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The use of extracorporeal membrane oxygenation (ECMO) is discussed to improve patients’ outcome in severe COVID-19 with respiratory failure, but data on ECMO remains controversial. The aim of the study was to determine the characteristics of patients under invasive mechanical ventilation (IMV) with or without veno-venous ECMO support and to evaluate outcome parameters. Ventilated patients with COVID-19 with and without additional ECMO support were analyzed in a retrospective multicenter study regarding clinical characteristics, respiratory and laboratory parameters in day-to-day follow-up. Recruitment of patients was conducted during the first three COVID-19 waves at four German university hospitals of the Ruhr University Bochum, located in the Middle Ruhr Region. From March 1, 2020 to August 31, 2021, the charts of 149 patients who were ventilated for COVID-19 infection, were included (63.8% male, median age 67 years). Fifty patients (33.6%) received additional ECMO support. On average, ECMO therapy was initiated 15.6 ± 9.4 days after symptom onset, 10.6 ± 7.1 days after hospital admission, and 4.8 ± 6.4 days after the start of IMV. Male sex and higher SOFA and RESP scores were observed significantly more often in the high-volume ECMO center. Pre-medication with antidepressants was more often detected in survivors (22.0% vs. 6.5%; p = 0.006). ECMO patients were 14 years younger and presented a lower rate of concomitant cardiovascular diseases (18.0% vs. 47.5%; p = 0.0004). Additionally, cytokine-adsorption (46.0% vs. 13.1%; p p = 0.0001) were carried out more frequently; in ECMO patients thrombocytes were transfused 12-fold more often related to more than fourfold higher bleeding complications. Undulating C-reactive protein (CRP) and massive increase in bilirubin levels (at terminal stage) could be observed in deceased ECMO patients. In-hospital mortality was high (Overall: 72.5%, ECMO: 80.0%, ns). Regardless of ECMO therapy half of the study population deceased within 30 days after hospital admission. Despite being younger and with less comorbidities ECMO therapy did not improve survival in severely ill COVID-19 patients. Undulating CRP levels, a massive increase of bilirubin level and a high use of cytokine-adsorption were associated with worse outcomes. In conclusion, ECMO support might be helpful in selected severe cases of COVID-19.

The G-protein-coupled receptor kinase 5 (GRK5) is a mediator of cardiovascular homeostasis and participates in inflammation and cardiac fibrosis, both being involved in the development of diastolic dysfunction (DD). While mechanisms of transcriptional regulation of the GRK5 promoter are unclear, we tested the hypotheses, that (1) GRK5 expression varies depending on functional single nucleotide polymorphisms (SNPs) in the GRK5 promoter and (2) this is associated with DD in patients undergoing coronary artery bypass graft (CABG) surgery.We amplified and sequenced the GRK5 promoter followed by cloning, reporter assays, and electrophoretic mobility shift assays (EMSA). GRK5 messenger ribonucleic acid (mRNA) expression was determined in right atrial tissue sampled from 50 patients undergoing CABG surgery. In another prospective study, GRK5 genotypes were associated with determinants of diastolic function using transesophageal echocardiography in 255 patients with CABG with normal systolic left ventricular (LV) function. Specifically, we measured ejection fraction (EF), transmitral Doppler early filling velocity (E), tissue Doppler early diastolic lateral mitral annular velocity (E' lateral), and calculated E/E', E' norm and the difference of E' lateral and E' norm to account for age-related changes in diastolic function.We identified 6 SNPs creating 3 novel haplotypes with the greatest promoter activation in haplotype tagging (ht) SNP T(-678)C T-allele constructs (P.001). EMSAs showed allele-specific transcription factor binding proving functional activity. GRK5 mRNA expression was greatest in TT genotypes (TT: 131 fg/µg [95% CI, 108-154]; CT: 109 [95% confidence interval {CI}, 93-124]; CC: 83 [95% CI, 54-112]; P = .012). Moreover, GRK5 genotypes were significantly associated with determinants of diastolic function. Grading of DD revealed more grade 3 patients in TT compared to CT and CC genotypes (58% vs 38% vs 4%; P = .023). E´ lateral was lowest in TT genotypes (P = .007) and corresponding E/E' measurements showed 1.27-fold increased values in TT versus CC genotypes (P = .01), respectively. While E' norm values were not different between genotypes (P = .182), the difference between E' lateral and E' norm was significantly higher in TT genotypes compared to CC and CT genotypes (-1.2 [interquartile range {IQR}, 2.7], -0.5 [IQR, 3.4], and -0.4 [IQR, 4.2; P = .035], respectively).A functional GRK5 SNP results in allele-dependent differences in GRK5 promoter activity and mRNA expression. This is associated with altered echocardiographic determinants of diastolic function. Thus, SNPs in the GRK5 promoter are associated with altered perioperative diastolic cardiac function. In the future, preoperative testing for these and other SNPs might allow to initiate more specific diagnostic and perioperative pathways to benefit patients at risk.

Background: Intraoperative hypotension is common in patients having non-cardiac surgery and associated with postoperative acute myocardial injury, acute kidney injury, and mortality. Avoiding intraoperative hypotension is a complex task for anesthesiologists. Using artificial intelligence to predict hypotension from clinical and hemodynamic data is an innovative and intriguing approach. The AcumenTM Hypotension Prediction Index (HPI) software (Edwards Lifesciences; Irvine, CA, USA) was developed using artificial intelligence-specifically machine learning-and predicts hypotension from blood pressure waveform features. We aimed to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery. Methods: We built up a European, multicenter, prospective, observational registry including at least 700 evaluable patients from five European countries. The registry includes consenting adults (?18 years) who were scheduled for elective major non-cardiac surgery under general anesthesia that was expected to last at least 120 min and in whom arterial catheter placement and HPI monitoring was planned. The major objectives are to quantify and characterize intraoperative hypotension (defined as a mean arterial pressure [MAP] < 65 mmHg) when using HPI monitoring. This includes the time-weighted average (TWA) MAP < 65 mmHg, area under a MAP of 65 mmHg, the number of episodes of a MAP < 65 mmHg, the proportion of patients with at least one episode (1 min or more) of a MAP < 65 mmHg, and the absolute maximum decrease below a MAP of 65 mmHg. In addition, we will assess causes of intraoperative hypotension and investigate associations between intraoperative hypotension and postoperative outcomes. Discussion: There are only sparse data on the effect of using HPI monitoring on intraoperative hypotension in patients having elective major non-cardiac surgery. Therefore, we built up a European, multicenter, prospective, observational registry to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery. Funding: Edwards Lifesciences SA, Department of Critical Care, Route de l’Etraz 70, 1260 Nyon, Switzerland funded the study and acts as the legal sponsor. The sponsor/funder had an active role in the design of the study. The collection, analysis, and interpretation of the data will be a collaborative effort of all investigators, who will also write the manuscript. Acknowledgments: We acknowledge the support of all participating patients and their physicians. We also acknowledge the tremendous contribution of the staff at Edwards Lifesciences, especially Edward Hembrow, Tim van den Boom, Anne Halfmann, Pierre Sibileau, Barbara Plasschaert, Volker Haag, Giulia Torricella and Alessia Longo. We further appreciate the excellent project management secured by Daniel Greinert, Marie Zielinksi and Claudia Lüske at the Institute for Pharmacology and Preventive Medicine (Cloppenburg, Germany). Data are captured using the s4trials software provided by Software for Trials Europe GmbH (Berlin, Germany).

Background and aims Coronary artery calcification (CAC) is one of the most sensitive and specific markers of coronary atherosclerosis and believed to be heritable. We hypothesized that functionally relevant single-nucleotide polymorphisms (SNPs) in the G-protein signal pathway, which have been previously related to coronary artery disease, are associated with CAC progression. Methods 3108 participants from the Heinz Nixdorf Recall study with CAC measurements at both baseline (CACb) and 5-year follow-up (CAC5y) were included. We genotyped SNPs rs1042714 (ADRB2), rs6026584 and rs12481583 (GNAS), and rs5443 (GNB3) and defined a priori risk alleles derived from literature data. Regression analyses were applied to measures of 5-year CAC progression, unadjusted, adjusted for age, sex, and adjusted for age, sex, log(CACb+1) as well as for cardiovascular risk factors. Results The presence of one or more risk alleles was associated with a 26.9% (95% CI 5.5–52.4) increase in 5-year CAC progression (p = 0.011) and a 29.2% (95% CI 5.9–57.6) accelerated increase of CAC over the 5-year period compared to what was expected with respect to the baseline CAC percentile value (p = 0.012). Each of those risk alleles increased the 5-year CAC progression by 4.4% (95% CI 1.3–7.6, p = 0.006) and resulted in a 4.9% accelerated increase of CAC over the 5-year period (95% CI 1.6–8.4, p = 0.004). These unadjusted data did not change after adjustment. Conclusions Genetic variations in the G-protein signal pathway are associated with CAC progression in a cumulative fashion, indicating the importance of the pathway for genetic heritability in CAC progression and coronary artery disease.

Background Postoperative nausea and vomiting (PONV) is the most frequent side effect following anaesthesia. Predisposition to developing PONV is multifactorial with patient risk factors and anaesthetic techniques both being contributory. However, there is also a genetic susceptibility to PONV, and several studies have aimed to identify polymorphisms contributing to a genetic PONV risk. Objective We summarised previous published studies investigating genetic contribution to PONV risk. Design Systematic review without meta-analysis. Data source We searched MEDLINE until June 2019. Eligibility criteria Articles were chosen for review when PONV and polymorphisms were included. Exclusion criteria were reviews/meta-analysis/comments, articles not in the English language, nonappropriate content (e.g. PONV not as primary aim of the study, study investigated opioid-induced nausea) or if articles were pharmacogenetic studies addressing treatment of PONV. Results A total of 59 studies were screened and 14 articles were reviewed including one genome-wide association study (GWAS). Seven studies were performed in East Asians, and seven in Caucasians. Seventeen polymorphisms have been positively associated with PONV in at least one study. Allele frequency of the investigated polymorphisms differs widely between the ethnicities. Furthermore, the anaesthesia regimen and the postoperative time point at which the association with PONV was reported were quite different. Only two polymorphisms, the CHRM3 rs2165870 and the KCNB2 rs349358 (both first associated with PONV in a GWAS), have been significantly associated with PONV incidence in Caucasians in independent studies. Conclusion There is a genetic susceptibility to the development of PONV. Two single nucleotide polymorphisms (SNPs), the CHRM3 rs2165870 and the KCNB2 rs349358 SNP, seem to have a major influence on PONV incidence, at least in Caucasians. Both SNPs were primarily identified in a GWAS and this association may lead to a better understanding of the disease aetiology. Further high-quality studies are needed to reveal more insights in genetic PONV susceptibility, particularly so in non-Caucasian ethnicities.

Purpose:We examined interdisciplinary variability using 2 established preoperative nephrometry scores to predict conversion to nephrectomy in patients with a renal mass who were scheduled for parti...

BACKGROUND Intraoperative hypotension is associated with increased morbidity and mortality. The Hypotension Prediction Index (HPI) is an advancement of the arterial waveform analysis to predict intraoperative hypotension minutes before episodes occur enabling preventive treatments. We tested the hypothesis that the HPI combined with a personalized treatment protocol reduces intraoperative hypotension when compared to arterial waveform analysis alone. METHODS We conducted a retrospective analysis of 100 adult consecutive patients undergoing moderate- or high-risk noncardiac surgery with invasive arterial pressure monitoring using either index guidance (HPI) or arterial waveform analysis (FloTrac) depending on availability (FloTrac, n = 50; HPI, n = 50). A personalized treatment protocol was applied in both groups. The primary endpoint was the incidence and duration of hypotensive events defined as MAP

The choice of the anesthetic regime is suggested to affect clinical outcomes following major surgery. Propofol was shown to exert beneficial effects on different cancer outcomes, while volatile anesthetics may be favorable in cardiac surgery. Recently, extracellular vesicles (EVs) were discovered as essential signal mediators in physiological and pathophysiological processes including carcinogenesis and metastasis. Furthermore, depending on their cell source, EVs fulfill therapeutic functions. In addition to extracorporally produced EVs, appropriate systemic intervention such as remote ischemic preconditioning (RIPC) is considered to promote endogenous release of therapeutically active EVs to mediate cardioprotective effects. EVs are assembled in cell-type specific manners and the composition of EVs is not only affected by the disease, but also by the applied anesthetic of anesthetized patients. Here, we compare known impacts of anesthetic agents on outcomes in cancer surgery and cardioprotection and link these effects to the composition and therapeutic potential of EVs.

BACKGROUND: We examined the association between emergent postoperative tracheal intubation and the use of supraglottic airway devices (SGAs) vs tracheal tubes. METHODS: We included data from adult noncardiac surgical cases under general anaesthesia between 2008 and 2018. We only included cases (n=59 991) in which both airways were deemed to be feasible options. Multivariable logistic regression, instrumental variable analysis, propensity matching, and mediation analysis were used. RESULTS: Use of a tracheal tube was associated with a higher risk of emergent postoperative intubation (adjusted absolute risk difference [ARD]=0.80%; 95% confidence interval (CI), 0.64–0.97; P

Remote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion reduces myocardial ischemia/reperfusion injury. In left ventricular (LV) biopsies from patients undergoing coronary artery bypass grafting (CABG), only the activation of signal transducer and activator of transcription 5 was associated with RIPC’s cardioprotection. We have now used an unbiased, non-hypothesis-driven proteomics and phosphoproteomics approach to analyze LV biopsies from patients undergoing CABG and from pigs undergoing coronary occlusion/reperfusion without (sham) and with RIPC. False discovery rate-based statistics identified a higher prostaglandin reductase 2 expression at early reperfusion with RIPC than with sham in patients. In pigs, the phosphorylation of 116 proteins was different between baseline and early reperfusion with RIPC and/or with sham. The identified proteins were not identical for patients and pigs, but in-silico pathway analysis of proteins with ≥2-fold higher expression/phosphorylation at early reperfusion with RIPC in comparison to sham revealed a relation to mitochondria and cytoskeleton in both species. Apart from limitations of the proteomics analysis per se, the small cohorts, the sampling/sample processing and the number of uncharacterized/unverifiable porcine proteins may have contributed to this largely unsatisfactory result.

ZusammenfassungDurch zunehmende Technisierung in der Anästhesiologie und Intensivmedizin steigen sowohl Anzahl der Geräte als auch deren visuelle und akustische Alarme. Die meisten aller Alarme sind jedoch Fehlalarme, was bei den Mitarbeitern zu Frustration, Aggression und Fehlverhalten führt. Dieser Übersichtsartikel fasst die Risikofaktoren für die Entstehung von „Alarm-Fatigue“ zusammen und gibt einen Ausblick auf mögliche Lösungsstrategien.

Background Remote ischemic preconditioning (RIPC) reduces myocardial injury and improves clinical outcome in patients undergoing coronary revascularization, but only in the absence of propofol-anesthesia. We investigated whether RIPC provides protection of heart, kidneys and brain and improves outcome in patients undergoing transfemoral transcatheter aortic valve implantation (TF-TAVI). Methods Patients undergoing TF-TAVI were randomized to receive RIPC (3cycles of 5min left upper arm ischemia and 5min reperfusion) or placebo. The primary endpoint was myocardial injury, reflected by the area under the curve for serum troponin I concentrations (AUC-TnI) over the first 72h. Secondary endpoints included the incidences of periprocedural myocardial infarction, delayed gadolinium enhancement on postprocedural cardiac MRI, acute kidney injury, periprocedural stroke, and the incidence and volume of new lesions on postprocedural cerebral MRI. All-cause and cardiovascular mortality and major adverse cardiac and cerebrovascular events (MACCE) were assessed over 1-year follow-up. A prespecified interim-analysis was performed after the last patient had completed 1-year follow-up (NCT02080299). Results 100 consecutive patients were enrolled between September 2013 and June 2015. There were no significant between-group differences in the primary endpoint of peri-interventional myocardial injury (ratio RIPC/placebo AUC-TnI: 0.87, 95% CI: 0.57–1.34, p =0.53) or the secondary endpoints of cardiac, renal and cerebral impairment. There was no significant treatment effect in subgroup-analyses of patients undergoing cardiac or cerebral MRI. Mortality and MACCE did not differ. No RIPC-related adverse events were observed. Conclusions RIPC did neither protect heart, kidneys and brain nor improve clinical outcome in patients undergoing TF-TAVI.

Clinical risk factors for postoperative nausea and vomiting (PONV) are usually stratified using the Apfel Score. While a genetic predisposition has recently been demonstrated with the muscarinic acetylcholine receptor (CHRM3) rs2165870 single nucleotide polymorphism (SNP), we investigated whether (1) other SNPs contribute to PONV risk and (2) a genetic risk score might summarise genetic PONV risk.We retrospectively analysed data from a study with 472 patients undergoing elective surgery. We investigated the SNPs rs3218315 (IL2RB), rs349358 (KCNB2), rs703363 (intergenic variant), rs1800497 (DRD2), rs1799971 (OPRM1), and rs1176713 (HTR3A). A genetic risk score was established and association with PONV investigated.Early PONV occurred in 37%. There was a significant association of the KCNB2 rs349358 SNP with nausea (P = 0.021), retching (P = 0.001), and PONV (P = 0.006). The rs349358 genotype distribution was TT in 310 and TC/CC in 155 patients. The KCNB2 SNP was associated with an Odds Ratio (OR) of 1.6 for CT/CC vs. TT (95% CI 1-2.5; P = 0.031) to develop PONV and this was independent from the Apfel Score, and the CHRM3 rs2165870 SNP. A genetic risk score based on the CHRM3 rs2165870 and the KCNB2 rs349358 SNP was created and this genetic score (OR per genetic risk score point: 1.6 (1.3-2.1), P 0.0001) was independent from the Apfel Score (OR per Apfel score point: 1.6 (1.3-1.9), P 0.0001) associated with PONV.The KCNB2 rs349358 SNP is also an independent PONV predictor and a genetic risk score has a similar impact on PONV susceptibility compared to the Apfel Score.

Objectives: During transcatheter aortic valve implantation (TAVI), ideal positioning is crucial. The latest-generation balloon expandable Sapien3™ transcatheter heart valve (THV) comes with a marke...

Pain after surgery remains a major health problem, calling for optimized treatment regimens to maximize the efficacy of pharmacological interventions. In this randomized controlled trial, we tested in a routine surgical treatment setting whether postoperative pain can be reduced by a brief preoperative intervention, ie, positive verbal suggestions in combination with sham acupuncture, designed to optimize treatment expectations. We hypothesized that the expectancy intervention as add-on to patient-controlled intravenous analgesia with morphine reduces patient-reported postoperative pain and improves satisfaction with analgesia. Ninety-six women undergoing breast cancer surgery were randomized at 2 stages: Before surgery, anesthesiologists delivered either positive or neutral verbal suggestions regarding the benefits of acupuncture needling on postoperative pain ("information condition"). Patients were then randomized to receive sham acupuncture or no sham acupuncture during postoperative care ("sham acupuncture condition"). Average pain during the 24-hour observation period after surgery as primary and satisfaction with analgesia as secondary outcome was assessed with standardized measures and analyzed with analysis of covariance accounting for morphine dose, surgery-related, and psychological parameters. Postoperative pain ratings were significantly reduced in patients who received positive treatment-related suggestions (F = 4.45, P = 0.038, main effect of information). Moreover, patients who received an intervention aimed at optimized treatment expectations reported significantly greater satisfaction with analgesia (F = 4.89, P = 0.030, interaction effect). Together, our proof-of-concept data support that optimizing treatment expectations through verbal suggestions may offer a promising approach to improve patient-reported outcomes. Future translational and clinical studies are needed to test such psychological strategies in different surgical interventions, patient groups, and pharmacological treatment regimens.

BACKGROUND Remote ischaemic preconditioning (RIPC) can attenuate myocardial ischaemia/reperfusion injury but its underlying mechanisms remain largely unknown. Recently, extracellular vesicles (EVs) containing microRNAs (miRNAs) were shown to mediate distant intercellular communication that may be involved in cardioprotection. We tested the hypothesis that RIPC in anaesthetized patients undergoing coronary artery bypass (CABG) surgery results in the release of EVs from the ischaemic/reperfused arm into the blood stream harbouring cardioprotective miRNAs. METHODS In 58 patients randomised to RIPC (three 5/5 minutes episodes of left arm ischaemia/reperfusion by suprasystolic blood pressure cuff inflations/deflations) or Sham, a subprotocol comprising of parallel right radial artery and regional (left subclavian) venous blood sampling before (awake) and 5 and 60 minutes after RIPC/Sham during isoflurane/sufentanil anaesthesia could be completed. EVs were extracted by polymer-based precipitation methods, their concentrations measured, and their miRNA signature analysed. RESULTS Five minutes after RIPC, regional venous EV concentrations downstream from the cuff increased and arterial concentrations increased after 60 minutes (fold change [fc]: RIPC: 1.33 ± 0.5, Sham: 0.91 ± 0.31; P = 0.003 for interaction). Already 5 minutes after RIPC, expression of 26 miRNAs (threshold fc: 3.0, P

Acute type I aortic dissection (AD) complicated by true lumen (TL) collapse and malperfusion downstream is associated with devastating prognosis. The study reports an institutional mid-term experience with TL stabilization by uncovered stents to restore perfusion as a supplement to proximal thoracic aortic surgery. Between January 2007 and May 2017, 181 out of 270 acute type A AD patients were operated on type I AD. Eighteen uncovered stents (10%) were used to expand the aortic TL in presence of visceral and/or peripheral malperfusion. The procedures took place in a hybrid operating room and were combined with proximal aortic surgery. During follow-up (mean ± standard deviation 3.44 ± 2.1 years), the fate of AD was evaluated by computed tomography. Indication for TL stenting included visceral (44%) or peripheral malperfusion (11%) or both (45%). Stenting of aortic branches followed in 33%. All patients underwent proximal repair and were combined with frozen elephant trunk (67%) or retrograde descending aorta stent grafting (11%). Thirty-day mortality was 16.7%. Two-year survival was 71.8%. The false lumen around the uncovered stents remained patent in 89% and the aortic diameter increased 0.1 cm/y. No intimal rupture or occlusion of arteries occurred. In 1 patient, the stented aortic lumen was visualized after 6.3 years and neointima ingrowth covering the nitinol frame was found. In acute type I AD, combined endovascular-surgical procedures in a hybrid operation room setting can be used safely to resolve distal malperfusion. Encapsulation of uncovered stents within the intimal wall provides a stable fundament for endovascular techniques to close entry tears and false lumen.

Background Remote ischemic preconditioning ( RIPC ) by repeated brief cycles of limb ischemia/reperfusion attenuates myocardial ischemia/reperfusion injury. We aimed to identify a functional parameter reflecting the RIPC ‐induced protection in human. Therefore, we measured mitochondrial function in right atrial tissue and contractile function of isolated right atrial trabeculae before and during hypoxia/reoxygenation from patients undergoing coronary artery bypass grafting with RIPC or placebo, respectively. Methods and Results One hundred thirty‐seven patients under isoflurane anesthesia underwent RIPC (3×5 minutes blood pressure cuff inflation on the left upper arm/5 minutes deflation, n=67) or placebo (cuff uninflated, n=70), and right atrial appendages were harvested before ischemic cardioplegic arrest. Myocardial protection by RIPC was assessed from serum troponin I/T concentrations over 72 hours after surgery. Atrial tissue was obtained for isolation of mitochondria ( RIPC /placebo: n=10/10). Trabeculae were dissected for contractile function measurements at baseline and after hypoxia/reoxygenation (60 min/30 min) and for western blot analysis after hypoxia/reoxygenation ( RIPC /placebo, n=57/60). Associated with cardioprotection by RIPC (26% decrease in the area under the curve of troponin I/T), mitochondrial adenosine diphosphate–stimulated complex I respiration (+10%), adenosine triphosphate production (+46%), and calcium retention capacity (+37%) were greater, whereas reactive oxygen species production (−24%) was less with RIPC than placebo. Contractile function was improved by RIPC (baseline, +7%; reoxygenation, +24%). Expression and phosphorylation of proteins, which have previously been associated with cardioprotection, were not different between RIPC and placebo. Conclusions Cardioprotection by RIPC goes along with improved mitochondrial and contractile function of human right atrial tissue. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01406678.

In severely injured patients, trauma-induced coagulopathy (TIC) present at hospital admission is associated with increased transfusion requirements, morbidity and mortality. Early and effective treatment contributes to improved survival rates. Laboratory coagulation assays have long turn-around times and evidence for their usefulness, especially in the context of TIC, is weak. Due to the lack of appropriate guidance, transfusion of allogeneic blood products frequently follows a ratio-based concept (e.g., transfusion of erythrocytes and plasma in a 1 : 1 ratio). Point-of-care (PoC) tests enable the assessment of prothrombin time (PT) and activated partial thromboplastin time in few minutes. However, although normal PT in these tests allows to rule out relevant effects of several anticoagulants, they are not able to detect patients with TIC and/or requiring subsequent massive transfusion. Viscoelastic tests (VETs) make it possible to assess defects in thrombin generation, hypofibrinogenaemia, thrombocytopenia, and hyperfibrinolysis, and thus enable targeted therapy. Impairment of platelet function is the common blind spot not detectable using both standard laboratory-based tests and VETs. However, PoC platelet function tests enable to detect platelet defects and patients taking anti-platelet. Furthermore, impaired platelet function has been identified as a strong predictor for coagulopathy and massive transfusion in trauma patients. In other clinical settings, coagulation management based on VETs is associated with decreased transfusion requirements, incidence of acute kidney failure, and mortality, respectively. Data of the first small prospective randomised trial indicate superiority of VET guided coagulation management solely using coagulation factor concentrates, when compared to plasma transfusions in severe trauma.Jeder 4. Schwerverletzte weist bereits bei Krankenhausaufnahme eine traumainduzierte Koagulopathie (TIK) auf, die mit einer 4-fach erhöhten Mortalität einhergeht. Rasche und zielgenaue Behandlung kann die TIK-assoziierte Sterblichkeit senken. Point-of-Care-Tests ermöglichen im Vergleich mit herkömmlichen Labormethoden eine zeitnahe und umfassende Bestimmung des Gerinnungsstatus sowie eine zielgerichtete Therapie.

BACKGROUND The risk of developing postoperative nausea and vomiting (PONV), apart from conventional risk factors, probably includes a genetic background. OBJECTIVES We examined the association of the DRD2 TaqIA polymorphism with PONV in a high-risk cohort of patients. DESIGN A prospective, double-blind observational trial. SETTING Single-centre primary care in Western Germany. PATIENTS A total of 306 patients undergoing elective strabismus surgery under anaesthesia with etomidate/alfentanil/mivacurium (induction) and sevoflurane in air (maintenance). MAIN OUTCOME MEASURES Nausea as well as retching/vomiting was recorded for 24 h postoperatively. The DRD2 TaqIA polymorphism (rs1800497) was genotyped using a Taqman assay and the relationship between DRD2 TaqIA polymorphism and PONV was examined by univariate and multivariate analysis. RESULTS Regarding known risk factors for developing PONV, no patient with the A1A1 genotype (n = 15) had a history of PONV, while A1A2 carriers (n = 115) and A2A2 carriers (n = 176) had a history of PONV in 22.6 and 10.8% of patients, respectively (P = 0.005). Overall, the incidence of nausea was 40.1% and the incidence of vomiting/retching was 32.7%. Univariate analysis showed that postoperative nausea was not associated with TaqIA genotypes, but the incidence of retching/vomiting in A1A2 and A2A2 genotypes was more than 34% compared with zero in A1A1 genotypes (P = 0.022). Age, sex, smoking status and a history of PONV were independent predictors for nausea as well as for retching/vomiting, as expected, while DRD2 TaqIA polymorphism showed no independent significant impact. CONCLUSION In a white cohort, the TaqIA A2 allele is significantly associated with a history of PONV, which may explain the increased incidence of PONV but has no further independent influence. TRIAL REGISTRATION German registry of clinical trials identifier: DRKS00005681.

Coronary artery-bypass-graft (CABG) surgery is associated with myocardial damage and increased blood concentrations of circulating microRNAs (miRNA). However, whether and to what extent these miRNAs relate to cardiac tissue miRNA expression have not yet been explored. Since plasma miRNA quantification in samples from cardiopulmonary bypass (CPB) patients is severely hampered by heparin, we established and validated successfully a protocol to reliably measure miRNA in 49 heparinized patients undergoing CABG so as to investigate the relationship between circulating and right atrial miRNAs. Plasma and right atrial expression of miR-1, miR-133a, miR-423-5p, and miR-499 were measured before and after CPB, as well as miRNAs in plasma 24 h thereafter. All plasma miRNAs increased significantly with surgery while cardiac tissue expression of only miR-133a (1.4-fold; p = 0.003) and miR-423-5p (1.3 fold; p = 0.025) increased as well. Right atrial and plasma miR-133a expression correlated positively before CPB (r = 0.288, p = 0.045) but miR-499 expression inversely (r = −0.484, p = 0.0004). There was a strong association between plasma miR-133a and miR-499 concentrations and postoperative troponin I concentrations, the marker for myocardial damage. Increased myocardial miR-133a and miR-423-5p expression together with unchanged miR-1 and miR-499 expression might suggest active release of these miRNAs rather than their origin from damaged cells.

Ischemic cardiomyopathy (ICM) is characterized by accumulation of p53 causing apoptosis of cardiomyocytes and resulting in upregulation of miRNA (miR)-192, which plays an important role in the development of heart failure after acute myocardial infarction. However, for other cardiomyopathies, miR-192 seems to have minor relevance. We tested in a prospective, observational study comprising 91 patients with diagnosed heart failure (59.3% ICM and 40.7% non-ICM), the hypothesis that miR-192 expression predicts survival in patients with ICM. Median follow-up was 59 months (range: 1–118). While miR-192 expression was significantly associated with age (p = 0.028), log-rank analysis revealed significant association with survival in ICM (p = 0.003) but not in non-ICM (p = 0.6). In ICM, median age at time of death was 84 years in patients with low miR-192 expression but 67 years with high miR-192 expression. Thus, miR-192 expression is associated with survival in ICM and represents a prognostic marker in ischemic heart failure.

The G-protein-coupled receptor kinase 2 (GRK2) plays a major role in cardiovascular diseases, and its expression is increased in heart failure. However, only little is known about factors being involved in up-regulation of GRK2 expression through transcriptional regulation of its promoter. Since the transcription factor early-growth response 1 (EGR-1) is also up-regulated in patients with heart failure, we tested the hypothesis that EGR-1 regulates GRK2 transcription. Stimulation of immortalized rat cardiomyocytes (H9c2) with phorbol 12-myristate 13-acetate (PMA) resulted in up-regulation of Egr-1 and subsequently of Grk2 mRNA expression, with maximum Grk2 expression (p = 0.008) 5 hr after PMA stimulation and being abolished by actinomycin D, indicating a transcriptional mechanism. To identify naturally occurring variants affecting promoter transcriptional activity, we identified a novel G(-43)A polymorphism (rs182084609), which surrounded a putative EGR-1-binding site. While the minor A allele frequency was rare (0.02), this variant was used to explore regulation by EGR-1 and promoter construct with altered alleles at nt-43 were subjected of reporter assays in human embryonic kidney cells (Hek293). Here, EGR-1 over-expression resulted in a more than twofold increase in GRK2 promoter activity but only in the presence of the G-allele (p = 0.04). In electrophoretic mobility shift assays, EGR-1 over-expression resulted in a specific binding of transcription factors only to the G oligonucleotide. Finally, EGR-1 over-expression resulted in increased GRK2 mRNA expression (p = 0.03). We identified EGR-1 as a regulator of GRK2 transcription. Suppression of GRK2 expression by inhibition of EGR-1 binding to GRK2 might be a promising approach to mitigate adrenergic desensitization.

ZusammenfassungJeder 4. Schwerverletzte weist bereits bei Krankenhausaufnahme eine traumainduzierte Koagulopathie (TIK) auf, die mit einer 4-fach erhöhten Mortalität einhergeht. Rasche und zielgenaue Behandlung kann die TIK-assoziierte Sterblichkeit senken. Point-of-Care-Tests ermöglichen im Vergleich mit herkömmlichen Labormethoden eine zeitnahe und umfassende Bestimmung des Gerinnungsstatus sowie eine zielgerichtete Therapie.

Coronary artery disease (CAD) is one of the leading causes of death and disability in Europe and worldwide. For patients with multi-vessel CAD, coronary artery bypass graft (CABG) surgery is a common approach for coronary revascularization, and is of proven symptomatic and prognostic benefit. Due to an aging population, higher prevalence of co-morbidities (such as diabetes mellitus, heart failure, hypertension, and renal failure), and a growing requirement for concomitant surgical procedures (such as valve and aortic surgery), higher risk patients are undergoing surgery.1–3 This has resulted in an increased risk of peri-operative myocardial injury (PMI)4 and Type 5 myocardial infarction (MI), both of which are associated with worsened clinical outcomes following CABG surgery. The aetiology and determinants of PMI and Type 5 MI are multi-factorial (see Tables ​Tables11 and ​and22 for summary). Although diagnostic criteria have been proposed for Type 5 MI (based on an elevation in cardiac biomarkers in the 48-h post-operative period and electrocardiogram/angiography/imaging evidence of MI5,13), there is currently no clear definition for prognostically significant PMI, in terms of the level of post-operative cardiac biomarker elevation, which is associated with worsened clinical outcomes following CABG surgery. Table 1 Causes of peri-operative myocardial injury in patients undergoing coronary artery bypass graft surgery

Clinical risk factors for postoperative nausea and vomiting (PONV) are evaluated with the Apfel score, however patients with low Apfel scores still experience PONV suggesting a genetic predisposition. PONV risk associates with specific M3 muscarinic acetylcholine receptor (CHRM3) rs 2165870 polymorphism. We investigated whether the Apfel score and this genetic variation independently contribute to PONV risk and whether prophylaxis reduces PONV in patients with low Apfel score but at high genetic risk.In a prospective, controlled study, 454 subjects undergoing elective surgery were genotyped for rs2165870 and its association with PONV was investigated with log-binomial regression analysis. Subjects were randomised to receive acustimulation/dexamethasone, acustimulation/vehicle, sham acustimulation/dexamethasone, or sham acustimulation/vehicle to investigate their effects on PONV risk.Early PONV occurred in 37% of subjects. The rs2165870 genotype distribution was GG in 191, GA in 207, and AA in 56 subjects. The CHRM3 polymorphism was associated with a relative risk (RR) of 1.5 for GA vs GG [95% confidence interval (CI): 1.1-1.9; P=0.003] and 1.6 for AA vs GG (95% CI: 1.1-2.2; P=0.009) genotypes to develop PONV, and this was independent from the Apfel score (RR per Apfel point: 1.3, 95% CI: 1.2-1.5; P0.0001). While dexamethasone and acustimulation each reduced the PONV risk by 30% in AA genotype carriers with low Apfel score, combined therapy reduced the risk by 86% (P=0.015).The CHRM3 polymorphism and the Apfel score independently predict PONV susceptibility. Dexamethasone/acustimulation should be considered in patients with low Apfel score but at high genetic risk.DRKS00005664.

Objective The C825T polymorphism of the gene encoding the human G protein beta-3 subunit ( GNB3 ) is associated with hypertension and obesity. Moreover, genotypes of the GNB3 polymorphism have been associated with development of coronary artery disease, and the 825T allele is thought to influence the process of atherosclerosis. However, the potential of the C825T polymorphism to predict coronary events has been poorly explored in a longitudinal setting at the population level. Methods In 4159 Caucasian subjects from the Heinz Nixdorf Recall study cohort (age: 45–75 years, 48% male), genotypes of the GNB3 C825T polymorphism (rs5443) were determined and associated with fatal and non-fatal myocardial infarction (hard coronary events). Established cardiovascular risk factors were used to adjust for confounders. Results The median follow-up time was 9.9 years (1st/3rd quartiles 9.5/10.2). 148 subjects (3.6%) experienced a hard coronary event. The 10-year event-free survival rate was CC, 96.1%; CT 96.9%, TT, 93.7% ( p = 0.018). Multivariable analysis showed that the TT genotype is a significant risk factor for hard coronary events (hazard ratio (HR) = 1.9 (95% confidence interval (CI) 1.2–2.9); p = 0.008) after adjustment for age, sex, diabetes, systolic blood pressure, body mass index, high-density lipoprotein, and coronary artery calcification as determined by electron beam computed tomography at baseline. While prognosis in females was independent of GNB3 genotypes, analysis in males even elevated the HR for TT versus C-allele to 2.6 (95% CI 1.6–4.2; p Conclusion The GNB3 825 TT genotype is a significant and independent risk factor for hard coronary events independent of other established cardiovascular risk factors at a population level in males.

Special AT-rich sequence binding protein 1 (SATB1) has regulatory effects on gene expression and appears to play an important role in tumor progression. The present study screened the promoter region of the SATB1 gene for polymorphisms, evaluated the corresponding haplotypes regarding alterations in promoter activity in vitro and analyzed the impact of these haplotypes on the clinical course of breast cancer patients. A cohort of 241 female Caucasian breast cancer patients who had been treated was enrolled in this retrospective analysis. The median follow-up time was 93 months (range, 4–155 months). PCR products from DNA of 10 healthy, unrelated volunteers were analyzed to identify new polymorphisms within the promoter region. Genotyping was conducted using restriction fragment length polymorphism and pyrosequencing. PCR constructs with the respective alleles from the four most frequent haplotypes were cloned into the vector pGEM®-T Easy and then transferred into the luc2-containing reporter vector pGl 4.10® for transfection of HEK293 cells. The pGl 4.73® vector, containing hRluc, was used for normalizing the transfection rates. Sequencing the region -3807 to -2828 bp upstream of ATG from ten healthy blood donors, three single nucleotide polymorphisms consisting of base exchanges were identified: -3600T>C, -3363A>G and -2984C>T. The SATB1 -3600T/-3363A/-2984C haplotype had lower promoter activity than all other constructs in vitro and exhibited a significant association with nodal status (P

Background Remote ischaemic pre-conditioning attenuates myocardial injury. Because sulphonylurea drugs interfere with ischaemic and anaesthetic pre-conditioning, we assessed whether remote ischaemic pre-conditioning effects are altered in sulphonylurea-treated diabetics. Methods Using the database of our ongoing randomised, placebo-controlled study (ClinicalTrials.gov NCT01406678), we assessed the troponin I concentration area under curve (measurements: baseline, 1, 6, 12, 24, 48, and 72 h post-operatively) in sulphonylurea-treated diabetics (n = 27) and non-diabetics (n = 230) without and with remote ischaemic pre-conditioning (three 5-min periods of left upper arm ischaemia with 5-min reperfusion each) during isoflurane anaesthesia before two- to three-vessel coronary artery surgery. Results Remote ischaemic pre-conditioning in non-diabetic patients evoked a 41% decrease in the troponin I concentration area under curve (514 ng/ml × 72 h ± 600 vs. 302 ± 190, P = 0.001) but no change (404 ng/ml × 72 h ± 224 vs. 471 ± 383, P = 0.62) in sulphonylurea-treated diabetics. There was no significant correlation between the troponin I concentration area under curve and arterial glucose concentrations, and the latter was not an independent confounder. Conclusion Cardioprotection by remote ischaemic pre-conditioning during isoflurane anaesthesia is abolished in sulphonylurea-treated diabetics.

Remote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion may reduce myocardial ischemia/reperfusion injury and improve patients‘ prognosis after elective coronary artery bypass graft (CABG) surgery. The signal transducer and activator of transcription (STAT)5 activation in left ventricular myocardium is associated with RIPC´s cardioprotection. Cytokines and growth hormones typically activate STATs and could therefore act as humoral transfer factors of RIPC´s cardioprotection. We here determined arterial plasma concentrations of 25 different cytokines, growth hormones, and other factors which have previously been associated with cardioprotection, before (baseline)/after RIPC or placebo (n = 23/23), respectively, and before/after ischemic cardioplegic arrest in CABG patients. RIPC-induced protection was reflected by a 35% reduction of serum troponin I release. With the exception of interleukin-1α, none of the humoral factors changed in their concentrations after RIPC or placebo, respectively. Interleukin-1α, when normalized to baseline, increased after RIPC (280 ± 56%) but not with placebo (97 ± 15%). The interleukin-1α concentration remained increased until after ischemic cardioplegic arrest and was also higher than with placebo in absolute concentrations (25 ± 6 versus 16 ± 3 pg/mL). Only interleukin-1α possibly fulfills the criteria which would be expected from a substance to be released in response to RIPC and to protect the myocardium during ischemic cardioplegic arrest.

Background Angiotensin II receptor type 1–mediated activation of the α-subunit of the heterotrimeric Gq protein evokes increased vasoconstriction and may promote hypertrophy-induced myocardial damage. The authors recently identified a TT(-695/-694)GC polymorphism in the human Gq promoter, the GC allele being associated with an increased prevalence of cardiac hypertrophy. In this article, the authors tested whether the TT(-695/-694)GC polymorphism is associated with differences in (1) myocardial Gq protein expression, (2) vascular reactivity, and (3) myocardial damage after coronary artery bypass grafting. Methods Gq protein expression was measured in right atrial muscle from 55 patients undergoing coronary artery bypass grafting as were skin perfusion changes (n = 18; laser Doppler imaging), saphenous vein ring vascular reactivity (n = 50, organ bath) in response to angiotensin II, and myocardial damage (227 patients undergoing coronary artery bypass grafting), as assessed by postoperative cardiac troponin I concentration. Results Myocardial Gq expression was greater in GC/GC genotypes (GC/GC vs. TT/TT: 1.27-fold change; P = 0.006). Skin perfusion after intradermal angiotensin II injection decreased only in GC/GC genotypes (P = 0.0002). Saphenous vein rings exposed to increasing angiotensin II concentrations showed an almost doubled maximum contraction in GC/GC compared with individuals with the TT/TT genotype (P = 0.022). In patients undergoing coronary artery bypass grafting, baseline cardiac ejection fraction was different (GC/GC: 55 ± 13%; GC/TT: 54 ± 14%; TT/TT: 48 ± 15%; P = 0.037) and postoperative peak cardiac troponin I was greater in patients with the GC/GC (11.5 ± 13.8 ng/ml) than in patients with the GC/TT (9.2 ± 9.2 ng/ml) or patients with the TT/TT genotype (6.6 ± 4.8 ng/ml, P = 0.015). Conclusions The GC/GC genotype of the TT(-695/-694)GC polymorphism is associated with increased Gq protein expression, augmented angiotensin II receptor type 1–related vasoconstriction, and increased myocardial injury after coronary artery bypass grafting, highlighting the impact of Gq genotype variation.

Real-time PCR is an indispensable technique for mRNA expression analysis but conclusions depend on appropriate reference gene selection. However, while reference gene selection has been a topic of publications, this issue is often disregarded when measuring target mRNA expression. Therefore, we (1) evaluated the frequency of appropriate reference gene selection, (2) suggest an easy-to-use tool for least variability reference gene selection, (3) demonstrate application of this tool, and (4) show effects on target gene expression profiles. All 2015 published articles in Naunyn-Schmiedeberg’s Archives of Pharmacology were screened for the use of quantitative real-time PCR analysis and selection of reference genes. Target gene expression (Vegfa, Grk2, Sirt4, and Timp3) in H9c2 cells was analyzed following various interventions (hypoxia, hyperglycemia, and/or isoflurane exposure with and without subsequent hypoxia) in relation to putative reference genes (Actb, Gapdh, B2m, Sdha, and Rplp1) using the least variability method vs. an arbitrarily selected but established reference gene. In the vast majority (18 of 21) of papers, no information was provided regarding selection of an appropriate reference gene. In only 1 of 21 papers, a method of appropriate reference gene selection was described and in 2 papers reference gene selection remains unclear. The method of reference gene selection had major impact on interpretation of target gene expression. With hypoxia, for instance, the least variability gene was Rplp1 and target gene expression (Vefga) heavily showed a 2-fold up-regulation (p = 0.022) but no change (p = 0.3) when arbitrarily using Gapdh. Frequency of appropriate reference gene selection in this journal is low, and we propose our strategy for reference gene selection as an easy tool for proper target gene expression.

Background In heart failure, β-adrenergic receptor (βAR) stimulation desensitizes the receptor, uncouples the downstream Gαs protein, and diminishes signal transduction. We tested the hypotheses that haplotype-tagging single-nucleotide polymorphisms (htSNPs) within the Gαs gene (GNAS) (i) are functionally active and alter Gαs expression, (ii) influence survival after coronary artery bypass grafting (CABG), and (iii) interact with βAR SNPs. Methods Amplification of GNAS intron 1 was followed by cloning, reporter assays, electrophoretic mobility shift assays, and western blots. In a pilot study, 185 patients on βAR blockade undergoing CABG were studied prospectively. The primary endpoint was cardiac-related mortality at 1 yr. Results Two htSNPs defined three common haplotypes with altered reporter activity, allele-specific transcription factor binding, and Gαs protein expression (highest in *3 carriers followed by *2 and *1 haplotypes, P=0.013). After CABG, mortality was GNAS diplotype-dependent: *3/*3: 0%; *3/*2: 2.4%; *3/*1: 2.9%; *2/*2: 4.5%; *2/*1: 9.1%; and *1/*1: 20.0% (P=0.004). While β1AR SNPs were not associated with mortality, β2AR Arg16 allele carriers were at higher risk than Gly16 allele carriers (P=0.008). Gene–gene interaction using gene-related risk alleles demonstrated the number of risk alleles to be independently associated with death (hazard ratio 2.3; 95% confidence interval: 1.5–3.5; P=0.0003). Carriers of the no-risk allele had higher maximum isoproterenol-stimulated adenylyl cyclase activities than risk allele carriers (P=0.003). Conclusions Interactions in the βAR/Gαs pathway may be associated with altered mortality after CABG. This could reconcile previously inconclusive data regarding the effects of βAR SNPs on cardiovascular prognosis.

Summary Surgical aortic valve replacement is the conventional treatment for symptomatic aortic valve stenosis; however, the technique of transfemoral transcatheter aortic valve implantation has recently been developed for older patients at high risk for surgery. We assessed whether this procedure could be safely performed under sedation in 100 patients. Their predicted surgical mortality was 21.6% and mean (SD) age 80 (6.6) years. Sedation was provided by remifentanil infusion (0–0.2 μg.kg−1.min−1) and midazolam (1–3 mg), as required. All patients were closely haemodynamically monitored throughout by an anaesthetist and inotropic drugs administered as indicated by invasive monitoring. Sedation alone was required in 83 patients; in 17 patients sedation had to be converted to general anaesthesia, mainly because of interventional complications (n = 12). All conversions to general anaesthesia occurred after successful valve implantation. Mean (SD) anaesthesia time was 31 (12) min and procedural time 107 (77) min; 30-day and 1-year all-cause mortality were 6% and 13%, respectively. In the majority of patients, transcatheter valve implantation can safely be facilitated by sedation, provided monitoring and drug administration are carried out by an experienced cardiac anaesthetist. You can respond to this article at http://www.anaesthesiacorrespondence.com

Background Because the aquaporin (AQP) 5 promoter -1364A/C polymorphism is associated with altered AQP5 expression, this association could have an impact on key mechanisms in sepsis, such as cell migration, activity of the rennin-angiotensin- aldosterone system (RAAS), and water transport across biologic membranes. Therefore, we tested the hypothesis that the AQP5 promoter -1364A/C polymorphism is associated with increased 30-day survival in severe sepsis. Methods In a prospective study, adults with severe sepsis (N = 154) were genotyped for the AQP5 promoter -1364A/C polymorphism. The clinical endpoint was 30-day survival. Kaplan-Meier plots and multivariate proportional hazard analyses were used to evaluate the relationship between genotypes and clinical outcomes. Results Thirty-day survival was significantly associated with AQP5 -1364A/C genotypes (P = 0.001). Survival rates were 57% for AA genotypes (n = 90) but 83% for combined AC/CC genotypes (56 vs. 8, respectively). Multivariate proportional hazard analysis including sex, age, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment score, body mass index, necessity for continuous hemofiltration/dialysis, concentrations of plasma angiotensin II, serum aldosterone, C-reactive protein, and interleukin 6 as covariates revealed the AQP5 -1364A/C polymorphism as a strong and independent prognostic factor for 30-day survival. In this analysis, homozygous AA subjects were at high risk for death within 30 days (hazard ratio, 3.59; 95% CI, 1.47-8.80; P = 0.005) compared with AC/CC genotypes. Conclusion The C-allele of the AQP5 -1364A/C polymorphism is associated with increased 30-day survival in patients with severe sepsis. This finding suggests the importance of variations in expression of AQP5 channels in severe sepsis.

Heart failure (HF) is characterized by impaired myocardial β-adrenergic signal transduction. Single nucleotide polymorphisms (SNPs) within the β(1)- (Ser49Gly, Arg389Gly) and β(2)-adrenoceptor (Arg16Gly, Gln27Glu, Thr164Ile) have been associated with alterations in adrenoceptor (AR) function sensitivity in vitro and in vivo and possibly contribute to HF progression. The present study evaluated the relation of those SNPs to morbidity and mortality in patients with end-stage HF. A total of 226 patients with end-stage HF (ejection fraction ≤35%) were genotyped for the two β(1)AR SNPs and the three β(2)AR SNPs. Outcome (death, heart transplantation (HTX)) was determined from May 2003 to June 2004. Heart rate, systolic and diastolic blood pressure, and peak oxygen uptake were measured during graded treadmill exercise. Left ventricular end-diastolic and end-systolic diameters, ejection fraction, and fractional shortening at rest were measured using two-dimensional echocardiography. Minor allele frequencies were 0.12 for Gly49 and 0.27 for Gly389 (β(1)AR) and 0.37 for Arg16, 0.43 for Glu27 and 0.01 for Ile164 (β(2)AR). During follow-up, 45 patients died (20%), and 27 patients underwent HTX (12%). No significant differences in the incidence or in the time-to-endpoint of death and HTX between genotypes of the different SNPs within the β(1)- and β(2)AR were detected. However, patients carrying the Arg16-β(2)AR tended to have lower exercise capacity and a higher probability for death/HTX within 45 months (survival proportion 46%) than patients carrying the Gly16Gly-β(2)AR (survival proportion 64%). In conclusion, the Arg16Gly-β(2)AR might impact on exercise capacity and outcome in end-stage heart failure.

Objectives The G-protein Gq, encoded by GNAQ, is involved in glucose metabolism. The GNAQ promoter harbours three polymorphisms. The TT(-695/-694)GC polymorphism was already shown to affect Gq transcription. Accordingly, we (i) characterized the GNAQ promoter polymorphisms G(-173)A and G(-168)A, (ii) investigated potential influences upon the TT(-695/ - 694)GC polymorphism and (iii) studied the associations with metabolic abnormalities in polycystic ovary syndrome (PCOS). Methods Characterization of the polymorphisms was performed with electrophoretic mobility shift assays and reporter assays. Inhibition of lipolysis and Gq expression were measured in adipocytes isolated from female mammary tissue. We genotyped 266 healthy Caucasians, 265 women with PCOS, and 293 healthy, age-matched female controls to associate GNAQ promoter polymorphisms and haplotypes with anthropometric and metabolic variables. Results The A(-168) allele was associated with significantly decreased transcriptional activity and altered transcription factor binding, whereas the G(-173)A polymorphism appeared functionally silent. Linkage and haplotype frequencies analysis resulted in four common haplotypes. In adipose tissue, a 44% higher Gq mRNA concentration was observed in homozygous GC(-695/ -694)-G(-168) haplotypes compared with homozygous TT(-695/-694)-G(-168) haplotypes (P= 0.046). This was associated with increased insulin inhibition of lipolysis in isolated adipocytes. In PCOS patients, the homozygous GC-G haplotype was associated with decreased insulin resistance and body mass index (BMI) compared with the homozygous TT-G haplotype (homeostatic model assessment of insulin resistance: 3.4 ± 0.4 vs. 5.6 ± 0.7 mmol/l × mmol/l 2 , P=0.001; fasting insulin: 86.6 ± 11.9 vs. 128.8 ± 16.5 pmol/I, P= 0.003; B MI: 29.3 ± 1.2 vs. 33.9 ± 1.3 kg/m 2 , P=0.002). No association with BMI was found in healthy women. Conclusion G(-168)A is functionally relevant and in linkage with TT(-695/-694)GC. GNAQ promoter diplotypes are associated with insulin resistance and obesity in PCOS.

Fc receptor-like 2 (FCRL2) is highly expressed on B-cell chronic lymphocytic leukemia (B-CLL) cells and could possibly influence disease pathogenesis. Therefore, we investigated FCRL2 mRNA expression in a large cohort with 152 CLL patients in order to assess its role in risk prediction in B-CLL. FCRL2 mRNA expression was found to be expressed at considerably higher levels in peripheral blood mononuclear cells (PBMC) of B-CLL patients compared to controls (range 1.35- to 210-fold upregulation; P < 0.0001) and cells of other hematological diseases. Patients with high FCRL2 expression (according to ROC-analysis) had a significantly longer treatment-free survival (TFS) and overall survival (OS) than patients with low FCRL2 expression (median TFS: 119 vs. 34 months, P < 0.0001; median OS: 321 months vs. not reached, P = 0.009). Univariate comparisons found that FCRL2 expression was weakly associated with IGHV mutation status (P = 0.05), CD38 status (P < 0.0001) and ZAP-70 status (P < 0.0001). Furthermore, we show that the combination of FCRL2 with ZAP70-, CD38- or IGHV-status could further significantly refine the prognostic information provided by either of the factors alone in TFS and OS. In multivariate analysis low FCRL2 expression was a significant independent prognostic factor (HR 2.4; P = 0.005). Here we demonstrate that the level of FCRL2 expression is correlated with prognosis in B-CLL.