Sex Differences in Outcomes of Acute Myocardial Injury After Stroke.

BACKGROUND: Sex differences in presentation, treatment, and prognosis of cardiovascular disorders are well recognized. Although an association between acute myocardial injury and mortality after ischemic stroke has been demonstrated, it is unclear whether prevalence and outcome of poststroke acute myocardial injury differ between women and men. METHODS AND RESULTS: We prospectively screened consecutive patients with acute ischemic stroke and serial high-sensitivity cardiac troponin T measurements admitted to our center. Acute myocardial injury was defined as at least 1 high-sensitivity cardiac troponin T value above the upper reference limit (14 ng/L) with a rise/fall of >20%. Rates of acute myocardial injury were also calculated using sex-specific high-sensitivity cardiac troponin T cutoffs (women upper reference limit, 9 ng/L; men upper reference limit, 16 ng/L). Logistic regression analyses were performed to evaluate the association between acute myocardial injury and outcomes. Of 1067 patients included, 494 were women (46%). Women were older, had a higher rate of known atrial fibrillation, were more likely to be functionally dependent before admission, had higher stroke severity, and more often had cardioembolic strokes (all P values <0.05). The crude prevalence of acute myocardial injury differed by sex (29% women versus 23% men, P=0.024). Statistically significant associations between acute myocardial injury and outcomes were observed in women (7-day in-hospital mortality: adjusted odds ratio [aOR], 3.2 [95% CI, 1.07-9.3]; in-hospital mortality: aOR, 3.3 [95% CI, 1.4-7.6]; modified Rankin Scale score at discharge: aOR, 1.6 [95% CI, 1.1-2.4]) but not in men. The implementation of sex-specific cutoffs did not increase the prognostic value of acute myocardial injury for unfavorable outcomes. CONCLUSIONS: The prevalence of acute myocardial injury after ischemic stroke and its association with mortality and greater disability might be sex-dependent. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03892226.

Heart rate turbulence in acute ischemic stroke.

BACKGROUND: Heart rate turbulence (HRT), an ECG-based marker of autonomic cardiac regulation, has shown high prognostic value in patients with established cardiovascular diseases, while data in patients with acute ischemic stroke are scarce. PATIENTS AND METHODS: The HRT parameters turbulence onset and turbulence slope were analyzed using Holter-ECG recordings from patients with acute ischemic stroke, consecutively enrolled in the prospective observational HEBRAS study. HRT was categorized as normal (category 0; both parameters normal), abnormal (category 1; one parameter abnormal), or severely abnormal (category 2; both parameters abnormal). Outcomes of interest were functional outcome according to modified Rankin Scale (mRS) score at 3 months, mortality at 1 year, newly detected atrial fibrillation (AF), and evidence of focal myocardial fibrosis on cardiovascular MRI. RESULTS: HRT was assessed in 335 patients in sinus rhythm (median age 69 years, 37% female, median NIHSS score 2 on admission), including 262 (78%) with normal HRT, 47 (14%) with abnormal and 26 (8%) with severely abnormal HRT. Compared with normal HRT, severely abnormal HRT was associated with increased disability [higher mRS] at 3 months (adjusted odds ratio [aOR]: 2.9, 95% confidence interval [CI]: 1.3-6.6), new AF (aOR: 3.5, 95% CI: 1.1-10.6), MRI-detected myocardial fibrosis (aOR: 5.8, 95% CI: 1.3-25.9), but not with mortality at 1 year after stroke (aOR: 3.0, 95% CI: 0.7-13.9). Abnormal HRT was not associated with the analyzed outcomes. CONCLUSIONS: Severely abnormal HRT was associated with increased disability and previously unknown cardiac comorbidities. The potential role of HRT in selecting patients for extended AF monitoring and cardiac imaging should be further investigated.

Automated acute ischemic stroke lesion delineation based on apparent diffusion coefficient thresholds.

Purpose: Automated lesion segmentation is increasingly used in acute ischemic stroke magnetic resonance imaging (MRI). We explored in detail the performance of apparent diffusion coefficient (ADC) thresholding for delineating baseline diffusion-weighted imaging (DWI) lesions. Methods: Retrospective, exploratory analysis of the prospective observational single-center 1000Plus study from September 2008 to June 2013 (clinicaltrials.org; NCT00715533). We built a fully automated lesion segmentation algorithm using a fixed ADC threshold (≤620 × 10-6 mm2/s) to delineate the baseline DWI lesion and analyzed its performance compared to manual assessments. Diagnostic capabilities of best possible ADC thresholds were investigated using receiver operating characteristic curves. Influential patient factors on ADC thresholding techniques' performance were studied by conducting multiple linear regression. Results: 108 acute ischemic stroke patients were selected for analysis. The median Dice coefficient for the algorithm was 0.43 (IQR 0.20-0.64). Mean ADC values in the DWI lesion (ß = -0.68, p < 0.001) and DWI lesion volumes (ß = 0.29, p < 0.001) predicted performance. Optimal individual ADC thresholds differed between subjects with a median of ≤691 × 10-6 mm2/s (IQR ≤660-750 × 10-6 mm2/s). Mean ADC values in the DWI lesion (ß = -0.96, p < 0.001) and mean ADC values in the brain parenchyma (ß = 0.24, p < 0.001) were associated with the performance of individual thresholds. Conclusion: The performance of ADC thresholds for delineating acute stroke lesions varies substantially between patients. It is influenced by factors such as lesion size as well as lesion and parenchymal ADC values. Considering the inherent noisiness of ADC maps, ADC threshold-based automated delineation of very small lesions is not reliable.

A Managed Care System with Telemedicine Support for Neurological Emergencies.

OBJECTIVES: Telemedicine is frequently used to provide remote neurological expertise for acute stroke workup and was associated with better functional outcomes when combined with a stroke unit system-of-care. We investigated whether such system-of-care yields additional benefits when implemented on top of neurological competence already available onsite. METHODS: Quality improvement measures were implemented within a "hub-and-spoke" teleneurology network in 11 hospitals already provided with onsite or telestroke expertise. Measures included dedicated units for neurological emergencies, standardization of procedures, multiprofessional training, and quality-of-care monitoring. Intervention effects were investigated in a controlled study enrolling patients insured at 3 participating statutory health insurances diagnosed with acute stroke or other neurological emergencies. Outcomes during the intervention period between November 2017 and February 2020 were compared with those pre-intervention between October 2014 and March 2017. To control for temporal trends, we compared outcomes of patients with respective diagnoses in 11 hospitals of the same region. Primary outcome was the composite of up-to-90-day death, new disability with the need of ambulatory or nursing home care, expressed by adjusted hazard ratio (aHR). RESULTS: We included 1,418 patients post-implementation (55% female, mean age 76.7 ± 12.8 year) and 2,306 patients pre-implementation (56%, 75.8 ± 13.0 year, respectively). The primary outcome occurred in 479/1,418 (33.8%) patients post-implementation and in 829/2,306 (35.9%) pre-implementation. The aHR for the primary outcome was 0.89 (95% confidence interval [CI]: 0.79-0.99, p = 0.04) with no improvement seen in non-participating hospitals between post- versus pre-implementation periods (aHR 1.04; 95% CI: 0.95-1.15). INTERPRETATION: Implementation of a multicomponent system-of-care was associated with a lower risk of poor outcomes. ANN NEUROL 2023;93:511-521.

Frequency, associated variables, and outcomes of acute myocardial injury according to the fourth Universal Definition of Myocardial Infarction in patients with acute ischemic stroke.

Background: Myocardial injury as indicated by elevation of cardiac troponin levels is common after acute ischemic stroke (AIS) and linked to poor outcomes. Previous studies rarely reported on serial hs-cTn measurements to distinguish whether myocardial injury is acute or chronic. Thus, little is known about frequency, associated variables, and outcome of acute myocardial injury in AIS. Methods and patients: In this single-centered observational cohort study, from 01/2019 to 12/2020, consecutive patients with neuroimaging-confirmed AIS <48 h after symptom onset, and serial troponin measurements within the first 2 days after admission (Roche Elecsys®, hs-cardiac troponin T) were prospectively registered. Acute myocardial injury was defined according to the fourth Universal Definition of Myocardial Infarction (troponin above the upper reference limit and rise/fall>20%). Outcomes of interest were in-hospital mortality and unfavorable functional status at discharge (modified Rankin Scale >1). Results: Out of 1067 analyzed patients, 25.3% had acute myocardial injury, 40.4% had chronic myocardial injury and 34.3% had no myocardial injury. Older age, higher stroke severity, thrombolytic treatment, and impaired kidney function were independently associated with acute myocardial injury. In-hospital mortality was higher in patients with acute myocardial injury than in those without (13% vs 3%, adjusted OR, 2.9% [95% CI, 1.6-5.5]). Compared with no myocardial injury, both acute and chronic myocardial injury were associated with unfavorable functional status at discharge (adjusted OR, 1.6 [95% CI, 1.1-2.5] and OR, 1.7 [95% CI, 1.2-2.4], respectively). Conclusions: A quarter of patients with AIS have evidence of acute myocardial injury according to the fourth Universal Definition of Myocardial Infarction. The strong association with in-hospital mortality highlights the need for clinical awareness and future studies on underlying mechanisms.

Can intracranial time-of-flight-MR angiography predict extracranial carotid artery stenosis?

OBJECTIVES: Extracranial stenosis of the internal carotid artery (ICA) is an important cause of ischemic stroke and transient ischemic attack (TIA). It can be diagnosed using contrast-enhanced CT or MR angiography (MRA) as well as Doppler ultrasound. In this study, we assessed the diagnostic value of intracranial time-of-flight (TOF) MRA to predict extracranial ICA stenosis (ICAS). METHODS: We retrospectively analyzed consecutive patients with acute ischemic stroke or TIA and middle- (50-69%) or high-grade (70-99%) unilateral extracranial ICAS according to NASCET criteria assessed by ultrasound between January 2016 and August 2018. The control group consisted of patients without extracranial ICAS. Intraluminal signal intensities (SI) of the intracranial ICA on the side of the extracranial stenosis were compared to the contralesional side on TOF-MRA source images. SI ratios (SIR) of contralesional:lesional side were compared between groups. RESULTS: In total, 151 patients were included in the main analysis. Contralesional:lesional SIR in the intracranial C4-segment was significantly higher in patients with ipsilateral extracranial ICA stenosis (n = 51, median 74 years, 57% male) compared to the control group (n = 100, median 68 years, 48% male). Mean SIR was 1.463 vs. 1.035 (p < 0.001) for right-sided stenosis and 1.362 vs. 1.000 (p < 0.001) for left-sided stenosis. Receiver-operating characteristic curve demonstrated a cut-off value of 1.086 for right-sided [sensitivity/specificity 75%/81%; area under the curve (AUC) 0.81] and 1.104 for left-sided stenosis (sensitivity/specificity 70%/84%; AUC 0.80) in C4 as a good predictor for high-grade extracranial ICAS. CONCLUSIONS: SIR on TOF-MRA can be a marker of extracranial ICAS.

Frequency of silent brain infarction in transient global amnesia.

BACKGROUND AND PURPOSE: To determine the frequency and distribution pattern of acute DWI lesions outside the hippocampus in patients clinically presenting with Transient Global Amnesia (TGA). METHODS: Consecutive patients clinically presenting with TGA between January 2010 and January 2017 admitted to our hospital were retrospectively evaluated. All patients fulfilled diagnostic criteria of TGA. We analyzed imaging and clinical data of all patients undergoing MRI with high-resolution diffusion-weighted imaging within 72 h from symptom onset. RESULTS: A total of 126 cases were included into the study. Fifty-three percent (n = 71/126) presented with one or more acute lesions in hippocampal CA1-area. Additional acute DWI lesions in other cortical regions were found in 11% (n = 14/126). All patients with DWI lesions outside the hippocampus presented with neurological symptoms typical for TGA (without additional symptoms.) CONCLUSIONS: In a relevant proportion of clinical TGA patients, MRI reveals acute ischemic cerebral lesions. Therefore, cerebral MRI should be performed in patients with TGA to identify a possible cardiac involvement and to detect stroke chameleons.

Time-to-care metrics in patients with interhospital transfer for mechanical thrombectomy in north-east Germany: Primary telestroke centers in rural areas vs. primary stroke centers in a metropolitan area.

Background: Mechanical thrombectomy (MT) is highly effective in large vessel occlusion (LVO) stroke. In north-east Germany, many rural hospitals do not have continuous neurological expertise onsite and secondary transport to MT capable comprehensive stroke centers (CSC) is necessary. In metropolitan areas, small hospitals often have neurology departments, but cannot perform MT. Thus, interhospital transport to CSCs is also required. Here, we compare time-to-care metrics and outcomes in patients receiving MT after interhospital transfer from primary stroke centers (PCSs) to CSCs in rural vs. metropolitan areas. Methods: Patients from ten rural telestroke centers (RTCs) and nine CSCs participated in this study under the quality assurance registry for thrombectomies of the Acute Neurological care in North-east Germany with TeleMedicine (ANNOTeM) telestroke network. For the metropolitan area, we included patients admitted to 13 hospitals without thrombectomy capabilities (metropolitan primary stroke centers, MPSCs) and transferred to two CSCs. We compared groups regarding baseline variables, time-to-care metrics, clinical, and technical outcomes. Results: Between October 2018 and June 2022, 50 patients were transferred from RTCs within the ANNOTeM network and 42 from MPSCs within the Berlin metropolitan area. RTC patients were older (77 vs. 72 yrs, p = 0.05) and had more severe strokes (NIHSS 17 vs. 10 pts., p < 0.01). In patients with intravenous thrombolysis (IVT; 34.0 and 40.5%, respectively), time from arrival at the primary stroke center to start of IVT was longer in RTCs (65 vs. 37 min, p < 0.01). However, RTC patients significantly quicker underwent groin puncture at CSCs (door-to-groin time: 42 vs. 60 min, p < 0.01). Despite longer transport distances from RTCs to CSCs (55 vs. 22 km, p < 0.001), there was no significant difference of times between arrival at the PSC and groin puncture (210 vs. 208 min, p = 0.96). In adjusted analyses, there was no significant difference in clinical and technical outcomes. Conclusion: Despite considerable differences in the setting of stroke treatment in rural and metropolitan areas, overall time-to-care metrics were similar. Targets of process improvement should be door-to-needle times in RTCs, transfer organization, and door-to-groin times in CSCs wherever such process times are above best-practice models.

Cardiac Troponin and Recurrent Major Vascular Events after Minor Stroke or Transient Ischemic Attack.

OBJECTIVE: This study was undertaken to investigate whether high-sensitivity cardiac troponin T (hs-cTnT) is associated with major adverse cardiovascular events (MACE) in patients with minor stroke or transient ischemic attack (TIA), and whether this association differs after risk stratification based on the Age, Blood Pressure, Clinical Features, Duration of Symptoms, Diabetes (ABCD2 ) score. METHODS: INSPiRE-TMS was a randomized controlled trial allocating patients with minor stroke or TIA to an intensified support program or conventional care. In this post hoc analysis, participants were categorized using hs-cTnT levels (5th generation; Roche Diagnostics, Manheim, Germany; 99th percentile upper reference limit [URL] = 14ng/l). Vascular risk was stratified using the ABCD2 score (lower risk = 0-5 vs higher risk = 6-7). Cox proportional hazard regression was performed using covariate adjustment and propensity score matching (PSM) for the association between hs-cTnT and MACE (stroke/nonfatal coronary event/vascular death). RESULTS: Among 889 patients (mean age = 70 years, 37% female), MACE occurred in 153 patients (17.2%) during a mean follow-up of 3.2 years. hs-cTnT was associated with MACE (9.3%/yr, >URL vs 4.4%/yr, ≤URL, adjusted hazard ratio [HR] = 1.63 [95% confidence interval (CI) = 1.13-2.35], adjusted HR [Q4 vs Q1 ] = 2.57 [95% CI = 1.35-4.97], adjusted HR [log-transformed] = 2.31 [95% CI = 1.37-3.89]). This association remained after PSM (adjusted HR = 1.76 [95% CI = 1.14-2.72]). There was a significant interaction between hs-cTnT and ABCD2 category for MACE occurrence (pinteraction  = 0.04). In the lower risk category, MACE rate was 9.5%/yr in patients with hs-cTnT > URL, which was higher than in those ≤URL (3.8%/yr) and similar to the overall rate in the higher risk category. INTERPRETATION: hs-cTnT levels are associated with incident MACE within 3 years after minor stroke or TIA and may help to identify high-risk individuals otherwise deemed at lower risk based on the ABCD2 score. If confirmed in independent validation studies, this might warrant intensified secondary prevention measures and cardiac diagnostics in stroke patients with elevated hs-cTnT. ANN NEUROL 2021;90:901-912.

High-Sensitivity Cardiac Troponin T and Recurrent Vascular Events After First Ischemic Stroke.

Background Recent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with recurrent vascular events and death in patients with first-ever, mild to moderate ischemic stroke. Methods and Results We used data from the PROSCIS-B (Prospective Cohort With Incident Stroke Berlin) study. We computed Cox proportional hazards regression analyses to assess the association between hs-cTnT levels upon study entry (Roche Elecsys, upper reference limit, 14 ng/L) and the primary outcome (composite of recurrent stroke, myocardial infarction, and all-cause death). A total of 562 patients were analyzed (mean age, 67 years [SD 13]; 38.6% women; median National Institutes of Health Stroke Scale=2; hs-cTnT above upper reference limit, 39.2%). During a mean follow-up of 3 years, the primary outcome occurred in 89 patients (15.8%), including 40 (7.1%) recurrent strokes, 4 (0.7%) myocardial infarctions, and 51 (9.1%) events of all-cause death. The primary outcome occurred more often in patients with hs-cTnT above the upper reference limit (27.3% versus 10.2%; adjusted hazard ratio, 2.0; 95% CI, 1.3-3.3), with a dose-response relationship when the highest and lowest hs-cTnT quartiles were compared (15.2 versus 1.8 events per 100 person-years; adjusted hazard ratio, 4.8; 95% CI, 1.9-11.8). This association remained consistent in sensitivity analyses, which included age matching and stratification for sex. Conclusions Hs-cTnT is dose-dependently associated with an increased risk of recurrent vascular events and death within 3 years after first-ever, mild to moderate ischemic stroke. These findings support further studies of the utility of hs-cTnT for individualized risk stratification after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.

Frequency, clinical presentation and outcome of vigilance impairment in patients with uni- and bilateral ischemic infarction of the paramedian thalamus.

Ischemic stroke of the paramedian thalamus is a rare differential diagnosis in sudden altered vigilance states. While efforts to describe clinical symptomatology exist, data on the frequency of paramedian thalamic stroke as a cause of sudden impaired vigilance and on accompanying clinical signs and outcome are scarce. We retrospectively analyzed consecutive patients admitted to a tertiary stroke center between 2010 and 2019 diagnosed with paramedian thalamic stroke. We evaluated frequency of vigilance impairment (VI) due to paramedian thalamic stroke, accompanying clinical signs and short-term outcome in uni- versus bilateral paramedian lesion location. Of 3896 ischemic stroke patients, 53 showed a paramedian thalamic stroke location (1.4%). VI was seen in 29/53 patients with paramedian thalamic stroke and in 414/3896 with any stroke (10.6%). Paramedian thalamic stroke was identified as causal to VI in 3.4% of all patients with initial VI in the emergency department and in 0.7% of all ischemic stroke patients treated in our center. Accompanying clinical signs were detected in 21 of these 29 patients (72.4%) and facilitated a timely diagnosis. VI was significantly more common after bilateral than unilateral lesions (92.0% vs. 21.4%; p < 0.001). Patients with bilateral paramedian lesions were more severely affected, had longer hospital stays and more frequently required in-patient rehabilitation. Paramedian thalamic lesions account for about 1 in 15 stroke patients presenting with impaired vigilance. Bilateral paramedian lesion location is associated with worse stroke severity and short-term outcome. Paying attention to accompanying clinical signs is of importance as they may facilitate a timely diagnosis.

Cardiomyocyte Injury Following Acute Ischemic Stroke: Protocol for a Prospective Observational Cohort Study.

BACKGROUND: Elevated cardiac troponin, which indicates cardiomyocyte injury, is common after acute ischemic stroke and is associated with poor functional outcome. Myocardial injury is part of a broad spectrum of cardiac complications that may occur after acute ischemic stroke. Previous studies have shown that in most patients, the underlying mechanism of stroke-associated myocardial injury may not be a concomitant acute coronary syndrome. Evidence from animal research and clinical and neuroimaging studies suggest that functional and structural alterations in the central autonomic network leading to stress-mediated neurocardiogenic injury may be a key underlying mechanism (ie, stroke-heart syndrome). However, the exact pathophysiological cascade remains unclear, and the diagnostic and therapeutic implications are unknown. OBJECTIVE: The aim of this CORONA-IS (Cardiomyocyte injury following Acute Ischemic Stroke) study is to quantify autonomic dysfunction and to decipher downstream cardiac mechanisms leading to myocardial injury after acute ischemic stroke. METHODS: In this prospective, observational, single-center cohort study, 300 patients with acute ischemic stroke, confirmed via cerebral magnetic resonance imaging (MRI) and presenting within 48 hours of symptom onset, will be recruited during in-hospital stay. On the basis of high-sensitivity cardiac troponin levels and corresponding to the fourth universal definition of myocardial infarction, 3 groups are defined (ie, no myocardial injury [no cardiac troponin elevation], chronic myocardial injury [stable elevation], and acute myocardial injury [dynamic rise/fall pattern]). Each group will include approximately 100 patients. Study patients will receive routine diagnostic care. In addition, they will receive 3 Tesla cardiovascular MRI and transthoracic echocardiography within 5 days of symptom onset to provide myocardial tissue characterization and assess cardiac function, 20-min high-resolution electrocardiogram for analysis of cardiac autonomic function, and extensive biobanking. A follow-up for cardiovascular events will be conducted 3 and 12 months after inclusion. RESULTS: After a 4-month pilot phase, recruitment began in April 2019. We estimate a recruitment period of approximately 3 years to include 300 patients with a complete cardiovascular MRI protocol. CONCLUSIONS: Stroke-associated myocardial injury is a common and relevant complication. Our study has the potential to provide a better mechanistic understanding of heart and brain interactions in the setting of acute stroke. Thus, it is essential to develop algorithms for recognizing patients at risk and to refine diagnostic and therapeutic procedures. TRIAL REGISTRATION: Clinicaltrials.gov NCT03892226; https://www.clinicaltrials.gov/ct2/show/NCT03892226. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24186.

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

Importance: Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. Objective: To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants: This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only). Exposure: Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). Main Outcomes and Measures: The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. Results: Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). Conclusions and Relevance: In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.

High-sensitivity cardiac troponin T and severity of cerebral white matter lesions in patients with acute ischemic stroke.

INTRODUCTION: Cardiac troponin (hs-cTnT) is a sensitive marker of myocardial injury and has been linked to incident dementia. The underlying mechanism of that observation is still unknown. Given that severity of cerebral small vessel disease is a predictor of cognitive decline, we aimed to explore whether there is an association between hs-cTnT and severity of white matter lesions (WML) as a marker of cerebral small vessel disease in patients with ischemic stroke. METHODS: We analyzed consecutive acute ischemic stroke patients admitted to Charité-University Hospital, Berlin from 2011 to 2013. Severity of WML was graded on 3T-MRI using the age-related white matter severity score (ARWMS). Patients with hs-cTnT elevation suggestive of acute coronary syndrome (ACS) were excluded (hs-cTnT > 52 ng/l or dynamic change of hs-cTnT > 50%, ESC guideline). We performed unadjusted and adjusted quantile regression models to assess the association between increased hs-cTnT (dichotomized at the 99th percentile, 14 ng/l) and severity of WML. RESULTS: A total of 860 patients was analyzed (median age 73 years, 44.8% female, median ARWMS 6). Patients with elevated hs-cTnT had more extensive WML than those without (median ARWMS 8 vs. 5, adjusted beta for 50th percentile 1.12, 95% CI 0.41-1.84). The association between WML and hs-cTnT elevation was strongest in patients with severe WML (adjusted beta 1.77, 95% CI 0.26-3.27 for 80th WML percentile). CONCLUSION: Elevated hs-cTnT levels were associated with extent of WML in acute stroke patients. Further studies are needed to assess whether hs-cTnT can be used to identify stroke patients at risk for cognitive decline.

Assessment of thrombus length in acute ischemic stroke by post-contrast magnetic resonance angiography.

OBJECTIVES: Post-contrast magnetic resonance angiography (PC-MRA) enables visualization of vessel segments distal to an intra-arterial thrombus in acute ischemic stroke. We hypothesized that PC-MRA also allows clot length measurement in different intracranial vessels. METHODS: Patients with MRI-confirmed ischemic stroke and intracranial artery occlusion within 24 hours of symptom onset were prospectively evaluated. PC-MRA was added to a standard stroke MRI protocol. Thrombus length was measured on thick slab maximum intensity projection images. Clinical outcome at hospital discharge was assessed by modified Rankin Scale (mRS). RESULTS: Thirty-four patients (median age 72 years) presenting with a median National Institutes of Health Stroke Scale score of 11 and a median onset to imaging time of 116 min were included. PC-MRA enabled precise depiction of proximal and distal terminus of the thrombus in 31 patients (91%), whereas in three patients (9%) PC-MRA presented a partial occlusion. Median thrombus length in patients with complete occlusion was 9.9 mm. In patients with poor outcome (mRS ≥3) median thrombus length was significantly longer than in those with good outcome (mRS ≤2;P=0.011). CONCLUSIONS: PC-MRA demonstrates intra-arterial thrombus length at different vessel occlusion sites. Longer thrombus length is associated with poor clinical outcome. CLINICAL TRIAL REGISTRATION: NCT02077582; Results.

Relationship Between Changes in the Temporal Dynamics of the Blood-Oxygen-Level-Dependent Signal and Hypoperfusion in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Changes in the blood-oxygen-level-dependent (BOLD) signal provide a noninvasive measure of blood flow, but a detailed comparison with established perfusion parameters in acute stroke is lacking. We investigated the relationship between BOLD signal temporal delay and dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) in stroke patients. METHODS: In 30 patients with acute (<24 hours) ischemic stroke, we performed Pearson correlation and multiple linear regression between DSC-MRI parameters (time to maximum [Tmax], mean transit time, cerebral blood flow, and cerebral blood volume) and BOLD-based parameters (BOLD delay and coefficient of BOLD variation). Prediction of severe hypoperfusion (Tmax >6 seconds) was assessed using receiver-operator characteristic (ROC) analysis. RESULTS: Correlation was highest between Tmax and BOLD delay (venous sinus reference; time shift range 7; median r=0.60; interquartile range=0.49-0.71). Coefficient of BOLD variation correlated with cerebral blood volume (median r= 0.37; interquartile range=0.24-0.51). Mean R2 for predicting BOLD delay by DSC-MRI was 0.54 (SD=0.2) and for predicting coefficient of BOLD variation was 0.37 (SD=0.17). BOLD delay (whole-brain reference, time shift range 3) had an area under the curve of 0.76 for predicting severe hypoperfusion (sensitivity=69.2%; specificity=80%), whereas BOLD delay (venous sinus reference, time shift range 3) had an area under the curve of 0.76 (sensitivity=67.3%; specificity=83.5%). CONCLUSIONS: BOLD delay is related to macrovascular delay and microvascular hypoperfusion, can identify severely hypoperfused tissue in acute stroke, and is a promising alternative to gadolinium contrast agent-based perfusion assessment in acute stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715533 and NCT02077582.

Reliability of Two Diameters Method in Determining Acute Infarct Size. Validation as New Imaging Biomarker.

BACKGROUND: In order to select patients most likely to benefit for thrombolysis and to predict patient outcome in acute ischemic stroke, the volumetric assessment of the infarcted tissue is used. However, infarct volume estimation on Diffusion weighted imaging (DWI) has moderate interrater variability despite the excellent contrast between ischemic lesion and healthy tissue. In this study, we compared volumetric measurements of DWI hyperintensity to a simple maximum orthogonal diameter approach to identify thresholds indicating infarct size >70 ml and >100 ml. METHODS: Patients presenting with ischemic stroke with an NIHSS of ≥ 8 were examined with stroke MRI within 24 h after symptom onset. For assessment of the orthogonal DWI lesion diameters (od-values) the image with the largest lesion appearance was chosen. The maximal diameter of the lesion was determined and a second diameter was measured perpendicular. Both diameters were multiplied. Od-values were compared to volumetric measurement and od-value thresholds identifying a lesion size of > 70 ml and > 100 ml were determined. In a selected dataset with an even distribution of lesion sizes we compared the results of the od value thresholds with results of the ABC/2 and estimations of lesion volumes made by two resident physicians. RESULTS: For 108 included patients (53 female, mean age 71.36 years) with a median infarct volume of 13.4 ml we found an excellent correlation between volumetric measures and od-values (r2 = 0.951). Infarct volume >100 ml corresponds to an od-value cut off of 42; > 70 ml corresponds to an od-value of 32. In the compiled dataset (n = 50) od-value thresholds identified infarcts > 100 ml / > 70 ml with a sensitivity of 90%/ 93% and with a specificity of 98%/ 89%. The od-value offered a higher accuracy in identifying large infarctions compared to both visual estimations and the ABC/2 method. CONCLUSION: The simple od-value enables identification of large DWI lesions in acute stroke. The cutoff of 42 is useful to identify large infarctions with volume larger than 100 ml. Further studies can analyze the therapeutic utility of this new method. TRAIL REGISTRATION: ClinicalTrials.org NCT00715533.

Adapting the computed tomography criteria of hemorrhagic transformation to stroke magnetic resonance imaging.

BACKGROUND: The main safety aspect in the use of stroke thrombolysis and in clinical trials of new pharmaceutical or interventional stroke therapies is the incidence of hemorrhagic transformation (HT) after treatment. The computed tomography (CT)-based classification of the European Cooperative Acute Stroke Study (ECASS) distinguishes four categories of HTs. An HT can range from a harmless spot of blood accumulation to a symptomatic space-occupying parenchymal bleeding associated with a massive deterioration of symptoms and clinical prognosis. In magnetic resonance imaging (MRI) HTs are often categorized using the ECASS criteria although this classification has not been validated in MRI. We developed MRI-specific criteria for the categorization of HT and sought to assess its diagnostic reliability in a retrospective study. METHODS: Consecutive acute ischemic stroke patients, who had received a 3-tesla MRI before and 12-36 h after thrombolysis, were screened retrospectively for an HT of any kind in post-treatment MRI. Intravenous tissue plasminogen activator was given to all patients within 4.5 h. HT categorization was based on a simultaneous read of 3 different MRI sequences (fluid-attenuated inversion recovery, diffusion-weighted imaging and T2* gradient-recalled echo). Categorization of HT in MRI accounted for the various aspects of the imaging pattern as the shape of the bleeding area and signal intensity on each sequence. All data sets were independently categorized in a blinded fashion by 3 expert and 3 resident observers. Interobserver reliability of this classification was determined for all observers together and for each group separately by calculating Kendall's coefficient of concordance (W). RESULTS: Of the 186 patients screened, 39 patients (21%) had an HT in post-treatment MRI and were included for the categorization of HT by experts and residents. The overall agreement of HT categorization according to the modified classification was substantial for all observers (W = 0.79). The degrees of agreement between experts (W = 0.81) and between residents (W = 0.87) were almost perfect. For the distinction between parenchymal hematoma and hemorrhagic infarction, the interobserver agreement was almost perfect for all observers taken together (W = 0.82) as well as when experts (W = 0.82) and residents (W = 0.91) were analyzed separately. CONCLUSION: The ECASS CT classification of HT was successfully adapted for usage in MRI. It leads to a substantial to almost perfect interobserver agreement and can be used for safety assessment in clinical trials.

HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology.

We present HepatoNet1, the first reconstruction of a comprehensive metabolic network of the human hepatocyte that is shown to accomplish a large canon of known metabolic liver functions. The network comprises 777 metabolites in six intracellular and two extracellular compartments and 2539 reactions, including 1466 transport reactions. It is based on the manual evaluation of >1500 original scientific research publications to warrant a high-quality evidence-based model. The final network is the result of an iterative process of data compilation and rigorous computational testing of network functionality by means of constraint-based modeling techniques. Taking the hepatic detoxification of ammonia as an example, we show how the availability of nutrients and oxygen may modulate the interplay of various metabolic pathways to allow an efficient response of the liver to perturbations of the homeostasis of blood compounds.