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Aims: To determine the interaction between HRV and inflammation and their association with cardiovascular/all-cause mortality in the general population.Methods and Results: Subjects of the CARLA study (n = 1671; 778 women, 893 men, 45-83 years of age) were observed for an average follow-up period of 8.8 years (226 deaths, 70 cardiovascular deaths). Heart rate variability parameters were calculated from 5-min segments of 20-min resting electrocardiograms. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and soluble tumour necrosis factor-alpha receptor type 1 (sTNF-R1) were measured as inflammation parameters. The HRV parameters determined included the standard deviation of normal-to-normal intervals (SDNN), the root-mean-square of successive normal-interval differences (RMSSD), the low- and high-frequency (HF) power, the ratio of both, and non-linear parameters [Poincaré plot (SD1, SD2, SD1/SD2), short-term detrended fluctuation analysis]. We estimated hazard ratios by using covariate-adjusted Cox regression for cardiovascular and all-cause mortality incorporating an interaction term of HRV/inflammation parameters. Relative excess risk due to interactions (RERIs) were computed. We found an interaction effect of sTNF-R1 with SDNN (RERI: 0.5; 99% confidence interval (CI): 0.1-1.0), and a weaker effect with RMSSD (RERI: 0.4; 99% CI: 0.0-0.9) and HF (RERI: 0.4; 99% CI: 0.0-0.9) with respect to cardiovascular mortality on an additive scale after covariate adjustment. Neither IL-6 nor hsCRP showed a significant interaction with the HRV parameters.Conclusion: A change in TNF-α levels or the autonomic nervous system influences the mortality risk through both entities simultaneously. Thus, TNF-α and HRV need to be considered when predicating mortality. [ABSTRACT FROM AUTHOR]

In critically ill patients regulation of heart-rate is often severely disturbed. Interaction of bacterial endotoxin (lipopolysaccharide, LPS) with hyperpolarization-activated cyclic nucleotide-gated cation-( HCN)-channels may interfere with heart-rate regulation. This study analyzes the effect of LPS, the HCN-channel blocker ivabradine or Ca2+-channel blockers (nifedipine, verapamil) on pacemaking in spontaneously beating neonatal rat cardiomyocytes ( CM) in vitro. In vivo, the effect of LPS on the heart-rate of adult CD1-mice with and without autonomic blockade is analyzed telemetrically. LPS (100 ng/mL) and ivabradine (5 μg/mL) reduced the beating-rate of CM by 20.1% and 24.6%, respectively. Coincubation of CM with both, LPS and ivabradine, did not further reduce the beating-rate, indicating interaction of both compounds with HCN-channels, while coincubation with Ca2+-channel blockers and LPS caused additive beating-rate reduction. In CD1-mice (containing an active autonomic-nervous-system), injection of LPS (0.4 mg/kg) expectedly resulted in increased heart-rate. However, if the autonomic nervous system was blocked by propranolol and atropine, in line with the in vitro data, LPS induced a significant reduction of heart-rate, which was not additive to ivabradine. The in vivo and in vitro results indicate that LPS interacts with HCN-channels of cardiomyocytes. Thus, LPS indirectly sensitizes HCN-channels for sympathetic activation (tachycardic-effect), and in parallel directly inhibits channel activity (bradycardic-effect). Both effects may contribute to the detrimental effects of septic cardiomyopathy and septic autonomic dysfunction. [ABSTRACT FROM AUTHOR]

Background: There is evidence that chronic inflammation is associated with the progression/development of chronic renal failure; however, relations in subjects with preserved renal function remain insufficiently understood. Objective: To examine the association of inflammation with the development of renal failure in a cohort of the elderly general population. Methods: After excluding subjects with reduced estimated glomerular filtration rate (eGFR<60 mL/min/1.73 m2) and missing data, the cohort incorporated 785 men and 659 women (aged 45–83 years). Follow-up was performed four years after baseline. Covariate adjusted linear and logistic regression models were used to assess the association of plasma/serum concentrations of soluble tumour necrosis factor receptor 1 (sTNF-R1), C-reactive protein (CRP), and interleukin 6 (IL-6) with change in eGFR/creatinine. The areas under the curve (AUCs) from receiver operating characteristics (ROCs) were estimated. Results: In adjusted models sTNF-R1 was distinctively associated with a decline in eGFR in men (0.6 mL/min/1.73 m2 per 100 pg/mL sTNF-R1; 95% CI: 0.4–0.8), but not in women. A similar association could not be found for CRP or IL-6. Estimates of sTNF-R1 in the cross-sectional analyses were similar between sexes, while CRP and IL-6 were not relevantly associated with eGFR/creatinine. Conclusion: In the elderly male general population with preserved renal function sTNF-R1 predicts the development of renal failure. [ABSTRACT FROM AUTHOR]

Background: Previous research found an association of CRP with QT time in population based samples. Even more, there is evidence of a substantial involvement of the tumor necrosis factor-alpha system in the pathophysiology of cardiac arrhythmia, while the role of Interleukin 6 remains inconclusive. Objective: To determine the association between inflammation with an abnormally prolonged QT-time (APQT) in men and women of the elderly general population. Methods: Data descend from the baseline examination of the prospective, population-based Cardiovascular Disease, Living and Ageing in Halle (CARLA) Study. After exclusion of subjects with atrial fibrillation and missing ECG recording the final study cohort consisted of 919 men and 797 women. Blood parameters of inflammation were the soluble TNF-Receptor 1 (sTNF-R1), the high-sensitive C-reactive protein (hsCRP), and Interleukin 6 (IL-6). In accordance with major cardiologic societies we defined an APQT above a QT time of 460 ms in women and 450 ms in men. Effect sizes and the corresponding 95% confidence intervals (CI) were estimated by performing multiple linear and logistic regression analyses including the analysis of sex differences by interaction terms. Results: After covariate adjustment we found an odds ratio (OR) of 1.89 (95% CI: 1.13, 3.17) per 1000 pg/mL increase of sTNF-R1 in women, and 0.74 (95% CI: 0.48, 1.15) in men. In the covariate adjusted linear regression sTNF-R1 was again positively associated with QT time in women (5.75 ms per 1000 pg/mL, 95% CI: 1.32, 10.18), but not in men. Taking possible confounders into account IL-6 and hsCRP were not significantly related to APQT in both sexes. Conclusion: Our findings from cross-sectional analyses give evidence for an involvement of TNF-alpha in the pathology of APQT in women. [ABSTRACT FROM AUTHOR]

Key points The regulation of cardiac function is seriously impaired in severe inflammatory diseases. One characteristic of this dysfunction is a strong reduction in heart rate variability (HRV) so that the cardiac cycle is more regular. This phenomenon is strongly correlated with an unfavourable prognosis in patients with systemic inflammation., Although the depression in HRV can be partially explained by the interplay between cardiac pacemaker channels and lipopolysaccharide (LPS) liberated from the outer walls of Gram-negative bacteria, the underlying mechanism is still elusive., Using HEK293 cells stably expressing a cardiac pacemaker channel, we demonstrate that only intact LPS molecules can intercalate into target cell membranes and then directly interact with extracellular parts of pacemaker channels. Intracellular signalling cascades do not contribute to LPS-dependent channel modulation., The present results help to elucidate how LPS interacts with pacemaker channels to attenuate the regularity of the cardiac cycle., Abstract Depressed heart rate variability in severe inflammatory diseases can be partially explained by the lipopolysaccharide (LPS)-dependent modulation of cardiac pacemaker channels. Recently, we showed that LPS inhibits pacemaker current in sinoatrial node cells and in HEK293 cells expressing cloned pacemaker channels, respectively. The present study was designed to verify whether this inhibition involves LPS-dependent intracellular signalling and to identify structures of LPS responsible for pacemaker current modulation. We examined the effect of LPS on the activity of human hyperpolarization-activated cyclic nucleotide-gated channel 2 (hHCN2) stably expressed in HEK293 cells. In whole-cell recordings, bath application of LPS decreased pacemaker current ( IhHCN2) amplitude. The same protocol had no effect on channel activity in cell-attached patch recordings, in which channels are protected from the LPS-containing bath solution. This demonstrates that LPS must interact directly with or close to the channel protein. After cleavage of LPS into lipid A and the polysaccharide chain, neither of them alone impaired IhHCN2, which suggests that modulation of channel activity critically depends on the integrity of the entire LPS molecule. We furthermore showed that β-cyclodextrin interfered with LPS-dependent channel modulation predominantly via scavenging of lipid A, thereby abrogating the capability of LPS to intercalate into target cell membranes. We conclude that LPS impairs IhHCN2 by a local mechanism that is restricted to the vicinity of the channels. Furthermore, intercalation of lipid A into target cell membranes is a prerequisite for the inhibition that is suggested to depend on the direct interaction of the LPS polysaccharide chain with cardiac pacemaker channels. [ABSTRACT FROM AUTHOR]

Introduction: In sepsis, the reduced systemic vascular resistance (SVR) can lead to a compensatory increase in cardiac output (CO). This may mimic a normal cardiac function although there is already a sepsis-induced myocardial depression. On a cohort of patients with septic multi-organ dysfunction syndrome, we have recently developed a method to correlate the actual CO to the afterload (estimated by SVR) and introduced the parameter 'afterload-related cardiac performance' (ACP), which indicates if the rise of CO is adequate for the particular SVR. In this present study it was to be investigated, if ACP can reveal septic cardiomyopathy in patients with community-acquired sepsis in the early state soon after admission to the emergency department (ED), and if there is a prognostic relevance of septic cardiomyopathy defined by ACP. Results were compared to cardiac index (CI) and cardiac power index (CPI). Methods: Adults presenting at the ED with sepsis were included. ACP, CI and CPI were calculated at the time of admission, after 24, and 72 h. They were correlated to severity of disease and the prognostic values were analyzed. Results: A total of 141 patients were included. Only ACP was significantly influenced by severity of sepsis, whereas CI and CPI were not. ACP was the only hemodynamic parameter predicting mortality: nonsurvivors had lower ACP values at the time of admission to the ED (66.9 vs. 88.9 %, p < 0.05) and ACP predicted non-survival with an AUC value of 0.72, p = 0.003. Cardiac impairment defined by an ACP value of 80 % or below determined worse prognosis. Conclusions: Septic cardiomyopathy occurs already at the early stage of disease and is of prognostic relevance. It might be recognized best, if cardiac function is correlated to afterload. [ABSTRACT FROM AUTHOR]

Background: The IABP-SHOCK-trial was a morbidity-based randomized controlled trial in patients with infarction-related cardiogenic shock (CS), which used the change of the quantified degree of multiorgan failure as determined by APACHE II score over a 4-day period as primary outcome measure. The prospective hypothesis was that adding IABP therapy to 'standard care' would improve CS-triggered multi organ dysfunction syndrome (MODS). The primary endpoint showed no difference between conventionally managed cardiogenic shock patients and those with IABP support. In an inflammatory marker substudy, we analysed the prognostic value of interleukin (IL)-1β, -6, -7, -8, and -10 in patients with acute myocardial infarction complicated by cardiogenic shock. Design: Inflammatory marker substudy of the prospective, randomized, controlled, open label IABP-SHOCK-trial (Clinical-Trials-gov-ID-NCT00469248). Setting and methods: A single-center study was performed in a 12-bed Intensive-Care-Unit in an university hospital in which 40 consecutive patients were enrolled with an observational period of 96 h. Results: The pro- and anti-inflammatory markers IL-6, -7, -8 and -10 showed a predictive power for mortality of infarct-related CS patients, while IL-1β did not discriminate. The maximal values during the observational period, in case of IL-7 the minimal value, showed the best power to predict mortality. Both, ROC and multivariate analyses confirmed these suggestions (area under the curve: IL-8, 0.80 ± 0.08; IL-6, 0.79 ± 0.08; IL-10, 0.76 ± 0.08; IL-7, 0.69 ± 0.08). Inflammatory markers were not affected by the presence of IABP support. Conclusion: The inflammatory response in patients with myocardial infarction complicated by cardiogenic shock, as reflected by the inflammatory markers IL-6, IL-7, IL-8 and IL-10, demonstrates a clinically relevant prognostic contribution to clinical outcome. [ABSTRACT FROM AUTHOR]

Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti-inflammatory capacities, in addition to their lipid-lowering effects. We investigated the anti-inflammatory effect of statins in the cytokine-mediated-interaction-model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis-related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic ( i.e. over-additive) IL-6 (interleukin-6) production as measured in ELISA. Recombinant IL-1, tumour necrosis factor-α and IL-6 mediated the synergistic IL-6 production. The standard anti-inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL-6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL-6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL-6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL-6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL-6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti-inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine-mediated innate inflammatory pathways in the vessel wall. [ABSTRACT FROM AUTHOR]

Inflammation is a central element of atherogenesis. Innate pathways contribute to vascular inflammation. However, the initial molecular process(es) starting atherogenesis remain elusive. The various risk factors, represented by particular compounds (activators), may cause altered cellular functions in the endothelium ( e.g. vascular endothelial cell activation or -dysfunction), in invading cells ( e.g. inflammatory mediator production) or in local vessel wall cells ( e.g. inflammatory mediators, migration), thereby triggering the innate inflammatory process. The cellular components of innate immunology include granulocytes, natural killer cells and monocytes. Among the molecular innate constituents are innate molecules, such as the toll-like receptors or innate cytokines. Interleukin-1 (IL-1) and IL-6 are among the innate cytokines. Cytokines are potent activators of a great number of cellular functions relevant to maintain or commove homeostasis of the vessel wall. Within the vessel wall, vascular smooth muscle cells (SMCs) can significantly contribute to the cytokine-dependent inflammatory network by: ( i) production of cytokines, ( ii) response to cytokines and ( iii) cytokine-mediated interaction with invading leucocytes. The cytokines IL-1 and IL-6 are involved in SMC-leucocyte interaction. The IL-6 effects are proposed to be mediated by trans-signalling. Dysregulated cellular functions resulting from dysregulated cytokine production may be the cause of cell accumulation, subsequent low-density lipoprotein accumulation and deposition of extracellular matrix (ECM). The deposition of ECM, increased accumulation of leucocytes and altered levels of inflammatory mediators may constitute an 'innate-immunovascular-memory' resulting in an ever-growing response to anew invasion. Thus, SMC-fostered inflammation, promoted by invading innate cells, may be a potent component for development and acceleration of atherosclerosis. [ABSTRACT FROM AUTHOR]

Zearalenone (ZON) is a mycotoxin with estrogenic activity, produced by members of Fusarium species, and is found worldwide in a number of cereal crops. It is known to have four active metabolites (?-zearalenol (?-ZOL), ?-zearalenol (?-ZOL),?-zearalanol (?-ZAL), and ?-zearalanol (?-ZAL). A highly sensitive analytical methodusing liquid chromatography/tandem mass spectrometry using electrospray ionization(LC-ESI-MS/MS) has been established and validated in order to analyze ZON and its metabolites in beer and malt samples. The metabolism of ZON in the course of beer fermentation was further characterized using the artificially contaminated wort by this established method. In the fermented sample, 85.9% of ZON was converted to ?-ZOL, which has lower estrogenic activity than that of ZON. These findings indicate that the health risk to humans due to ZON in beer is reduced during the fermentation process. [ABSTRACT FROM AUTHOR]

Inflammatory mechanisms contribute to atherogenesis. Monocyte chemoattractant protein (MCP)- 1 and IL-6 are potent mediators of inflammation. Both contribute to early atherogenesis by luring monocytes and regulating cell functions in the vessel wall. MCP-1 and IL-6 production resulting from the interaction of invading monocytes with local vessel wall cells may accelerate atherosclerosis. We investigated the influence of the interaction of human vascular smooth muscle cells (SMCs) with human mononuclear cells (MNCs) or monocytes on IL-6 and MCP-1 production in a coculture model. Interaction synergistically enhanced IL-6 and MCP-l production (up to 30- and 10-fold, respectively) compared with separately cultured cells. This enhancement was mediated by CD 14-positive monocytes. It was dependent on the SMC- to-MNC/monocyte ratio, and as few as 0.2 monocytes/SMC induced the synergism. Synergistic IL-6 production was observed at the protein, mRNA, and functional level. It was mediated by soluble factors, and simultaneous inhibition of IL-i, TNF-α, and IL-6 completely blocked the synergism. IL-1, TNF-α, and IL-6 were present in the cultures. Blockade of the synergism by soluble glycoprotein 130Fc/soluble IL-6 receptor, as well as the induction of synergistic IL-6 production by costimulation of SMCs with IL-1, TNF-α, and hyper-IL-6, suggested the involvement of IL-6 trans-signaling. The contribution of IL-6 was consistent with enhanced STAT3 phosphorylation. The present data suggest that SMC/monocyte interactions may augment the proinflammatory status in the tissue, contributing to the acceleration of early atherogenesis. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the human diseases with the highest death rate and atherosclerosis is one of the major underlying causes of cardiovascular diseases. Inflammatory and innate immune mechanisms, employing monocytes, innate receptors, innate cytokines, or chemokines are suggested to be involved in atherogenesis. Among the inflammatory pathways the cytokines are central players. Plasma levels of cytokines and related proteins, such as CRP, have been investigated in cardiovascular patients, tissue mRNA expression was analyzed and correlations to vascular diseases established. Consistent with these findings the generation of cytokine-deficient animals has provided direct evidence for a role of cytokines in atherosclerosis. In vitro cell culture experiments further support the suggestion that cytokines and other innate mechanisms contribute to atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs), including the endotoxin receptor TLR4. On the other hand, innate cytokines, such as IL-1 or TNF, or even autoimmune triggers may activate the cells. ytokines potently activate multiple functions relevant to maintain or spoil homeostasis within the vessel wall. Vascular cells, not least smooth muscle cells, can actively contribute to the inflammatory cytokine-dependent network in the blood vessel wall by: (i) production of cytokines; (ii) response to these potent cell activators; and (iii) cytokine-mediated interaction with invading cells, such as monocytes, T-cells, or mast cells. Activation of these pathways results in accumulation of cells and increased LDL- and ECM-deposition which may serve as an 'immunovascular memory' resulting in an ever-growing response to subsequent invasions. Thus, vascular cells may potently contribute to the inflammatory pathways involved in development and acceleration of atherosclerosis. [ABSTRACT FROM AUTHOR]

Interleukin-1 (IL-1) is a potent regulator of cardiovascular proliferation, apoptosis, contraction or production of inflammatory mediators. Thus, we investigated expression and function of IL-1 in cultured neonatal rat heart cells upon endotoxin stimulation. We show that cultured neonatal rat cardiomyocytes expressed IL—1α and IL—1β mRNA. The cells expressed functional cell-associated IL—1 activity and a specific anti-IL—1α-antibody inhibited the activity. Biologically active IL—1α was present at the cell surface of the cardiomyocytes, as indicated in co-culture experiments. Immunohistochemistry showed IL—1α-staining of the neonatal cardiomyocytes. Although the cells also expressed IL—1β mRNA, we did not detect IL—1β in the supernatants of cultured cardiomyocytes by ELISA or in immunohistochemical staining. Furthermore, neonatal and adult rat heart tissues expressed IL—1α mRNA, whereas fetal, but not adult, human cardiac tissues expressed detectable IL—1α mRNA. In contrast, IL-1β mRNA was present in rat and human fetal and adult samples. Furthermore, in patients with dilated or ischemic cardiomyopathy, we measured IL—1β, but not IL—1α, mRNA. These results provide evidence for the presence of functionally active IL—1α on the cell surface of neonatal rat cardiomyocytes and may suggest a differential role of IL—1α in regulation of cellular functions during development, aging and disease in rat and human heart cells. [ABSTRACT FROM PUBLISHER]

Interleukin-1 (IL-1) is a potent regulator of cardiovascular proliferation, apoptosis, contraction or production of inflammatory mediators. Thus, we investigated expression and function of IL-1 in cultured neonatal rat heart cells upon endotoxin stimulation. We show that cultured neonatal rat cardiomyocytes expressed IL-1α and IL-1β mRNA. The cells expressed functional cell-associated IL-I activity and a specific anti-IL-lα-antibody inhibited the activity. Biologically active IL-1α was present at the cell surface of the cardiomyocytes, as indicated in co-culture experiments. Immunohistochemistry showed IL-1α-staining of the neonatal cardiomyocytes. Although the cells also expressed IL-1β mRNA, we did not detect 1L-1β in the supernatants of cultured cardiomyocytes by ELISA or in immunohistochemical staining. Furthermore, neonatal and adult rat heart tissues expressed IL-1α mRNA, whereas fetal, but not adult, human cardiac tissues expressed detectable IL-1α mRNA. In contrast, IL-1β mRNA was present in rat and human fetal and adult samples. Furthermore, in patients with dilated or ischemic cardiomyopathy, we measured IL-1β, but not IL-1α, mRNA. These results provide evidence for the presence of functionally active IL-1α on the cell surface of neonatal rat cardiomyocytes and may suggest a differential role of IL-1α in regulation of cellular functions during development, aging and disease in rat and human heart cells. [ABSTRACT FROM AUTHOR]

Examines the biological activities of lipopolysaccharides (LPS). Determination of the activities by the shape of LPS lipid A portion; Responsibility of lipid A for the expression of pathophysiological effects; Correlation between biological activities and molecular shape of lipid A; Structure of lipid A.

Recognition of LPS, one of the most potent prokaryotic stimulators of immune and non-immune cells of higher organisms, appears to be a complex and highly differentiated process. In CD14-positive cells a model involving two major elements for LPS recognition and uptake, i.e. LBP and cellular CD14, is becoming apparent. The involvement of LBP in the stimulation of CD14-negative cells, such as EC or SMC remains unclear, whereas in this case sCD14 appears to be the acceptor of LPS. In Fig. 2 these considerations are summarized in a simplified model. For both CD14-positive and CD14-negative cell systems, an as-yet-undefined membrane-associated receptor has been postulated, transducing the 'endotoxin' signal into the cell. Further work is necessary to define this signal transduction protein and to ultimately clarify the cellular LPS recognition mechanism. The molecular characterization of LPS-binding, -transport and -signaling events will hopefully lead to long-awaited, and effective novel intervention strategies in endotoxemia and Gramnegative septic shock. [ABSTRACT FROM AUTHOR]