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Background Embolic stroke of undetermined source (ESUS) constitutes a substantial proportion of ischemic strokes. Its distinction from cardioembolic stroke (CES) may carry prognostic implications. This study aimed to compare early and long-term outcomes between ESUS and CES. Methods We conducted a prospective cohort study of patients with ESUS and CES who underwent standardized diagnostic evaluation and prolonged cardiac monitoring. Stroke severity was assessed with the NIHSS, and functional outcome with the mRS at discharge, 30 days, and 12 months. ESUS patients were additionally evaluated for short-duration atrial fibrillation. Results During a 6-month prospective enrollment period, 771 patients with suspected stroke were screened, of whom 529 had ischemic stroke confirmed by neuroimaging. After applying ESUS criteria, 98 patients were classified as ESUS and 209 as CES (total study cohort, n  = 307; 41% women; mean age 72 ± 9 years). Patients with ESUS presented with significantly lower stroke severity and achieved better functional outcomes than those with CES. The mean NIHSS score on admission was 6 (95% CI, 5–7) in the ESUS group and 11 (95% CI, 10–12) in the cardioembolic group (  p < 0.001). At discharge, the mean mRS score was 2.1 (95% CI, 1.8–2.4) for ESUS and 3.8 (95% CI, 3.5–4.1) for CES ( p  < 0.001). A favorable outcome (mRS 0–2) was more common in ESUS (68% vs. 34%; p  < 0.001). In-hospital mortality occurred in 10.0% of cardioembolic patients and in none of the ESUS patients ( p  = 0.02). At 12 months, ESUS patients continued to show more favorable recovery, with higher rates of functional independence (60% vs. 28%; p  < 0.001) and lower cumulative mortality (7.1% vs. 21.5%; p < 0.001). Conclusions Compared with CES, ESUS was associated with less severe neurological deficits and more favorable outcomes, both early and at 12 months, including lower mortality and better functional recovery.

Background The IABP-SHOCK-trial was a morbidity-based randomized controlled trial in patients with infarction-related cardiogenic shock (CS), which used the change of the quantified degree of multiorgan failure as determined by APACHE II score over a 4-day period as primary outcome measure. The prospective hypothesis was that adding IABP therapy to “standard care” would improve CS-triggered multi organ dysfunction syndrome (MODS). The primary endpoint showed no difference between conventionally managed cardiogenic shock patients and those with IABP support. In an inflammatory marker substudy, we analysed the prognostic value of interleukin (IL)-1β, -6, -7, -8, and -10 in patients with acute myocardial infarction complicated by cardiogenic shock. Design Inflammatory marker substudy of the prospective, randomized, controlled, open label IABP-SHOCK-trial (Clinical-Trials-gov-ID-NCT00469248). Setting and methods A single-center study was performed in a 12-bed Intensive-Care-Unit in an university hospital in which 40 consecutive patients were enrolled with an observational period of 96 h. Results The pro- and anti-inflammatory markers IL-6, -7, -8 and -10 showed a predictive power for mortality of infarct-related CS patients, while IL-1β did not discriminate. The maximal values during the observational period, in case of IL-7 the minimal value, showed the best power to predict mortality. Both, ROC and multivariate analyses confirmed these suggestions (area under the curve: IL-8, 0.80 ± 0.08; IL-6, 0.79 ± 0.08; IL-10, 0.76 ± 0.08; IL-7, 0.69 ± 0.08). Inflammatory markers were not affected by the presence of IABP support. Conclusion The inflammatory response in patients with myocardial infarction complicated by cardiogenic shock, as reflected by the inflammatory markers IL-6, IL-7, IL-8 and IL-10, demonstrates a clinically relevant prognostic contribution to clinical outcome.

Background and purpose Atrial fibrillation (AF) episodes ≥ 30 s are currently considered clinically relevant in stroke diagnostics. However, shorter AF episodes may signal a significant embolic risk, especially in patients with embolic stroke of undetermined source (ESUS). This study investigates the prevalence, risk profile, and stroke severity associated with short-duration AF (SDAF < 30 s) across ischemic stroke subtypes. Methods We prospectively enrolled 714 consecutive patients with ischemic stroke or Transient ischemic attacks who underwent ≥ 48-hour ECG monitoring. AF episodes were classified as 0–14 s, 15–29 s, or ≥ 30 s. Stroke subtypes were defined using TOAST and ESUS criteria. Risk profiles, NIH Stroke Scale scores, and CHA₂DS₂-VASc scores were analyzed by AF duration. Results AF of any duration was detected in 53.8% of patients; 22.8% had episodes ≥ 30 s and 29.9% had SDAF. Among ESUS patients, 35.7% exhibited SDAF, and 80.2% of these had CHA₂DS₂-VASc scores ≥ 2. Stroke severity and risk scores were significantly higher in patients with SDAF than those without AF. SDAF was more prevalent in women (37.0%) and in individuals aged > 65 years (89.4%). Conclusions SDAF is common across stroke subtypes—particularly ESUS—and is associated with elevated thromboembolic risk despite falling below current diagnostic thresholds. These findings highlight a diagnostic blind spot in stroke workup and support reevaluation of duration-based criteria for post-stroke AF detection and risk profiling.

Background Acute kidney injury (AKI) is common in cardiogenic shock (CS) and increases mortality, but the prognostic impact of onset timing in infarct-related CS is unclear. We examined whether early versus late AKI onset is associated with differences in patient characteristics and outcomes. Methods In this retrospective observational study, 369 patients with infarct-related CS were classified by AKI timing within the first 96 h of admission: early (≤ 48 h) or late (> 48 h), according to KDIGO criteria. Clinical, hemodynamic, and inflammatory parameters and outcomes were compared. Multivariable logistic regression identified independent predictors of early AKI and in-hospital mortality. Results AKI occurred in 143 patients (38.8%), with 56.6% early-onset. In-hospital mortality was higher with early AKI than late AKI (71.6% vs. 54.8%; absolute difference 16.8%, 95% CI 3.1–30.5; p  = 0.018). Early AKI patients had higher lactate at admission (median 4.3 vs. 3.1 mmol/L; p  = 0.028), greater norepinephrine requirements (0.34 vs. 0.21 µg/kg/min; p  = 0.044), and more frequent mechanical ventilation (81.5% vs. 61.3%; p  = 0.011). In multivariable analysis, early AKI independently predicted in-hospital mortality (adjusted OR 2.12, 95% CI 1.16–3.87; p  = 0.015), and was associated with baseline creatinine (OR 5.68 per 1 mg/dL, p  = 0.008) and 24-h lactate (OR 2.67 per mmol/L, p  < 0.001). Conclusions In infarct-related CS, AKI within 48 h marks a high-risk hemodynamic phenotype with markedly increased mortality, driven by renal vulnerability and early hypoperfusion. Incorporating AKI timing into risk stratification may help target early renoprotective interventions. Keywords: Acute kidney injury; cardiogenic shock; myocardial infarction; AKI timing; early-onset AKI; hemodynamic instability; lactate; renal dysfunction; in-hospital mortality

Aims Worldwide applications of extracorporeal circulation for mechanical support in cardiac and circulatory failure, which are referred to as extracorporeal life support (ECLS) or veno‐arterial extracorporeal membrane oxygenation (va‐ECMO), have dramatically increased over the past decade. In spite of the expanding use and the immense medical as well as socio‐economic impact of this therapeutic approach, there has been a lack of interdisciplinary recommendations considering the best available evidence for ECLS treatment. Methods and Results In a multiprofessional, interdisciplinary scientific effort of all scientific societies involved in the treatment of patients with acute cardiac and circulatory failure, the first evidence‐ and expert consensus‐based guideline (level S3) on ECLS/ECMO therapy was developed in a structured approach under regulations of the AWMF (Association of the Scientific Medical Societies in Germany) and under use of GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. This article presents all recommendations created by the expert panel, addressing a multitude of aspects for ECLS initiation, continuation, weaning and aftercare as well as structural and personnel requirements. Conclusions This first evidence‐ and expert consensus‐based guideline (level S3) on ECLS/ECMO therapy should be used to apply the best available care nationwide. Beyond clinical practice advice, remaining important research aspects for future scientific efforts are formulated.

Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti‐inflammatory capacities, in addition to their lipid‐lowering effects. We investigated the anti‐inflammatory effect of statins in the cytokine‐mediated‐interaction‐model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis‐related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over‐additive) IL‐6 (interleukin‐6) production as measured in ELISA. Recombinant IL‐1, tumour necrosis factor‐α and IL‐6 mediated the synergistic IL‐6 production. The standard anti‐inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL‐6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL‐6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL‐6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL‐6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL‐6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti‐inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine‐mediated innate inflammatory pathways in the vessel wall.

•  Introduction •  Atherosclerosis ‐ overview ‐  General remarks ‐  Early atherosclerosis ‐  Exogenous and/or infectious activators ‐  Endogenous activators ‐  Later phases of atherosclerosis •  Innate and inflammatory pathways in atherogenesis •  Innate receptors ‐  PAMP and DAMP ‐  Pentraxins ‐  NOD‐like proteins/receptors (NLRs) ‐  toll‐like receptors (TLRs) ‐  Knockout of pattern recognition molecules reduces atherosclerosis •  Innate cytokines ‐  The innate cytokines interleukin‐1 (IL‐1) and tumor necrosis factor‐α (TNF‐α) ‐  TNF−/− ApoE−/− mice are less atherosclerotic ‐  IL‐1−/− ApoE−/− mice are less atherosclerotic ‐  Monocyte chemoattractant protein‐1 and fractalkine ‐  IL‐6 activates innate pathways and is produced by cardiovascular cells ‐  Functions of IL‐6 important for atherogenesis ‐  Role of trans‐signalling in cardiovascular inflammation ‐  Animal experiments suggest a role for the IL‐6 system in atherosclerosis •  Cytokine‐mediated interaction of vessel wall cells and leucocytes ‐  Endothelial cell (EC)‐monocyte interaction ‐  Smooth muscle cell (SMC)‐EC interaction ‐  SMC‐monocyte and SMC‐T cell interaction •  Summary and conclusion •  Future perspectives ‐  Which initiator(s) starts atherogenesis? ‐  Is there more than one starting point? ‐  What are the specific roles of the various cytokines in the vessel wall? ‐  Are treatments addressing different phases of atherogenesis of advantage? ‐  What about prevention? ‐  What are the expectations? Inflammation is a central element of atherogenesis. Innate pathways contribute to vascular inflammation. However, the initial molecular process(es) starting atherogenesis remain elusive. The various risk factors, represented by particular compounds (activators), may cause altered cellular functions in the endothelium (e.g. vascular endothelial cell activation or ‐dysfunction), in invading cells (e.g. inflammatory mediator production) or in local vessel wall cells (e.g. inflammatory mediators, migration), thereby triggering the innate inflammatory process. The cellular components of innate immunology include granulocytes, natural killer cells and monocytes. Among the molecular innate constituents are innate molecules, such as the toll‐like receptors or innate cytokines. Interleukin‐1 (IL‐1) and IL‐6 are among the innate cytokines. Cytokines are potent activators of a great number of cellular functions relevant to maintain or commove homeostasis of the vessel wall. Within the vessel wall, vascular smooth muscle cells (SMCs) can significantly contribute to the cytokine‐dependent inflammatory network by: (i) production of cytokines, (ii) response to cytokines and (iii) cytokine‐mediated interaction with invading leucocytes. The cytokines IL‐1 and IL‐6 are involved in SMC‐leucocyte interaction. The IL‐6 effects are proposed to be mediated by trans‐signalling. Dysregulated cellular functions resulting from dysregulated cytokine production may be the cause of cell accumulation, subsequent low‐density lipoprotein accumulation and deposition of extracellular matrix (ECM). The deposition of ECM, increased accumulation of leucocytes and altered levels of inflammatory mediators may constitute an ‘innate‐immunovascular‐memory’ resulting in an ever‐growing response to anew invasion. Thus, SMC‐fostered inflammation, promoted by invading innate cells, may be a potent component for development and acceleration of atherosclerosis.

The mortality of patients with MI has significantly decreased in recent decades, mainly due to early reperfusion therapy with a probability of surviving of more than 90% if the patient reaches the hospital [...]

While obesity is a known risk factor for ischemic stroke, its prognostic value remains uncertain. We examined the independent and combined effects of body mass index (BMI) and waist-to-hip ratio (WHR) on early stroke outcomes across subtypes. In this prospective cohort study, 714 patients with acute ischemic stroke or TIA were enrolled over six months. BMI and WHR were assessed on admission. Stroke severity (NIHSS) and functional outcome at discharge (modified Rankin Scale, mRS) were recorded. Stroke aetiology was classified using TOAST and ESUS criteria. Multivariable regression and restricted cubic spline models were applied. A U-shaped association emerged between BMI and both stroke severity and recovery, with overweight patients (BMI 25.0-29.9 kg/m²) showing the lowest NIHSS and highest independence rate (mRS 0-1: 65%). Underweight and obese patients had significantly worse outcomes (p < 0.001). WHR was an independent predictor of higher stroke severity (β = +2.8; 95% CI: 2.1-3.5) and poor outcome (OR = 0.70; 95% CI: 0.52-0.94), and showed additive prognostic value when combined with BMI. A sex-specific interaction suggested a greater benefit from overweight in women (OR = 1.72; p = 0.02). Subtype analysis revealed a U-shaped BMI association in cardioembolic stroke (p = 0.014), but not in ESUS. BMI and WHR show distinct, nonlinear, and sex- and subtype-specific associations with stroke severity and outcome. WHR outperforms BMI and enhances prognostication when combined. These findings challenge the obesity paradox and support integrating adiposity phenotypes into individualized stroke risk models.

The frequency and severity of bacteremic infections has increased over the last decade and bacterial endovascular infections (i.e., sepsis or endocarditis) are associated with high morbidity and mortality. Bacteria or secreted bacterial products modulate platelet function and, as a result, affect platelet accumulation at sites of vascular infection and inflammation. However, whether bacterial products regulate synthetic events in platelets is not known. In the present study, we determined if prolonged contact with staphylococcal α-toxin signals platelets to synthesize B-cell lymphoma (Bcl-3), a protein that regulates clot retraction in murine and human platelets. We show that α-toxin induced αIIbβ3-dependent aggregation (EC50 2.98 µg/mL ± 0.64 µg/mL) and, over time, significantly altered platelet morphology and stimulated de novo accumulation of Bcl-3 protein in platelets. Adherence to collagen or fibrinogen also increased the expression of Bcl-3 protein by platelets. α-toxin altered Bcl-3 protein expression patterns in platelets adherent to collagen, but not fibrinogen. Pretreatment of platelets with inhibitors of protein synthesis or the mammalian Target of Rapamycin (mTOR) decreased Bcl-3 protein expression in α-toxin stimulated platelets. In conclusion, Staphylococcus aureus-derived α-toxin, a pore forming exotoxin, exerts immediate (i.e., aggregation) and prolonged (i.e., protein synthesis) responses in platelets, which may contribute to increased thrombotic events associated with gram-positive sepsis or endocarditis.