Background
Subclinical atrial fibrillation (AF) is the underlying cause in a relevant part of patients with embolic stroke of unknown source (ESUS). This pilot study aims to identify novel ...echocardiographic parameters predicting AF subsequently detected in patients originally hospitalized with ESUS.
Methods and results
Patients with acute ischemic stroke baseline diagnosis of ESUS (
n
= 69), stroke of macro- or microvascular cause (
n
= 16/25), stroke caused by AF (
n
= 5) and controls with paroxysmal AF without acute ischemic stroke (n = 22) as well as healthy controls of young and old age (
n
= 21/17) in sinus rhythm were included (overall
n
= 175). Echocardiography was performed in all participants. Prolonged Holter-ECG-monitoring was performed in all stroke patients. In the overall cohort, septal total atrial conduction time (sPA-TDI), left atrial (LA) volume index to tissue Doppler velocity (LAVI/a`) and second negative peak strain rate during LA contraction (SRa), representing echocardiographic parameters of LA remodelling and function, were statistically significant different in patients with and without AF and predictive for subclinical AF (multivariate regression analysis: sPA-TDI: HR 1.06 1.04–1.08,
p
< 0.001; LAVI/a`: HR 0.85, 0.74–0.97, p = 0.02; SRa: HR 2.35 0.9–5.5,
p
= 0.05). Multivariate Cox regression analysis revealed sPA-TDI as an independent predictor of AF in ESUS patients (sPA-TDI: HR 1.10 1.04–1.17,
p
= 0.001). A sPA-TDI of 126 ms strictly discriminated between presence and absence of subclinical AF within 48 h after initiation of Holter-ECG-monitoring in ESUS patients.
Conclusions
sPA-TDI seems to be a strong independent predictor of subclinical AF in patients hospitalized for ESUS and might support risk-stratified clinical decision making in these patients.
Graphic abstract
Septal Total Atrial Conduction Time (sPA-TDI) determined by echocardiography for prediction of Atrial Fibrillation in Embolic Stroke of Unknown Source (ESUS).
Inflammatory processes are crucial in atherosclerosis and atherothrombosis. This study aimed to identify a cytokine-pattern that is associated with plaque-vulnerability or symptomatic state in ...comprehensively investigated patients with symptomatic (sCS) and asymptomatic carotid stenosis (aCS). Twenty-two patients with sCS and twenty-four patients with aCS undergoing carotid endarterectomy (CEA) were considered. A cytokine-panel was measured in plasma-specimens prior to surgery and at a 90 day follow-up. Doppler-ultrasound detecting microembolic signals (MES) in the ipsilateral middle cerebral artery was performed. Carotid plaques were analysed regarding histopathological criteria of plaque-vulnerability and presence of chemokine receptor CXCR4. Correction for multiple comparisons and logistic regression analysis adjusting for vascular risk factors, grade of stenosis, antithrombotic and statin pretreatment were applied. In sCS-patients higher plasma-levels of Fractalkine (CX
CL1), IFN-α2, IL-1β, IL-2, IL-3, IL-7 were found compared to aCS-patients. CXCR4-expression on inflammatory cells was more evident in sCS- compared to aCS-plaques and was associated with vulnerability-criteria. In contrast, plasma-cytokine-levels were not related to CXCR4-expression or other vulnerability-criteria or MES. However, in both groups distinct inter-cytokine correlation patterns, which persisted at follow-up and were more pronounced in the sCS-group could be detected. In conclusion, we identified a distinct cytokine/chemokine-network in sCS-patients with elevated and closely correlated mediators of diverse functions.
(1) Background: Patients with acute ischaemic stroke (AIS) are at high risk for stroke-associated infections (SAIs). We hypothesised that increased concentrations of systemic inflammation markers ...predict SAIs and unfavourable outcomes; (2) Methods: In 223 patients with AIS, blood samples were taken at ≤24 h, 3 d and 7d after a stroke, to determine IL-6, IL-10, CRP and LBP. The outcome was assessed using the modified Rankin Scale at 90 d. Patients were thoroughly examined regarding the development of SAIs; (3) Results: 47 patients developed SAIs, including 15 lower respiratory tract infections (LRTIs). IL-6 and LBP at 24 h differed, between patients with and without SAIs (IL-6: p < 0.001; LBP: p = 0.042). However, these associations could not be confirmed after adjustment for age, white blood cell count, reduced consciousness and NIHSS. When considering the subgroup of LRTIs, in patients who presented early (≤12 h after stroke, n = 139), IL-6 was independently associated with LRTIs (OR: 1.073, 95% CI: 1.002−1.148). The ROC-analysis for prediction of LRTIs showed an AUC of 0.918 for the combination of IL-6 and clinical factors; (4) Conclusions: Blood biomarkers were not predictive for total SAIs. At early stages, IL-6 was independently associated with outcome-relevant LRTIs. Further studies need to clarify the use of biochemical markers to identify patients prone to SAIs.
Background:
In acute ischemic stroke, timely treatment is of utmost relevance. Identification of delaying factors and knowledge about challenges concerning hospital structures are crucial for ...continuous improvement of process times in stroke care.
Objective:
In this study, we report on our experience in optimizing the door-to-needle time (DNT) at our tertiary care center by continuous quality improvement.
Methods:
Five hundred forty patients with acute ischemic stroke receiving intravenous thrombolysis (IVT) at Hannover Medical School were consecutively analyzed in two phases. In study phase I, including 292 patients, process times and delaying factors were collected prospectively from May 2015 until September 2017. In study phase II, process times of 248 patients were obtained from January 2019 until February 2021. In each study phase, a new clinical standard operation procedure (SOP) was implemented, considering previously identified delaying factors. Pre- and post-SOP treatment times and delaying factors were analyzed to evaluate the new protocols.
Results:
In study phase I, SOP I reduced the median DNT by 15 min. The probability to receive treatment within 30 min after admission increased by factor 5.35 95% confidence interval (CI): 2.46–11.66. Further development of the SOP with implementation of a mobile thrombolysis kit led to a further decrease of DNT by 5 min in median in study phase II. The median DNT was 29 (25th–75th percentiles: 18–44) min, and the probability to undergo IVT within 15 min after admission increased by factor 4.2 (95% CI: 1.63–10.83) compared with study phase I.
Conclusion:
Continuous process analysis and subsequent development of targeted workflow adjustments led to a substantial improvement of DNT. These results illustrate that with appropriate vigilance, there is constantly an opportunity for improvement in stroke care.
Background
Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under ...dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran.
Aims
To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage.
Methods
Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used.
Results
Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0–3 in 67%. Overall, mortality was low with 6.5% (one patient in each group).
Conclusion
Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.
During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications ...following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.
Although intravenous thrombolysis (IVT) with recombinant tissue-plasminogen-activator represents a highly effective treatment in acute ischemic stroke patients, not every patient benefits. We ...hypothesized that pretreatment levels of mediators of hemostasis (VWF and ADAMTS13) and dimethylarginines (ADMA and SDMA) are associated with early neurological improvement and outcome after IVT in ischemic stroke. Moreover we aimed to investigate the link between ADAMTS13 and markers of inflammation (CRP, IL-6, MMP-9 and MCP-1). In 43 patients with acute ischemic stroke treated with IVT blood samples for determination of the different markers were strictly taken before treatment, as well as at 24 h, 3, 7 and 90 days after symptom onset. Early neurological improvement was assessed using the shift between National Institutes of Health Stroke Scale (NIHSS) at baseline and at 24 h. Outcome at 90 days was assessed using the modified Rankin Scale. The lowest quartile of ADAMTS13 activity was independently associated with less improvement in NIHSS (baseline-24 h) (OR 1.298, p = 0.050). No independent association of ADMA or SDMA levels at baseline with outcome could be shown. Furthermore, IL-6, MCP-1 and CRP levels at 90 days significantly differed between patients with low and high ADAMTS13 activity. Thus, ADAMTS13 might indicate or even influence efficacy of IVT.
The identification of the underlying mechanism in ischemic stroke has important implications for secondary prevention. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 ...(ADAMTS-13) has antithrombotic properties and was repeatedly implicated in the pathophysiology of stroke. In this study, we, therefore, aimed to investigate whether ADAMTS-13 is associated with stroke etiology and the burden of vascular risk factors.
We determined ADAMTS-13 activity in two prospectively recruited stroke cohorts in the long-term course after the event. Cohort 1 (
= 88) consisted of patients who suffered a stroke due to embolic stroke of undetermined source (ESUS), cardioembolic stroke due to atrial fibrillation (AF), large-artery atherosclerosis, or small vessel disease. In cohort 2, patients with cryptogenic stroke and patent foramen ovale (PFO) scheduled for PFO closure (
= 38) were enrolled. As measures of vascular risk factor burden, the CHA
DS
VASC score, the Essen Stroke Risk Score (ESRS), and the Risk of Paradoxical Embolism (RoPE) score were calculated, as appropriate.
ADAMTS-13 activity was lower in patients with AF-related stroke compared to patients with ESUS (
= 0.0227), which was, however, due to confounding by vascular risk factors. ADAMTS-13 activity inversely correlated with the ESRS (
= -0.452,
< 0.001) and CHA
DS
VASC (
= -0.375,
< 0.001) in cohort 1. In accordance with these findings, we found a positive correlation between ADAMTS-13 activity and the RoPE score in cohort 2 (
= 0.413,
= 0.010).
ADAMTS-13 activity is inversely correlated with the number of vascular risk factors across different stroke etiologies. Further study is warranted to establish ADAMTS-13 as a mediator of cerebrovascular risk.
A relevant part of embolic strokes of undetermined source (ESUS) is assumed to be due to non-detected atrial fibrillation (AF). In this study, we aimed to investigate if markers of endothelial ...dysfunction and damage may indicate AF risk in embolic stroke. Eighty-eight patients with ischemic stroke confirmed by imaging were assigned to one of three groups: ESUS, AF, or micro-/macroangiopathy. ESUS patients underwent prolonged Holter electrocardiography scheduled for three days. The National Institutes of Health Stroke Scale (NIHSS), the CHA₂DS₂VASC score, and the carotid intima⁻media thickness (CIMT) were obtained. Markers of endothelial (dys)function (L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA)) were measured at day seven after stroke. ESUS patients were younger and had fewer cardiovascular risk factors than patients with determined stroke etiology. Compared with AF patients, ESUS patients showed significantly lower values of SDMA (
= 0.004) and higher values of L-arginine (
= 0.031), L-arginine/ADMA ratio (
= 0.006), L-arginine/SDMA ratio (
= 0.002), and ADMA/SDMA ratio (
= 0.013). Concordant differences could be observed comparing ESUS patients with those with newly diagnosed AF (
= 0.026;
= 0.03;
= 0.009;
= 0.004; and
= 0.046, respectively). CIMT was significantly larger in AF than in ESUS patients (
< 0.001), and was identified as an AF risk factor independent from CHA₂DS₂VASC in the regression analysis (
= 0.014). These findings may support future stratification for AF risk in patients who have suffered embolic stroke.
Carotid stenosis (CS) is an important cause of ischemic stroke. However, reliable markers for the purpose of identification of high-risk, so-called vulnerable carotid plaques, are still lacking. ...Monocyte subsets are crucial players in atherosclerosis and might also contribute to plaque rupture. In this study we, therefore, aimed to investigate the potential role of monocyte subsets and associated chemokines as clinical biomarkers for vulnerability of CS. Patients with symptomatic and asymptomatic CS (n = 21), patients with cardioembolic ischemic strokes (n = 11), and controls without any cardiovascular disorder (n = 11) were examined. Cardiovascular risk was quantified using the Essen Stroke Risk Score (ESRS). Monocyte subsets in peripheral blood were measured by quantitative flow cytometry. Plaque specimens were histologically analyzed. Furthermore, plasma levels of monocyte chemotactic protein 1 (MCP-1) and fractalkine were measured. Intermediate monocytes (Mon2) were significantly elevated in symptomatic and asymptomatic CS-patients compared to controls. Mon2 counts positively correlated with the ESRS. Moreover, stroke patients showed an elevation of Mon2 compared to controls, independent of the ESRS. MCP-1 levels were significantly higher in patients with symptomatic than in those with asymptomatic CS. Several histological criteria significantly differed between symptomatic and asymptomatic plaques. However, there was no association of monocyte subsets or chemokines with histological features of plaque vulnerability. Due to the multifactorial influence on monocyte subsets, the usability as clinical markers for plaque vulnerability seems to be limited. However, monocyte subsets may be critically involved in the pathology of CS.
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