[Preclinical loading in patients with acute chest pain and acute coronary syndrome - PRELOAD survey]. / Präklinisches Loading bei Patienten mit akutem Thoraxschmerz und akutem Koronarsyndrom ­ PRELOAD-Umfrage.

BACKGROUND: Guidelines on myocardial infarction (MI) recommend antithrombotic and anticoagulatory treatment at time of diagnosis. MI with ST segment elevation (STEMI) is mostly a certain diagnosis. Acute coronary syndrome without ST segment elevation (NSTE-ACS) has diagnostic uncertainty and remains a working diagnosis in the prehospital setting. OBJECTIVE: Assessment of prehospital loading with aspirin and heparin depending on ACS subtype and pretreatment with oral anticoagulants. METHODS: The PRELOAD survey was a nationwide German study. STEMI/NSTE-ACS scenarios were designed and varied in pretreatment: I) no pretreatment, II) new oral anticoagulants (NOAC), III) vitamin K antagonist (VKA). Loading strategy was assessed and included: a) aspirin (ASA), b) unfractionated heparin (UFH), c) ASA + UFH, d) no loading. RESULTS: A total of 708 emergency physicians were included. In NSTE-ACS without pretreatment, 79% chose loading (p < 0.001). ASA + UFH (71.4%) was the preferred option. In corresponding STEMI scenario, 100% chose loading and 98.6% preferred ASA + UFH (p < 0.001). In NSTE-ACS with NOAC pretreatment, 69.8% favored loading (p < 0.001); in VKA pretreatment the corresponding rate was 72.3% (p < 0.001). In each scenario, ASA was the preferred option. In STEMI with NOAC pretreatment, 97.5% chose loading (p < 0.001); analogous rate was 96.8% in STEMI with VKA pretreatment (p < 0.001). ASA was the preferred option again. CONCLUSIONS: Prehospital loading was the preferred treatment strategy despite the diagnostic uncertainty in NSTE-ACS and guidelines recommending loading at time of diagnosis. Pretreatment with oral anticoagulants resulted in a strategy shift to loading with only aspirin. In STEMI patients, this indicates potential undertreatment.

Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy.

Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo-/- mice. Accordingly, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with DOX and MPO aggravated loss of hiPSC-CM-contractility compared to DOX treatment alone. DOX-treated animals exhibited pronounced cardiac apoptosis and inflammation, which was attenuated in MPO-deficient animals. Finally, genetic MPO deficiency and pharmacological MPO inhibition protected mice from the development of AICM. The anticancer efficacy of DOX was unaffected by MPO deficiency. Herein we identify MPO as a critical mediator of AICM. We demonstrate that DOX induces cardiac neutrophil infiltration and release of MPO, which directly impairs cardiac contractility through promoting oxidation of sarcomeric proteins, cardiac inflammation and cardiomyocyte apoptosis. MPO thus emerges as a promising pharmacological target for prevention of AICM.

Outcome of Out-of-Hospital Cardiac Arrest Patients Stratified by Pre-Clinical Loading with Aspirin and Heparin: A Retrospective Cohort Analysis.

Background: Out-of-hospital cardiac arrest (OHCA) has a high prevalence of obstructive coronary artery disease and total coronary occlusion. Consequently, these patients are frequently loaded with antiplatelets and anticoagulants before hospital arrival. However, OHCA patients have multiple non-cardiac causes and high susceptibility for bleeding. In brief, there is a gap in the evidence for loading in OHCA patients. Objective: The current analysis stratified the outcome of patients with OHCA according to pre-clinical loading. Material and Methods: In a retrospective analysis of an all-comer OHCA registry, patients were stratified by loading with aspirin (ASA) and unfractionated heparin (UFH). Bleeding rate, survival to hospital discharge and favorable neurological outcomes were measured. Results: Overall, 272 patients were included, of whom 142 were loaded. Acute coronary syndrome was diagnosed in 103 patients. One-third of STEMIs were not loaded. Conversely, 54% with OHCA from non-ischemic causes were pretreated. Loading was associated with increased survival to hospital discharge (56.3 vs. 40.3%, p = 0.008) and a more favorable neurological outcome (80.7 vs. 62.6% p = 0.003). Prevalence of bleeding was comparable (26.8 vs. 31.5%, p = 0.740). Conclusions: Pre-clinical loading did not increase bleeding rates and was associated with favorable survival. Overtreatment of OHCA with non-ischemic origin, but also undertreatment of STEMI-OHCA were documented. Loading without definite diagnosis of sustained ischemia is debatable in the absence of reliable randomized controlled data.

Acute Chest Pain­Diagnostic Accuracy and Pre-Hospital Use of Anticoagulants and Platelet Aggregation Inhibitors

BACKGROUND: Acute chest pain (aCP) can be a symptom of life-threatening diseases such as acute coronary or aortic syndrome, but often has a non-cardiac cause. The recommendations regarding pre-hospital drug treatment of patients with aCP are ambiguous. METHODS: A retrospective cohort study was conducted of 822 patients with aCP who were attended by emergency physicians. The cause of aCP was classified as follows: acute coronary syndrome without ST-segment elevation (NSTE-ACS), acute aortic syndrome, hypertensive crisis, cardiac arrhythmias, musculoskeletal, or other. The suspected and discharge diagnoses were compared, and the pre-hospital administration of acetylsalicylic acid (ASA) and unfractionated heparin (UFH) was analyzed. Furthermore, the parameters that improved diagnostic accuracy were investigated. RESULTS: The positive predictive value of the diagnosis assigned by the emergency physician (EP diagnosis) was 39.7%. NSTEACS was the most commonly suspected cause of aCP (74.7%), but was confirmed after hospital admission in only 26.3% of patients. ASA was administered in 51%, UFH in 55%, and both substances in 46.4% of cases. A large proportion of patients received anticoagulants in the pre-hospital setting although the discharge diagnosis was not NSTE-ACS: ASA 62.9%, UFH 66.0%, both substances 56.5%. CONCLUSION: ASA and UFH are often given to EP-accompanied patients with aCP despite the low accuracy of diagnosis in the pre-hospital setting. Pre-hospital measurement of high-sensitivity troponin T (hs Trop-T) might improve discrimination between NSTE-ACS and other causes of aCP. This is important, as the current guidelines contain no clear recommendations for prehospital drug treatment in NSTE-ACS.

Coronary angiography after cardiac arrest without ST-elevation myocardial infarction: a network meta-analysis.

AIMS: This network meta-analysis aimed to assess the effect of early coronary angiography (CAG) compared with selective CAG (late and no CAG) for patients after out-of-hospital cardiac arrest without ST-elevation myocardial infarction (NSTE-OHCA). METHODS AND RESULTS: A systematic literature search was performed using the EMBASE, MEDLINE and Web of Science databases without restrictions on publication date. The last search was performed on 15 July 2022. Randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing the effect of early CAG to selective CAG after NSTE-OHCA on survival and/or neurological outcomes were included. Meta-analyses were performed based on a DerSimonian-Laird random effects model. A total of 18 studies were identified by the literature search. After the exclusion of two studies due to high risk of bias, 16 studies (six RCTs, ten NRS) were included in the final analyses. Meta-analyses showed a statistically significant increase in survival after early CAG compared with selective CAG in the overall analysis [OR: 1.40, 95% confidence interval (CI): (1.12-1.76), P < 0.01, I2 = 68%]. This effect was lost in the subgroup analysis of RCTs [OR: 0.89, 95% CI: (0.73-1.10), P = 0.29, I2 = 0%]. Random effects model network meta-analysis of NRS based on a Bayesian method showed statistically significant increased survival after late compared with early CAG [OR: 4.20, 95% CI: (1.22, 20.91)]. CONCLUSION: The previously reported superiority of early CAG after NSTE-OHCA is based on NRS at high risk of selection and survivorship bias. The meta-analysis of RCTs does not support routinely performing early CAG after NSTE-OHCA.

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production.

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein­coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome and induces interleukin-1ß secretion in human and mouse macrophages. We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.

Is there a benefit of ICD treatment in patients with persistent severely reduced systolic left ventricular function after TAVI?

BACKGROUND: In patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) and heart failure with severely reduced ejection fraction, prediction of postprocedural left ventricular ejection fraction (LVEF) improvement is challenging. Decision-making and timing for implantable cardioverter defibrillator (ICD) treatment are difficult and benefit is still unclear in this patient population. OBJECTIVE: Aims of the study were to analyse long-term overall mortality in TAVI-patients with a preprocedural LVEF ≤ 35% regarding LVEF improvement and effect of ICD therapy. METHODS AND RESULTS: Retrospective analysis of a high-risk TAVI-population suffering from severe AS and heart failure with a LVEF ≤ 35%. Out of 1485 TAVI-patients treated at this center between January 2013 and April 2018, 120 patients revealed a preprocedural LVEF ≤ 35% and had sufficient follow-up. 36.7% (44/120) of the patients suffered from persistent reduced LVEF without a postprocedural increase above 35% within 1 year after TAVI or before death, respectively. Overall mortality was neither significantly reduced by LVEF recovery above 35% (p = 0.31) nor by additional ICD treatment in patients with persistent LVEF ≤ 35% (p = 0.33). CONCLUSION: In high-risk TAVI-patients suffering from heart failure with LVEF ≤ 35%, LVEF improvement to more than 35% did not reduce overall mortality. Patients with postprocedural persistent LVEF reduction did not seem to benefit from ICD treatment. Effects of LVEF improvement and ICD treatment on mortality are masked by the competing risk of death from relevant comorbidities.

Extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: first results and outcomes of a newly established ECPR program in a large population area.

OBJECTIVES: Out-of-hospital cardiac arrest (OHCA) is associated with excessively high mortality rates. Recent studies suggest benefits from extracorporeal cardiopulmonary resuscitation (ECPR) performed in selected patients. We sought to present the first results from our interdisciplinary ECPR program with a particular focus on early outcomes and potential risk factors associated with in-hospital mortality. METHODS: Between January 2016 and December 2019, 44 patients who underwent ECPR selected according to our institutional ECPR protocol were retrospectively analyzed regarding pre-hospital, in-hospital, and early outcome parameters. Patients were divided into survivors (S) and non-survivors (NS). Statistical analysis of risk factors regarding in-hospital mortality of the patient cohort analyzed was performed. RESULTS: The mean age of the population was 53 ± 12 years, with most patients being male (n = 40). The leading cause of cardiac arrest (CA) was myocardial infarction (n = 24, 55%). The median hospital stay was 1 (1;13) day. Twenty-three percent of patients (n = 10) were discharged from hospital including eight patients (18%) with CPC 1-2. Survivors showed a trend toward shorter pre-hospital CPR duration (60 (59;60) min (S) vs 60 (55;90) min (NS), p = 0.07). CONCLUSION: Establishing ECPR programs in large population areas offers the option to improve survival rates for OHCA patients. Stringent compliance of institutional criteria (mainly age, witnessed arrest, and time of pre-hospital resuscitation) and providing ECPR to strictly selected patients seems to be a vital factor for such programs' success. Pre-clinical settings and therapeutic measures must be adjusted in this regard to improve outcomes for this highly demanding patient cohort.

Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome.

AIMS: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS. METHODS AND RESULTS: Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II. CONCLUSION: NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.

Absolute serum neurofilament light chain levels and its early kinetics predict brain injury after out-of-hospital cardiac arrest.

OBJECTIVES: To test if the early kinetics of neurofilament light (NFL) in blood adds to the absolute values of NFL in the prediction of outcome, and to evaluate if NFL can discriminate individuals with severe hypoxic-ischemic brain injury (sHIBI) from those with other causes of poor outcome after out-of-hospital cardiac arrest (OHCA). DESIGN AND SETTING: Monocentric retrospective study involving individuals following non-traumatic OHCA between April 2014 and April 2016. NFL concentrations were determined on a SiMoA HD-1 device using NF-Light Advantage Kits. PARTICIPANTS: Of 73 patients screened, 53 had serum samples available for NFL measurement at three timepoints (after 3, 24, and 48 h of admission). Of these 53 individuals, 43.4% had poor neurologic outcome at discharge as assessed by Glasgow-Pittsburgh cerebral performance categories, and, according to a current prognostication algorithm, poor outcome due to sHIBI in 20.7%. MAIN OUTCOME MEASURE: Blood NFL and its early kinetics for prognostication of outcome and prediction of sHIBI after OHCA. RESULTS: An absolute NFL > 508.6 pg/ml 48 h after admission, or a change in NFL > 494 pg/ml compared with an early baseline value predicted outcome, and discriminated severe sHIBI from other causes of unfavorable outcome after OHCA with high sensitivity (100%, 95%CI 70.0-100%) and specificity (91.7%, 95%CI 62.5-100%). CONCLUSIONS: Not only absolute values of NFL, but also early changes in NFL predict the outcome following OHCA, and may differentiate sHIBI from other causes of poor outcome after OHCA with high sensitivity and specificity. Our study adds to published data, overall corroborating that NFL measured in blood should be implemented in prognostication algorithms used in clinical routine.

Protective Effects of Therapeutic Neutrophil Depletion and Myeloperoxidase Inhibition on Left Ventricular Function and Remodeling in Myocardial Infarction.

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Improved survival has led to an increasing incidence of ischemic cardiomyopathy, making it a major reason for hospitalization in the western world. The inflammatory response in the ischemic myocardium determines the extent of structural remodeling and functional deterioration, with neutrophils (PMN) being a key modulator of the propagation and resolution of inflammation. The heme enzyme myeloperoxidase (MPO) is abundantly expressed in PMN and is an important mediator of their inflammatory capacities. Here, we examine the effects of PMN reduction, MPO deficiency and MPO inhibition in two murine models of MI. Reduction in PMN count resulted in less scar formation and improved cardiac function. Similar results were obtained in genetically MPO deficient mice, suggesting that MPO is a critical factor in PMN-mediated cardiac remodeling. To test our findings in a therapeutic approach, we orally administered the MPO inhibitor AZM198 in the context of MI and could demonstrate improved cardiac function and reduced structural remodeling. Therefore, MPO appears to be a favorable pharmacological target for the prevention of long-term morbidity after MI.

Meta-analysis of extracorporeal membrane oxygenation in combination with intra-aortic balloon pump vs. extracorporeal membrane oxygenation only in patients with cardiogenic shock due to acute myocardial infarction.

Background: Incidence and mortality of cardiogenic shock (CS) in patients with acute myocardial infarction (AMI) remain high despite substantial therapy improvements in acute percutaneous coronary intervention over the last decades. Unloading the left ventricle in patients with Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can be performed by using an intra-aortic balloon pumps' (IABP) afterload reduction, which might be especially beneficial in AMI patients with CS. Objective: The objective of this meta-analysis was to assess the effect of VA-ECMO + IABP vs. VA-ECMO treatment on the mortality of patients with CS due to AMI. Methods: A systematic literature search was performed using EMBASE, COCHRANE, and MEDLINE databases. Studies comparing the effect of VA-ECMO + IABP vs. VA-ECMO on mortality of patients with AMI were included. Meta-analyses were performed to analyze the effect of the chosen treatment on 30-day/in-hospital mortality. Results: Twelve studies were identified by the literature search, including a total of 5,063 patients, 81.5% were male and the mean age was 65.9 years. One thousand one hundred and thirty-six patients received treatment with VA-ECMO in combination with IABP and 2,964 patients received VA-ECMO treatment only. The performed meta-analysis showed decreased mortality at 30-days/in-hospital after VA-ECMO + IABP compared to VA-ECMO only for patients with cardiogenic shock after AMI (OR 0.36, 95% CI 0.30-0.44, P≤0.001). Combination of VA-ECMO + IABP was associated with higher rates of weaning success (OR 0.29, 95% CI 0.16-0.53, P < 0.001) without an increase of vascular access complications (OR 0.85, 95% CI 0.35-2.08, P = 0.72). Conclusion: In this meta-analysis, combination therapy of VA-ECMO + IABP was superior to VA-ECMO only therapy in patients with CS due to AMI. In the absence of randomized data, these results are hypothesis generating only.

Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation.

The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2's protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2-/- ) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2-/- hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2-/- animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-κB activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2-/- mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.

Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis.

Nitro-oleic acid (NO2-OA), a nitric oxide (NO)- and nitrite (NO2-)-derived electrophilic fatty acid metabolite, displays anti-inflammatory and anti-fibrotic signaling actions and therapeutic benefit in murine models of ischemia-reperfusion, atrial fibrillation, and pulmonary hypertension. Muscle LIM protein-deficient mice (Mlp-/-) develop dilated cardiomyopathy (DCM), characterized by impaired left ventricular function and increased ventricular fibrosis at the age of 8 weeks. This study investigated the effects of NO2-OA on cardiac function in Mlp-/- mice both in vivo and in vitro. Mlp-/- mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneous osmotic minipumps. Wildtype (WT) littermates treated with vehicle served as controls. Mlp-/- mice exhibited enhanced TGFß signalling, fibrosis and severely reduced left ventricular systolic function. NO2-OA treatment attenuated interstitial myocardial fibrosis and substantially improved left ventricular systolic function in Mlp-/- mice. In vitro studies of TGFß-stimulated primary cardiac fibroblasts further revealed that the anti-fibrotic effects of NO2-OA rely on its capability to attenuate fibroblast to myofibroblast transdifferentiation by inhibiting phosphorylation of TGFß downstream targets. In conclusion, we demonstrate a substantial therapeutic benefit of NO2-OA in a murine model of DCM, mediated by interfering with endogenously activated TGFß signaling.

Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B.

Atherosclerosis is a chronic, lipid-driven disease of medium sized arteries which causes myocardial infarction and stroke. Recently, an adaptive immune response against the plaque-associated autoantigen Apolipoprotein B100 (ApoB), the structural protein component of low-density lipoprotein, has been implicated in atherogenesis. In healthy individuals, CD4+ T cells responding to ApoB mainly comprised regulatory T cells, which confer immune tolerance and atheroprotection. Mice and patients with atherosclerosis harbor increased numbers of proatherogenic ApoB-reactive T-helper cell subsets. Given the lack of therapies targeting proatherogenic immunity, clarification of the underlying mechanisms is of high clinical relevance. T cells develop in the thymus, where strong autoreactive T cells are eliminated in the process of negative selection. Herein, we investigated whether the transcription factor autoimmune regulator (AIRE), which controls expression of numerous tissue-restricted self-antigens in the thymus, is involved in mediating tolerance to ApoB and whether Aire deficiency might contribute to atherogenesis. Mice deficient for Aire were crossbred to apolipoprotein E-deficient mice to obtain atherosclerosis-prone Aire -/- Apoe -/- mice, which were fed a regular chow diet (CD) or western-type diet (WD). CD4+ T cells responding to the ApoB peptide p6 were analyzed by flow cytometry. We demonstrate that Aire deficiency influences neither generation nor activation of ApoB-reactive T cells and has only minor and overall inconsistent impacts on their phenotype. Furthermore, we show that atherosclerotic plaque size is not affected in Aire -/- Apoe -/- compared to Aire +/+ Apoe -/-, irrespective of diet and gender. In conclusion, our data suggests that AIRE is not involved in regulating thymic expression of ApoB or atherosclerosis. Alternative mechanisms how ApoB-reactive CD4 T cells are selected in the thymus will have to be investigated.

Gender-related differences in treatment and outcome of extracorporeal cardiopulmonary resuscitation-patients.

Extracorporeal cardiopulmonary resuscitation (eCPR) is a rapidly growing treatment strategy due to significant improvement in selected patients' survival rates. Gender-related differences might impact the outcome of therapeutic measures. Therefore, we sought to investigate patients with eCPR at our interdisciplinary extracorporeal membrane oxygenation center regarding sex-related differences with the view to potentially adjusting current selection criteria. From January 2016 to December 2019, 71 patients underwent eCPR at our institution. Data before eCPR and early outcome parameters were analyzed comparing male and female patients. The cohort analyzed consisted of 60 male (84%) and 11 female (15%) patients. Comparing both groups, male patients significantly more frequently suffered out-of-hospital cardiac arrest (68% male vs. 36% female, P = .04), whereas female patients were associated with more in-hospital cardiac arrest (32% male vs. 64% female, P = .04). Creatinine levels differed significantly (1.5 (1.1;2.1) mg/dL in male vs. 1.0 (0.7;1.5) mg/dL in female patients, P = .03). Also, several hepatic parameters showed a significant difference between the groups: aspartate aminotransferase 423 (249;804) U/L in male vs. 115 (61;408) U/L in female patients, P = .01; alanine aminotransferase 174 (102;446) U/L in male vs. 86 (36;118) U/L in female patients, P = .01). Renal failure requiring hemodialysis occurred more frequently in men than in women (P < .01). There is a significant effect of male sex regarding renal failure with subsequent continuous venovenous hemodialysis (CVVH) (R2  = 0.11, ANOVA P = .01, 95% CI = -0.79--0.079). However, in-hospital mortality was comparable between the groups (78% in male vs. 72% in female patients, P = .68). Our retrospective study showed several gender-related differences associated with different cardiac arrest scenarios. Male sex was associated with a significantly higher risk for renal failure requiring CVVH. Survival rates were comparable between the groups. Further investigations should include gender in the evaluation of risk stratification for eCPR-related complications to further improve selection criteria for this demanding therapy.

Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis.

Nitro-fatty acids are electrophilic anti-inflammatory mediators which are generated during myocardial ischemic injury. Whether these species exert anti-arrhythmic effects in the acute phase of myocardial ischemia has not been investigated so far. Herein, we demonstrate that pretreatment of mice with 9- and 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA) significantly reduced the susceptibility to develop acute ventricular tachycardia (VT). Accordingly, epicardial mapping revealed a markedly enhanced homogeneity in ventricular conduction. NO2-OA treatment of isolated cardiomyocytes lowered the number of spontaneous contractions upon adrenergic isoproterenol stimulation and nearly abolished ryanodine receptor type 2 (RyR2)-dependent sarcoplasmic Ca2+ leak. NO2-OA also significantly reduced RyR2-phosphorylation by inhibition of increased CaMKII activity. Thus, NO2-OA might be a novel pharmacological option for the prevention of VT development.

How long is long enough? Good neurologic outcome in out-of-hospital cardiac arrest survivors despite prolonged resuscitation: a retrospective cohort study.

BACKGROUND: Despite all efforts, mortality of out of hospital cardiac arrest (OHCA) remains high. Patients with OHCA due to a primary shockable rhythm typically have a better prognosis. However, outcome worsens if return of spontaneous circulation (ROSC) cannot be achieved quickly. There is insufficient evidence for maximum duration of resuscitation in these patients and it is unclear, which patients profit from transport under ongoing CPR. OBJECTIVE: Investigate predictors for favourable neurologic outcome in OHCA patients with presumed cardiac cause due to refractory shockable rhythm (rSR). METHODS: Retrospective analysis of OHCA patients that presented to a tertiary hospital due to a rSR. RESULTS: One hundred seventy-five OHCA patients with presumed cardiac cause due to rSR were included. Overall hospital mortality was 50% and 83% of initial survivors were discharged with a good neurologic outcome [cerebral performance category (CPC) 1-2]. In patients with a time from cardiac arrest to ROSC of > 45 min, 18% survived to CPC 1-2. Independent predictors for good neurologic outcome were age, lower no-flow time and lower serum lactate levels at hospital arrival. CONCLUSION: In an urban setting, a significant proportion of OHCA patients with rSR can survive to a good neurologic outcome, despite very long time to ROSC.

One year experience with fast track algorithm in patients with refractory out-of-hospital cardiac arrest.

BACKGROUND: Overall prognosis in patients with out-of-hospital cardiac arrest (OHCA) remains poor, especially when return of spontaneous circulation (ROSC) cannot be achieved at the scene. It is unclear if rapid transport to the hospital with ongoing cardiopulmonary resuscitation (CPR) improves outcome in patients with refractory OHCA (rOHCA). The aim of this study was to evaluate the effect of a novel fast track algorithm (FTA) in patients with rOHCA. METHODS: This prospective single-center study analysed outcome in rOHCA patients treated with FTA. Historical patients before FTA-implementation served as controls. rOHCA was defined as: persistent shockable rhythm after three shocks and 300mg of amiodarone or persistent non-shockable rhythm and continuous CPR for 10min without ROSC after exclusion of treatable arrest causes. RESULTS: 110 consecutive patients with rOHCA (mean age 56±14 years) were included. 40 patients (36%) were treated with FTA, 70 patients (64%) served as historical controls. Pre-hospital time was significantly shorter after FTA implementation (69±18 vs. 79±24min, p=0.02). Favourable neurological outcome (defined as cerebral performance categories Score 1 or 2) was significantly more frequent in FTA patients (27.5% vs. 11.4%, p=0.038). FTA-implementation showed a trend towards improved mortality (70.0% vs. 82.9%, p=0.151). Extracorporeal Life Support was similar between the two groups. CONCLUSION: Our study suggests that a rapid transport algorithm with ongoing CPR is feasible, improves neurological outcome and may improve survival in carefully selected patients with rOHCA.

S100A4 as a Target of the E3-Ligase Asb2ß and Its Effect on Engineered Heart Tissue.

Background: S100A4 has recently emerged as an important player in cardiac disease, affecting phenotype development in animal models of myocardial infarction and pathological cardiac hypertrophy, albeit it is unclear whether S100A4 exerts a detrimental or beneficial function. The goal of the current study was to analyze S100A4 expression in models of cardiac pathology, investigate its degradation by the ubiquitin-proteasome system (UPS), and furthermore examine the functional effects of S100A4 levels in a 3D model of engineered heart tissue (EHT). Methods and Results: S100A4 mRNA and protein levels were analyzed in different models of cardiac pathology via quantitative RT-PCR and Western blot, showing a higher S100A4 steady-state protein concentration in hearts of Mybpc3-knock-in (KI) hypertrophic cardiomyopathy (HCM) mice. COS-7 cells co-transfected with plasmids encoding mutant (MUT) Asb2ß lacking the E3 ligase activity in combination with V5-tagged S100A4 plasmid presented higher S100A4-V5 protein steady-state concentrations than cells co-transfected with the Asb2ß wild type (WT) plasmid. This effect was blunted by treatment with the specific proteasome inhibitor epoxomicin. Adeno-associated virus serotype 6 (AAV6)-mediated S100A4 overexpression in a 3D model of EHT did not affect contractile parameters. Immunofluorescence analysis showed a cytosolic and partly nuclear expression pattern of S100A4. Gene expression analysis in EHTs overexpressing S100A4-V5 showed markedly lower steady-state concentrations of genes involved in cardiac fibrosis and pathological cardiac hypertrophy. Conclusion: We showed that S100A4 protein level is higher in cardiac tissue of Mybpc3-KI HCM mice probably as a result of a lower degradation by the E3 ligase Asb2ß. While an overexpression of S100A4 did not alter contractile parameters in EHTs, downstream gene expression analysis points toward modulation of signaling cascades involved in fibrosis and hypertrophy.