The in vitro gastrointestinal digestion-associated protein corona of polystyrene nano- and microplastics increases their uptake by human THP-1-derived macrophages.

BACKGROUND: Micro- and nanoplastics (MNPs) represent one of the most widespread environmental pollutants of the twenty-first century to which all humans are orally exposed. Upon ingestion, MNPs pass harsh biochemical conditions within the gastrointestinal tract, causing a unique protein corona on the MNP surface. Little is known about the digestion-associated protein corona and its impact on the cellular uptake of MNPs. Here, we systematically studied the influence of gastrointestinal digestion on the cellular uptake of neutral and charged polystyrene MNPs using THP-1-derived macrophages. RESULTS: The protein corona composition was quantified using LC‒MS-MS-based proteomics, and the cellular uptake of MNPs was determined using flow cytometry and confocal microscopy. Gastrointestinal digestion resulted in a distinct protein corona on MNPs that was retained in serum-containing cell culture medium. Digestion increased the uptake of uncharged MNPs below 500 nm by 4.0-6.1-fold but did not affect the uptake of larger sized or charged MNPs. Forty proteins showed a good correlation between protein abundance and MNP uptake, including coagulation factors, apolipoproteins and vitronectin. CONCLUSION: This study provides quantitative data on the presence of gastrointestinal proteins on MNPs and relates this to cellular uptake, underpinning the need to include the protein corona in hazard assessment of MNPs.

Model Complexity as Determining Factor for In Vitro Nanosafety Studies: Effects of Silver and Titanium Dioxide Nanomaterials in Intestinal Models.

With the rising interest in the effects of orally ingested engineered nanomaterials (ENMs), much effort is undertaken to develop and advance intestinal in vitro models. The cytotoxic, proinflammatory, and DNA damaging properties of polyvinylpyrrolidone-capped silver (Ag-PVP) and titanium dioxide (TiO2 , P25) ENM in four in vitro models of increasing complexity-from proliferating Caco-2 and HT29-MTX-E12 monocultures to long-term transwell triple cultures including THP-1 macrophages to reproduce the human intestine in healthy versus inflamed-like state-are studied. Results are compared against in vivo effects of the same ENM through intestinal tissue analysis from 28-day oral exposure studies in mice. Adverse responses are only observed in monocultures and suggest toxic potential for both ENM, typically showing stronger effects for Ag-PVP than for TiO2 . By contrast, no adverse effects are observed in either the transwell cultures or the analyzed murine tissues. The data provide further support that monoculture models represent a cost and time efficient tool for early-phase hazard assessment. However, the observed similarities in morphology and ENM effects in murine intestinal tissue and the in vitro triple culture model suggest that advanced multifacetted research questions concerning oral ENM exposure are more adequately addressed by the more complex and time intensive models.

Investigations of acute effects of polystyrene and polyvinyl chloride micro- and nanoplastics in an advanced in vitro triple culture model of the healthy and inflamed intestine.

The continuous degradation of plastic waste in the environment leads to the generation of micro- and nanoplastic fragments and particles. Due to the ubiquitous presence of plastic particles in natural habitats as well as in food, beverages and tap water, oral exposure of the human population with plastic particles occurs worldwide. We investigated acute toxicological effects of polystyrene (PS) and polyvinyl chloride (PVC) micro- and nanoparticles in an advanced in vitro triple culture model (Caco-2/HT29-MTX-E12/THP-1) mimicking the healthy and inflamed human intestine to study the effect of inflammatory processes on plastic particle toxicity. We monitored barrier integrity, cytotoxicity, cell layer integrity, DNA damage, the release of pro-inflammatory cytokines (IL-1ß, IL-6, IL-8 and TNF-α) and mucus distribution after 24 h of particle exposure. In addition, we investigated cytotoxicity, DNA damage and IL-1ß release in monocultures of the three cell lines. Amine-modified polystyrene nanoparticles (PS-NH2) served as a positive control for particle-induced toxicity. No acute effects in the investigated endpoints were observed in the model of the healthy intestine after PS or PVC exposure. However, during active inflammatory processes, exposure to PVC particles was found to augment the release of IL-1ß and to cause a loss of epithelial cells. Our results suggest that prevalent intestinal inflammation might be an important factor to consider when assessing the hazard of ingested micro- and nanoplastic particles.

Impella Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock.

BACKGROUND: Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS. METHODS: Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality. RESULTS: In total, 237 patients treated with an Impella could be matched to 237 patients from the IABP-SHOCK II trial. Baseline parameters were similarly distributed after matching. There was no significant difference in 30-day all-cause mortality (48.5% versus 46.4%, P=0.64). Severe or life-threatening bleeding (8.5% versus 3.0%, P<0.01) and peripheral vascular complications (9.8% versus 3.8%, P=0.01) occurred significantly more often in the Impella group. Limiting the analysis to IABP-treated patients as a control group did not change the results. CONCLUSIONS: In this retrospective analysis of patients with AMI-CS, the use of an Impella device was not associated with lower 30-day mortality compared with matched patients from the IABP-SHOCK II trial treated with an IABP or medical therapy. To further evaluate this, a large randomized trial is warranted to determine the effect of the Impella device on outcome in patients with AMI-CS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03313687.

Advanced In Vitro Testing Strategies and Models of the Intestine for Nanosafety Research.

There is growing concern about the potential adverse effects of oral exposure to engineered nanomaterials (ENM). Recent years have witnessed major developments in and advancement of intestinal in vitro models for nanosafety evaluation. The present paper reviews the key factors that should be considered for inclusion in nonanimal alternative testing approaches to reliably reflect the in vivo dynamics of the physicochemical properties of ENM as well the intestinal physiology and morphology. Currently available models range from simple cell line-based monocultures to advanced 3D systems and organoids. In addition, in vitro approaches exist to replicate the mucous barrier, digestive processes, luminal flow, peristalsis, and interactions of ENM with the intestinal microbiota. However, while the inclusion of a multitude of individual factors/components of particle (pre)treatment, exposure approach, and cell model approximates in vivo-like conditions, such increasing complexity inevitably affects the system's robustness and reproducibility. The selection of the individual modules to build the in vitro testing strategy should be driven and justified by the specific purpose of the study and, not least, the intended or actual application of the investigated ENM. Studies that address health hazards of ingested ENM likely require different approaches than research efforts to unravel the fundamental interactions or toxicity mechanisms of ENM in the intestine. Advanced reliable and robust in vitro models of the intestine, especially when combined in an integrated testing approach, offer great potential to further improve the field of nanosafety research.

Clinical evaluation of a small implantable cardiac monitor with a long sensing vector.

INTRODUCTION: We conducted this study to show the safety and efficacy of a new implantable cardiac monitor (ICM), the BioMonitor 2 (Biotronik SE & Co. KG; Berlin, Germany), and to describe the arrhythmia detection performance. METHODS: The BioMonitor 2 has an extended sensing vector and is implanted close to the heart. It can transmit up to six subcutaneous electrocardiogram strips by Home Monitoring each day. We enrolled 92 patients with a standard device indication for an ICM in a single-arm, multicenter prospective trial. Patients were followed for 3 months, and 48-h Holter recordings were used to evaluate the arrhythmia detection performance. RESULTS: One patient withdrew consent and in one patient, the implantation failed. Two study device-related serious adverse events were reported, satisfying the primary safety hypothesis. Implantations took 7.4 ± 4.4 min from skin cut to suture. At 1 week, the R-wave amplitude was 0.75 ± 0.53 mV. In the 82 patients with completed Holter recordings, all patients with arrhythmias were correctly identified. False positive detections of arrhythmia were mostly irregular rhythms wrongly detected as atrial fibrillation (episode-based positive predictive value 72.5%). Daily Home Monitoring transmission was 94.9% successful. CONCLUSION: Safety and efficacy of the new device has been demonstrated. The detected R-wave amplitudes are large, leading to a low level of inappropriate detections due to over- or undersensing.

The apelin receptor influences biomechanical and morphological properties of endothelial cells.

The adaption of endothelial cells to local flow conditions is a multifunctional process which leads to distinct alterations in cell shape, the subcellular distribution of structural proteins, and cellular function. G-protein-coupled receptors (GPCRs) have been identified to be fundamentally involved in such processes. Recently, we and others have shown that the expression of the endothelial GPCR apelin receptor (APJ) is regulated by fluid flow and that activation of APJ participates in signaling pathways which are related to processes of mechanotransduction. The present study aims to illuminate these findings by further visualization of APJ function. We show that APJ is located to the cellular junctions and might thus be associated with platelet endothelial cell adhesion molecule-1 (PECAM-1) in human umbilical vein endothelial cells (HUVEC). Furthermore, siRNA-mediated silencing of APJ expression influences the shear-induced adaption of HUVEC in terms of cytoskeletal remodeling, cellular elasticity, cellular motility, attachment, and distribution of adhesion complexes. Taken together, our results demonstrate that APJ is crucial for complemented endothelial adaption to local flow conditions.

Impact of atrial fibrillation detected by extended monitoring-A population-based cohort study.

BACKGROUND: The clinical relevance of extended monitoring of AF in the general population is unclear. The study evaluated the detection of AF using transtelephonic electrocardiography and the clinical relevance of additional AF findings, especially with regard to stroke risk and mortality. METHODS: The data of 1678 volunteers participating in the tele-ECG-subproject of the Study of Health in Pomerania was evaluated. Occurrence of AF as revealed by tele-ECG and conventional ECG was evaluated. Associations with mortality, history of stroke, and other clinical parameters were analyzed. RESULTS: AF was detected in 21 subjects (1.3%) by conventional ECG (ECG-AF) and in 43 (2.6%) by tele-ECG. All individuals with AF revealed by conventional ECG were also diagnosed to have AF by tele-ECG; 22 were diagnosed by tele-ECG only (Tele-AF). During follow-up (median: 6.3 years) 42/1635, 1/22, and 5/21 participants died in the no-AF-, tele-AF-, and ECG-AF groups (p < .001). Whereas, in comparison to the no-AF group, the risk of death was higher in the ECG-AF group (HR 9.4; 3.7-23.8; p < .001), there was no significant increase in mortality in the tele-AF group (HR 1.9; 0.26-14.0; p = .52). Prevalence of stroke history was higher in the ECG-AF group (19%; 5.5-42%) than with the no-AF (1.9%; 1.3-2.7%; p = .001) and the tele-AF groups (0%; 0-15%; p = .05). CONCLUSIONS: Tele-ECG identifies significantly more AF cases in a population-based setting compared to conventional ECG. The impact of AF diagnosed only by extended monitoring differs from conventionally diagnosed AF. Additional studies are warranted, since this might have an impact on clinical management.

Stiffness of left ventricular cardiac fibroblasts is associated with ventricular dilation in patients with recent-onset nonischemic and nonvalvular cardiomyopathy.

BACKGROUND: Ventricular dilation is known as a pivotal predictor in recent-onset cardiomyopathy (ROCM), but its pathophysiology is not fully understood. In the present study we investigated whether single-cell stiffness of right and left ventricular-derived fibroblasts has an effect on cardiac phenotype in patients with ROCM. METHODS AND RESULTS: Patients with endomyocardial biopsy-proven ROCM were included (n=10). Primary cardiac fibroblasts (CFBs) were cultured from left and right ventricular endomyocardial biopsies and their single-cell stiffness was analyzed by quantification of Young's modulus using colloidal probe atomic force microscopy. Cardiac fibrosis was analyzed by Masson's trichrome staining. CFBs from the left ventricle showed significantly decreased stiffness when compared with CFBs from the right ventricle, indexed by decreased stiffness (Young's modulus 3,374±389 vs. 4,837±690 Pa; P<0.05). Young's modulus of CFBs derived from the left ventricle correlated negatively with the left ventricular end-diastolic dimension derived from 2-dimensional echocardiography (R(2)=0.77; P<0.01). Neither left nor right ventricular fibrosis correlated with the respective ventricular dimensions. CONCLUSIONS: Our data suggest that a decrease in single-cell stiffness of left ventricular fibroblasts could trigger left ventricular dilation in patients with ROCM. This implies a new potential mechanism for the ventricular dilation with this disease.

Investigating nanoplastics toxicity using advanced stem cell-based intestinal and lung in vitro models.

Plastic particles in the nanometer range-called nanoplastics-are environmental contaminants with growing public health concern. As plastic particles are present in water, soil, air and food, human exposure via intestine and lung is unavoidable, but possible health effects are still to be elucidated. To better understand the Mode of Action of plastic particles, it is key to use experimental models that best reflect human physiology. Novel assessment methods like advanced cell models and several alternative approaches are currently used and developed in the scientific community. So far, the use of cancer cell line-based models is the standard approach regarding in vitro nanotoxicology. However, among the many advantages of the use of cancer cell lines, there are also disadvantages that might favor other approaches. In this review, we compare cell line-based models with stem cell-based in vitro models of the human intestine and lung. In the context of nanoplastics research, we highlight the advantages that come with the use of stem cells. Further, the specific challenges of testing nanoplastics in vitro are discussed. Although the use of stem cell-based models can be demanding, we conclude that, depending on the research question, stem cells in combination with advanced exposure strategies might be a more suitable approach than cancer cell lines when it comes to toxicological investigation of nanoplastics.

Inhalable Saharan dust induces oxidative stress, NLRP3 inflammasome activation, and inflammatory cytokine release.

Desert dust is increasingly recognized as a major air pollutant affecting respiratory health. Since desert dust exposure cannot be regulated, the hazardousness of its components must be understood to enable health risk mitigation strategies. Saharan dust (SD) comprises about half of the global desert dust and contains quartz, a toxic mineral dust that is known to cause severe lung diseases via oxidative stress and activation of the NLRP3 inflammasome-interleukin-1ß pathway. We aimed to assess the physicochemical and microbial characteristics of SD responsible for toxic effects. Also, we studied the oxidative and pro-inflammatory potential of SD in alveolar epithelial cells and the activation of the NLRP3 inflammasome in macrophage-like cells in comparison to quartz dusts and synthetic amorphous silica (SAS). Characterization revealed that SD contained Fe, Al, trace metals, sulfate, diatomaceous earth, and endotoxin and had the capacity to generate hydroxyl radicals. We exposed A549 lung epithelial cells and wild-type and NLRP3-/- THP-1 macrophage-like cells to SD, three well-investigated quartz dusts, and SAS. SD induced oxidative stress in A549 cells after 24 h more potently than the quartz dusts. The quartz dusts and SAS upregulated interleukin 8 expression after 4 h and 24 h while SD only caused a transient upregulation. SD, the quartz dusts, and SAS induced interleukin-1ß release from wild-type THP-1 cells>20-fold stronger than from NLRP3-/- THP-1 cells. Interleukin-1ß release was lower for SD, in which microbial components including endotoxin were heat-destructed. In conclusion, microbial components in SD are pivotal for its toxicity. In the epithelium, the effects of SD contrasted with crystalline and amorphous silica in terms of potency and persistence. In macrophages, the strong involvement of the NLRP3 inflammasome emphasizes the acute and chronic health risks associated with desert dust exposure.

Investigating the Role of the NLRP3 Inflammasome Pathway in Acute Intestinal Inflammation: Use of THP-1 Knockout Cell Lines in an Advanced Triple Culture Model.

The NLRP3 inflammasome plays an important role in intestinal homeostasis as well as inflammation. However, in vivo studies investigating the role of the NLRP3 inflammasome in inflammatory bowel disease (IBD) report contrasting results, leaving it unclear if the NLRP3 inflammasome augments or attenuates intestinal inflammation. To investigate the role of the NLRP3/caspase-1 pathway in a model of acute intestinal inflammation, we modified a previously established in vitro triple culture model of the healthy and inflamed intestine (Caco-2/HT29-MTX-E12/THP-1). Using THP-1 knockout cell lines, we analyzed how the NLRP3 inflammasome and its downstream enzyme caspase-1 (CASP1) affect inflammatory parameters including barrier integrity and cytotoxicity, as well as gene expression and secretion of pro-inflammatory cytokines and mucus. Furthermore, we investigated differences in inflammation-mediated cytotoxicity towards enterocyte-like (Caco-2) or goblet-like (HT29-MTX-E12) epithelial cells. As a complementary approach, inflammation-related cytotoxicity and gene expression of cytokines was analyzed in intestinal tissue explants from wildtype (WT) and Nlrp3-/- mice. Induction of intestinal inflammation impaired the barrier, caused cytotoxicity, and altered gene expression of pro-inflammatory cytokines and mucins in vitro, while the knockout of NLRP3 and CASP1 in THP 1 cells led to attenuation of these inflammatory parameters. The knockout of CASP1 tended to show a slightly stronger attenuating effect compared to the NLRP3 knockout model. We also found that the inflammation-mediated death of goblet-like cells is NLRP3/caspase-1 dependent. Furthermore, inflammation-related cytotoxicity and upregulation of pro-inflammatory cytokines was present in ileal tissue explants from WT, but not Nlrp3-/- mice. The here presented observations indicate a pro-inflammatory and adverse role of the NLRP3 inflammasome in macrophages during acute intestinal inflammation.

Assessing the NLRP3 Inflammasome Activating Potential of a Large Panel of Micro- and Nanoplastics in THP-1 Cells.

Due to the ubiquity of environmental micro- and nanoplastics (MNPs), inhalation and ingestion by humans is very likely, but human health effects remain largely unknown. The NLRP3 inflammasome is a key player of the innate immune system and is involved in responses towards foreign particulate matter and the development of chronic intestinal and respiratory inflammatory diseases. We established NLRP3-proficient and -deficient THP-1 cells as an alternative in vitro screening tool to assess the potential of MNPs to activate the NLRP3 inflammasome. By investigating cytokine release (IL-1ß and IL-8) and cytotoxicity after treatment with engineered nanomaterials, this in vitro approach was compared to earlier published ex vivo murine bone marrow-derived macrophages and in vivo data. This approach showed a strong correlation with previously published data, verifying that THP-1 cells are a suitable model to investigate NLRP3 inflammasome activation. We then investigated the proinflammatory potential of eight MNPs of different size, shape, and chemical composition. Only amine-modified polystyrene (PS-NH2) acted as a direct NLRP3 activator. However, polyethylene terephthalate (PET), polyacrylonitrile (PAN), and nylon (PA6) induced a significant increase in IL-8 release in NLRP3-/- cells. Our results suggest that most MNPs are not direct activators of the NLRP3 inflammasome, but specific MNP types might still possess pro-inflammatory potential via other pathways.

Telemedical cardiac risk assessment by implantable cardiac monitors in patients after myocardial infarction with autonomic dysfunction (SMART-MI-DZHK9): a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial.

BACKGROUND: Cardiac autonomic dysfunction after myocardial infarction identifies patients at high risk despite only moderately reduced left ventricular ejection fraction. We aimed to show that telemedical monitoring with implantable cardiac monitors in these patients can improve early detection of subclinical but prognostically relevant arrhythmic events. METHODS: We did a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial at 33 centres in Germany and Austria. Survivors of acute myocardial infarction with left ventricular ejection fraction of 36-50% had biosignal analysis for assessment of cardiac autonomic function. Patients with abnormal periodic repolarisation dynamics (≥5·75 deg2) or abnormal deceleration capacity (≤2·5 ms) were randomly assigned (1:1) to telemedical monitoring with implantable cardiac monitors or conventional follow-up. Primary endpoint was time to detection of serious arrhythmic events defined by atrial fibrillation 6 min or longer, atrioventricular block class IIb or higher and fast non-sustained (>187 beats per min; ≥40 beats) or sustained ventricular tachycardia or fibrillation. This study is registered with ClinicalTrials.gov, NCT02594488. FINDINGS: Between May 12, 2016, and July 20, 2020, 1305 individuals were screened and 400 patients at high risk were randomly assigned (median age 64 years [IQR 57-73]); left ventricular ejection fraction 45% [40-48]) to telemedical monitoring with implantable cardiac monitors (implantable cardiac monitor group; n=201) or conventional follow-up (control group; n=199). During median follow-up of 21 months, serious arrhythmic events were detected in 60 (30%) patients of the implantable cardiac monitor group and 12 (6%) patients of the control group (hazard ratio 6·33 [IQR 3·40-11·78]; p<0·001). An improved detection rate by implantable cardiac monitors was observed for all types of serious arrhythmic events: atrial fibrillation 6 min or longer (47 [23%] patients vs 11 [6%] patients; p<0·001), atrioventricular block class IIb or higher (14 [7%] vs 0; p<0·001) and ventricular tachycardia or ventricular fibrillation (nine [4%] patients vs two [1%] patients; p=0·054). INTERPRETATION: In patients at high risk after myocardial infarction and cardiac autonomic dysfunction but only moderately reduced left ventricular ejection fraction, telemedical monitoring with implantable cardiac monitors was highly effective in early detection of subclinical, prognostically relevant serious arrhythmic events. FUNDING: German Centre for Cardiovascular Research (DZHK) and Medtronic Bakken Research Center.

Asymptomatic sustained ventricular fibrillation in a patient with left ventricular assist device.

Optimal medical treatment, cardiac resynchronization, and the use of an implantable cardioverter defibrillator are established therapies of severe congestive heart failure. In refractory cases, left ventricular assist devices are more and more used not only as bridging to cardiac transplantation but also as destination therapy. Ventricular arrhythmias may represent a life-threatening condition and often result in clinical deterioration in patients with congestive heart failure. We report a case of asymptomatic sustained ventricular fibrillation with preserved hemodynamics caused by a nonpulsatile left ventricular assist device. Consecutive adequate but unsuccessful discharges of the implantable cardioverter defibrillator were the only sign of the usually fatal arrhythmia, prompting the patient to consult emergency services. Electrolyte supplementation and initiation of therapy with amiodarone followed by external defibrillation resulted in successful restoration of a stable cardiac rhythm after 3.5 hours.

An inverted in vitro triple culture model of the healthy and inflamed intestine: Adverse effects of polyethylene particles.

As environmental pollution with plastic waste is increasing, numerous reports show the contamination of natural habitats, food and drinking water with plastic particles in the micro- and nanometer range. Since oral exposure to these particles is virtually unavoidable, health concerns towards the general population have been expressed and risk assessment regarding ingested plastic particles is of great interest. To study the intestinal effects of polymeric particles with a density of <1 g/cm³ in vitro, we spatially inverted a triple culture transwell model of the healthy and inflamed intestine (Caco-2/HT29-MTX-E12/THP-1), which allows contact between buoyant particles and cells. We validated the inverted model against the original model using the enterotoxic, non-steroidal anti-inflammatory drug diclofenac and subsequently assessed the cytotoxic and pro-inflammatory effects of polyethylene (PE) microparticles. The results show that the inverted model exhibits the same distinct features as the original model in terms of barrier development and inflammatory parameters. Treatment with 2 mM diclofenac causes severe cytotoxicity, DNA damage and complete barrier disruption in both models. PE particles induced cytotoxicity and pro-inflammatory effects in the inverted model, which would have remained undetected in conventional in vitro approaches, as no effect was observed in non-inverted control cultures.

Platelet apelin receptor expression is reduced in patients with acute myocardial infarction.

BACKGROUND: The G-protein-coupled apelin receptor and its apelin ligand are an emerging regulatory system of the vascular homeostasis. To date, the implications of the apelin/apelin receptor system in athero-thrombosis are not completely clarified yet. This study determines the expression of the apelin receptor on human platelets, the effect of different apelin isoforms on platelet aggregation and the potential role of the apelin/apelin receptor system in acute myocardial infarction. METHODS: We applied immunofluorescence staining, Western Blot analysis, aggregometry, and flow cytometry to elucidate the role of the apelin receptor in activated platelets. Furthermore, in an observational pilot study, we assessed platelet apelin recpetor expression and apelin-17 plasma levels in patients with acute myocardial infarction (AMI, n = 27). RESULTS: Immunofluorescence staining indicates that the apelin receptor is located at the cell membrane in resting platelets and diminishes upon activation with a selective thrombin receptor-activating peptide (AP1, 3 to 100 µM). Western Blot analyses of AP1-activated platelets and their supernatants suggest that the apelin receptor is not predominantly internalized but is released from activated platelets. The isoform apelin-17 attenuated AP-1-induced platelet activation in-vitro, presumably via a NO-dependent mechanism. Furthermore, platelet apelin receptor expression was significantly reduced in patients with AMI (n = 27) compared to age-matched controls (n = 14; p < 0.05) and inversely correlated with troponin I plasma levels (r = -0.46; p = 0.03). Besides that, circulating apelin-17 was significantly reduced in MI patients compared to the control group. CONCLUSION: Taken together, our data support a crucial role of the platelet apelinergic system assuming an antithrombotic effect and therefore holding a potential diagnostic and therapeutic impact.

Reduction of inappropriate implantable cardioverter-defibrillator therapies using enhanced supraventricular tachycardia discriminators: the ReduceIT study.

PURPOSE: Inappropriate implantable cardioverter-defibrillator (ICD) shocks are associated with greater healthcare resource utilization, poorer quality-of-life, and higher mortality. We aimed to investigate the performance of enhanced supraventricular tachycardia (SVT) discrimination algorithms (morphology discrimination, rate stability, and sudden or chamber onset) for reducing inappropriate ICD therapies in patients with ICD/cardiac resynchronization therapy devices. METHODS: This prospective, non-randomized, multicenter study (ReduceIT) study took place at 56 sites across Germany and Estonia. Adults at risk of sudden cardiac death undergoing St. Jude Medical™ ICD or CRT-D implantation were included. The primary endpoint was freedom from inappropriate ICD shock at 12 months and was analyzed in the intention to treat (ITT) and per-protocol population. RESULTS: Overall, 733 patients (65.9 ± 11.4 years) were included, of which 40.9% and 59.1% received a single- and dual-chamber detection device, respectively. During follow-up (median 11.9 [0-21.6] months), 96.3% of patients experienced no inappropriate therapy (ITT). The sensitivity, specificity, and accuracy for VT/VF were 91.9%, 95.5%, and 94.7%, respectively. In the per-protocol population (n = 620), the proportion of patients free from inappropriate shock at 12 months was 98.4% (n = 610; 95% CI 97.1-99.2%) and exceeded the expected value of 93% (p < 0.0001) which was derived from the rates in the SPICE, ATPonFastVT, and DECREASE studies. A total of 44 patients (6.0%) died during follow-up, 19 deaths were cardiac-related which is consistent with a meta-analysis of EMPIRIC, MADIT-RIT, ADVANCE III, and PROVIDE. Serious device and procedure-related adverse effects occurred in 9.8% of patients. CONCLUSIONS: In ICD/CRT-D devices with advanced SVT discriminators, device programming according to clinical setting and detection chamber significantly reduces the rate of inappropriate ICD shocks without compromising patient safety. The algorithms and settings described herein have particular clinical importance and their employment may be of benefit to ICD recipients.

Impella versus extracorporal life support in cardiogenic shock: a propensity score adjusted analysis.

AIMS: The mortality in cardiogenic shock (CS) is high. The role of specific mechanical circulatory support (MCS) systems is unclear. We aimed to compare patients receiving Impella versus ECLS (extracorporal life support) with regard to baseline characteristics, feasibility, and outcomes in CS. METHODS AND RESULTS: This is a retrospective cohort study including CS patients over 18 years with a complete follow-up of the primary endpoint and available baseline lactate level, receiving haemodynamic support either by Impella 2.5 or ECLS from two European registries. The decision for device implementation was made at the discretion of the treating physician. The primary endpoint of this study was all-cause mortality at 30 days. A propensity score for the use of Impella was calculated, and multivariable logistic regression was used to obtain adjusted odds ratios (aOR). In total, 149 patients were included, receiving either Impella (n = 73) or ECLS (n = 76) for CS. The feasibility of device implantation was high (87%) and similar (aOR: 3.14; 95% CI: 0.18-56.50; P = 0.41) with both systems. The rates of vascular injuries (aOR: 0.95; 95% CI: 0.10-3.50; P = 0.56) and bleedings requiring transfusions (aOR: 0.44; 95% CI: 0.09-2.10; P = 0.29) were similar in ECLS patients and Impella patients. The use of Impella or ECLS was not associated with increased odds of mortality (aOR: 4.19; 95% CI: 0.53-33.25; P = 0.17), after correction for propensity score and baseline lactate level. Baseline lactate level was independently associated with increased odds of 30 day mortality (per mmol/L increase; OR: 1.29; 95% CI: 1.14-1.45; P < 0.001). CONCLUSIONS: In CS patients, the adjusted mortality rates of both ECLS and Impella were high and similar. The baseline lactate level was a potent predictor of mortality and could play a role in patient selection for therapy in future studies. In patients with profound CS, the type of device is likely to be less important compared with other parameters including non-cardiac and neurological factors.

Acupuncture for Relief of Gag Reflex in Patients Undergoing Transoesophageal Echocardiography-A Protocol for a Randomized Placebo-Controlled Trial.

Background: Gagging during transesophageal echocardiography examination (TEE) can be distressing and even dangerous for patients. The needling of acupuncture point CV24 was described to be effective in reducing the gag reflex during TEE in patients with ischemic stroke or transient ischemic attack. Methods: We describe a proposal for a prospective, randomized, patient, practitioner and assessor-blinded, single-center trial with two arms/groups; real acupuncture will be compared to placebo acupuncture. A total of 60 (30 per group) patients scheduled for elective TEE in order to exclude a cardiac embolic source, endocarditis or for valve failure evaluation will be recruited according to patients' selection criteria and receive either indwelling fixed intradermal needles at acupoints CV24 and bilateral PC6 or placebo needles at the same areas. Patients, the practitioners who will perform the TEE procedure, and the assessor of the outcome measures will be unaware of the group's (real or placebo) allocation. Results: The primary outcome is the intensity of gagging, measured using verbal rating scale (VRS-11) from 0 = no gagging to 10 = intolerable gagging. Secondary outcomes include the incidence of gagging, the use of rescue medication, patients' satisfaction with relief of unwanted side effects during TEE procedure, success of patients' blinding (patients' opinion to group allocation), heart rate and oxygen saturation measured by pulse oxymetry. Conclusions: To study the effects of acupuncture against gagging during TEE, we test the needling of acupoints CV24 and PC6 bilaterally. A placebo acupuncture is used for the control group. Trial registration number: NCT NCT0382142.