Max Lenz

Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients.

Objectives:Despite underlying pathologies leading to ICU admittance are heterogeneous, many patients develop a systemic inflammatory response syndrome often in the absence of microbial pathogens. Mitochondrial DNA that shows similarities to bacterial DNA may be released after tissue damage and activates the innate immune system by binding to toll-like receptor-9 on immune cells. The aim of this study was to analyze whether levels of mitochondrial DNA are associated with 30-day survival and whether this predictive value is modified by the expression of its receptor toll-like receptor-9. Design:Single-center, prospective, observational study. Setting:A tertiary ICU in a university hospital. Patients:Two hundred twenty-eight consecutive patients admitted to a medical ICU between August 2012 and August 2013. Interventions:None. Measurements and Main Results:Blood was taken within 24 hours after ICU admission, and the levels of circulating mitochondrial DNA were quantified by real-time polymerase chain reaction. Toll-like receptor-9 expression in monocytes was measured by flow cytometry. Median acute physiology and chronic health evaluation II score was 20, and 30-day mortality was 25%. Median mitochondrial DNA levels at admission were significantly higher in nonsurvivors when compared with survivors (26.9, interquartile range = 11.2–60.6 ng/mL vs 19.7, interquartile range = 9.5–34.8 ng/mL; p < 0.05). Patients with plasma levels of mitochondrial DNA in the highest quartile (mitochondrial DNA > 38.2 ng/mL) had a 2.6-fold higher risk (p < 0.001) of dying, independently of age, gender, diagnosis, and acute physiology and chronic health evaluation II score. Mitochondrial DNA improved the c-statistic of acute physiology and chronic health evaluation II score (p < 0.05) and showed enhancement in individual risk prediction indicated by a net reclassification improvement of 32.3% (p < 0.05). Stratification of patients according to toll-like receptor-9 expression above/below median demonstrated that only patients with high expression of toll-like receptor-9 showed an increased risk associated with increased mitochondrial DNA levels (odds ratio, 2.7; p < 0.01), whereas circulating mitochondrial DNA was not associated with mortality in patients with low toll-like receptor-9 expression (odds ratio, 1.1; p = 0.98). Conclusions:Circulating levels of mitochondrial DNA at ICU admission predict mortality in critically ill patients. This association was in particular present in patients with elevated toll-like receptor-9 expression.

Association of small dense LDL serum levels and circulating monocyte subsets in stable coronary artery disease.

Objective Atherosclerosis is considered to be an inflammatory disease in which monocytes and monocyte-derived macrophages play a key role. Circulating monocytes can be divided into three distinct subtypes, namely in classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+) and non-classical monocytes (NCM; CD14+CD16++). Low density lipoprotein particles are heterogeneous in size and density, with small, dense LDL (sdLDL) crucially implicated in atherogenesis. The aim of this study was to examine whether monocyte subsets are associated with sdLDL serum levels. Methods We included 90 patients with angiographically documented stable coronary artery disease and determined monocyte subtypes by flow cytometry. sdLDL was measured by an electrophoresis method on polyacrylamide gel. Results Patients with sdLDL levels in the highest tertile (sdLDL≥4mg/dL;T3) showed the highest levels of pro-inflammatory NCM (15.2±7% vs. 11.4±6% and 10.9±4%, respectively; p<0.01) when compared with patients in the middle (sdLDL=2-3mg/dL;T2) and lowest tertile (sdLDL=0-1mg/dL;T1). Furthermore, patients in the highest sdLDL tertile showed lower CM levels than patients in the middle and lowest tertile (79.2±8% vs. 83.9±7% and 82.7±5%; p<0.01 for T3 vs. T2+T1). Levels of IM were not related to sdLDL levels (5.6±4% vs. 4.6±3% vs. 6.4±3% for T3, T2 and T1, respectively). In contrast to monocyte subset distribution, levels of circulating pro- and anti-inflammatory markers were not associated with sdLDL levels. Conclusion The atherogenic lipoprotein fraction sdLDL is associated with an increase of NCM and a decrease of CM. This could be a new link between lipid metabolism dysregulation, innate immunity and atherosclerosis.

Predictive value of low interleukin-33 in critically ill patients

HighlightsIn critically ill patients IL‐33 is higher in 30‐day survivors.Low levels of IL‐33 and increased levels of sST2 additively predict mortality risk.sST2 correlated with both IL‐6 and CRP in critically ill patients.IL‐33 and sST2 in addition to APACHE II score could improve risk stratification. Abstract Patients admitted to a medical intensive care unit (ICU) are characterized by an activated immune system and exhibit a high mortality rate irrespective of the underlying cause of admission. Interleukin (IL)‐33 has been shown to be protective in experimental sepsis models and it has been demonstrated that circulating levels of its “decoy” receptor soluble ST2 (sST2) are associated with outcome in critically ill patients. The aim of the present study was to investigate whether circulating IL‐33 is associated with 30‐day mortality in patients admitted to a medical ICU. In this prospective, observational study, both IL‐33 and sST2 levels were assessed in 223 consecutive patients at ICU admission using specific enzyme‐linked immunosorbent assays (ELISAs). During the 30‐day follow‐up, 58 patients (26%) died. Circulating IL‐33 was detectable in 166 patients and in 57 patients, serum IL‐33 was below the detection limit. Both detectable IL‐33 and sST2 below the median were strong predictors of survival in critically ill patients independent of acute physiology and chronic health evaluation II (APACHE II) score. IL‐33 and sST2 predicted risk independent from each other. Patients with both, non‐detectable levels of IL‐33 and sST2 levels above the median, showed a dramatically increased mortality risk (HR 6.9 95% CI 3.0–16.2; p < 0.001). Low levels of IL‐33 and increased levels of sST2 predict mortality risk in critically ill patients independent from each other and APACHE II score. Both together showed additive predictive value suggesting a pathogenic role of the IL‐33/ST2 system in critically ill patients.

Copeptin Predicts Mortality in Critically Ill Patients.

Background Critically ill patients admitted to a medical intensive care unit exhibit a high mortality rate irrespective of the cause of admission. Besides its role in fluid and electrolyte balance, vasopressin has been described as a stress hormone. Copeptin, the C-terminal portion of provasopressin mirrors vasopressin levels and has been described as a reliable biomarker for the individual’s stress level and was associated with outcome in various disease entities. The aim of this study was to analyze whether circulating levels of copeptin at ICU admission are associated with 30-day mortality. Methods In this single-center prospective observational study including 225 consecutive patients admitted to a tertiary medical ICU at a university hospital, blood was taken at ICU admission and copeptin levels were measured using a commercially available automated sandwich immunofluorescent assay. Results Median acute physiology and chronic health evaluation II score was 20 and 30-day mortality was 25%. Median copeptin admission levels were significantly higher in non-survivors as compared with survivors (77.6 IQR 30.7–179.3 pmol/L versus 45.6 IQR 19.6–109.6 pmol/L; p = 0.025). Patients with serum levels of copeptin in the third tertile at admission had a 2.4-fold (95% CI 1.2–4.6; p = 0.01) increased mortality risk as compared to patients in the first tertile. When analyzing patients according to cause of admission, copeptin was only predictive of 30-day mortality in patients admitted due to medical causes as opposed to those admitted after cardiac surgery, as medical patients with levels of copeptin in the highest tertile had a 3.3-fold (95% CI 1.66.8, p = 0.002) risk of dying independent from APACHE II score, primary diagnosis, vasopressor use and need for mechanical ventilation. Conclusion Circulating levels of copeptin at ICU admission independently predict 30-day mortality in patients admitted to a medical ICU.

Monocyte subset distribution is associated with mortality in critically ill patients

Although patients admitted to an intensive care unit (ICU) suffer from various pathologies, many develop a systemic inflammatory response syndrome (SIRS). As key regulators of innate immunity, monocytes may be crucially involved in SIRS development. Monocytes can be distinguished into three subsets: Classical monocytes (CD14++CD16-; CM), non-classical monocytes (CD14+CD16++CCR2-; NCM) and intermediate monocytes (CD14++CD16+CCR2+; IM). The aim of this prospective, observational study was to analyse whether monocyte subset distribution is associated with 30-day survival in critically ill patients. A total of 195 consecutive patients admitted to a cardiac ICU at a tertiary-care centre were enrolled, blood was taken at admission and after 72 hours and monocyte subset distribution was analysed. Mean APACHE II score was 19.5 ± 8.1 and 30-day mortality was 25.4 %. At admission, NCM were significantly lower in non-survivors as compared to survivors [2.7 (0.4-5.5) vs 4.2 (1.6-7.5)%; p=0.012] whereas CM and IM did not differ according to 30-day survival. In contrast, 72 hours after admission, monocyte subset distribution shifted towards an increased proportion of IM [8.2 (3.9-13.2) vs 4.2 (2.3-7.9)%; p=0.003] with a concomitant decrease of CM [86.9 (78.6-89.2) vs 89.6 (84.9-93.1)%; p=0.02] in non-survivors vs survivors, respectively. NCM at day 3 were not associated with death at 30 days. These results were independent from age, gender, CRP, APACHE II score and primary diagnosis. In conclusion, circulating monocyte subsets are associated with 30-day mortality in critically ill patients. The innate immune system as reflected by monocyte subset distribution may play a major role in ICU outcome despite varying admittance pathologies.

Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue

Interleukin (IL)‐33 is a member of the IL‐1 family and is able to act cardioprotective. The aim of this study was to investigate the regulation of IL‐33 by 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A (HMG‐CoA) reductase inhibitors (statins) and bisphosphonates (BPs) in human cardiac tissue. The lipophilic fluvastatin, simvastatin, atorvastatin, and lovastatin as well as the nitrogenous BPs alendronate and ibandronate, but not hydrophilic pravastatin increased IL‐33 mRNA and intracellular IL‐33 protein levels in both human adult cardiac myocytes (HACM) and fibroblasts (HACF). Additionally, fluvastatin reduced soluble ST2 secretion from HACM. IL‐33 was also up‐regulated by the general inhibitor of prenylation perillic acid, a RhoA kinase inhibitor Y‐27632, and by latrunculin B, but statin‐induced IL‐33 expression was inhibited by mevalonate, geranylgeranyl pyrophosphate (GGPP) and RhoA activator U‐46619. The IL‐33 promoter was 2.3‐fold more accessible in statin‐treated HACM compared to untreated cells (P = 0.037). In explanted hearts of statin‐treated patients IL‐33 protein was up‐regulated as compared with the hearts of non‐statin‐treated patients (P = 0.048). As IL‐33 was previously shown to exert cardioprotective effects, one could speculate that such up‐regulation of IL‐33 expression in human cardiac cells, which might happen mainly through protein geranylgeranylation, could be a novel mechanism contributing to known cardioprotective effects of statins and BPs.

N-terminal pro-brain natriuretic peptide and high-sensitivity troponin T exhibit additive prognostic value for the outcome of critically ill patients:

Background: Patients treated at medical intensive care units suffer from various pathologies and often present with elevated troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Both markers may reflect different forms of cardiac involvement in critical illness. Therefore, the aim of our study was to examine the synergistic prognostic potential of NT-proBNP and high-sensitivity TnT (hs)TnT in unselected critically ill patients. Methods: We included all consecutive patients admitted to our intensive care unit within one year, excluding those suffering from acute myocardial infarction or undergoing cardiac surgery and measured NT-proBNP and TnT plasma levels on the day of admission and 72 hours thereafter. Results: Of the included 148 patients, 52% were male, mean age was of 64.2 ± 16.8 years and 30-day mortality was 33.2%. Non-survivors showed significantly higher NT-proBNP and TnT plasma levels as compared with survivors (p<0.01). An elevation of both markers exhibited an additive effect on mortality, as those with both NT-proBNP and TnT levels above the median had a 30-day mortality rate of 51.0%, while those with both markers below the median had a 16.7% mortality rate (hazard ratio 3.7). These findings were independent of demographic and clinical parameters (p<0.05). Conclusions: Our findings regarding the individual predictive properties of NT-proBNP and TnT are in line with literature. However, we were able to highlight that they exhibit additive prognostic potential which exceeds their individual value. This might be attributed to a difference in underlying pathomechanisms and an assessment of synergistic risk factors.

CIRCULATING MITOCHONDRIAL DNA IS ASSOCIATED WITH MORTALITY IN PATIENTS WITH ACUTE HEART FAILURE

Background: Patients suffering from acute heart failure (AHF) requiring admission to an intensive care unit (ICU) have a poor prognosis. Activation of the innate immune system contributes to the pathogenesis of AHF. Mitochondrial DNA that shows similarities to bacterial DNA may be released after