6 transcription factor induced ace2 transcription by enhancing its promoter activity under GPR30 activation in septic hearts. The adenovirus-mediated inhibition of ACE2 targeting c-FOS expression reversed the deterioration, restored cardiac function, and improved survival in female ACE2-knockout mice. These results demonstrate the essential role of GPR30/STAT6/ACE2/c-FOS-mediated necroptosis in G1-mediated protection and provide novel insight into the pathogenesis of sepsis-related organ damage.

Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g. ventilation, dialysis), there are no specific interventions that prevent or reduce MOF in patients with sepsis. To identify possible intervention targets, we re-analyzed the publicly accessible Gene Expression Omnibus accession GSE131761 dataset, which revealed an increased expression of spleen tyrosine kinase (SYK) in the whole blood of septic patients compared to healthy volunteers. This result suggests a potential involvement of SYK in the pathophysiology of sepsis. Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis. PRT062607 or vehicle (saline) was administered to 10-weeks-old C57BL/6 mice at 1h after the onset of sepsis induced by cecal ligation and puncture (CLP). Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP. After 24h, cardiac function was assessed in vivo by echocardiography and, after termination of the experiments, serum and cardiac samples were collected to evaluate the effects of SYK inhibition on the systemic release of inflammatory mediators and the degree of organ injury and dysfunction. Our results show that treatment of CLP-mice with PRT062607 significantly reduces systolic and diastolic cardiac dysfunction, renal dysfunction and liver injury compared to CLP-mice treated with vehicle. In addition, the sepsis-induced systemic inflammation (measured as an increase in inflammatory cytokines and chemokines in the serum) and the cardiac activation of NF-kB (IKK) and the NLRP3 inflammasome were significantly reduced in CLP-mice treated with PRT062607. These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis.

The study aimed to investigate the clinical significance of serum cytokine-induced apoptosis inhibitor 1 (CIAPIN1) and its potential impact on cardiac dysfunction and inflammatory response induced by sepsis. A cross-sectional study was conducted in an intensive care unit (ICU) involving 80 healthy individuals and 95 severe sepsis patients. The data were analyzed to establish the correlation between CIAPIN1 levels and the onset of cardiac dysfunction in patients with sepsis. The associations have been established by the Pearson correlation test, one-way ANOVA, Bonferroni post hoc test, and plotting the receiver operating characteristic (ROC). H9c2 cells were treated with LPS (1 μg/mL) for 24 h to establish an in vitro model of septic cardiomyopathy. Meanwhile, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were detected by enzyme-linked immunosorbent assay (ELISA). Serum CIAPIN1 levels were considerably lower in sepsis patients with cardiac dysfunction. CIAPIN1 expression levels were negatively correlated with TNF-α (r = -0.476, P<0.001), IL-1β (r = -0.584, P<0.001), IL-6 (r = -0.618, P<0.001), creatine kinase- MB (CK-MB) (r = -0.454, P<0.001), and high-sensitive cardiac troponin T (hs-cTnT) (r = -0.586, P<0.001). The ROC curve showed that CIAPIN1 significantly identify sepsis patients from healthy individuals. CIAPIN1 knockdown decreases cardiomyocyte proliferation and increases apoptosis induced by LPS. In addition, CIAPIN1 knockdown reduced cardiac dysfunction and increased inflammatory response in H9c2 rat cardiomyocytes. CIAPIN1 could be a potential biomarker for detecting sepsis patients and suppressing CIAPIN1 expression in H9c2 rat cardiomyocytes, attenuating sepsis-induced cardiac dysfunction.

Marked elevation in aminotransferases (≥1000 IU/l) is typically associated with acute liver injury. Here, we hypothesized that the cause of elevation in aminotransferases ≥1000 in patients with cirrhosis is likely due to a limited number of disorders and may be associated with poor outcomes.

We aimed to investigate the most common etiologies of acute elevations in aminotransferases in patients with cirrhosis, and to examine their associated outcomes.

From May 2012 to December 2022, all hospitalized patients with cirrhosis and an aspartate aminotransferase or alanine aminotransferase ≥ 1000 IU/l were identified through Medical University of South Carolina's Clinical Data Warehouse. Complete clinical data were abstracted for each patient, and in-hospital mortality was examined.

The cohort was made up of 152 patients, who were 57 ± 12 years old, with 51 (34%) women. Underlying liver disease included mainly hepatitis C cirrhosis, alcohol-related cirrhosis, metabolic dysfunction-associated steatohepatitis cirrhosis, autoimmune cirrhosis, primary sclerosing cholangitis cirrhosis, and cryptogenic cirrhosis. The most common cause of marked elevation in aminotransferases in cirrhotic patients was ischemic hepatitis (71%), followed by chemoembolization (7%), autoimmune hepatitis (6%), drug-induced liver injury (3%), post-transjugular intrahepatic portosystemic shunt placement (3%), rhabdomyolysis (3%), and hepatitis C (2%). During hospitalization and over a 1-month follow-up period, the mortality rate in patients with ischemic hepatitis was 73% (79/108), while that for other causes of liver injury was 20% (9/44).

Ischemic hepatitis is the leading cause of marked elevation of aminotransferases in patients with cirrhosis, with distinctive clinical characteristics than other etiologies, and significantly poorer outcomes.

Sepsis-induced myocardial dysfunction presents significant challenges in clinical management and is associated with increased mortality. Anisodamine (654-1/-2) has potentials in alleviating cardiac and endothelial impairments associated with sepsis. Exosomes, small vesicles secreted by cells, carry various bioactive molecules, such as nucleic acids, proteins, and lipids. These vesicles can travel to target cells to influence their function and modulating biological processes. In the context of endothelial-cardiac crosstalk, exosomes derived from endothelial cells can transfer signals that either exacerbate or mitigate myocardial injury, playing a crucial role in the progression of cardiovascular diseases. However, the precise role of endothelial-cardiac crosstalk, particularly through exosomes, in mediating the cardioprotective effects of anisodamine remains unclear. This study evaluated the effects of anisodamine on myocardial and endothelial injuries induced by LPS. Mechanisms were analyzed through network pharmacology, molecular docking, Western blotting, and RT-qPCR. The interaction between endothelial and cardiomyocyte inflammatory responses to anisodamine was assessed using a co-culture assay. Furthermore, both in vivo and in vitro assays were conducted to evaluate the effects of anisodamine-/LPS- treated HUVECs exosomes on A16 cell and myocardial function in mice. Anisodamine effectively mitigated apoptosis, inflammation, mitochondrial and myocardial injury, glycocalyx degradation, and oxidative stress by regulating the PI3K-AKT, NLRP-3/Caspase-1/ASC, TNF-α/PKCα/eNOs/NO, and NF-κB/iNOs/NO pathways in A16 cells and HUVECs. Moreover, in vivo and in vitro assays confirmed the protective effects of anisodamine against myocardial injuries mediated by exosomes derived from LPS-treated HUVECs. In summary, anisodamine ameliorated inflammation-induced endothelial and cardiomyocyte dysfunction. The in vitro and in vivo assays demonstrated that anisodamine could alleviate myocardial dysfunction through exosome-mediated mechanisms, offering new therapeutic avenues for treating myocardial injury and highlighting the potential of targeted exosome therapy in clinical settings.

Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin-like growth factor-II receptor α (IGF-IIRα) acts as a stress-inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF-IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)-induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF-IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF-IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy-related and inflammation-related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF-IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS-treated H9c2 cardiac myoblasts with IGF-IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis-related cardiac mechanisms. Our study suggests that under sepsis-like conditions in the heart with IGF-IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF-IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function.

Chest pain is a frequent complaint in emergency departments, with various differential diagnoses from benign to life-threatening. Hereby, we described a 60-year-old man presented with chest pain and hypotension who initially misdiagnosed as acute coronary syndrome, but was ultimately diagnosed with necrotizing fasciitis. This case highlights the importance of considering rare causes of chest pain.

Sepsis is a systemic inflammatory disease that can cause multiple organ damage. Septic patients with cardiac dysfunction have a significantly higher mortality. Based on the results of bioinformatics analysis, weighted gene co-expression network analysis (WGCNA), we found that Erbin is vital in cardiomyocyte. However, the function of Erbin in sepsis-induced cardiomyopathy (SIC) has not been explicitly studied. We discussed the role of Erbin in SIC by employing the Erbin-/- mice and HL-1 cardiomyocyte. An in vitro model of inflammation in HL-1 was used to confirm stimulation with lipopolysaccharide (LPS) and a mouse model of cecal ligation and puncture (CLP) to study the molecular mechanisms under SIC. Transmission electron microscopy (TEM) was used to characterize the morphological characteristics at the ultrastructural level. The expressions of Erbin, p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL, MLKL, p-PKA, PKA, p-CREB and CREB were detected by western blot. qPCR analysis was applied to detect TNF-α, IL-1β, IL-6, RIPK1 and MLKL mRNA expression. Cell survival was detected by CCK-8 assay and the levels of c TnI concentration were detected by ELISA kit. Our study revealed that necroptosis and inflammation were activated in cardiomyocytes during sepsis and deficiency of Erbin aggravated them. Furthermore, deficiency of Erbin exacerbated systolic dysfunction including the decline of LVEF and LVFS induced by CLP. Overexpression of Erbin alleviated necroptosis and inflammation by activating PKA/CREB pathway. Our research elucidates a noval mechanism whereby Erbin participates in SIC, providing a promising therapeutic target for myocardial dysfunction during sepsis.

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

Non-invasive, real-time monitorable indicators for early assessment of sepsis-associated myocardial injury (SMI) are still lacking. We aimed to develop non-invasive, real-time indicators for early assessment of SMI using bedside heart rate (HR) and diastolic arterial pressure (DAP) monitors. In this multi-center cohort study, piece-wise exponential additive mixed models were used to estimate the exposure window and time fraction of the hazardous exposure proportion, and secondarily to analyze the exposure characterization on this basis to identify high-risk exposure pattern. In total, 20,043 patients were finally included; we found that SMI patients had the highest survival rate when HR was <90 bpm or DAP was between 50 and 70 mmHg. Further investigation revealed that the SMI high-risk exposure pattern was the H1D-1 (HR ≥ 90 bpm and DAP ≤ 50 mmHg, exposure proportion > 0.3 and 0.2, respectively, and exposure window on admission day 1). H1D-1 exposure pattern using glucocorticoids significantly increased the risk of mortality in H1D-1. Validation against various methodologies and data sources demonstrated acceptable consistency.

Septic cardiomyopathy is a life-threatening heart dysfunction caused by severe infection. Considering the complexity of pathogenesis and high mortality, the identification of efficient biomarkers are needed to guide clinical practice. Based on multimicroarray analysis, this study aimed to explore the pathogenesis of septic cardiomyopathy and the related immune landscape. The results showed that septic cardiomyopathy resulted in organ dysfunction due to extreme pro- and anti-inflammatory effects. In this process, KLRG1, PRF1, BCL6, GAB2, MMP9, IL1R1, JAK3, IL6ST, and SERPINE1 were identified as the hub genes regulating the immune landscape of septic cardiomyopathy. Nine transcription factors regulated the expression of these genes: SRF, STAT1, SP1, RELA, PPARG, NFKB1, PPARA, SMAD3, and STAT3. The hub genes activated the Th17 cell differentiation pathway, JAK-STAT signaling pathway, and cytokine‒cytokine receptor interaction pathway. These pathways were mainly involved in regulating the inflammatory response, adaptive immune response, leukocyte-mediated immunity, cytokine-mediated immunity, immune effector processes, myeloid cell differentiation, and T-helper cell differentiation. These nine hub genes could be considered biomarkers for the early prediction of septic cardiomyopathy.

Minocycline (Min), as an antibiotic, possesses various beneficial properties such as anti-inflammatory, antioxidant, and anti-apoptotic effects. Despite these known qualities, the precise cardioprotective effect and mechanism of Min in protecting against sepsis-induced cardiotoxicity (SIC) remain unspecified. To address this, our study sought to assess the protective effects of Min on the heart. Lipopolysaccharide (LPS) was utilized to establish a cardiotoxicity model both in vivo and in vitro. Min was pretreated in the models. In the in vivo setting, evaluation of heart tissue histopathological injury was performed using hematoxylin and eosin (H&E) staining and TUNEL. Immunohistochemistry (IHC) was employed to evaluate the expression levels of NLRP3 and Caspase-1 in the heart tissue of mice. During in vitro experiments, the viability of H9c2 cells was gauged utilizing the CCK8 assay kit. Intracellular ROS levels in H9c2 cells were quantified using a ROS assay kit. Both in vitro and in vivo settings were subjected to measurement of oxidative stress indexes, encompassing glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Additionglly, myocardial injury markers like lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) activity were quantified using appropriate assay kits. Western blotting (WB) analysis was conducted to detect the expression levels of NOD-like receptor protein-3 (NLRP3), caspase-1, IL-18, and IL-1β, alongside apoptosis-related proteins such as Bcl-2 and Bax, and antioxidant proteins including superoxide dismutase-1 (SOD-1) and antioxidant proteins including superoxide dismutase-1 (SOD-2), both in H9c2 cells and mouse heart tissues. In vivo, Min was effective in reducing LPS-induced inflammation in cardiac tissue, preventing cell damage and apoptosis in cardiomyocytes. The levels of LDH and CK-MB were significantly reduced with Min treatment. In vitro studies showed that Min improved the viability of H9C2 cells, reduced apoptosis, and decreased ROS levels in these cells. Further analysis indicated that Min decreased the protein levels of NLRP3, Caspase-1, IL-18, and IL-1β, while increasing the levels of SOD-1 and SOD-2 both in vivo and in vitro. Min alleviates LPS-induced SIC by suppressing the NLRP3/Caspase-1 signalling pathway in vivo and in vitro.

There is a continuous cycle of activation and contraction in the immune response against pathogens and other threats to human health in life. This intrinsic yin-yang of the immune response ensures that inflammatory processes can be appropriately controlled once that threat has been resolved, preventing unnecessary tissue and organ damage. Various factors may contribute to a state of perpetual immune activation, leading to a failure to undergo immune contraction and development of cytokine storm syndromes. A literature review was performed to consider how the trajectory of the immune response in certain individuals leads to cytokine storm, hyperinflammation, and multiorgan damage seen in cytokine storm syndromes. The goal of this review is to evaluate how underlying factors contribute to cytokine storm syndromes, as well as the symptomatology, pathology, and long-term implications of these conditions. Although the recognition of cytokine storm syndromes allows for universal treatment with steroids, this therapy shows limitations for symptom resolution and survival. By identifying cytokine storm syndromes as a continuum of disease, this will allow for a thorough evaluation of disease pathogenesis, consideration of targeted therapies, and eventual restoration of the balance in the yin-yang immune response.

Sepsis-induced cardiac injury is the leading cause of death in patients. Recent studies have reported that reactive oxygen species (ROS)-mediated ferroptosis and macrophage-induced inflammation are the two main key roles in the process of cardiac injury. The combination of ferroptosis and inflammation inhibition is a feasible strategy in the treatment of sepsis-induced cardiac injury.

In the present study, ceria nanozyme coordination with curcumin (CeCH) was designed by a self-assembled method with human serum albumin (HSA) to inhibit ferroptosis and inflammation of sepsis-induced cardiac injury.

The formed CeCH obtained the superoxide dismutase (SOD)-like and catalase (CAT)-like activities from ceria nanozyme to scavenge ROS, which showed a protective effect on cardiomyocytes in vitro. Furthermore, it also showed ferroptosis inhibition to reverse cell death from RSL3-induced cardiomyocytes, denoted from curcumin. Due to the combination therapy of ceria nanozyme and curcumin, the formed CeCH NPs could also promote M2 macrophage polarization to reduce inflammation in vitro. In the lipopolysaccharide (LPS)-induced sepsis model, the CeCH NPs could effectively inhibit ferroptosis, reverse inflammation, and reduce the release of pro-inflammatory factors, which markedly alleviated the myocardial injury and recover the cardiac function.

Overall, the simple self-assembled strategy with ceria nanozyme and curcumin showed a promising clinical application for sepsis-induced cardiac injury by inhibiting ferroptosis and inflammation.

Myocardial injury and cardiovascular dysfunction are the most common complications of sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in myocardial injury of lipopolysaccharide-induced sepsis and its related signalling pathways. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout mice, as well as H9c2 cardiomyocytes cultures treated with lipopolysaccharide (LPS) were used as models of septic myocardial injury. H9c2 cardiomyocytes culture showed that oxycodone protected cells from pyroptosis induced by LPS. Mice model confirmed that oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function demonstrated by increased ejection fraction (EF) and fractional shortening (FS), as well as decreased cardiac troponin I (cTnI) and creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including: Nod-like receptor protein 3 (NLRP3), Caspase 1, Apoptosis-associated speck-like protein contain a CARD (ASC), and Gasdermin D (GSDMD). These changes were mediated by Nrf2 and heme oxygenase-1 (HO-1) because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings yielded that oxycodone therapy reduces LPS-induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signalling pathway in vivo and in vitro.

In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone-TLR interactions and their mechanisms.

Septic shock is associated with increases in end-diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The mechanism is unknown.

Purpose-bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular-arterial coupling, and circumferential strain. Early during sepsis, (0-24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes.

The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.

Lipopolysaccharide (LPS) triggers an inflammatory response, causing impairment of cardiomyocyte Ca2+ and Na + regulation. This study aimed to determine whether piscidin-1 (PCD-1), an antimicrobial peptide, improves intracellular Ca2+ and Na + regulation in LPS-challenged atrial cardiomyocytes. Rabbit atrial cardiomyocytes were enzymatically isolated from the left atria. Patch-clamp ionic current recording, intracellular Ca2+ monitoring using Fluo-3, and detection of cytosolic reactive oxygen species production were conducted in control, LPS-challenged, and LPS + PCD-1-treated atrial cardiomyocytes. LPS-challenged cardiomyocytes showed shortened durations of action potential at their 50% and 90% repolarizations, which was reversed by PCD-1 treatment. LPS-challenged cardiomyocytes showed decreased L-type Ca2+ channel currents and larger Na+/Ca2+ exchange currents compared to controls. While LPS did not affect the sodium current, an enhanced late sodium current with increased cytosolic Na+ levels was observed in LPS-challenged cardiomyocytes. These LPS-induced alterations in the ionic current were ameliorated by PCD-1 treatment. LPS-challenged cardiomyocytes displayed lowered Ca2+ transient amplitudes and decreased Ca2+ stores and greater Ca2+ leakage in the sarcoplasmic reticulum compared to the control. Exposure to PCD-1 attenuated LPS-induced alterations in Ca2+ regulation. The elevated reactive oxygen species levels observed in LPS-challenged myocytes were suppressed after PCD-1 treatment. The protein levels of NF-κB and IL-6 increased following LPS treatment. Decreased sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a protein levels were observed in LPS-challenged cardiomyocytes. PCD-1 modulates LPS-induced alterations in inflammatory and Ca2+ regulatory protein levels. Our results suggest that PCD-1 modulates LPS-induced alterations in intracellular Ca2+ and Na + homeostasis, reactive oxygen species production, and the NF-κB inflammatory pathway in atrial cardiomyocytes.

High Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), Platelet-to-Lymphocyte Ratio (PLR) were associated with worse prognosis of patients with sepsis. In-hospital mortality has been reported to be higher in patients with coronary artery disease (CAD) and sepsis than those with sepsis alone. However, the relationship between NLR, MLR, PLR and mortality in septic patients with coronary artery disease (CAD) remains unclear. The study aimed to explore the association between NLR, MLR, PLR and 28-day all-cause mortality in septic patients with CAD.

We performed an observational cohort study of septic patients with CAD from the Medical Information Mart for Intensive Care (MIMIC)-IV database between 2008 and 2019. The patients were categorized by three group (Q1: low levels, Q2: medium levels, Q3: high levels) based on tertiles of NLR, MLR, and PLR. The associations between NLR, MLR, PLR and 28-day all-cause mortality were examined using the Cox proportional hazards model. Subsequently, we applied receiver operating characteristic (ROC) analysis for predicting 28-day mortality in septic patients with CAD by combining NLR, MLR and PLR with the modified sequential organ failure assessment (mSOFA) scores.

Overall 1,175 septic patients with CAD were included in the study. Observed all-cause mortality rates in 28 days were 27.1%. Multivariate Cox proportional hazards regression analysis results showed that 28-day all-cause mortality of septic patients with CAD was significantly related to rising NLR levels (adjusted hazard ratio [aHR]: 1.02; 95% confidence interval [CI]: 1.01-1.02; P < 0.001), MLR levels (aHR: 1.29; 95%CI: 1.18-1.41; P < 0.001), and PLR levels (aHR: 1.0007; 95%CI: 1.0004-1.0011; P < 0.001). Meanwhile, the higher levels (Q3) group of NLR, MLR, and PLR also had a higher risk of 28-day all-cause mortality than the lower (Q1) group. The area under the ROC curve of NLR, MLR, PLR, and mSOFA score were 0.630 (95%CI 0.595-0.665), 0.611 (95%CI 0.576-0.646), 0.601 (95%CI 0.567-0.636) and 0.718 (95%CI 0.689-0.748), respectively. Combining NLR, MLR, and PLR with mSOFA scores may improve ability of predicting 28-day mortality (AUC: 0.737, 95%CI 0.709-0.766).

Higher levels of NLR, MLR and PLR were associated with 28-day all-cause mortality in septic patients with CAD. Further investigation will be needed to improve understanding of the pathophysiology of this relationship.