Controlled Hypoxia Acutely Prevents Physical Inactivity-Induced Peripheral BDNF Decline.

Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neuronal plasticity. Here, we investigated the effects of controlled normobaric hypoxia (NH) combined with physical inactivity on BDNF blood levels and executive functions. A total of 25 healthy adults (25.8 ± 3.3 years, 15 female) were analyzed in a randomized controlled cross-over study. Each intervention began with a 30 min resting phase under normoxia (NOR), followed by a 90 min continuation of NOR or NH (peripheral oxygen saturation [SpO2] 85-80%). Serum and plasma samples were collected every 15 min. Heart rate and SpO2 were continuously measured. Before and after each exposure, cognitive tests were performed and after 24 h another follow-up blood sample was taken. NH decreased SpO2 (p < 0.001, ηp2 = 0.747) and increased heart rate (p = 0.006, ηp2 = 0.116) significantly. The 30-min resting phase under NOR led to a significant BDNF reduction in serum (p < 0.001, ηp2 = 0.581) and plasma (p < 0.001, ηp2 = 0.362). Continuation of NOR further significantly reduced BDNF after another 45 min (p = 0.018) in serum and after 30 min (p = 0.040) and 90 min (p = 0.005) in plasma. There was no significant BDNF decline under NH. A 24 h follow-up examination showed a significant decline in serum BDNF, both after NH and NOR. Our results show that NH has the potential to counteract physical inactivity-induced BDNF decline. Therefore, our study emphasizes the need for a physically active lifestyle and its positive effects on BDNF. This study also demonstrates the need for a standardized protocol for future studies to determine BDNF in serum and plasma.

Analysis of a nurse-provided on-call peritoneal dialysis support in an outpatient reference care centre.

BACKGROUND: To analyse the nature of medical or technical emergency issues of ambulatory peritoneal dialysis (PD) patients calling a nurse-provided emergency PD support service of a reference centre that is provided all year in the after-hours. METHODS: We retrospectively analysed patients' chief complaint, urgency, resolution of and association to current PD treatment and modality directed to an on-call nurse-provided PD support service from 2015-2021 based on routinely collected health data. Calls were systematically categorized being technical/procedural-, medical-, material-related or type of correspondence. Call urgency was categorized to have "immediate consequence", inquiry was eligible for "processing next working day" or whether there was "no need for further action". Call outcomes were classified according to whether patients were able to initiate, resume or finalize their treatments or whether additional interventions were required. Unexpected adverse events such as patients' acute hospitalization or need for nurses' home visits were evaluated and quantified. RESULTS: In total 753 calls were documented. Most calls were made around 7:30 a.m. (5:00-9:00; median, 25-75th CI) and 6:30 p.m. (5:00-8:15). 645 calls were assigned to continuous ambulatory- (CAPD) or automated PD (APD). Of those, 430 calls (66.7%) had an "immediate consequence". Of those 77% (N = 331) were technical/procedural-, 12.8% (N = 55) medical- and 6.3% (N = 27) material related issues. 4% (N = 17) were categorized as other correspondence. Issues disrupting the course of PD were identified in 413 cases. In 77.5% (N = 320) patients were able to initiate, resume or finalize their treatment after phone consultation. Last-bag exchange was used in 6.1% enabling continued therapy in 83.6%. In 35 cases a nurse visit at patients' home or patients' visit to the practice at the earliest possible date were required, while hospitalization was required in seven medical category cases (5.4% and 1.09% of total assessed calls, respectively). CONCLUSION: The on-call PD-nurse provides patient support for acute and imminent issues enabling them to successfully initiate, resume or finalize their prescribed treatment. Nurses triage of acute conditions facilitated rapid diagnostics and therapy. Maintaining quality PD homecare, the provision of trained personnel is indispensable. The information gathered in this study may therefore be used as a foundation to tailor educational programs for nephrology nurses and doctors to further develop their competencies in PD.

Catheter navigation by intracardiac echocardiography enables zero-fluoroscopy linear lesion formation and bidirectional cavotricuspid isthmus block in patients with typical atrial flutter.

INTRODUCTION: One of the most helpful aspects of intracardiac echocardiography (ICE) implementation in electrophysiological studies (EPS) is the real-time visualisation of catheters and cardiac structures. In this prospective study, we investigated ICE-guided zero-fluoroscopy catheter navigation during radiofrequency (RF) ablation of the cavotricuspid isthmus (CTI) in patients with typical atrial flutter (AFL). METHODS AND RESULTS: Thirty consecutive patients (mean age 72.9 ± 11.4 years, 23 male) with ongoing (n = 23) or recent CTI-dependent AFL underwent an EPS, solely utilizing ICE for catheter navigation. Zero-fluoroscopy EPS could be successfully accomplished in all patients. Mean EPS duration was 41.4 ± 19.9 min, and mean ablation procedure duration was 20.8 ± 17.1 min. RF ablation was applied for 6.0 ± 3.1 min (50W, irrigated RF ablation). Echocardiographic parameters, such as CTI length, prominence of the Eustachian ridge (ER), and depth of the CTI pouch on the ablation plane, were assessed to analyse their correlation with EPS- or ablation procedure duration. The CTI pouch was shallower in patients with an ablation procedure duration above the median (4.8 ± 1.1 mm vs. 6.4 ± 0.9 mm, p = 0.04), suggesting a more lateral ablation plane in these patients, where the CTI musculature is stronger. CTI length or ER prominence above the respective median did not correlate with longer EPS duration. CONCLUSIONS: Zero-fluoroscopy CTI ablation guided solely by intracardiac echocardiography in patients with CTI-dependent AFL is feasible and safe. ICE visualisation may help to localise the optimal ablation plane, detect and correct poor tissue contact of the catheter tip, and recognise early potential complications during the ablation procedure.

A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms.

Approximately 30% of COVID-19 cases may experience chronic symptoms, known as post-COVID-19 syndrome (PCS). Common PCS symptoms can include fatigue, cognitive impairment, and persistent physical, neurological, and neuropsychiatric complaints. To improve healthcare and management of the current and future pandemics, we highlight the need for establishing interdisciplinary post-viral outpatient clinics comprised of specialists in fields such as psychiatry, psychotherapy, neurology, cardiology, pneumology, and immunology. In this way, PCS patients with a high health burden can receive modern diagnostics and targeted therapeutic recommendations. A key objective is to distinguish the "sick recovered" from the "healthy recovered." Our hypothesis is that there is a PCS subgroup with autoimmune-mediated systemic and brain-vascular dysregulation, which may lead to circulatory disorders, fatigue, cognitive impairment, depression, and anxiety. This can be clarified using a combination of specific antibody diagnostics and precise clinical, psychological, and apparative testing.

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation in patients with normal electrocardiograms: results from a multicentre long-term registry.

AIMS: To define the clinical characteristics and long-term clinical outcomes of a large cohort of patients with idiopathic ventricular fibrillation (IVF) and normal 12-lead electrocardiograms (ECGs). METHODS AND RESULTS: Patients with ventricular fibrillation as the presenting rhythm, normal baseline, and follow-up ECGs with no signs of cardiac channelopathy including early repolarization or atrioventricular conduction abnormalities, and without structural heart disease were included in a registry. A total of 245 patients (median age: 38 years; males 59%) were recruited from 25 centres. An implantable cardioverter-defibrillator (ICD) was implanted in 226 patients (92%), while 18 patients (8%) were treated with drug therapy only. Over a median follow-up of 63 months (interquartile range: 25-110 months), 12 patients died (5%); in four of them (1.6%) the lethal event was of cardiac origin. Patients treated with antiarrhythmic drugs only had a higher rate of cardiovascular death compared to patients who received an ICD (16% vs. 0.4%, P = 0.001). Fifty-two patients (21%) experienced an arrhythmic recurrence. Age ≤16 years at the time of the first ventricular arrhythmia was the only predictor of arrhythmic recurrence on multivariable analysis [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.18-0.92; P = 0.03]. CONCLUSION: Patients with IVF and persistently normal ECGs frequently have arrhythmic recurrences, but a good prognosis when treated with an ICD. Children are a category of IVF patients at higher risk of arrhythmic recurrences.

Cerebrovascular events, bleeding complications and device related thrombi in atrial fibrillation patients with chronic kidney disease and left atrial appendage closure with the WATCHMAN™ device.

BACKGROUND: Impaired renal function increases the bleeding risk, leading to a conservative prescription and frequent discontinuation of oral anticoagulation in atrial fibrillation patients with chronic kidney disease (CKD). Interventional left atrial appendage closure (LAAC) might be an alternative therapeutic strategy for these patients. METHODS: We aimed to prospectively assess cerebrovascular (CE) and bleeding events, as well as peri-procedural and long-term complications in a cohort of consecutive patients undergoing interventional LAAC using the WATCHMAN™ device, with focus on CKD patients. RESULTS: One hundred and eighty-nine consecutive patients undergoing interventional LAAC were included in this analysis; 171 (90.5%) patients had a reduced estimated glomerular filtration rate (eGFR; patients for each CKD stage: II = 66; IIIa = 32; IIIb = 43; IV = 18; V = 12). During a follow-up of 310 patient years three (1.0%) patients suffered a CE (two strokes, one transitory ischemic attack) and five (1.6%) other ones a bleeding complication. The observed stroke rate was more than two-thirds and the bleeding risk more than half lower than expected. Device related thrombi (DRT) were detected in twelve (6.5%) patients; women had significantly more DRT than men (12.5% vs. 2.6%; p = 0.009). Patients with an eGFR< 30 ml/min/1.73m2 showed a trend to a higher DRT rate as compared to the opposite group (13.3% vs. 5.1%; p = 0.10). Thrombus resolved with temporary oral anticoagulation therapy in ten patients without sequelae; thrombus consolidation was confirmed by serial TEE controls in the remaining two patients. CONCLUSIONS: Atrial fibrillation patients with CKD have low CE and bleeding rates after LAAC with the WATCHMAN™ device. DRT risk is higher in female and patients with severe CKD. More frequent post-interventional TEE controls might be justified for early DRT detection and safe management of patients at high DRT risk. TRIAL REGISTRATION: (German Clinical Trials Register ID: DRKS00 010768 ; Registration Date 07.07.2016).

Intracardiac echocardiography versus fluoroscopy for endovascular and endocardial catheter navigation during cryo-ablation of the slow pathway in AVNRT patients.

BACKGROUND: A new zero-fluoroscopy technique for electrophysiology catheter navigation relying on intracardiac echocardiography (ICE) has been recently reported (Ice&ICE trial). We investigated potential differences in efficacy, safety or procedural performance between conventional fluoroscopy- and ICE-guided cryothermal ablation (CA) in symptomatic AVNRT patients. METHODS: Clinical and electrophysiological data of AVNRT patients included in the Ice&ICE trial (22 patients, 16 females; =zero-fluoroscopy group) were compared to those of consecutive AVNRT patients, who underwent fluoroscopy-guided CA (25 patients, 17 females; = fluoroscopy group) during the last 2 years in our institution. RESULTS: Slow pathway ablation or modulation was successful in all patients. Fluoroscopy time and radiation dose in the fluoroscopy group were 11.2 ± 9.0 min and 20.3 ± 16.2Gycm2, whereas no fluoroscopy was used in the opposite group (p <  0.001, respectively). EPS duration was not different between the groups (zero-fluoroscopy:101.6 ± 40.2 min, fluoroscopy:99.4 ± 37.2 min, p = n.s.). Catheter placement time was significantly shorter in the fluoroscopy group (2.2 ± 1.6 min vs. 12.0 ± 7.5 min, p <  0.05), whereas cryo-application duration (from the first cryo-mapping to the last CA) was significantly shorter in the zero-fluoroscopy group (27.5 ± 37.0 min vs. 38.1 ± 33.9 min, p <  0.05). Mean cryo-mapping and CA applications were numerically lower in the zero-fluoroscopy group (CM:7.5 ± 5.7 vs. 8.8 ± 6.2; CA:3.1 ± 1.7 vs. 3.2 ± 2.0, p = n.s.). No major adverse events occurred in both groups. After 15.0 ± 4.2 months, arrhythmia recurrence was not different between the groups (4.5% vs. 8.0%, p = n.s.). CONCLUSIONS: Zero-fluoroscopy ICE-guided EP catheter navigation shows comparable efficacy and safety to fluoroscopic guidance during CA in AVNRT patients. ICE visualization of catheters and endocardial structures within the triangle of Koch shortens the cryo-application duration, though time needed for catheter placement is longer, when compared with conventional fluoroscopic guidance, which results in similar mean EPS duration with both navigation techniques. TRIAL REGISTRATION: (German Clinical Trials Register ID: DRKS00011360 ; Registration Date 14.12.2016).

Zero-fluoroscopy cryothermal ablation of atrioventricular nodal re-entry tachycardia guided by endovascular and endocardial catheter visualization using intracardiac echocardiography (Ice&ICE Trial).

INTRODUCTION: Stochastic damage of the ionizing radiation to both patients and medical staff is a drawback of fluoroscopic guidance during catheter ablation of cardiac arrhythmias. Therefore, emerging zero-fluoroscopy catheter-guidance techniques are of great interest. METHODS AND RESULTS: We investigated, in a prospective pilot study, the feasibility and safety of the cryothermal (CA) slow-pathway ablation in patients with symptomatic atrioventricular-nodal-re-entry-tachycardia (AVNRT) using solely intracardiac echocardiography (ICE) for endovascular and endocardial catheter visualization. Twenty-five consecutive patients (mean age 55.6 ± 12.0 years, 17 female) with ECG-documentation or symptoms suggesting AVNRT underwent an electrophysiology study (EPS) in our laboratory utilizing ICE for catheter navigation. Supraventricular tachycardia was inducible in 23 (92%) patients; AVNRT was confirmed by appropriate stimulation maneuvers in 20 (80%) patients. All EPS in the AVNRT subgroup could be accomplished without need for fluoroscopy, relying solely on ICE-guidance. CA guided by anatomical location and slow-pathway potentials was successful in all patients, median cryo-mappings = 6 (IQR:3-10), median cryo-ablations = 2 (IQR:1-3). Fluoroscopy was used to facilitate the trans-septal puncture and localization of the ablation substrate in the remaining 3 patients (one focal atrial tachycardia and two atrioventricular-re-entry-tachycardias). Mean EPS duration in the AVNRT subgroup was 99.8 ± 39.6 minutes, ICE guided catheter placement 11.9 ± 5.8 minutes, time needed for diagnostic evaluation 27.1 ± 10.8 minutes, and cryo-application duration 26.3 ± 30.8 minutes. CONCLUSIONS: ICE-guided zero-fluoroscopy CA in AVNRT patients is feasible and safe. Real-time visualization of the true endovascular borders and cardiac structures allow for safe catheter navigation during the ICE-guided EPS and might be an alternative to visualization technologies using geometry reconstructions.

Serial Assessment of Natriuretic Peptides in Patients Undergoing Interventional Closure of the Left Atrial Appendage.

BACKGROUND: Closure of the left atrial appendage (LAA) to prevent cardioembolic events is an alternative therapy to oral anticoagulation in patients with non-valvular atrial fibrillation. The LAA is an important source of natriuretic peptides and its exclusion from the circulation may alter the blood level of these hormones, thereby influencing their diagnostic value and clinical effects. METHODS: We aimed to prospectively assess potential changes in mid-regional pro A-type natriuretic peptide (MR-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels 6 weeks and 6 months after interventional LAA closure using the WATCHMAN device. RESULTS: In 29 consecutive patients with successful LAA closure baseline MR-proANP level was 274±208pmol/l and decreased by -24.5±68 (p=0.07) and -15.0±44pmol/l (p=0.10) after 6 weeks and 6 months, respectively. The drop in the MR-proANP level after 6 weeks and 6 months was significant in patients with elevated (≥214pmol/l) baseline MR-proANP level (n=15: -54.3±78.0, p<0.01 and -31.8±45.4pmol/l, p=0.03, respectively) and those with reduced left ventricular ejection fraction (LVEF<45%, n=7: -87.4±97.3, p=0.02 and -60.3±42.6pmol/l, p=0.01, respectively). Baseline NT-proBNP level (median 1054pg/ml; IQR 621-1977pg/ml), sodium, potassium, mean systolic or diastolic blood pressure did not change significantly in the mentioned patient groups. CONCLUSIONS: After LAA closure, MR-proANP level decreased significantly in patients with elevated baseline MR-proANP level or reduced LVEF, whereas NT-proBNP level remained unchanged, thereby altering the correlation coefficient between the two biomarkers. Our findings should be considered when using these biomarkers for diagnostic or prognostic evaluation in patients with interventional LAA closure.

Left atrial enlargement and clinical considerations in patients with or without a residual interatrial shunt after closure of the left atrial appendage with the WATCHMAN™-device.

BACKGROUND: Interventional closure of the left atrial appendage (LAA) in patients with non-valvular atrial fibrillation, high thromboembolic and bleeding risk or bleeding history is an alternative therapeutic strategy to oral anticoagulation. It is not known if the exclusion of the LAA from the blood circulation affects the left atrial volume (LAV) and consequently its prognostic value or the circulatory performance of the heart in humans. METHODS: We aimed to prospectively assess potential changes in baseline LAV, left ventricular ejection fraction (LVEF), NT-proBNP-level and the covered distance in the 6-min walk-test 6 weeks and 6 months after LAA closure with the WATCHMAN™ device. We used serial 3-dimensional transthoracic and transesophageal echocardiography to assess LAV, residual interatrial shunt and device performance in 58 consecutive patients with successful LAA closure. RESULTS: Accurate 3D-echocardiographic data for LAV measurements were evaluable for 51 (91%) patients. Maximum LAV (LAVmax) at baseline was 102.8 ± 30.8 ml and increased significantly to 107.7 ± 32.8 ml after 6 weeks (p < 0.01) and 113.5 ± 34.2 ml after 6 months (p < 0.01). Minimal LAV (LAVmin) increased from 76.9 ± 29.5 ml at baseline to 81.8 ± 30.2 ml after 45 days (p < 0.01) and 82.1 ± 33.3 ml after 6 months (p < 0.01). Similarly, their indexes to BSA (LAVImax and LAVImin) increased significantly, as well. Patients without a residual left-to-right interatrial shunt showed a significantly higher increase in LAVmax or LAVmin. Baseline LVEF, NT-proBNP-level or the distance covered at the 6-min walk test did not significantly change 6 weeks or 6 months after LAA closure. CONCLUSIONS: LAVmax and LAVmin increase significantly after interventional LAA closure. LA enlargement does not correlate with clinical progression of heart failure. Persistent left-to-right interatrial shunt counteracts the LA enlargement. A reduced LA compliance after exclusion of the LAA from the blood circulation with consecutive increase in LA pressure may be a potential cause of LA enlargement and warrants further investigation. TRIAL REGISTRATION: German Clinical Trials Register ID: DRKS00010768 ; Registration Date 07.07.2016.

Ephrin-A1/EphA4-mediated adhesion of monocytes to endothelial cells.

The Eph receptors represent the largest family of receptor tyrosine kinases. Both Eph receptors and their ephrin ligands are cell-surface proteins, and they typically mediate cell-to-cell communication by interacting at sites of intercellular contact. The major aim of the present study was to investigate the involvement of EphA4-ephrin-A1 interaction in monocyte adhesion to endothelial cells, as this process is a crucial step during the initiation and progression of the atherosclerotic plaque. Immunohistochemical analysis of human atherosclerotic plaques revealed expression of EphA4 receptor and ephrin-A1 ligand in major cell types within the plaque. Short-time stimulation of endothelial cells with the soluble ligand ephrin-A1 leads to a fourfold increase in adhesion of human monocytes to endothelial cells. In addition, ephrin-A1 further increases monocyte adhesion to already inflamed endothelial cells. EphrinA1 mediates its effect on monocyte adhesion via the activated receptor EphA4. This ephrinA1/EphA4 induced process involves the activation of the Rho signaling pathway and does not require active transcription. Rho activation downstream of EphA4 leads to increased polymerization of actin filaments in endothelial cells. This process was shown to be crucial for the proadhesive effect of ephrin-A1. The results of the present study show that ephrin-A1-induced EphA4 forward signaling promotes monocyte adhesion to endothelial cells via activation of RhoA and subsequent stress-fiber formation by a non-transcriptional mechanism.

Uncoupled eNOS annihilates neuregulin-1ß-induced cardioprotection: a novel mechanism in pharmacological postconditioning in myocardial infarction.

Myocardial infarct size can be limited by pharmacological postconditioning (pPC) with cardioprotective agents. Cardioprotective effects of neuregulin-1ß (NRG) via activation of protein kinase B (Akt) and downstream pathways like endothelial nitric oxide synthase (eNOS) have been postulated based on results from cell culture experiments. The purpose of this study was to investigate if eNOS may be involved in pPC with NRG. NRG application in an ex vivo mouse model (C57Bl6) of ischemia-reperfusion injury was analyzed. Unexpectedly, the infarct size increased when NRG was infused starting 5 min prior to reperfusion, even though protective Akt and GSK3ß phosphorylation were enhanced. In eNOS deficient mice, however, NRG significantly reduced the infarct size. Co-infusion of NRG and L-arginine (Arg) lead to a reduction in infarct size in wild type animals. Electron paramagnetic resonance measurements revealed that NRG treatment prior to reperfusion leads to an enhanced release of reactive oxygen species compared to controls and this effect is blunted by co-infusion of Arg. This study documents the cardioprotective mechanisms of NRG signaling to be mediated by GSK3ß inactivation. This is the first study to show that this protection fails in situations with dysfunctional eNOS. In eNOS deficient mice NRG exerts its protective effect via the GSK3ß pathway, suggesting that the eNOS can limit cardioprotection. As dysfunctional eNOS has been described in cardiovascular risk factors like diabetes, hypertension, and hypercholesterolemia these findings can help to explain lack of postconditioning performance in models of cardiovascular co-morbidities.

Confusion in a patient with premature ventricular complexes originating in the left ventricular summit.

Background: Premature ventricular complexes (PVCs) originating in the ventricular outflow tracts are mostly of benign character. Case Summary: We describe a rare case of pulmonary hypertension with severe hypoxaemia and confusion caused by a significant mitral regurgitation (MR) during PVC originating in the left ventricle summit. After successful PVC ablation, all above-mentioned clinical parameters had normalized. Discussion: Premature ventricular complexes originating in the outflow tracts should be considered as a potential though rare cause of severe MR and pulmonary hypertension.

[Innovative facultative seminar concepts regarding clinical teaching and preparing practice-oriented phases, such as medical clerkships and the final clinical internship from a surgical perspective]. / Innovative fakultative Seminarkonzepte besonders klinisch-praktisch ausgerichteter Lehre zur Famulatur- und PJ-Vorbereitung aus spezifisch chirurgischer Sicht.

BACKGROUND: Practice-oriented phases, such as the mandatory clinical traineeships and the final clinical internship, are of great importance in the teaching curriculum and skilful learning of medical students. AIM: With respect to the practical phases, such as clinical clerkship and medical internship, the concept of two innovative courses to prepare and evaluate these crucial training sections is presented including initial experiences from teaching practice. METHOD: A narrative review is given. RESULTS: A common aim of facultatively initiated lectures is a better qualification of medical students to fulfil the requirements of clerkship and the last practical year of the study of human medicine to facilitate taking first steps towards professional work as a clinical physician, in particular, the self-confidence of the medical students is to be substantially increased. The experiences obtained during clerkship and the last practical year influence interest, motivation and final choice for a certain medical speciality. In that respect, this period is of great importance for the whole professional career. The content of the preparation courses for the first medical clerkships and the final clinical internship provide a valuable contribution to prepare for challenging clinical work as a physician with sole responsibility. In particular, they aim to introduce students to the concept of a multiprofessional and extensive patient care. Taking into account the different practical experiences obtained in previous study sections, students are taught according to the overall aim to achieve an interdisciplinary competence in clinical care. CONCLUSION: The improvement of teaching and optimized preparation for practical phases in medical studies promotes a more successful learning process during the clerkship and last practical year.

Neutrophil Gelatinase-Associated Lipocalin Cutoff Value Selection and Acute Kidney Injury Classification System Determine Phenotype Allocation and Associated Outcomes.

Background: We explored the extent to which neutrophil gelatinase-associated lipocalin (NGAL) cutoff value selection and the acute kidney injury (AKI) classification system determine clinical AKI-phenotype allocation and associated outcomes. Methods: Cutoff values from ROC curves of data from two independent prospective cardiac surgery study cohorts (Magdeburg and Berlin, Germany) were used to predict Kidney Disease: Improving Global Outcome (KDIGO)- or Risk, Injury, Failure, Loss of kidney function, End-stage (RIFLE)-defined AKI. Statistical methodologies (maximum Youden index, lowest distance to [0, 1] in ROC space, sensitivity≍specificity) and cutoff values from two NGAL meta-analyses were evaluated. Associated risks of adverse outcomes (acute dialysis initiation and in-hospital mortality) were compared. Results: NGAL cutoff concentrations calculated from ROC curves to predict AKI varied according to the statistical methodology and AKI classification system (10.6-159.1 and 16.85-149.3 ng/mL in the Magdeburg and Berlin cohorts, respectively). Proportions of attributed subclinical AKI ranged 2%-33.0% and 10.1%-33.1% in the Magdeburg and Berlin cohorts, respectively. The difference in calculated risk for adverse outcomes (fraction of odds ratios for AKI-phenotype group differences) varied considerably when changing the cutoff concentration within the RIFLE or KDIGO classification (up to 18.33- and 16.11-times risk difference, respectively) and was even greater when comparing cutoff methodologies between RIFLE and KDIGO classifications (up to 25.7-times risk difference). Conclusions: NGAL positivity adds prognostic information regardless of RIFLE or KDIGO classification or cutoff selection methodology. The risk of adverse events depends on the methodology of cutoff selection and AKI classification system.

Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial.

BACKGROUND: In current guidelines, intraaortic balloon pumping (IABP) is considered a class 1 indication in cardiogenic shock complicating acute myocardial infarction. However, evidence is mainly based on retrospective or prospective registries with a lack of randomized clinical trials. Therefore, IABP is currently only used in 20% to 40% of cardiogenic shock cases. The hypothesis of this trial is that IABP in addition to early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting will improve clinical outcome of patients in cardiogenic shock. STUDY DESIGN: The IABP-SHOCK II study is a 600-patient, prospective, multicenter, randomized, open-label, controlled trial. The study is designed to compare the efficacy and safety of IABP versus optimal medical therapy on the background of early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting. Patients will be randomized in a 1:1 fashion to 1 of the 2 treatments. The primary efficacy end point of IABP-SHOCK II is 30-day all-cause mortality. Secondary outcome measures, such as hemodynamic, laboratory, and clinical parameters, will serve as surrogate end points for prognosis. Furthermore, an intermediate and long-term follow-up at 6 and 12 months will be performed. Safety will be assessed, by the GUSTO bleeding definition, peripheral ischemic complications, sepsis, and stroke. CONCLUSIONS: The IABP-SHOCK II trial addresses important questions regarding the efficacy and safety of IABP in addition to early revascularization in patients with cardiogenic shock complicating myocardial infarction.

Cell-specific and hypoxia-dependent regulation of human HIF-3α: inhibition of the expression of HIF target genes in vascular cells.

Hypoxia-inducible factors (HIF) are transcription factors responding to reduced oxygen levels and are of utmost importance for regulation of a widespread of cellular processes, e.g., angiogenesis. In contrast to HIF-1α/HIF-2α, the relevance of HIF-3α for the regulation of the HIF pathway in human vascular cells is largely unknown. HIF-3α mRNA increases under hypoxia in endothelial and vascular smooth muscle cells. Analysis of HIF-3α isoforms revealed a cell type-specific pattern, but only one isoform, HIF-3α2, is hypoxia-inducible. Reporter gene assays of the appropriate promoter localized a 31-bp fragment, mediating this hypoxic regulation. The contribution of HIF-1/2 and NFκB to the HIF-3α induction was verified. Functional studies focused on overexpression of HIF-3α isoforms, which decrease the hypoxia-mediated expression of VEGFA and Enolase2. These data support the notion of a hypoxia-induced inhibitory function of HIF-3α and demonstrate for the first time the existence of this negative regulation of HIF-signaling in vascular cells.

OxLDL and macrophage survival: essential and oxygen-independent involvement of the Hif-pathway.

Atherosclerotic plaques are characterized by hypoxic even anoxic areas and by high concentrations of oxidized lipoproteins. Moreover, unstable plaques attract a high number of macrophages despite the proapoptotic background within these plaques. Recently, it was shown that these macrophages are positive for Hif-1α. This subunit is a part of hypoxia-inducible factor 1 (Hif-1), a key transcriptional factor under hypoxia. Till date, it is not understood whether the Hif-system (consisting of Hif-1, Hif-2 and Hif-3) is involved in protection of macrophages under these proatherogenic conditions. The present study delineates that oxLDL causes fundamental changes in the regulation of the Hif-system in primary human macrophages. First, both oxLDL and hypoxia mediate accumulation of Hif-1α protein. Second, treatment with a combination of oxLDL and hypoxia is acting in an additive manner on Hif-1α protein content. Third, oxLDL alone does not increase Hif-2α protein, but abolishes the hypoxic induction of Hif-2α completely. OxLDL treatment alone was not toxic for macrophages under neither normoxia nor hypoxia. But, inhibition of Hif-pathway by adenoviral expression of a dominant-negative mutant combined with oxLDL treatment independently of the oxygen tension leads to apoptosis, as determined by caspase-3 activation and induction of DNA fragmentation. Furthermore, this inhibition also mediates the opening of the mitochondrial permeability transition pore. In conclusion, the present data show that Hif-1α regulation is essential for survival of oxLDL-treated macrophages independent of the oxygen tension. Therefore, this newly characterized mechanism might also have an important influence for the vulnerability of atherosclerotic plaques.