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Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. Results: The median age was 68 years, 23% of participants were women, 51% had ST-segment–elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71–1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69–1.61]). Conclusions: In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search ; Unique identifier: 2019-003244-79.

A promising strategy to increase the numbers of hematopoietic stem cells (HSCs) for clinical applications, like stem cell transplantation, is offered by advanced in vitro culture systems. We developed artificial 3D bone marrow-like scaffolds made of polydimethylsiloxane (PDMS) mimicking the natural HSC niche in vitro. These 3D PDMS scaffolds in combination with an optimized culture medium allow the amplification of high numbers of undifferentiated HSCs by activating specific molecular signaling pathways.

Background: Maladapted endothelial cells (ECs) secrete ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2; autotaxin)—a lysophospholipase D that generates lysophosphatidic acids (LPAs). ENPP2 derived from the arterial wall promotes atherogenic monocyte adhesion induced by generating LPAs, such as arachidonoyl-LPA (LPA20:4), from oxidized lipoproteins. Here, we aimed to determine the role of endothelial ENPP2 in the production of LPAs and atherosclerosis. Methods: We quantified atherosclerosis in mice harboring loxP-flanked Enpp2 alleles crossed with Apoe –/– mice expressing tamoxifen-inducible Cre recombinase under the control of the EC-specific bone marrow X kinase promoter after 12 weeks of high-fat diet feeding. Results: A tamoxifen-induced EC-specific Enpp2 knockout decreased atherosclerosis, accumulation of lesional macrophages, monocyte adhesion, and expression of endothelial CXCL (C-X-C motif chemokine ligand) 1 in male and female Apoe –/– mice. In vitro, ENPP2 mediated the mildly oxidized LDL (low-density lipoprotein)-induced expression of CXCL1 in aortic ECs by generating LPA20:4, palmitoyl-LPA (LPA16:0), and oleoyl-LPA (LPA18:1). ENPP2 and its activity were detected on the endothelial surface by confocal imaging. The expression of endothelial Enpp2 established a strong correlation between the plasma levels of LPA16:0, stearoyl-LPA (LPA18:0), and LPA18:1 and plaque size and a strong negative correlation between the LPA levels and ENPP2 activity in the plasma. Moreover, endothelial Enpp2 knockout increased the weight of high-fat diet–fed male Apoe –/– mice. Conclusions: We demonstrated that the expression of ENPP2 in ECs promotes atherosclerosis and endothelial inflammation in a sex-independent manner. This might be due to the generation of LPA20:4, LPA16:0, and LPA18:1 from mildly oxidized lipoproteins on the endothelial surface.

ObjectivesThe aim of this study was to find out if the decrease in acute myocardial infarction (AMI) admissions during the first COVID-19 lockdowns (LD), which was described by previous studies, occurred equally in all LD periods (LD1, LD2, LD2021), which had identical restrictions. Further, we wanted to analyse if the decrease of AMI admission had any association with the 1-year mortality rate.Design and settingThis study is a prospective observational study of two centres that are participating in the Vienna ST-elevation myocardial infarction network.ParticipantsA total of 1732 patients who presented with AMI according to the 4th universal definition of myocardial infarction in 2019, 2020 and the LD period of 2021 were included in our study. Patients with myocardial infarction with non-obstructive coronary arteries were excluded from our study.Main outcome measuresThe primary outcome of this study was the frequency of AMI during the LD periods and the all-cause and cardiac-cause 1-year mortality rate of 2019 (pre-COVID-19) and 2020.ResultsOut of 1732 patients, 70% (n=1205) were male and median age was 64 years. There was a decrease in AMI admissions of 55% in LD1, 28% in LD2 and 17% in LD2021 compared with 2019.There were no differences in all-cause 1-year mortality between the year 2019 (11%; n=110) and 2020 (11%; n=79; p=0.92) or death by cardiac causes [10% (n=97) 2019 vs 10% (n=71) 2020; p=0.983].ConclusionAll LDs showed a decrease in AMI admissions, though not to the same extent, even though the regulatory measures were equal. Admission in an LD period was not associated with cardiac or all-cause 1-year mortality rate in AMI patients in our study.

Recent trends in 3D cell culturing has placed organotypic tissue models at another level. Now, not only is the microenvironment at the cynosure of this research, but rather, microscopic geometrical parameters are also decisive for mimicking a tissue model. Over the years, technologies such as micromachining, 3D printing, and hydrogels are making the foundation of this field. However, mimicking the topography of a particular tissue-relevant substrate can be achieved relatively simply with so-called template or morphology transfer techniques. Over the last 15 years, in one such research venture, we have been investigating a micro thermoforming technique as a facile tool for generating bioinspired topographies. We call them MatriGrid

Background and aims: IKK alpha is an important regulator of gene expression. As IKK alpha kinase inactivity in bone marrow-derived cells does not affect atherosclerosis, we here investigate the impact of a whole body-IKK alpha kinase inactivity on atherosclerosis.Methods: Apolipoprotein E (Apoe)-deficient mice homozygous for an activation-resistant Ikk alpha-mutant (Ikk alpha(AA/AA)Apoe(-/-)) and Ikk alpha(+/+)Apoe(-/-) controls received a Western-type diet. Atherosclerotic lesion size and cellular content were analyzed using histology and immunofluorescence. Vascular protein expression and IKK alpha kinase activity were quantified by Luminex multiplex immuno-assay and ELISA.Results: A vascular site-specific IKK alpha expression and kinase activation profile was revealed, with higher total IKK alpha protein levels in aortic root but increased IKK alpha phosphorylation, representing activated IKK alpha, in the aortic arch. This was associated with a vascular site-specific effect of Ikk alpha(AA/AA) knock-in on atherosclerosis: in the aortic root, Ikk alpha(AA/AA) knock-in decreased lesion size by 22.0 +/- 7.7% (p Conclusions: A non-activatable IKK alpha kinase differentially affects atherosclerosis in aortic root vs. aortic arch/brachiocephalic artery, associated with a differential vascular IKK alpha expression and kinase activation profile as well as with a vascular site-dependent impact on lesional smooth muscle cell accumulation and protein expression profiles.

BACKGROUND Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation. METHODS In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35. FINDINGS Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. INTERPRETATION The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. FUNDING Bayer.

Introduction In 2020 the Austrian government has ordered two complete lockdowns and two lockdown lights to maintain control over the infection rate of Covid-19. Several studies have analysed the frequency and outcome of patients with acute coronary syndrome (ACS) during the pandemic. Some have described a decrease in the admission rate of patients with ST-elevated-myocardial-infarction (STEMI) and no-ST-elevated-myocardial-infarction (NSTEMI), with the reasons still being discussed. Purpose The aim of this study is to analyse possible differences in frequency, comorbidities and outcome of all STEMI and NSTEMI admissions over various lockdown (L) periods in Austria and to provide a possible explanation for the results. Methods Analysis of prospectively gathered data on ACS patients in our heart center in the year 2020. Patients were split into 4 groups: no lockdown (NL): n=136; duration (dur): 36 weeks (w); lockdown 1 (L1): n=24; dur: 7w; lockdown 2 (L2): n=16; dur: 2.5w; lockdown light (LL): n=22; dur: 5.5w. To account for the different durations, we divided patients by lockdown duration (n/w). End of a L was defined as re-opening of shops; in LL period schools and restaurants were closed but shops were open. To compare the different groups, age, sex, BMI, comorbidities, cardiovascular risk factors (CVRF) duration of preclinical-symptomatic phase (onset of chest pain to PCI), blood parameters, indication, vascular access (femoral/radial) and target vessel were recorded. As outcome we defined CPR, shock and in hospital death. Results Out of 198 patients 126 were male (63.6%) and 72 female (36.4%), with a mean age of 65±12 years. There were no statistically significant differences in age, BMI or CVRF between the 4 groups. A 50% higher number of diabetics in the LL group as compared to 25.3% in the NL group (p=0.005) was noticed. STEMI admissions from 2.2 patients/week (n/w) without L decreased to 1.4/w during L1. During L2, the frequency rate rose to 3.2/w in the LL group and admission rates to 2/w, which is almost as high as in the NL group. No differences in NSTEMI admissions between the NL (1.3/w), the L1 (1.4/w) and the LL group (1.8/w) were found. During L2 the frequency of NSTEMI patients increased to 3.2/w. We found a rise in in-hospital death rates from 4.4% without L to 9.1% during LL, though with boarder line statistical significance (p=0.05). Conclusion Compared to the NL group, our data show a decrease of STEMI and NSTEMI admissions during L1. This trend was not confirmed during L2, despite identical government's restrictions. We, thus, postulate that the decrease of ACS admissions in L1 was caused by patients' concern regarding in-hospital Covid-19 infection rather than by actual restrictions. Funding Acknowledgement Type of funding sources: None.

Background: The necrotic core partly formed by ineffective efferocytosis increases the risk of an atherosclerotic plaque rupture. Microribonucleic acids contribute to necrotic core formation by regulating efferocytosis and macrophage apoptosis. Atherosclerotic plaque rupture occurs at increased frequency in the early morning, indicating diurnal changes in plaque vulnerability. Although circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear. Methods: Circadian gene expression, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated at different times of the day in Apoe –/– Mir21 +/+ mice and Apoe –/– Mir21 –/– mice after consumption of a high-fat diet for 12 weeks. Genome-wide gene expression and lesion formation were analyzed in bone marrow–transplanted mice. Diurnal changes in apoptosis and clock gene expression were determined in human atherosclerotic lesions. Results: The expression of molecular clock genes, lesional apoptosis, and necrotic core size were diurnally regulated in Apoe –/– mice. Efferocytosis did not match the diurnal increase in apoptosis at the beginning of the active phase. However, in parallel with apoptosis, expression levels of oscillating Mir21 strands decreased in the mouse atherosclerotic aorta. Mir21 knockout abolished circadian regulation of apoptosis and reduced necrotic core size but did not affect core clock gene expression. Further, Mir21 knockout upregulated expression of proapoptotic Xaf1 (XIAP-associated factor 1) in the atherosclerotic aorta, which abolished circadian expression of Xaf1. The antiapoptotic effect of Mir21 was mediated by noncanonical targeting of Xaf1 through both Mir21 strands. Mir21 knockout in bone marrow cells also reduced atherosclerosis and necrotic core size. Circadian regulation of clock gene expression was confirmed in human atherosclerotic lesions. Apoptosis oscillated diurnally in phase with XAF1 expression, demonstrating an early morning peak antiphase to that of the Mir21 strands. Conclusions: Our findings suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mir21 expression in macrophages that is not matched by efferocytosis, thus increasing the size of the necrotic core.

Aim Whether time of day influences survival after out-of-hospital cardiac arrest (OHCA) remains controversial. We compared outcomes after OHCA between day and night and explored whether characteristics of pre-hospital advanced life support (ALS)-quality varied by time of day. Methods We conducted a prospective cohort study of individuals that suffered a non-traumatic OHCA in the city of Vienna between August 2013 and August 2015 and who received resuscitative efforts by EMS. We compared clinical outcomes between day and night, defined as 7:00 pm–7:00 am based on EMS shift time including rates of sustained return of spontaneous circulation (ROSC), 30-day survival and favourable neurologic outcome (cerebral performance category 1 or 2). ALS quality measures included time to first medical contact, time to first shock, total dose of epinephrine, and multiple ALS performance measures. Results We included 1811 patients (37% female) with a mean age of 67 ± 16 years in our analyses. Rates of ROSC and 30-day survival with favourable neurological outcome did not differ between day or night (30% vs 28%, p = 0.33; 12% vs. 11%, p = 0.51, respectively). These results remained unchanged after multivariate adjustment for ROSC (RR, 1.1; 95% CI, 1.0–1.3, p = 0.19) and 30-day survival with favourable neurological outcome (RR, 1.2; 95% CI, 1.0–1.5, p = 0.10). The quality of ALS did not differ between day and night. Conclusions In contrast to previous studies, there was no significant difference in sustained ROSC rates and 30-day survival with favourable neurological outcome after OHCA between day and night in the city of Vienna. This is likely due to nearly identical high bystander CPR rates and identical ALS performance provided by EMS personnel irrespective of time of the day.

Finding the optimal workforce qualification is important in many different industries. Cross-qualifications play an important role if workers are required to perform various tasks during working hours. This is especially crucial in production plants where workforce has to be trained to operate multiple machines throughout the day, and is closely connected to staff planning and job scheduling. In this paper, a flow shop system consisting of two lines is used to analyse various predefined workforce qualification profiles. To measure the performance, a simulation model is applied where the sum of qualifications is compared with the achieved service levels. Scenarios that differ in the number of available workers as well as the amount of transition times needed by workers to switch between stations and lines are analysed. Furthermore, multi-objective simulation-based optimization is conducted in order to find improved qualification profiles. The achieved results from both, the predefined and the optimized qualification profiles, are promising and managerial insight is gained for future research in this domain.

Background Extracorporeal life support (ECLS) describes the use of blood perfusion devices to provide advanced cardiac or respiratory support. Advances in percutaneous vascular cannula insertion, centrifugal pump technologies, and the miniaturization of extracorporeal devices have simplified ECLS. The intention of this discussion is to review the role of ECLS as a potential rescue method for emergency department (ED) clinicians in critical clinical scenarios and to focus on the prerequisites for managing an ECLS program in an ED setting. Discussion Possible indications for ECLS cannulation in the ED include ongoing circulatory arrest, shock or refractory hypoxemia and pulmonary embolism with refractory shock. Severe trauma, foreign body obstruction, hypothermia and near drowning are situations in which patients may potentially benefit from ECLS. Early stabilization in the ED can provide a time window for a diagnostic workup and/or urgent procedures, including percutaneous coronary intervention, rewarming or damage control surgery in trauma. The use of ECLS is resource intensive and can be associated with a high risk of complications, especially when performed without previous training. Therefore, ECLS should only be used when the underlying problem is potentially reversible, and the resources are available to address the etiology of organ dysfunction. Conclusion Emergent ECLS has a role in the ED for selected indications in the face of life-threatening conditions. ECLS provides a bridge to recovery, definitive therapy, intervention or surgery. ECLS program requires an appropriately trained staff (physicians, nurses and ECLS specialists), equipment resources and logistical planning.

BACKGROUND Identification of heart transplant (HTx) rejection currently relies on immunohistology and immunohistochemistry. We aimed to identify specific sets of microRNAs (miRNAs) to characterize acute cellular rejection (ACR), antibody-mediated rejection (pAMR), and mixed rejection (MR) in monitoring formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies (EMBs) in HTx patients. METHODS In this study we selected 33 adult HTx patients. For each, we chose the first positive EMB for study of each type of rejection. The next-generation sequencing (NGS) IonProton technique and reverse transcript quantitative polymerase chain reaction (RT-qPCR) analysis were performed on FFPE EMBs. Using logistic regression analysis we created unique miRNA signatures as predictive models of each rejection. In situ PCR was carried out on the same EMBs. RESULTS We obtained >2,257 mature miRNAs from all the EMBs. The 3 types of rejection showed a different miRNA profile for each group. The logistic regression model formed by miRNAs 208a, 126-5p, and 135a-5p identified MR; that formed by miRNAs 27b-3p, 29b-3p, and 199a-3p identified ACR; and that formed by miRNAs 208a, 29b-3p, 135a-5p, and 144-3p identified pAMR. The expression of miRNAs on tissue, through in situ PCR, showed different expressions of the same miRNA in different rejections. miRNA 126-5p was expressed in endothelial cells in ACR but in cardiomyocytes in pAMR. In ACR, miRNA 29b-3p was significantly overexpressed and detected in fibroblasts, whereas in pAMR it was underexpressed and detected only in cardiomyocytes. CONCLUSIONS miRNA profiling on FFPE EMBs differentiates the 3 types of rejection. Localization of expression of miRNAs on tissue showed different expression of the same miRNA for different cells, suggesting different roles of the same miRNA in different rejections.

The need to detect and identify trace amounts of airborne biological hazards with ever increasing sensitivity and selectivity is the main driver in sensor research. However, the low concentration of airborne hazardous entities requires the concentration of the analyte at the biosensor of choice. Here, we present a robust implementation of an effective “Airborne Analyte Transporter”, which (i) permits time-course sampling of airborne particles, (ii) precise localization and concentration of airborne particles at a designated location of a given biosensor (iii) and allows the biological downstream analysis of viable pathogens. The Airborne Analyte Transporter implements a corona discharge based analyte charging method in combination with an electrodynamic funnel concentration concept. The Airborne Analyte Transporter achieves a 1000-fold increase in particle concentration compared to diffusion and settling based transport and allows the precise and local collection of viable pollen, yeasts, spores, bacteria and virus particles with an additional lateral concentration. Potential biological hazards with concentrations down to 20 ppm can still be analyzed using different microscopy techniques and bacterial cultures. The Airborne Analyte Transporter provides a localized collection of airborne particles on a biosensor of choice to be utilized in monitoring air in the health care sector or in hygiene-sensitive areas.

Regulatory RNAs like microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) control vascular and immune cells' phenotype and thus play a crucial role in atherosclerosis. Moreover, the mutual interactions between miRNAs and lncRNAs link both types of regulatory RNAs in a functional network that affects lesion formation. In this review, we deduce novel concepts of atherosclerosis from the analysis of the current data on regulatory RNAs' role in endothelial cells (ECs) and macrophages. In contrast to arterial ECs, which adopt a stable phenotype by adaptation to high shear stress, macrophages are highly plastic and quickly change their activation status. At predilection sites of atherosclerosis, such as arterial bifurcations, ECs are exposed to disturbed laminar flow, which generates a dysadaptive stress response mediated by miRNAs. Whereas the highly abundant miR-126-5p promotes regenerative proliferation of dysadapted ECs, miR-103-3p stimulates inflammatory activation and impairs endothelial regeneration by aberrant proliferation and micronuclei formation. In macrophages, miRNAs are essential in regulating energy and lipid metabolism, which affects inflammatory activation and foam cell formation.Moreover, lipopolysaccharide-induced miR-155 and miR-146 shape inflammatory macrophage activation through their oppositional effects on NF-kB. Most lncRNAs are not conserved between species, except a small group of very long lncRNAs, such as MALAT1, which blocks numerous miRNAs by providing non-functional binding sites. In summary, regulatory RNAs' roles are highly context-dependent, and therapeutic approaches that target specific functional interactions of miRNAs appear promising against cardiovascular diseases.

Automation and digitalization have had profound effects on job losses as well as on skill requirements in advanced economies. This chapter analyzes the spatial distribution of ICT-skills requirements by analyzing some 73,000 job offers for the Austrian region of Styria. This region is characterized by a large variability of specialization patterns throughout its districts as well as differences regarding population density and infrastructure accessibility. The analysis allows to draw conclusions on the need for both basic and special ICT-skills for different education levels for 287 municipalities. The results also draw light on problems related to the new “digital divide” indicating the phenomenon that people have access to digital infrastructure but not yet acquired the digital competences to find work. One interesting conclusion is also that high-skill ICT-requiring jobs have the highest level of agglomeration – both compared with other skill-levels and with non-ICT related academic job positions.

Background Implantable cardioverter-defibrillator (ICD) therapy is well established for secondary prevention, but studies on the efficacy and safety in elderly patients are still lacking. This retrospective study compared the outcome after ICD implantation between octogenarians and other age groups. Methods Data were obtained from a local ICD registry. Patients who received ICD implantation for secondary prevention at our department were included. All-cause mortality, appropriate ICD therapy and acute adverse events requiring surgical intervention were compared between different age groups. Results 519 patients were enrolled, 34 of whom were aged ≥ 80 years. During the median follow-up of 35 months after ICD implantation 129 patients (annual mortality rate 5.0%) had died, including 16 patients aged ≥ 80 years (annual mortality rate 9.4%). The mortality rate of patients aged ≥ 80 years was significantly higher than that of patients aged ≤ 69 years (p p n = 13) and not age-related. Conclusion Age is an independent predictor of mortality after ICD implantation for secondary prevention. Mortality rates did not differ significantly between octogenarians and other elderly aged 70–79 years. Appropriate ICD therapy and acute adverse events leading to surgical intervention were not age-related. Implantable cardioverter-defibrillator therapy for secondary prevention seems to be an effective and safe treatment modality in octogenarians.

Objective: Inflammatory activation changes the mitochondrial function of macrophages from oxidative phosphorylation to reactive oxygen species production, which may promote necrotic core formation in atherosclerotic lesions. In hypoxic and cancer cells, HIF-1α (hypoxia-inducible factor) promotes oxygen-independent energy production by microRNAs. Therefore, we studied the role of HIF-1α in the regulation of macrophage energy metabolism in the context of atherosclerosis. Approach and Results: Myeloid cell–specific deletion of Hif1a reduced atherosclerosis and necrotic core formation by limiting macrophage necroptosis in apolipoprotein E-deficient mice. In inflammatory bone marrow–derived macrophages, deletion of Hif1a increased oxidative phosphorylation, ATP levels, and the expression of genes encoding mitochondrial proteins and reduced reactive oxygen species production and necroptosis. microRNA expression profiling showed that HIF-1α upregulates miR-210 and downregulates miR-383 levels in lesional macrophages and inflammatory bone marrow–derived macrophages. In contrast to miR-210 , which inhibited oxidative phosphorylation and enhanced mitochondrial reactive oxygen species production, miR-383 increased ATP levels and inhibited necroptosis. The effect of miR-210 was due to targeting 2,4-dienoyl-CoA reductase, which is essential in the β oxidation of unsaturated fatty acids. miR-383 affected the DNA damage repair pathway in bone marrow–derived macrophages by targeting poly(ADP-ribose)-glycohydrolase (Parg), which reduced energy consumption and increased cell survival. Blocking the targeting of Parg by miR-383 prevented the protective effect of Hif1a deletion in macrophages on atherosclerosis and necrotic core formation in mice. Conclusions: Our findings unveil a new mechanism by which activation of HIF-1α in inflammatory macrophages increases necroptosis through microRNA-mediated ATP depletion, thus increasing atherosclerosis by necrotic core formation.

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions., The role of neutrophils in the development of atherosclerosis has long been an enigma, with few neutrophils detected within the plaque. Here, the authors show that microvesicles released from neutrophils increase vascular inflammation and enhance atherosclerotic plaque formation through delivery of miR-155.

Background Early outcome prediction in out-of-hospital cardiac arrest is still a challenge. End-tidal carbon dioxide (ETCO2) has been shown to be a reliable parameter to reflect the quality of cardiopulmonary resuscitation and the chance of return of spontaneous circulation (ROSC). Objectives This study assessed the validity of early capnography as a predictive factor for ROSC and survival in out-of-hospital cardiac arrest victims with an underlying nonshockable rhythm. Design Retrospective observational study. Setting/patients During a 2-year observational period, data from 2223 out-of-hospital cardiac arrest victims within the city of Vienna were analysed. The focus was on the following patients: age more than 18 years, an underlying nonshockable rhythm, and advanced airway management within the first 15 min of advanced life support with subsequent capnography. Intervention No specific intervention was set in this observational study. Main outcome measures The first measured ETCO2, assessed immediately after placement of an advanced airway, was used for further analysis. The primary outcome was defined as sustained ROSC, and the secondary outcome was 30-day survival. Results A total of 526 patients met the inclusion criteria. These were stratified into three groups according to initial ETCO2 values ( 45 mmHg). Baseline data and resuscitation factors were similar among all groups. The odds of sustained ROSC and survival were significantly higher for patients presenting with higher values of initial ETCO2 (>45 mmHg): 3.59 [95% CI, 2.19 to 5.85] P = 0.001 and 5.02 [95% CI, 2.25 to 11.23] P = 0.001, respectively. On the contrary ETCO2 levels less than 20 mmHg were associated with significantly poorer outcomes. Conclusion Patients with a nonshockable out-of-hospital cardiac arrest who presented with higher values of initial ETCO2 had an increased chance of sustained ROSC and survival. This finding could help decision making as regards continuation of resuscitation efforts.