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Three groups of conscious canines were given different intravenous doses of human recombinant tumor necrosis factor (TNF) over 1 h, and the resulting cardiovascular abnormalities were examined for 10 days. As TNF dose increased [0 (controls), 30, 60, and 120 micrograms/kg body wt], the number of deaths increased (P less than 0.025; 0 of 6, 1 of 8, 4 of 8, number of deaths in each group, respectively). In all three groups receiving TNF, the mean left ventricular ejection fraction (LVEF) at 2 h after infusion decreased (P less than 0.003) compared with controls. The group receiving the highest dose of TNF (120 micrograms/kg body wt) had the greatest decrease (P less than 0.05) in LVEF from 0 to 2 h. At 8 h, all three groups receiving TNF had similar LVEF. In these three groups, other multiple measures of LV function at 8 h showed significant and similar decreases in cardiac contractility compared with controls. From 24 to 240 h, however, the time required for cardiac performance (LVEF) to return to normal was dose dependent (30 less than 60 less than 120 micrograms/kg body wt; P less than 0.05). Canines receiving the lowest dose of TNF had near normal cardiac function (LVEF) at 24 h, whereas canines receiving the highest dose had persistent cardiac abnormalities at 240 h. Thus, at 8 h, the severity of cardiac dysfunction is independent of TNF dose, but the rate of onset and the duration of cardiac abnormality are markedly dependent of dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic response to inhalation anesthesia is influenced by three factors: 1) the specific drug, 2) the dose, and 3) individual characteristics of the subject. To investigate the importance of these factors on the cardiovascular response, we administered five doses [0, 0.5, 1.0, 1.5, and 2.0 minimum alveolar concentration (MAC)] of enflurane, halothane, and isoflurane to each of six dogs. Twelve hemodynamic variables were measured. For all variables, a change in the dose of each drug produced a consistent effect in each dog. Increases in dose resulted in significant decreases in seven variables [left ventricular ejection fraction, cardiac index (CI), stroke volume index (SVI), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), left ventricular stroke work index (LVSWI), and heart rate (HR)] and a significant increase in one variable [central venous pressure (CVP)]. In contrast, the response of individual dogs to different drugs was not consistent. For seven variables [MAP, MPAP, LVSWI, CVP, pulmonary capillary wedge pressure (PCWP), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI)], a significant difference in the responses of a dog to two drugs was greater than zero, whereas a significant difference in the response of at least one other dog to the same two drugs was less than zero (discordant dog-drug interactions). Thus, in contrast to the consistency of the cardiovascular response to changes in dose, the hemodynamic response to different drugs was inconsistent among dogs. We also studied the effect of fluid challenge on hemodynamic response at 1.5 or 2.0 MAC of the three drugs given to each dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Copyright of Canadian Veterinary Journal / Revue Vétérinaire Canadienne is the property of Canadian Veterinary Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Survivors of both human and animal bacterial shock develop a characteristic pattern of progressive changes in cardiovascular function over a period of 7-10 d. In this present study, we examined whether endotoxin (a product of Gram-negative bacteria) or TNF (a cytokine released from macrophages) could reproduce the same complex cardiovascular changes observed in septic shock over a period of 7-10 d. To test this hypothesis, we implanted a thrombin-fibrin clot containing purified endotoxin from E. coli into the peritoneal cavity of eight dogs, and infused TNF into eight different dogs. Over the next 10 d, serial simultaneous heart scans and thermodilution cardiac outputs were performed in these awake nonsedated animals. By day 2 after challenge with either endotoxin or TNF, animals developed a decrease (p less than 0.05) in both mean arterial pressure and left ventricular ejection fraction. With fluid resuscitation, animals manifested left ventricular dilatation (increased [p less than 0.05] end diastolic volume index), increased or normal cardiac index, and decreased or normal systemic vascular resistance index. In surviving animals, these changes returned to normal with 7-10 d. The time course of these changes was concordant (p less than 0.05) with that previously described in a canine model of septic shock using viable bacteria. During the 10-d study, control animals receiving sterile clots or heat-inactivated TNF had not significant changes in hemodynamics. The results from this canine model demonstrate that either endotoxin or TNF alone can produce many of the same hemodynamic abnormalities seen in human septic shock and in a canine septic shock model induced by live bacteria. These findings support the hypothesis that the action of endogenous mediators (TNF) responding to bacterial products (endotoxin) is the common pathway that produces the serial cardiovascular changes found in septic shock.

Sepsis is a life-threatening organ dysfunction caused by abnormal host response to infection. Millions of people are affected annually worldwide. Derangement of the inflammatory response is crucial in sepsis pathogenesis. However, metabolic, coagulation, and thermoregulatory alterations also occur in patients with sepsis. Fatty acid mobilization and oxidation changes may assume the role of a protagonist in sepsis pathogenesis. Lipid oxidation and free fatty acids (FFAs) are potentially valuable markers for sepsis diagnosis and prognosis. Herein, we discuss inflammatory and metabolic dysfunction during sepsis, focusing on fatty acid oxidation (FAO) alterations in the liver and muscle (skeletal and cardiac) and their implications in sepsis development. [ABSTRACT FROM AUTHOR]

Using markers for early diagnosis can help to reduce mortality and morbidity in systemic inflammatory response syndrome (SIRS). This study investigates the role of procalcitonin (PCT) as a prognostic value in dogs with SIRS in the intensive care unit. Fifty-five dogs were selected and studied. Blood samples were collected and investigated for PCT, white and red blood cells, iron, creatinine, platelet, glucose, albumin, urea, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), bandcell, body temperature, and hospitalized days and costs. The animals were grouped into survivors and deceased groups, and their results were compared. The results showed negative significant relations between PCT with hematocrit (r2 = 0.294, P < 0.05) and the serum concentration of iron (r2 = 0.280, P < 0.05) and also positive relation with IL-6 (r2 = 0.456, P < 0.01) and TNF-α (r2 = 0.391, P < 0.01). Significant relations were not seen between PCT with other parameters (P > 0.05). The results also showed a significant relation between glucose and albumin with body temperature (P < 0.05). The results showed that the serum concentrations of PCT, IL-6, and TNF-α were significantly higher in deceased dogs compared with survivors, while white blood cells, glucose, albumin, urea, lymphocyte, neutrophil, and body temperature were higher in survivors compared with others. PCT can be utilized as a prognostic value and helps early diagnosis in dogs with SIRS. [ABSTRACT FROM AUTHOR]

Sepsis-associated myocardial injury, an invertible myocardial depression, is a common complication of sepsis. Neogambogic acid is an active compound in garcinia and exerts anthelmintic, anti-inflammatory, and detoxification properties. The role of neogambogic acid in sepsis-associated myocardial injury was assessed. Firstly, mice were pretreated with neogambogic acid and then subjected to lipopolysaccharide treatment to induce sepsis. Results showed that lipopolysaccharide treatment induced up-regulation of biomarkers involved in cardiac injury, including lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and troponin I (cTnI). However, pretreatment with neogambogic acid reduced levels of LDH, CK-MB, and cTnI, and ameliorated histopathological changes in the heart tissues of septic mice. Secondly, neogambogic acid also improved cardiac function in septic mice through reduction in left ventricular end-diastolic pressure, and enhancement of ejection fraction, fractional shortening, and left ventricular systolic mean pressure. Moreover, neogambogic acid suppressed cardiac apoptosis and inflammation in septic mice and reduced cardiac fibrosis. Lastly, protein expression of p-p38, p-JNK, and p-NF-κB in septic mice was decreased by neogambogic acid. In conclusion, neogambogic acid exerted anti-apoptotic, anti-fibrotic, and anti-inflammatory effects in septic mice through the inactivation of MAPK/NF-κB pathway. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Present investigation was carried out to evaluate the mRNA level of TNF receptor type 1 (TNFR1) and TNF receptor type 2 (TNFR2) in peripheral-blood cells in patients with premature CAD over healthy controls. BACKGROUND: TNFa as a pleiotropic cytokine could be concerned in cardiovascular pathophysiology regarding its special effects on endothelial cells. TNFa exerts its activities through its receptors, TNFR1 and TNFR2. METHODS: Totally, 40 patients with premature CAD and 40 healthy controls were studied. The qRT-PCR technique was used to determine the mRNA level of TNFR1 and TNFR2 in tested groups. RESULTS: The results of this study show that the relative expression was 1.32 ± 0.34 in cases and 1.11 ± 0.16 in controls for TNFR1. The relative expression was 0.96 ± 0.13 in cases and 1.49 ± 0.41 in controls for TNFR2. There is no significant difference in the level of gene expression in the studied groups regarding TNFR1 and TNFR2 genes (p > 0.05). CONCLUSION: It can be concluded that the mRNA levels of TNFR1 and TNFR2 were not associated with CAD risk. Studies with more details, larger sample size, and new risk loci are necessary to reveal disease-causing mechanisms in the pathogenesis of CAD (Fig. 3, Ref. 21). [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the role of plasmacytoma variant translocation gene 1 (PVT1) in the occurrence and development of sepsis-induced inflammation and cardiac dysfunction and its underlying mechanism. A sepsis rat model was first established by cecal ligation and puncture. The mRNA levels of PVT1 and microRNA-143 in the myocardial tissues of rats were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Cardiac function, levels of myocardial injury markers and inflammatory indicators were detected following PVT1 knockdown. The regulatory effect of microRNA-143 on PVT1 was assessed using a luciferase reporter gene assay and RT-qPCR analysis. The specific role of PVT1 in regulating the mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB pathway was detected using western blot analysis. PVT1 was downregulated and microRNA-143 was upregulated in the myocardial tissues of sepsis rats. The left ventricular peak pressure was markedly decreased in the sepsis rats. By contrast, the left ventricular end diastolic pressure, levels of inflammatory indicators, myocardial injury markers and complement proteins of C5 and C5a were increased in the sepsis rats. The above changes were reversed by PVT1 knockdown or the upregulation of microRNA-143. MicroRNA-143 was confirmed as being bound to PVT1 using the luciferase reporter gene assay and RT-qPCR analysis. Upregulated PVT1 was capable of activating the MAPK/NF-κB pathway. Taken together, PVT1 was upregulated in the myocardial tissues of sepsis rats, which inhibited cardiac function and promoted the secretion of inflammatory factors; and the mechanism was associated with the MAPK/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Aims Remote ischaemic preconditioning (RIPC) by inducing brief ischaemia in distant tissues protects the heart against myocardial ischaemia-reperfusion injury (IRI) in children undergoing open-heart surgery, although its effectiveness in adults with comorbidities is controversial. The effectiveness and mechanism of RIPC with respect to myocardial IRI in children with tetralogy of Fallot (ToF), a severe cyanotic congenital cardiac disease, undergoing open heart surgery are unclear. We hypothesized that RIPC can confer cardioprotection in children undergoing ToF repair surgery. Methods and results Overall, 112 ToF children undergoing radical open cardiac surgery using cardiopulmonary bypass (CPB) were randomized to either a RIPC group (n = 55) or a control group (n = 57). The RIPC protocol consisted of three cycles of 5-min lower limb occlusion and 5-min reperfusion using a cuff-inflator. Serum inflammatory cytokines and cardiac injury markers were measured before surgery and after CPB. Right ventricle outflow tract (RVOT) tissues were collected during the surgery to assess hypoxia-inducible factor (Hif)-1α and other signalling proteins. Cardiac mitochondrial injury was assessed by electron microscopy. The primary results showed that the length of stay in the intensive care unit (ICU) was longer in the control group than in the RIPC group (52.30 ± 13.43 h vs. 47.55 ± 10.34 h, respectively, P = 0.039). Patients in the control group needed longer post-operative ventilation time compared to the RIPC group (35.02 ± 6.56 h vs. 31.96 ± 6.60 h, respectively, P = 0.016). The levels of post-operative serum troponin-T at 12 and 18 h, CK-MB at 24 h, as well as the serum h-FABP levels at 6 h, after CPB were significantly lower, which was coincident with significantly higher protein expression of cardiac Hif-1α, p-Akt, p-STAT3, p-STAT5, and p-eNOS and less vacuolization of mitochondria in the RIPC group compared to the control group. Conclusion In ToF children undergoing open heart surgery, RIPC attenuates myocardial IRI and improves the short-term prognosis. [ABSTRACT FROM AUTHOR]

Objective To evaluate C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) kinetics in dogs with a systemic inflammatory response syndrome (SIRS) presented to an emergency service. We hypothesized serum CRP concentrations would increase and vary during hospitalization, and would correlate with plasma IL-6 and TNF-α concentrations, vary in magnitude according to the underlying disease, and predict survival. Design Prospective, observational, clinical study. Setting University emergency department. Animals Sixty-nine dogs with SIRS weighing over 5 kg who could tolerate the blood sampling. Interventions Serum and plasma were collected (and stored at -80°C) at presentation (T0), after 6 (T6), 12 (T12), 24 (T24), and 72 (T72) hours, and at a follow-up visit at least 1 month after discharge (T1m). Underlying diseases were categorized as infection (I), neoplasia (N), trauma (T), gastric-dilation and volvulus (GDV), other gastrointestinal (GI), renal (R), and miscellaneous (M) disease. Measurements and Main Results Serum CRP concentration was measured using a canine-specific immunoturbidimetric assay. Biologically active plasma IL-6 and TNF-α concentrations were assessed using bioassays. Forty-four dogs survived, 8 died, and 17 were euthanized. Nineteen dogs had follow-up visits. At T0, serum CRP concentration was above the reference interval in 73.1% (49/67), and was within the reference interval (0-141.9 nmol/L) throughout hospitalization in only 6% (4/67). Serum CRP concentrations were significantly higher ( P < 0.0001) at T0 (882.9 ± 1082.9 nmol/L) and at all time points during hospitalization ( P < 0.0001) compared to T1m, with highest concentrations observed at T24 (906. 7 ± 859.0 nmol/L). At T1m, serum CRP concentrations were within the reference interval (22.9 ± 42.9 nmol/L) in 95% (18/19) of dogs. Logarithmic concentrations of serum CRP and plasma IL-6 were significantly correlated ( P < 0.001, r = 0.479). None of the measured cytokines were associated with disease category or outcome. Conclusions Serum CRP concentration is increased in dogs with SIRS, and decreases during treatment and hospitalization. Serum CRP, plasma IL-6, and plasma TNF-α concentrations cannot predict outcome in dogs with SIRS. [ABSTRACT FROM AUTHOR]

Sepsis is a lethal syndrome with a high incidence and a weighty economy burden. The pathophysiology of sepsis includes inflammation, immune dysfunction, and dysfunction of coagulation, while sepsis-induced cardiomyopathy (SIC), defined as a global but reversible dysfunction of both sides of the heart induced by sepsis, plays a significant role in all of the aspects above in the pathogenesis of sepsis. The complex pathogenesis of SIC involves a combination of dysregulation of inflammatory mediators, mitochondrial dysfunction, oxidative stress, disorder of calcium regulation, autonomic nervous system dysregulation, and endothelial dysfunction. The treatments for SIC include the signal pathway intervention, Chinese traditional medicine, and other specific therapy. Here, we reviewed the latest literatures on the mechanisms and treatments of SIC and hope to provide further insights to researchers and create a new road for the therapy of sepsis. [ABSTRACT FROM AUTHOR]

Abstract: Sepsis is a severe systemic response to infection; its ensuing organ failure commonly portends an unfavorable prognosis. Despite the fact that sepsis has been studied for decades, the molecular mechanisms underlying sepsis-induced organ dysfunction remain elusive and more complex than previously thought, and effective therapies are extremely limited. Calpain is a type of calcium-dependent cysteine protease that includes dozens of isoforms. Calpain, as well as its endogenous-specific inhibitor calpastatin, have been implicated in the pathogenesis of sepsis-induced organ dysfunction. Further, there is an accumulating body of evidence supporting the beneficial effect of calpain inhibition or regulation on multiple organ failure in sepsis. Better understanding of the underlying molecular mechanisms is helpful in the development of calpain/calpastatin-targeted therapeutic strategies to protect against sepsis-induced organ injury. The aim of this review is to summarize the recent literature and evidence surrounding the role of the calpain/calpastatin system in the process of organ dysfunction caused by sepsis-including regulation of cell death, modulation of inflammatory response, and disruption of critical proteins-to provide guidance for future research and therapy development., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Introduction: Sepsis remains associated with a high mortality rate. Endotoxin has been shown to influence viscoelastic coagulation parameters, thus suggesting a link between endotoxin levels and the altered coagulation phenotype in septic patients. This study evaluated the effects of systemic polyspecific IgM-enriched immunoglobulin (IgM-IVIg) (Pentaglobin® [Biotest, Dreieich, Germany]) on endotoxin activity (EA), inflammatory markers, viscoelastic and conventional coagulation parameters. Methods: Patients with severe sepsis were identified by daily screening in a tertiary, academic, surgical ICU. After the inclusion of 15 patients, the application of IgM-IVIg (5 mg/kg/d over three days) was integrated into the unit’s standard operation procedure (SOP) to treat patients with severe sepsis, thereby generating “control” and “IgM-IVIg” groups. EA assays, thrombelastometry (ROTEM®) and impedance aggregometry (Multiplate®) were performed on whole blood. Furthermore, routine laboratory parameters were determined according to unit’s standards. Results: Data from 26 patients were included. On day 1, EA was significantly decreased in the IgM-IVIg group following 6 and 12 hours of treatment (0.51 ±0.06 vs. 0.26 ±0.07, p<0.05 and 0.51 ±0.06 vs. 0.25 ±0.04, p<0.05) and differed significantly compared with the control group following 6 hours of treatment (0.26 ±0.07 vs. 0.43 ±0.07, p<0.05). The platelet count was significantly higher in the IgM-IVIg group following four days of IgM-IVIg treatment (200/nl ±43 vs. 87/nl ±20, p<0.05). The fibrinogen concentration was significantly lower in the control group on day 2 (311 mg/dl ±37 vs. 475 mg/dl ±47 (p = 0.015)) and day 4 (307 mg/dl ±35 vs. 420 mg/dl ±16 (p = 0.017)). No differences in thrombelastometric or aggregometric measurements, or inflammatory markers (interleukin-6 (IL-6), leukocyte, lipopolysaccharide binding protein (LBP)) were observed. Conclusion: Treatment with IgM-enriched immunoglobulin attenuates the EA levels in patients with severe sepsis and might have an effect on septic thrombocytopenia and fibrinogen depletion. Viscoelastic, aggregometric or inflammatory parameters were not influenced. Trial Registration: clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Sepsis is aggravated by an inappropriate immune response to invading microorganisms, which occasionally leads to multiple organ failure. Several lines of evidence suggest that the ventricular myocardium is depressed during sepsis with features of diastolic dysfunction. Potential candidates responsible for septic cardiomyopathy include pathogen-associated molecular patterns (PAMPs), cytokines, and nitric oxide. Extracellular histones and high-mobility group box 1 that function as endogenous damage-associated molecular patterns (DAMPs) also contribute to the myocardial dysfunction associated with sepsis. If untreated, persistent shock causes cellular injury and the liberation of further DAMPs. Like PAMPs, DAMPs have the potential to activate inflammation, creating a vicious circle. Early infection control with adequate antibiotic care is important during septic shock to decrease PAMPs arising from invasive microorganisms. Early aggressive fluid resuscitation as well as the administration of vasopressors and inotropes is also important to reduce DAMPs generated by damaged cells although excessive volume loading, and prolonged administration of catecholamines might be harmful. This review delineates some features of septic myocardial dysfunction, assesses its most common underlying mechanisms, and briefly outlines current therapeutic strategies and potential future approaches. [ABSTRACT FROM AUTHOR]

Interleukin-18 (IL-18), a proinflammatory cytokine, has been implicated in pathologic left ventricular hypertrophy and is elevated in plasma of heart failure patients. However, IL-18 blockade strategies have been conflicting. The purpose of these experiments was to determine whether genetic ablation of IL-18 would protect mice against hypobaric hypoxia (HH)-induced right ventricular (RV) hypertrophy, a condition in which chamber-specific inflammation is prominent. We hypothesized that IL-18 knockout (KO) mice would be protected while wild-type (WT) mice would demonstrate RV hypertrophy in response to HH exposure. KO and WT mice were exposed to HH for 7 wk, and control mice were exposed to normoxic ambient air. Following echocardiography, the RV was dissected and flashfrozen for biochemical analyses. HH exposure increased IL-18 mRNA (P < 0.08) in RV from WT mice. Genetic ablation of IL-18 mildly attenuated RV hypertrophy as assessed by myocyte size. However, IL-18 KO mice were not protected against HH-induced organ-level remodeling, as evidenced by higher RV weights, elevated RV systolic pressure, and increased RV anterior wall thickness compared with normoxic KO mice. These RV changes were similar to those seen in HH-exposed WT mice. Compensatory upregulation of other proinflammatory cytokines IL-2 and stromal cell-derived factor-1 was seen in the HH-KO animals, suggesting that activation of parallel inflammatory pathways might mitigate the effect of IL-18 KO. These data suggest targeted blockade of IL-18 alone is not a viable therapeutic strategy in this model. [ABSTRACT FROM AUTHOR]

Sepsis-induced cardiomyopathy is a reversible myocardial dysfunction that typically resolves in 7-10 days. It is characterized by left ventricular dilatation and depressed ejection fraction. However, many uncertainties exist regarding the mechanisms, characteristics, and treatments of this condition. Therefore, this review attempts to summarize our current knowledge of sepsis-induced cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background Tumor necrosis factor-α elaborated soon after myocardial ischemic injury. The intracellular adhesion molecule-1 is required for polymorphonuclear emigration, the primary cause of inflammatory tissue damage due to ischemia-reperfusion. Objective Detect the serum level of tumor necrosis factor-α and to look for the percentage of expression of intracellular adhesion molecule-1 in atherosclerotic coronary heart disease. Methods Fifty patients (40 males and 10 females) were enrolled in this study with age range (42-80) years, and fifteen, age and sex matched, apparently healthy individuals. The patients group was further classified into acute and chronic cases. Blood sample was taken from each subject and divided into 2 parts. One part used for lymphocyte separation by using immunocytochmistry to detect intracellular adhesion molecule-1 and the other one for serum separation by using ELISA technique to detect tumor necrosis alpha-α. Results Significant difference in the concentrations of tumor necrosis factor-α was found between patients and control groups and it was elevated in acute cases compared to chronic cases. Similarly, intracellular adhesion molecule-1 was elevated in patients compared o control groups and more in acute than chronic cases. Conclusions TNF-α is an important marker that acts on coronary arteries which may contribute to the development of congestive heart disease. Elevation of intracellular adhesion molecule-1 level correlates well with the development of acute events in the disease. [ABSTRACT FROM AUTHOR]

Multiple organ dysfunction syndrome ( MODS), defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention, is a cause of high morbidity and mortality in humans and animals. Many advances have been made in understanding the pathophysiology and treatment of this syndrome in human medicine, but much still is unknown. This comparative review will provide information regarding the history and pathophysiology of MODS in humans and discuss how MODS affects each major organ system in animals. [ABSTRACT FROM AUTHOR]

Copyright of Cardiologia Croatica is the property of Croatian Cardiac Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Development of cardiac dysfunction is associated with increased morbidity and mortality in patients with sepsis. Increasing evidence shows that gender determines the degree of inflammatory response of the host and that females tolerate sepsis better than males. It is unknown whether gender affects the cardiac dysfunction in animals or patients with sepsis. To investigate this, male or female C57BL/6 mice were subjected to either lipopolysaccharide (LPS)/peptidoglycan (PepG) co-administration or cecal ligation and puncture (CLP). At 18 hours after LPS/PepG injection or 24 hours after CLP, cardiac function was evaluated by echocardiography. The septic insult caused a significant cardiac dysfunction in both genders. However, the cardiac dysfunction was significantly less pronounced in females in comparison with males subjected to LPS (3 mg/kg)/PepG (0.1 mg/kg) or CLP. Compared with males injected with LPS (3 mg/kg)/PepG (0.1 mg/kg), western blotting analysis of the myocardium from females injected with LPS/PepG revealed i) profound increases in phosphorylation of Akt and eNOS; ii) significant decreases in phosphorylation of IκBα, nuclear translocation of the NF-κB subunit p65, decreased expression of iNOS and decreased synthesis of TNF-α and IL-6 in the heart. However, the gender dimorphism of the cardiac dysfunction secondary to LPS/PepG was not observed when higher doses of LPS (9 mg/kg)/PepG (1 mg/kg) were used. In conclusion, the cardiac dysfunction caused by sepsis was less pronounced in female than in male mice. The protection of female hearts against the dysfunction associated with sepsis is (at least in part) attributable to cardiac activation of the Akt/eNOS survival pathway, decreased activation of NF-κB, and decreased expression of iNOS, TNF-α and IL-6. It should be noted that the observed gender dimorphism of the cardiac dysfunction in sepsis was not seen when a very severe stimulus (high dose of LPS/PepG co-administration) was used to cause cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Recent studies in septic models have shown that myocardial calpain activity and TNF-α expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-α expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IκBα/NF-κB signaling linked myocardial calpain activity and TNF-α expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IκBα/NF-κB signaling activity, and TNF-α expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-α expression were increased and IκBα protein was degraded. Furthermore, NF-κB was activated, as indicated by increased NF-κB p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor κ and PD-150606 prevented the LPS-induced degradation of myocardial IκBα, NF-κB activation, and TNF-α expression and ultimately improved myocardial function. In calpastatin transgenic mice, an endogenous calpain inhibitor and cultured neonatal mouse cardiomyocytes overexpressing calpastatin also inhibited calpain activity, IκBα protein degradation, and NF-κB activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-κB activation, TNF-α expression, and myocardial dysfunction in septic mice through IκBα protein cleavage. [ABSTRACT FROM AUTHOR]

Cardiomyocyte tumour necrosis factor α ( TNF-α) production contributes to myocardial depression during sepsis. This study was designed to observe the effect of norepinephrine ( NE) on lipopolysaccharide ( LPS)-induced cardiomyocyte TNF-α expression and to further investigate the underlying mechanisms in neonatal rat cardiomyocytes and endotoxaemic mice. In cultured neonatal rat cardiomyocytes, NE inhibited LPS-induced TNF-α production in a dose-dependent manner. α1- adrenoceptor ( AR) antagonist (prazosin), but neither β1- nor β2- AR antagonist, abrogated the inhibitory effect of NE on LPS-stimulated TNF-α production. Furthermore, phenylephrine ( PE), an α1- AR agonist, also suppressed LPS-induced TNF-α production. NE inhibited p38 phosphorylation and NF-κB activation, but enhanced extracellular signal-regulated kinase 1/2 ( ERK1/2) phosphorylation and c-Fos expression in LPS-treated cardiomyocytes, all of which were reversed by prazosin pre-treatment. To determine whether ERK1/2 regulates c-Fos expression, p38 phosphorylation, NF-κB activation and TNF-α production, cardiomyocytes were also treated with U0126, a selective ERK1/2 inhibitor. Treatment with U0126 reversed the effects of NE on c-Fos expression, p38 mitogen-activated protein kinase ( MAPK) phosphorylation and TNF-α production, but not NF-κB activation in LPS-challenged cardiomyocytes. In addition, pre-treatment with SB202190, a p38 MAPK inhibitor, partly inhibited LPS-induced TNF-α production in cardiomyocytes. In endotoxaemic mice, PE promoted myocardial ERK1/2 phosphorylation and c-Fos expression, inhibited p38 phosphorylation and IκBα degradation, reduced myocardial TNF-α production and prevented LPS-provoked cardiac dysfunction. Altogether, these findings indicate that activation of α1- AR by NE suppresses LPS-induced cardiomyocyte TNF-α expression and improves cardiac dysfunction during endotoxaemia via promoting myocardial ERK phosphorylation and suppressing NF-κB activation. [ABSTRACT FROM AUTHOR]

Copyright of Der Kardiologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The square root of time (SqRT) model had been used to predict the uptake of volatile agents. Methods: We studied the rate of uptake of isoflurane in 10 patients using liquid isoflurane infusion through syringe pump into the closed circuit. The infusion rates were titrated to maintain a constant end tidal concentration of isoflurane of 1.5%. The predicted uptake values were also calculated from the square root principle and compared with the derived uptake. Results: The observed rate of uptake was higher than predicted from the Lowe and Ernst equation (P<0.001). There exists considerable inter-individual variability in uptake pharmacokinetics and it showed statistically significant correlation with ideal body weight, body weight (P<0.01), body surface area, and body weight3/4 from 30 min of start of isoflurane infusion (P<0.05). Conclusion: SqRT model is inaccurate in predicting isoflurane uptake and underestimates it during closed circuit anaesthesia. [ABSTRACT FROM AUTHOR]

Background: Recent studies have demonstrated that myocardial calpain triggers caspase-3 activation and myocardial apoptosis in models of sepsis, whereas the inhibition of calpain activity down-regulates myocardial caspase-3 activation and apoptosis. However, the mechanism underlying this pathological process is unclear. Therefore, in this study, our aim was to explore whether the Hsp90/Akt signaling pathway plays a role in the induction of myocardial calpain activity, caspase-3 activation and apoptosis in the septic mice. Methods: Adult male C57 mice were injected with lipopolysaccharide (LPS, 4 mg/kg, i.p.) to induce sepsis. Next, myocardial caspase-3 activity and the levels of Hsp90/p-Akt (phospho-Akt) proteins were detected, and apoptotic cells were assessed by performing the TUNEL assay. Results: In the septic mice, there was an increase in myocardial calpain and caspase-3 activity in addition to an increase in the number of apoptotic cells; however, there was a time-dependent decrease in myocardial Hsp90/p- Akt protein levels. The administration of calpain inhibitors (calpain inhibitor-? or PD150606) prevented the LPSinduced degradation of myocardial Hsp90/p-Akt protein and its expression in cardiomyocytes in addition to inhibiting myocardial caspase-3 activation and apoptosis. The inhibition of Hsp90 by pretreatment with 17-AAG induced p-Akt degradation, and the inhibition of Akt activity by pretreatment with wortmannin resulted in caspase- 3 activation in wildtype C57 murine heart tissues. Conclusions: Myocardial calpain induces myocardial caspase-3 activation and apoptosis in septic mice via the activation of the Hsp90/Akt pathway. [ABSTRACT FROM AUTHOR]

There is current awareness about the central role of mitochondrial dysfunction in the development of cardiac dysfunction in systemic inflammatory syndromes, especially in sepsis and endotoxemia. The aim of this work was to elucidate the mechanism that governs the link between the severity of the systemic inflammatory insult and mitochondrial function, analysing the consequences on heart function, particularly in cardiac contractile state. Female Sprague-Dawley rats were subjected to low-grade endotoxemia (i.p. injection LPS 0.5 mg kg -1 body weight) and severe endotoxemia (i.p. injection LPS 8 mg kg -1 body weight) for 6 h. Blood NO, as well as cardiac TNF-α and IL-1β mRNA, were found increased as the severity of the endotoxemia increases. Cardiac relaxation was altered only in severe endotoxemia, although contractile and lusitropic reserves were found impaired in both treatments in response to work-overload. Cardiac ultrastructure showed disorientation of myofibrillar structure in both endotoxemia degrees, but mitochondrial swelling and cristae disruption were only observed in severe endotoxemia. Mitochondrial ATP production, O 2 consumption and mitochondrial inner membrane potential decreases were related to blood NO levels and mitochondrial protein nitration, leading to diminished ATP availability and impairment of contractile state. Co-treatment with the NOS inhibitor L-NAME or the administration of the NO scavenger c-PTIO leads to the observation that mitochondrial bioenergetics status depends on the degree of the inflammatory insult mainly determined by blood NO levels. Unravelling the mechanisms involved in the onset of sepsis and endotoxemia improves the interpretation of the pathology, and provides new horizons for novel therapeutic targets.

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