[Clinical acute and emergency medicine curriculum-focus on internal medicine : Recommendations for advanced training in internal medicine in the emergency department]. / Curriculum Klinische Akut- und Notfallmedizin ­ Schwerpunkt Innere Medizin : Empfehlung zu Weiterbildungsinhalten der Inneren Medizin in der Notaufnahme.

In Germany, physicians qualify for emergency medicine by combining a specialty medical training-e.g. internal medicine-with advanced training in emergency medicine according to the statutes of the State Chambers of Physicians largely based upon the Guideline Regulations on Specialty Training of the German Medical Association. Internal medicine and their associated subspecialities represent an important column of emergency medicine. For the internal medicine aspects of emergency medicine, this curriculum presents an overview of knowledge, skills (competence levels I-III) as well as behaviours and attitudes allowing for the best treatment of patients. These include general aspects (structure and process quality, primary diagnostics and therapy as well as indication for subsequent treatment; resuscitation room management; diagnostics and monitoring; general therapeutic measures; hygiene measures; and pharmacotherapy) and also specific aspects concerning angiology, endocrinology, diabetology and metabolism, gastroenterology, geriatric medicine, hematology and oncology, infectiology, cardiology, nephrology, palliative care, pneumology, rheumatology and toxicology. Publications focussing on contents of advanced training are quoted in order to support this concept. The curriculum has primarily been written for internists for their advanced emergency training, but it may generally show practising emergency physicians the broad spectrum of internal medicine diseases or comorbidities presented by patients attending the emergency department.

[Recommendations of the S3 Guideline "Use of Extracorporeal Circulation (ECLS/ ECMO) for Cardiac and Circulatory Failure" of the Association of Scientific Medical Societies in Germany]. / Empfehlungen der S3-Leitlinie (AWMF) "Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen".

In recent years, the use of mechanical support for patients with cardiac or circulatory failure has continuously increased, leading to 3,000 ECLS/ECMO (extracorporeal life support/extracorporeal membrane oxygenation) implantations annually in Germany. Due to the lack of guidelines, there is an urgent need for evidence-based recommendations addressing the central aspects of ECLS/ECMO therapy. In July 2015, the generation of a guideline level S3 according to the standards of the Association of the Scientific Medical Societies in Germany (AWMF) was announced by the German Society for Thoracic and Cardiovascular Surgery (GSTCVS). In a well-structured consensus process, involving experts from Germany, Austria and Switzerland, delegated by 16 scientific societies and the patients' representation, the guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" was created under guidance of the GSTCVS, and published in February 2021. The guideline focuses on clinical aspects of initiation, continuation, weaning and aftercare, herein also addressing structural and economic issues. This article presents an overview on the methodology as well as the final recommendations.

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline]. / Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen : Kurzversion der AWMF-S3-Leitlinie.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline]. / Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen : Kurzversion der AWMF-S3-Leitlinie.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.

The German-Austrian S3 Guideline "Cardiogenic Shock Due to Myocardial Infarction: Diagnosis, Monitoring, and Treatment".

Despite advances in the treatment of acute myocardial infarction with subsequent mortality reduction, which are mainly caused by the early timing of revascularization, cardiogenic shock still remains the leading cause of death with mortality rates still approaching 40 to 50%. Cardiogenic shock is characterized by a multiorgan dysfunction syndrome, often complicated by a systemic inflammatory response syndrome that affects the outcome more than the reduction of the cardiac contractile function. However, both European and American guidelines on myocardial infarction focus on interventional or surgical aspects only. Therefore, experts from eight German and Austrian specialty societies including the German Society for Thoracic and Cardiovascular Surgery published the German-Austrian S3 guideline "cardiogenic shock due to myocardial infarction: diagnosis, monitoring, and treatment" to provide evidence-based recommendations for the diagnosis and treatment of infarction-related cardiogenic shock in 2010 covering the topics of early revascularization, revascularization techniques, intensive care unit treatment including ventilation, transfusion regimens, adjunctive medical therapy, and mechanical support devices. Within the last 3 years, this guideline was updated as some major recommendations were outdated, or new evidence had been found. This review will therefore outline the management of patients with cardiogenic shock complicating acute myocardial infarction according to the updated guideline with a major focus on evidence-based recommendations which have been found relevant for cardiac surgery.

The differential statin effect on cytokine production of monocytes or macrophages is mediated by differential geranylgeranylation-dependent Rac1 activation.

Monocytes and macrophages contribute to pathogenesis of various inflammatory diseases, including auto-inflammatory diseases, cancer, sepsis, or atherosclerosis. They do so by production of cytokines, the central regulators of inflammation. Isoprenylation of small G-proteins is involved in regulation of production of some cytokines. Statins possibly affect isoprenylation-dependent cytokine production of monocytes and macrophages differentially. Thus, we compared statin-dependent cytokine production of lipopolysaccharide (LPS)-stimulated freshly isolated human monocytes and macrophages derived from monocytes by overnight differentiation. Stimulated monocytes readily produced tumor necrosis factor-α, interleukin-6, and interleukin-1ß. Statins did not alter cytokine production of LPS-stimulated monocytes. In contrast, monocyte-derived macrophages prepared in the absence of statin lost the capacity to produce cytokines, whereas macrophages prepared in the presence of statin still produced cytokines. The cells expressed indistinguishable nuclear factor-kB activity, suggesting involvement of separate, statin-dependent regulation pathways. The presence of statin was necessary during the differentiation phase of the macrophages, indicating that retainment-of-function rather than costimulation was involved. Reconstitution with mevalonic acid, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate blocked the retainment effect, whereas reconstitution of cholesterol synthesis by squalene did not. Inhibition of geranylgeranylation by GGTI-298, but not inhibition of farnesylation or cholesterol synthesis, mimicked the retainment effect of the statin. Inhibition of Rac1 activation by the Rac1/TIAM1-inhibitor NSC23766 or by Rac1-siRNA (small interfering RNA) blocked the retainment effect. Consistent with this finding, macrophages differentiated in the presence of statin expressed enhanced Rac1-GTP-levels. In line with the above hypothesis that monocytes and macrophages are differentially regulated by statins, the CD14/CD16-, merTK-, CX3CR1-, or CD163-expression (M2-macrophage-related) correlated inversely to the cytokine production. Thus, monocytes and macrophages display differential Rac1-geranylgeranylation-dependent functional capacities, that is, statins sway monocytes and macrophages differentially.

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome.

BACKGROUND: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) as complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery are life-threatening conditions. While there is a broad body of evidence for the treatment of people with acute coronary syndrome under stable haemodynamic conditions, the treatment strategies for people who become haemodynamically unstable or develop CS remain less clear. We have therefore summarised here the evidence on the treatment of people with CS or LCOS with different inotropic agents and vasodilative drugs. This is the first update of a Cochrane review originally published in 2014. OBJECTIVES: To assess efficacy and safety of cardiac care with positive inotropic agents and vasodilator strategies in people with CS or LCOS due to AMI, HF or cardiac surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in June 2017. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials in people with myocardial infarction, heart failure or cardiac surgery complicated by cardiogenic shock or LCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 13 eligible studies with 2001 participants (mean or median age range 58 to 73 years) and two ongoing studies. We categorised studies into eight comparisons, all against cardiac care and additional other active drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo, epinephrine versus norepinephrine-dobutamine, amrinone versus dobutamine, dopexamine versus dopamine, enoximone versus dopamine and nitric oxide versus placebo.All trials were published in peer-reviewed journals, and analysis was done by the intention-to-treat (ITT) principle. Twelve of 13 trials were small with few included participants. Acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements emerged in five of 13 trials. In general, confidence in the results of analysed studies was reduced due to serious study limitations, very serious imprecision or indirectness. Domains of concern, which show a high risk of more than 50%, include performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events.Levosimendan may reduce short-term mortality compared to a therapy with dobutamine (RR 0.60, 95% CI 0.37 to 0.95; 6 studies; 1776 participants; low-quality evidence; NNT: 16 (patients with moderate risk), NNT: 5 (patients with CS)). This initial short-term survival benefit with levosimendan vs. dobutamine is not confirmed on long-term follow up. There is uncertainty (due to lack of statistical power) as to the effect of levosimendan compared to therapy with placebo (RR 0.48, 95% CI 0.12 to 1.94; 2 studies; 55 participants, very low-quality evidence) or enoximone (RR 0.50, 95% CI 0.22 to 1.14; 1 study; 32 participants, very low-quality evidence).All comparisons comparing other positive inotropic, inodilative or vasodilative drugs presented uncertainty on their effect on short-term mortality with very low-quality evidence and based on only one RCT. These single studies compared epinephrine with norepinephrine-dobutamine (RR 1.25, 95% CI 0.41 to 3.77; 30 participants), amrinone with dobutamine (RR 0.33, 95% CI 0.04 to 2.85; 30 participants), dopexamine with dopamine (no in-hospital deaths from 70 participants), enoximone with dobutamine (two deaths from 40 participants) and nitric oxide with placebo (one death from three participants). AUTHORS' CONCLUSIONS: Apart from low quality of evidence data suggesting a short-term mortality benefit of levosimendan compared with dobutamine, at present there are no robust and convincing data to support a distinct inotropic or vasodilator drug-based therapy as a superior solution to reduce mortality in haemodynamically unstable people with cardiogenic shock or LCOS.Considering the limited evidence derived from the present data due to a generally high risk of bias and imprecision, it should be emphasised that there remains a great need for large, well-designed randomised trials on this topic to close the gap between daily practice in critical care medicine and the available evidence. It seems to be useful to apply the concept of 'early goal-directed therapy' in cardiogenic shock and LCOS with early haemodynamic stabilisation within predefined timelines. Future clinical trials should therefore investigate whether such a therapeutic concept would influence survival rates much more than looking for the 'best' drug for haemodynamic support.

Practical Applications for Single Pill Combinations in the Cardiovascular Continuum.

Despite the availability of new drugs and devices, the treatment of cardiovascular disease remains suboptimal. Single-pill combination therapy offers a number of potential advantages. It can combine different classes of drugs to increase efficacy while mitigating the risks of treatment-related adverse events, reduce pill burden, lower medical cost, and improve patient adherence. Furthermore, in hypertension, single pill combinations include standard to lower doses of each drug than would be necessary to achieve goals with monotherapy, which may explain their better tolerability compared with higher dose monotherapy. Combination therapy is now established in the treatment of hypertension. In ischaemic heart disease, the concept of a preventative polypill has been studied, but its benefits have not been established conclusively. However, the combination of ivabradine and beta-blockers has proven efficacy in patients with stable angina pectoris. This combination has also demonstrated benefits in patients with chronic heart failure.

Prognostic relevance of the interaction between short-term, metronome-paced heart rate variability, and inflammation: results from the population-based CARLA cohort study.

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.

"Smoker's paradox" in patients with cardiogenic shock complicating myocardial infarction - A substudy of the IABP-SHOCK II-trial and registry.

BACKGROUND: Several studies in patients with acute myocardial infarction (AMI) without cardiogenic shock (CS) indicate a better survival in smokers, the so called "smoker's paradox". For CS, this relationship has not been investigated so far in the primary percutaneous coronary intervention (PCI) era. METHODS: In a predefined substudy of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial and its accompanying registry including patients with CS complicating AMI we investigated differences in outcome of smokers compared to non-smokers. All-cause-mortality at 1year was used as primary endpoint. RESULTS: Of 772 patients with available smoking status 263 patients were smokers (34%). Smokers were more often male (79% vs. 65%; p<0.001), of younger age (61 [interquartile range IQR 52-70] vs. 73 [IQR 64-79] years; p<0.001), had less comorbidity including arterial hypertension (62% vs. 71%; p=0.007) and diabetes mellitus (26% vs. 38%; p<0.001) and had lower levels of serum creatinine (13% vs. 25%; p<0.001). There was no significant difference between the 2 groups regarding left ventricular ejection fraction, initial revascularization strategy or use of IABP. Smokers had lower rates of mortality at 12months in univariable analysis (43% vs. 59%; p<0.001) but not after adjustment for important confounders using Cox-regression analysis (hazard ratio 0.77, 95% confidence interval 0.59-1.03; p=0.08). CONCLUSION: Smoking is not predictive of outcome in patients with CS complicating AMI. The observed survival benefit in univariable analysis seems to be explained by the younger age and lower risk profile of smokers.

Association of Serum Thyrotropin with Anthropometric Markers of Obesity in the General Population.

BACKGROUND: Except from associations study with body weight, there are few longitudinal data regarding the association between thyroid function and anthropometric measurements such as waist circumference, waist-to-hip ratio, or waist-to height ratio. OBJECTIVE: This study aimed to investigate the association of thyrotropin (TSH) at baseline with changes in different anthropometric markers between baseline and follow-up in the general population. METHOD: Data were used from four population-based longitudinal cohort studies and one population-based cross-sectional study. A total of 16,902 (8204 males) subjects aged 20-95 years from the general population were studied. Body mass index, waist circumference, waist-to-hip ratio, and waist-to-height ratio were measured. Multivariable median regression models were calculated adjusting for the following covariates: age, sex, baseline value of the respective anthropometric marker, smoking status, follow-up-time period, and study site. RESULTS: In cross-sectional analyses, serum TSH within the reference range was positively associated with waist circumference (ß = 0.94 cm [confidence interval (CI) 0.56-1.32]) and waist-to-height-ratio (ß = 0.029 [CI 0.017-0.042]). These associations were also present for the full range of TSH. In the longitudinal analyses, serum TSH at baseline was inversely associated with a five-year change of all considered anthropometric measures within the prior defined study-specific reference range, as well as in the full range of serum TSH. CONCLUSION: High TSH serum levels were positively associated with current anthropometric markers, even in the study-specific reference ranges. In contrast, high TSH serum levels were associated with decreased anthropometric markers over a time span of approximately five years. Further research is needed to determine possible clinical implications as well as public health consequences of these findings.

Culprit lesion location and outcome in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial.

BACKGROUND: In myocardial infarction without cardiogenic shock (CS), the affected coronary vessel has significant influence on the final infarct size and patient prognosis. CS data on this relation are scarce. The objective of this study was to determine the prognostic relevance of the culprit lesion location in patients with CS complicating acute myocardial infarction. METHODS: In the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial patients with CS were randomized to therapy with intraaortic balloon pump or control. Additional CS patients not eligible for the randomized trial were included in a registry. We compared the location of the culprit lesions in these patients with regard to the affected coronary vessel [left main (LM), left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA)] and location within the vessel (proximal, mid or distal) regarding short- and long-term outcome. RESULTS: Of 758 patients, the majority had the culprit lesion in the LAD (44 %) compared to RCA (27 %), LCX (19 %) or LM (10 %). Proximal lesions were more frequent than mid or distal culprit lesions (60 vs. 27 vs. 13 %, p < 0.001). No differences were observed for mortality with respect to either culprit vessel (log-rank p value = 0.54). In contrast, a higher mortality was observed for patients with distal culprit lesions after 1 year (log-rank p value = 0.04). This difference persisted after multivariable adjustment (hazard ratio for distal lesions 1.40; 95 % confidential interval 1.03-1.90; p = 0.03). CONCLUSION: For patients with CS complicating myocardial infarction, the culprit vessel seems to be unrelated with mortality whereas distal culprit lesions may have a worse outcome.

[Update cardiogenic shock]. / Update kardiogener Schock.

Although IABP support induces left ventricular unloading, these beneficial effect does not lead to improved microcirculation and survival. The use of percutaneous extracorporeal support systems (ECLS, ECMO) as well as left ventricular assist devices (pVAD) for adjunctive treatment of STEMI has increased during the recent years, but without sufficient evidence for a survival benefit. The PCI-access via the radial artery may lead to improved outcomes, especially in regard to survival. A liberal transfusion regimen for red cell packages in the perioperative phase of cardiac surgery seems to improve outcomes in regard to lower incidence of cardiogenic shock postoperatively.

ADP receptor antagonists in patients with acute myocardial infarction complicated by cardiogenic shock: a post hoc IABP-SHOCK II trial subgroup analysis.

AIMS: The aim of this post hoc subgroup analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II trial was to compare the clinical outcome of patients treated with either clopidogrel or the newer, more potent P2Y12 receptor inhibitors prasugrel or ticagrelor. METHODS AND RESULTS: The primary endpoint was one-year mortality with respect to different P2Y12 receptor inhibitors. Secondary safety endpoints were GUSTO bleedings until hospital discharge. After exclusion of 117 patients (patients who died before or during PCI, patients with unavailable information on P2Y12 receptor inhibitor treatment, patients not receiving or receiving a combination of different P2Y12 receptor inhibitors as acute antiplatelet therapy), 483 patients were analysed. Of these, 373 patients (77.2%) received clopidogrel and 110 patients (22.8%) either prasugrel or ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality did not differ between prasugrel/ticagrelor and clopidogrel treated patients (HR: 0.83, 95% CI: 0.59-1.19, padj=0.31). GUSTO bleedings did not differ between groups (14.3% for prasugrel/ticagrelor and 16.4% for clopidogrel, HR: 0.91, 95% CI: 0.55-1.5, padj=0.7). CONCLUSIONS: This IABP-SHOCK II trial subgroup analysis shows that the use of potent P2Y12 receptor inhibitors like prasugrel or ticagrelor is feasible and might not be harmful in selected patients with cardiogenic shock complicating acute myocardial infarction. However, the superiority in comparison to clopidogrel remains to be proven.

Prognostic impact of established and novel renal function biomarkers in myocardial infarction with cardiogenic shock: A biomarker substudy of the IABP-SHOCK II-trial.

BACKGROUND: In cardiogenic shock (CS) renal dysfunction is an important parameter of inadequate end-organ perfusion and an independent predictor of adverse outcome. Early detection of renal dysfunction is therefore important, and novel biomarkers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule 1 (KIM1) and Cystatin C (CysC) have been suggested. However, in high-risk CS patients their role for assessing renal injury has not yet been investigated in comparison to the most widely used serum creatinine. METHODS: This predefined substudy included 190 patients of the randomized Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II)-trial. Blood samples were collected directly during primary percutaneous coronary intervention, one day and two days after randomization. The primary endpoint for outcome assessment was 1 year mortality. RESULTS: Creatinine, NGAL and KIM-1 were significantly higher in non-survivors in comparison to survivors over time in ANOVA (p<0.001; p=0.002 and p=0.04, respectively). In contrast, CysC levels were not associated with the primary endpoint (p=0.15). Receiver operator characteristics revealed that creatinine at any time point had the best predictive value for 1 year mortality. This was also true when comparing creatinine to different equations for glomerular filtration rate. In multivariable Cox-regression analysis creatinine remained the only significant independent predictor of kidney biomarkers of time to death during the first year. CONCLUSIONS: Assessment of novel biomarkers such as CysC, NGAL and KIM-1 or calculation of glomerular filtration rate provide no additional prognostic information in patients with CS complicating acute myocardial infarction in comparison to creatinine.

Gender differences in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial.

BACKGROUND: Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) is associated with high mortality. Previous studies regarding gender-specific differences in CS are conflicting and there are insufficient data for the presence of gender-associated differences in the contemporary percutaneous coronary intervention era. Aim of this study was therefore to investigate gender-specific differences in a large cohort of AMI patients with CS undergoing contemporary treatment. METHODS: In the randomized Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, 600 patients with CS complicating AMI undergoing early revascularization were assigned to therapy with or without intra-aortic balloon pump. We compared sex-specific differences in these patients with regard to baseline and procedural characteristics as well as short- and long-term clinical outcome. RESULTS: Of 600 patients 187 (31%) were female. Women were significantly older than men and had a significantly lower systolic and diastolic blood pressure at presentation (p < 0.05 for all). Diabetes mellitus and hypertension were more frequent in women, whereas smoking was more frequent in men (p < 0.05 for all). Women showed a higher mortality within the first day after randomization (p = 0.004). However, after multivariable adjustment this numerical difference was no longer statistically significant. No gender-related differences in clinical outcome were observed after 1, 6 and 12 months of follow-up. CONCLUSION: In this large-scale multicenter study in patients with CS complicating AMI, women had a worse-risk profile in comparison to men. No significant gender-related differences in treatment as well as short- and long-term outcome were observed.

Interleukin-1 potently contributes to 25-hydroxycholesterol-induced synergistic cytokine production in smooth muscle cell-monocyte interactions.

OBJECTIVES: Inflammation is essential for atherogenesis. Cholesterol, a cardiovascular risk factor, may activate inflammation in the vessel wall during this process. Cytokine-mediated interactions of human monocytes with vascular smooth muscle cells (SMCs) may perpetuate this process. METHODS: We investigated the capacity of the cholesterol metabolite 25-hydroxycholesterol to induce inflammatory mediators in cocultures of freshly isolated monocytes with SMCs. We determined the role of interleukin-(IL)-1 in this interaction using qPCR, bioassays, ELISA and western blot. Cocultures with SMC to monocyte ratios from 1:4 to 1:20 were tested. RESULTS: In separate SMC and monocyte cultures (monocultures) 25-hydroxycholesterol only poorly activated IL-1, IL-6 and MCP-1 production, whereas LPS stimulated much higher cytokine levels than unstimulated cultures. In contrast, cocultures of SMCs and monocytes stimulated with 25-hydroxycholesterol produced hundredfold higher cytokine levels than the corresponding monocultures. Blocking experiments with IL-1-receptor antagonist showed that IL-1 decisively contributed to the 25-hydroxycholesterol-induced synergistic IL-6 and MCP-1 production. The presence of intracellular IL-1ß precursor, released mature IL-1ß, and caspase-1 p10 indicated that the inflammasome was involved in this process. Determination of IL-1-mRNA in Transwell experiments indicated that the monocytes are the major source of IL-1, which subsequently activates the SMCs, the primary source of IL-6 in the coculture. CONCLUSION: Taken together, these interactions between local vessel wall cells and invading monocytes may multiply cholesterol-triggered inflammation in the vessel wall, and IL-1 may play a key role in this process. The data also indicate that lower cholesterol levels than expected from monocultures may suffice to initiate inflammation in the tissue.

Inflammation and renal function after a four-year follow-up in subjects with unimpaired glomerular filtration rate: results from the observational, population-based CARLA cohort.

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.

Growth-differentiation factor 15 and osteoprotegerin in acute myocardial infarction complicated by cardiogenic shock: a biomarker substudy of the IABP-SHOCK II-trial.

AIMS: This study investigates the role of osteoprotegerin (OPG) and growth-differentiation factor 15 (GDF-15) as predictors of outcome in cardiogenic shock (CS) complicating acute myocardial infarction. The novel biomarkers OPG and GDF-15 have shown prognostic impact in various cardiovascular diseases including myocardial infarction. In acute myocardial infarction complicated by CS, the diagnostic and prognostic impact of these biomarkers has not been investigated yet. OPG and GDF-15 may have additional prognostic impact on early prognosis assessment, being potentially useful for decision-making in CS. METHODS AND RESULTS: In the randomized Intra-aortic Balloon Pump in cardiogenic Shock II (IABP-SHOCK II)-trial, 600 patients with CS complicating acute myocardial infarction undergoing early revascularization were assigned to therapy with or without IABP. Within a pre-defined substudy, blood samples were collected from 190 patients during PCI. GDF-15 and OPG serum levels were measured with standard enzyme-linked immunosorbent assay kits. Patients with GDF-15 and OPG levels greater than the median showed higher rates of death at 30 days by χ(2) testing (OPG, 51% vs. 32%, P = 0.01; GDF-15, 52% vs. 31%, P = 0.005) and log rank testing [GDF-15, hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.21-2.94; P = 0.005; OPG, HR 1.74, 95% CI 1.11-2.71; P = 0.01]. Both markers were significantly predictive of 30-day mortality in univariable logistic regression analysis. In a multivariable logistic stepwise regression model, GDF-15, TIMI (Thrombolysis In Myocardial Infarction) flow grade <3 after PCI, age, LVEF, and serum lactate remained significant predictors of 30-day mortality. CONCLUSION: GDF-15 on admission is a significant independent predictor of short-term mortality in infarct-related CS. Trail registration: NCT00491036.

Inflammation and prolonged QT time: results from the Cardiovascular Disease, Living and Ageing in Halle (CARLA) study.

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.