Sepsis-induced Cardiomyopathy Research Articles

Cardiac-targeted delivery of nuclear receptor RORα via ultrasound targeted microbubble destruction optimizes the benefits of regular dose of melatonin on sepsis-induced cardiomyopathy

BackgroundLarge-dose melatonin treatment in animal experiments was hardly translated into humans, which may explain the dilemma that the protective effects against myocardial injury in animal have been challenged by clinical trials. Ultrasound-targeted microbubble destruction (UTMD) has been considered a promising drug and gene delivery system to the target tissue. We aim to investigate whether cardiac gene delivery of melatonin receptor mediated by UTMD technology optimizes the efficacy of clinically equivalent dose of melatonin in sepsis-induced cardiomyopathy.MethodsMelatonin and cardiac melatonin receptors in patients and rat models with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis were assessed. Rats received UTMD-mediated cardiac delivery of RORα/cationic microbubbles (CMBs) at 1, 3 and 5 days before CLP surgery. Echocardiography, histopathology and oxylipin metabolomics were assessed at 16–20 h after inducing fatal sepsis.ResultsWe observed that patients with sepsis have lower serum melatonin than healthy controls, which was observed in the blood and hearts of Sprague–Dawley rat models with LPS- or CLP-induced sepsis. Notably, a mild dose (2.5 mg/kg) of intravenous melatonin did not substantially improve septic cardiomyopathy. We found decreased nuclear receptors RORα, not melatonin receptors MT1/2, under lethal sepsis that may weaken the potential benefits of a mild dose of melatonin treatment. In vivo, repeated UTMD-mediated cardiac delivery of RORα/CMBs exhibited favorable biosafety, efficiency and specificity, significantly strengthening the effects of a safe dose of melatonin on heart dysfunction and myocardial injury in septic rats. The cardiac delivery of RORα by UTMD technology and melatonin treatment improved mitochondrial dysfunction and oxylipin profiles, although there was no significant influence on systemic inflammation.ConclusionsThese findings provide new insights to explain the suboptimal effect of melatonin use in clinic and potential solutions to overcome the challenges. UTMD technology may be a promisingly interdisciplinary pattern against sepsis-induced cardiomyopathy.

S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction.

Sepsis-induced cardiomyopathy (SIC) is the main complication and a leading cause of death in intensive care units. S100a8/a9 is a calcium-binding protein that participates in various inflammatory diseases; however, its role in sepsis-induced cardiomyopathy and the underlying mechanism remains to be explored. Here, septic cardiomyopathy was induced with cecal ligation and puncture (CLP) in S100a9-knockout (KO) mice lacking the heterodimer S100a8/a9 or wild-type (WT) mice administered with an S100a9-specific inhibitor Paquinimod (Paq), which prevents the binding of S100a9 toTLR4. Our results showed that S100a8/a9 expression in the heart peaked 24h following the CLP operation, declined at 48h and returned to baseline at 72h. Loss of S100a9 by knockout in mice protected against CLP-induced mortality, cardiac dysfunction, myocyte apoptosis, recruitment of Mac-2+ macrophages, superoxide production, and the expression of pro-inflammatory cytokines genes compared with WT mice. Moreover, S100a9-KO significantly attenuated CLP-induced activation of the ERK1/2-Drp1 (S616) pathway, excessive mitochondrial fission, and mitochondrial respiration dysfunction. In contrast, activation of ERK1/2 with its agonist tBHQ reversed the inhibitory effects of S100a9-knockout on CLP-induced cardiomyopathy and mitochondrial dysfunction. Finally, administration of Paq to WT mice markedly prevented the CLP-induced cardiomyopathy mitochondrial fission and dysfunction compared with vehicle control. In summary, our data reveal, for the first time, that S100a8/a9 plays a critical role in mediating SIC, presumably by activating TLR4-ERK1/2-Drp1-dependent mitochondrial fission and dysfunction and highlight that blockage of S100a8/a9 may be a promising therapeutic strategy to prevent SIC in patients with sepsis.

Cardiac-resident macrophages protect against sepsis-induced cardiomyopathy.

Cardiac-resident macrophages protect against sepsis-induced cardiomyopathy.

MiR-150-5p in neutrophil-derived extracellular vesicles associated with sepsis-induced cardiomyopathy in septic patients

IntroductionEarly diagnosis and potential therapeutic targets of sepsis-induced cardiomyopathy (SIC) remain challenges clinically. Circulating extracellular vesicles from immune cells carrying crucial injurious mediators, including miRNAs in sepsis. However, the impacts of neutrophil-derived extracellular vesicles and their miRNAs in the SIC development are unknown.ObjectivesThe present study focused on the in-depth miRNA expression profiles of neutrophil-derived extracellular vesicles and explored the potential molecular biomarkers during the process of SIC.MethodsNeutrophil-derived extracellular vesicles were isolated from the blood samples in three sepsis patients with or without cardiomyopathy on day 1 and day 3 after ICU admission in comparison with three healthy controls. miRNAs were determined by RNA sequencing. The closely related differentially expressed miRNAs with SIC were further validated through qRT-PCR in the other cohorts of sepsis patients with (30 patients) or without cardiomyopathy (20 patients) and the association between miRNAs and the occurrence or disease severity of septic cardiomyopathy were stratified with logistic regression analysis.ResultsSixty-eight miRNAs from neutrophil-derived extracellular vesicles were changed significantly between healthy controls and without septic cardiomyopathy patients (61 miRNAs upregulated and seven downregulated). Thirty-eight miRNAs were differentially expressed in the septic cardiomyopathy patients. 27 common differentially expressed miRNAs were found in both groups with similar kinetics (23 miRNAs upregulated and four downregulated). The enriched cellular signaling pathway mediated by miRNAs from sepsis to septic cardiomyopathy was the HIF-1 signaling system modulated septic inflammation. Using multivariate logistic regression analysis, miR-150-5p coupled with NT-pro BNP, LVEF, and SOFA score (AUC = 0.941) were found to be the independent predictors of septic cardiomyopathy.ConclusionmiRNAs derived from neutrophil-derived extracellular vesicles play an important role in septic disease severity development towards cardiomyopathy. miR-150-5p may be a predictor of sepsis severity development but warrants further study.

High-throughput technologies and bioinformatic tools to clarify the molecular mechanisms behind sepsis-induced cardiomyopathy

High-throughput technologies and bioinformatic tools to clarify the molecular mechanisms behind sepsis-induced cardiomyopathy

Exploring the molecular mechanism of notoginsenoside R1 in sepsis-induced cardiomyopathy based on network pharmacology and experiments validation.

Sepsis-induced cardiomyopathy (SIC) is an important manifestation of sepsis, and abnormal cardiac function affects the development of sepsis. Notoginsenoside R1 (NG-R1) is a unique bioactive component of Panax notoginseng with anti-inflammatory and antioxidant effects. However, the effects and possible mechanisms of NG-R1 on SIC are not clear. The purpose of this study was to identify the potential targets and regulatory mechanisms of the action of NG-R1 on SIC. To investigate the potential mechanism, we used network pharmacology, molecular docking, qRT-PCR, and immunofluorescence. The results showed that NG-R1 ameliorated myocardial fibrosis in septic mice. Validation of network pharmacology and molecular docking results revealed that NG-R1 reduced tumor necrosis factor-Alpha (TNF-α) expression in myocardial tissues and AC16 cardiomyocytes in mice, as well as inflammatory factor release in AC16 cells, so TNF-α may be a potential target of NG-R1 against SIC. The present study demonstrated that NG-R1 could protect against SIC and by regulating the expression of TNF-α inflammatory factors, providing a new idea for sepsis drug development.

Angiotensin-(1–7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-κB and MAPK pathways

BackgroundThere is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1–7) affect SIC.MethodsPeripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1–7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1–7) levels, along with the protective function of exogenous Ang-(1–7) on SIC.ResultsPeripheral plasma Ang II and the Ang II/Ang-(1–7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1–7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1–7), and Ang-(1–7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1–7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC.ConclusionsPlasma Ang-(1–7), Ang II, and Ang II/Ang-(1–7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1–7), may exert protective roles against myocardial damage.

TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi). TREM2hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.

Resveratrol Attenuates Sepsis-Induced Cardiomyopathy in Rats through Anti-Ferroptosis via the Sirt1/Nrf2 Pathway

Background: Sepsis-induced cardiomyopathy (SIC) is a severe myocardial dysfunction secondary to septicemia. It is a major concern owing to the high mortality and morbidity, which are greatly influenced by ferroptosis. Resveratrol (RSV) is a naturally existing agonist of the silent information regulator 1 (Sirt1). It has cardioprotective effects against sepsis-induced myocardial injury, However, the detailed mechanism is unknown. Methods: In this study, cecal ligation and puncture (CLP)-induced septic rats were employed to assess the changes in ferroptosis with RSV administration. According to the different treatments the rats were divided into the following groups: (1) the Sham, (2) CLP, (3) CLP + RSV at various doses (10, 30, and 50 mg/kg), and (4) CLP + Fer-1(a ferroptotic inhibitor) groups. After 24 h, the structure and function of the cardiac system in rats were evaluated, and mitochondrial morphology, ferroptosis-related biomarkers, and the levels of Sirt1/Nrf2 were assessed. Results: The rats that underwent CLP had suffered cardiac dysfunction, accompanied with myocardial damage, impaired mitochondria, elevated lipid peroxidation, and reduced Sirt1/Nrf2 expression in the myocardium. High-dose RSV successfully improved heart function, reversing the abnormalities in a dose-dependent manner. We then used EX527, a selective Sirt1 inhibitor, to further identify the intermediate signaling targets of RSV that regulate ferroptosis. EX527 diminished the curative effects of high-doses RSV. Conclusions: Summarily, our findings suggest a novel mechanism of RSV in reducing SIC: ferroptosis inhibition via upregulation of Sirt1/Nrf2 signaling pathways. This may be an effective therapeutic approach against organ failure in sepsis, particularly SIC.

PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis

Sepsis is a life-threatening syndrome with multi-organ dysfunction in critical care medicine. With the occurrence of sepsis-induced cardiomyopathy (SIC), characterized by reduced ventricular contractility, the mortality of sepsis is boosted to 70–90%. Pyruvate kinase M2 (PKM2) functions in a variety of biological processes and diseases other than glycolysis, and has been documented as a cardioprotective factor in several heart diseases. It is currently unknown whether PKM2 influences the development of SIC. Here, we found that PKM2 was upregulated in cardiomyocytes treated with LPS both in vitro and in vivo. Pkm2 inhibition exacerbated the LPS-induced cardiac damage to neonatal rat cardiomyocytes (NRCMs). Furthermore, cardiomyocytes lacking PKM2 aggravated LPS-induced cardiomyopathy, including myocardial damage and impaired contractility, whereas PKM2 overexpression and activation mitigated SIC. Mechanism investigation revealed that PKM2 interacted with sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), a key regulator of the excitation-contraction coupling, to maintain calcium homeostasis, and PKM2 deficiency exacerbated LPS-induced cardiac systolic dysfunction by impairing SERCA2a expression. In conclusion, these findings highlight that PKM2 plays an essential role in gram-negative sepsis-induced cardiomyopathy, which provides an attractive target for the prevention and treatment of septic cardiomyopathy.

Rosmarinic acid protects against lipopolysaccharide-induced cardiac dysfunction via activating Sirt1/PGC-1α pathway to alleviate mitochondrial impairment.

Sepsis-induced cardiomyopathy is a decisive factor that plays a critical role in the high mortality of septic patients in the critically ill. Mitochondrial dysfunction occurring during sepsis is a vital contributor to the pathogenesis of myocardial damage. Rosmarinic acid (RA), a natural poly-phenolic compound, has showed cardio-protective and mitochondrial protective effect. The present study was aimed to investigate the effect of RA on sepsis-induced cardiomyopathy. Adult mice were subjected to intraperitoneal injection of saline (control) or lipopolysaccharide (LPS, 5mg/kg) to mimic sepsis-induced cardiomyopathy. Immediately after LPS challenge, vehicle or RA (100 mg/kg/day) was administrated via gavage. Cardiac function was examined with echocardiographic analyses 12 hours after LPS challenge and cumulative survival of mice was recorded for 8 days. Heart tissues were harvested 12 hours after LPS challenge to perform histological analyses and determine mitochondrial function. We found RA significantly improved cardiac function and survival of LPS-injected mice. Histologically, RA attenuated LPS-mediated cardiomyocyte damage, indicated by decreased cardiomyocyte apoptosis and improved myocardial swollen and disarrangement. Moreover, RA attenuated LPS-mediated myocardial mitochondrial dysfunction, indicated by improved mitochondrial ultrastructure, increased mitochondrial membrane potential (MMP), synthesis of adenosine triphosphate (ATP), markedly decreased reactive oxygen species (ROS) level and alleviated oxidative stress in heart tissues. RA treatment downregulated protein expression of Sirt1 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and Sirt1 inhibition blocked protective effect of RA on LPS-induced myocardial damage and mitochondrial dysfunction. Collectively, RA attenuates LPS-induced cardiac dysfunction via activating Sirt1/PGC-1α pathway to alleviate mitochondrial impairment. It may be a promising cardio-protective drug to be used for septic patients.

1177: PREVALENCE AND PROGNOSIS OF SEPSIS-INDUCED CARDIOMYOPATHY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Introduction: Sepsis is a critical systemic inflammatory syndrome caused by infection, leading to various organ failures. Sepsis-induced cardiomyopathy (SICM), which can be defined as new-onset left ventricular (LV) systolic dysfunction, is one of such sepsis-induced organ failures. Although previous meta-analyses suggested that LV systolic dysfunction defined by reduced LV ejection fraction in patients with sepsis was not associated with higher or lower mortality, studies included in these meta-analyses did not exclude patients with underlying myocardial diseases. Hence, the prevalence and prognosis of the new-onset LV dysfunction during sepsis remains unknown. Therefore, we conducted a systematic review and meta-analysis on the prevalence and prognosis of SICM. Methods: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, and Embase. Inclusion criteria were as follows: (1), randomized controlled, cohort, or cross-sectional study, (2) adult patients (≥ 18 years) with sepsis, and (3) investigated the prevalence of SICM or compared short-term mortality between patients with and without SICM. Hereby, we defined SICM as a new-onset reduced LVEF during sepsis. We presented the results of all analyses with the use of random-effects models. The primary outcome was the prevalence of SICM and its impact on short-term mortality. P-value < 0.05 was considered statistically significant. Results: Thirty studies including 7,920 patients were included in the final meta-analysis. The sample size ranged from 35 to 3,530. All studies reported the prevalence of SICM in patients with sepsis and the pooled prevalence of SICM was 28% [95% confidence interval (CI), 23 to 34%]. Seventeen studies reported short-term mortality. The pooled odds ratio of short-term mortality associated with the presence of SICM was 1.88 (95% CI, 1.40–2.52; P< 0.001). Conclusions: In the meta-analysis, SICM was common in patients with sepsis, and it was associated with higher short-term mortality. This study suggests the importance of further investigation of personalized treatment in patients with SICM.

Association of sepsis-induced cardiomyopathy and mortality: a systematic review and meta-analysis

BackgroundThe implication of sepsis-induced cardiomyopathy (SIC) to prognosis is controversial, and its association with mortality at different stages remains unclear. We conducted a systematic review and meta-analysis to understand the association between SIC and mortality in septic patients.MethodsWe searched and appraised observational studies regarding the mortality related to SIC among septic patients in PubMed and Embase from inception until 8 July 2021. Outcomes comprised in-hospital and 1-month mortality. We adopted the random-effects model to examine the mortality risk ratio in patients with and without SIC. Meta-regression, subgroup, and sensitivity analyses were applied to examine the outcome’s heterogeneity.ResultsOur results, including 20 studies and 4,410 septic patients, demonstrated that SIC was non-statistically associated with increased in-hospital mortality, compared to non-SIC (RR 1.28, [0.96–1.71]; p = 0.09), but the association was statistically significant in patients with the hospital stay lengths longer than 10 days (RR 1.40, [1.02–1.93]; p = 0.04). Besides, SIC was significantly associated with a higher risk of 1-month mortality (RR 1.47, [1.17–1.86]; p < 0.01). Among SIC patients, right ventricular dysfunction was significantly associated with increased 1-month mortality (RR 1.72, [1.27–2.34]; p < 0.01), while left ventricular dysfunction was not (RR 1.33, [0.87–2.02]; p = 0.18).ConclusionsWith higher in-hospital mortality in those hospitalized longer than 10 days and 1-month mortality, our findings imply that SIC might continue influencing the host’s system even after recovery from cardiomyopathy. Besides, right ventricular dysfunction might play a crucial role in SIC-related mortality, and timely biventricular assessment is vital in managing septic patients.

Jujuboside A attenuates sepsis-induced cardiomyopathy by inhibiting inflammation and regulating autophagy

BackgroundJujuboside A (JuA), as a main effective component of Jujubogenin, has long been known as a sedative-hypnotic drug. The aim of the current study was to investigate the potential effect of JuA on sepsis-induced cardiomyopathy (SIC) induced by lipopolysaccharide (LPS). MethodWide type C57BL/6 mice and neonatal rat cardiomyocytes (NRCMs) were exposed to LPS to establish myocardial toxicity models. Cardiac function of septic mice was detected by echocardiography. Moreover, the survival rate was calculated for 7 days. ELISA assays were used to analyze inflammatory factors in serum. Furthermore, western blotting, flow cytometry and TUNEL staining were performed to assess cell apoptosis and transmission electron microscopy detect the number of autophagosomes in myocardium. Finally, the expression of proteins related to pyroptosis, autophagy and oxidative stress was analyzed by western blotting and immunohistochemistry staining. ResultsResults showed that JuA pretreatment significantly improved the survival rate and cardiac function, and suppressed systemic inflammatory response in septic mice. Further study revealed that JuA could decrease cell apoptosis and pyroptosis; instead, it strengthened autophagy in SIC. Moreover, JuA also significantly decreased oxidative stress and nitrodative stress, as evidenced by suppressing the superoxide production and downregulating iNOS and gp91 expression in vivo. In addition, the autophagy inhibitor 3-MA significantly abolished the effect of JuA on autophagic activity in SIC. ConclusionIn conclusion, the findings indicated that JuA attenuates cardiac function via blocking inflammasome-mediated apoptosis and pyroptosis, at the same time by enhancing autophagy in SIC, heralding JuA as a potential therapy for sepsis.

Is venoarterial extracorporeal membrane oxygenation an option for managing septic shock.

To describe sepsis-induced cardiomyopathy. Discuss indications and current evidence of using venoarterial extracorporeal membrane oxygenation (VA-ECMO) in setting of sepsis-induced cardiomyopathy. Recent data suggests a survival benefit with the use of VA-ECMO in patients with septic shock complicated by septic-induced cardiomyopathy with severe left ventricular systolic dysfunction. VA-ECMO was associated with poor outcomes in adults with septic shock without severe systolic dysfunction. The evidence is generated from retrospective and meta-analysis of observational studies. Sepsis-induced cardiomyopathy is an increasingly recognized entity characterized by reversible ventricular dysfunction in the setting of sepsis. When hypotension persists despite standard management of septic shock (e.g. adequate fluid resuscitation, vasopressors, inotropes) and there is evidence of severe cardiac systolic dysfunction and end-organ hypoperfusion, VA-ECMO should be considered as a bridge therapy to recovery. VA-ECMO should not be used for isolated vasodilatory septic shock without significant myocardial dysfunction.

Gut microbiota dysbiosis is associated with sepsis-induced cardiomyopathy in patients: A case-control study.

Myocardial injury is a major complication of sepsis and a key factor affecting prognosis. Therefore, early and accurate diagnosis and timely management of sepsis-induced cardiomyopathy (SICM) are of great significance for the prevention and treatment of sepsis. The gut microbiota has been shown to be closely associated with sepsis or myocardial injury, but the association between the gut microbiota and SICM is not fully understood. This study aimed to explore the link between gut microbiota composition and SICM. A case-control and single-center study of clinical features and gut microbiota profiles by Metagenome and Virome was conducted in SICM patients (n = 15) and sepsis-uninduced cardiomyopathy patients (SNICM, n = 16). Compared with SNICM patients, SICM patients showed significant myocardial injury and higher 28-day mortality, SOFA scores, lactate levels, and infection levels on admission. Meanwhile, differences in the composition of gut bacteria, archaea, fungi, and viruses were analyzed between the two groups. Differential gut bacteria or viruses were found to have a good predictive effect on SICM. Furthermore, gut bacteria and viruses that differed between the two groups were strongly related. The abundance of Cronobacter and Cronobacter phage was higher in the SICM group than in the SNICM group, and the receiver operating characteristic curve showed that Cronobacter and Cronobacter phage both had a good predictive effect on SICM. SICM patients may have specific gut microbiota signatures, and Cronobacter and Cronobacter phages have a good ability to identify and diagnose SICM.

Abstract 9812: Abracadabra Alakazam: Sudden Invasion of the Pericardium by Haemophilus Influenzae

A 25 year old man presented with three days of cough, shortness of breath, and pleuritic chest pain. Initial vital signs in the ED were normal, and exam demonstrated tonsillar erythema without exudate. Labs revealed a leukocytosis of 18.9k/μL, D-dimer of 690 ng/mL, C-reactive protein of 5.7 mg/dL, and lactate elevated to 2.9 mmol/L. High-sensitivity troponin, NT-proBNP, and SARS-CoV-2 RT-PCR were all negative. Presenting electrocardiogram demonstrated PR elevation in aVR with diffuse ST-segment elevation in the inferior and anterolateral leads. Point-of-care echocardiogram demonstrated normal biventricular function without pericardial effusion. CTPA was negative for pulmonary embolism, and he was observed for presumed acute viral pericarditis. Fourteen-hours later, he became febrile to 38.3°C, tachycardic to 133 bpm, and hypotensive to 97/65 mmHg with diffuse abdominal pain. Repeat lactate was 9.0 mmol/L. This prompted an emergent CT scan which now showed a new large pericardial effusion and bilateral pleural effusions ( Panel A ). Repeat echocardiogram confirmed a large circumferential pericardial effusion with early signs of tamponade including right atrial inversion in late diastole ( Panel B ). Emergent pericardiocentesis yielded 560 mL of brown, purulent fluid ( Panel C ) with immediate improvement in hemodynamics. Bacterial gram stain and culture grew Haemophilus influenzae ( Panel D ). Immunodeficiency screening was negative. Transient severe biventricular systolic dysfunction was noted, consistent with sepsis-induced cardiomyopathy. He completed a targeted antibiotic course with partial recovery of his ejection fraction by discharge. Purulent pericarditis is rare in developed countries, and invasive H. influenzae in a young, immunocompetent adult is particularly unusual. This case illustrates the importance of early diagnosis and management of purulent pericarditis given its potential for rapid progression and high mortality.

CARDIOMYOCYTE REPROGRAMMING IN ANIMAL MODELS OF SEPTIC SHOCK.

Cardiomyocyte reprogramming plays a pivotal role in sepsis-induced cardiomyopathy through the induction or overexpression of several factors and enzymes, ultimately leading to the characteristic decrease in cardiac contractility. The initial trigger is the binding of LPS to TLR-2, -3, -4, and -9 and of proinflammatory cytokines, such as TNF, IL-1, and IL-6, to their respective receptors. This induces the nuclear translocation of nuclear factors, such as NF-κB, via activation of MyD88, TRIF, IRAK, and MAPKs. Among the latter, ROS- and estrogen-dependent p38 and ERK 1/2 are proinflammatory, whereas JNK may play antagonistic, anti-inflammatory roles. Nuclear factors induce the synthesis of cytokines, which can amplify the inflammatory signal in a paracrine fashion, and of several effector enzymes, such as NOS-2, NOX-1, and others, which are ultimately responsible for the degradation of cardiomyocyte contractility. In parallel, the downregulation of enzymes involved in oxidative phosphorylation causes metabolic reprogramming, followed by a decrease in ATP production and the release of fragmented mitochondrial DNA, which may augment the process in a positive feedback loop. Other mediators, such as NO, ROS, the enzymes PI3K and Akt, and adrenergic stimulation may play regulatory roles, but not all signaling pathways that mediate cardiac dysfunction of sepsis do that by regulating reprogramming. Transcription may be globally modulated by miRs, which exert protective or amplifying effects. For all these mechanisms, differentiating between modulation of cardiomyocyte reprogramming versus systemic inflammation has been an ongoing but worthwhile experimental challenge.

Omega-3 polyunsaturated fatty acids inhibit cardiomyocyte apoptosis and attenuate sepsis-induced cardiomyopathy

ObjectivesSepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. Fish oil rich in omega-3 polyunsaturated fatty acids (PUFAs) in ultralong chains has immunomodulatory effects and can inhibit the production of various critically ill proinflammatory cytokines. Therefore, this study focused on whether ω-3 PUFAs have a protective effect on sepsis-induced cardiomyopathy (SIC). MethodsMale 6-8 weeks old C57BL/6 mice were pretreated with 3% special fish oil supplement rat food for seven consecutive days prior to surgery. Cecal ligation and puncture (CLP) was perfromed to induce polymicrobial sepsis.The cardiac function was assessed by echocardiography, apoptosis of cardiomyocyte were detected by TUNEL assay and Western blotting, and the level of TNF-α, IL-6, and IL-1β in plasma was determined 24h after CLP. ResultsPretreatment with omega-3 PUFAs attenuated cardiomyocyte apoptosis, decreased the production of proinflammatory cytokines, attenuated the SIC, and improved the survival rate of septic mice induced by CLP. Conclusionsω-3 PUFAs alleviate SIC through attenuating cardiomyocyte apoptosis, which provides a new direction for the prevention and treatment of SIC.

Photoactivated adenylyl cyclases attenuate sepsis-induced cardiomyopathy by suppressing macrophage-mediated inflammation.

Sepsis-induced myocardiopathy, characterized by innate immune cells infiltration and proinflammatory cytokines release, may lead to perfusion failure or even life-threatening cardiogenic shock. Macrophages-mediated inflammation has been shown to contribute to sepsis-induced myocardiopathy. In the current study, we introduced two photoactivated adenylyl cyclases (PACs), Beggiatoa sp. PAC (bPAC) and Beggiatoa sp. IS2 PAC (biPAC) into macrophages by transfection to detect the effects of light-induced regulation of macrophage pro-inflammatory response and LPS-induced sepsis-induced myocardiopathy. By this method, we uncovered that blue light-induced bPAC or biPAC activation considerably inhibited the production of pro-inflammatory cytokines IL-1 and TNF-α, both at mRNA and protein levels. Further, we assembled a GelMA-Macrophages-LED system, which consists of GelMA-a type of light crosslink hydrogel, gene modulated macrophages and wireless LED device, to allow light to regulate cardiac inflammation in situ with murine models of LPS-induced sepsis. Our results showed significant inhibition of leukocytes infiltration, especially macrophages and neutrophils, suppression of pro-inflammatory cytokines release, and alleviation of sepsis-induced cardiac dysfunction. Thus, our study may represent an emerging means to treat sepsis-induced myocardiopathy and other cardiovascular diseases by photo-activated regulating macrophage function.