Objective: Cardiac diseases are established risk factors for ischemic stroke incidence and severity. Conversely, there is increasing evidence that brain ischemia can cause cardiac dysfunction. The mechanisms underlying this neurogenic heart disease are incompletely understood. Although it is established that ischemic stroke is associated with cardiac arrhythmias, myocardial damage, elevated cardiac enzymes, and plasma catecholamines in the acute phase, nothing is known about the delayed consequences of ischemic stroke on cardiovascular function.Methods: To determine the long‐term cardiac consequences of a focal cerebral ischemia, we subjected young and aged mice to a 30‐minute transient middle cerebral artery occlusion and analyzed cardiac function by serial transthoracic echocardiography and hemodynamic measurements up to week 8 after surgery. Finally, animals were treated with metoprolol to evaluate a pharmacologic treatment option to prevent the development of heart failure.Results: Focal cerebral ischemia induced a long‐term cardiac dysfunction with a reduction in left ventricular ejection fraction and an increase in left ventricular volumes; this development was associated with higher peripheral sympathetic activity. Metoprolol treatment prevented the development of chronic cardiac dysfunction by decelerating extracellular cardiac remodeling and inhibiting sympathetic signaling relevant to chronic autonomic dysfunction.Interpretation: Focal cerebral ischemia in mice leads to the development of chronic systolic dysfunction driven by increased sympathetic activity. If these results can be confirmed in a clinical setting, treating physicians should be attentive to clinical signs of heart failure in every patient after ischemic stroke. Therapeutically, the successful β‐blockade with metoprolol in mice could also have future clinical implications. Ann Neurol 2017;82:729–743

Lymphocytes have been shown to play an important role in the pathophysiology of acute ischemic stroke, but the properties of B cells remain controversial. The aim of this study was to unravel the role of B cells during acute cerebral ischemia using pharmacologic B cell depletion, B cell transgenic mice, and adoptive B cell transfer experiments. Transient middle cerebral artery occlusion (60 min) was induced in wild-type mice treated with an anti-CD20 antibody 24 h before stroke onset, JHD −/− mice and Rag1 −/− mice 24 h after adoptive B cell transfer. Stroke outcome was assessed at days 1 and 3. Infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections, and neurological scores were evaluated. The local inflammatory response was determined by real-time PCR and immunohistochemistry. Apoptosis was analyzed by TUNEL staining, and astrocyte activation was revealed using immunohistochemistry and Western blot. Pharmacologic depletion of B cells did not influence infarct volumes and functional outcome at day 1 after stroke. Additionally, lack of circulating B cells in JHD −/− mice also failed to influence stroke outcome at days 1 and 3. Furthermore, reconstitution of Rag1 −/− mice with B cells had no influence on infarct volumes. Targeting B cells in experimental stroke did not influence lesion volume and functional outcome during the acute phase. Our findings argue against a major pathophysiologic role of B cells during acute ischemic stroke.

Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke.

Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO. Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls. In acute ischemic stroke, thrombus formation and inflammation are closely intertwined (“thrombo-inflammation”). Blocking of platelet GPIb can ameliorate thrombo-inflammation.

Background and Purpose—: Despite the medical and socioeconomic effect of ischemic stroke and extensive preclinical research, treatment options for ischemic stroke are limited. We recently identified and characterized essential steps of thrombus formation in stroke and demonstrated that inhibition of the platelet glycoprotein (GP) receptors Ib and VI, but not IIb/IIIa, protects young and healthy mice from ischemic neurodegeneration. Whether these findings translate to the clinic remains unclear. Considering that the typical stroke patient is elderly with comorbidity, we aimed to analyze the efficacy and safety of novel preclinical antithrombotics in adult and comorbid mice with acute experimental stroke. Methods—: We subjected adult, healthy, atherosclerotic ( Ldlr ^−/− ), diabetic (streptozotocin treated), and hypertensive ( RenTgMK ) mice to a 60-minute transient middle cerebral artery occlusion. Animals were pretreated with anti-GPVI antibodies or treated 1 hour after stroke induction with anti-GPIb or anti-GPIIb/IIIa antigen–binding fragments, respectively. Isotype treatment served as control. Twenty-four hours after transient middle cerebral artery occlusion, we visually assessed the intracerebral hemorrhage rate and measured infarct volumes (using 2,3,5-triphenyltetrazolium chloride–stained brain slices) and functional outcome (using Bederson and grip-test scores). Results—: GPIb and GPVI inhibition protected the mice from ischemic stroke without increasing bleeding complications. In contrast, GPIIb/IIIa inhibition was not protective but increased the intracerebral hemorrhage rate. Conclusions—: Inhibition of early steps of thrombus formation protects adult and comorbid mice from ischemic stroke. The use of clinically meaningful mouse strains might improve the translation of preclinical stroke research to the clinic.

Background: Data from European countries consistently show that guideline-conform secondary prevention after stroke/transient ischemic attack is being realized in only 50–80% of patients. Use of telemedicine to support long-term secondary prevention has been effective in other cardiovascular diseases. Aims: We reviewed current evidence for telemedical-supported strategies for the improvement of secondary prevention after stroke/transient ischemic attack. A systematic review was performed in accordance with the PRISMA statement searching MEDLINE, the Cochrane Central Register of Controlled Trials, and reference lists of articles published until 18 May 2016. Randomized controlled trials and observational studies were included if they analyzed the effect of a telemedical strategy for supporting secondary prevention after stroke/transient ischemic attack compared to usual care and reported primary (behavior according to guidelines, e.g., medication adherence) or surrogate outcomes (consequences of primary outcome, e.g., blood pressure). Summary of review: The review included 13 of 100 identified studies involving 2672 patients. Telemedical support mainly comprised telephone interventions, predominantly done by nurses. Outcomes were heterogeneous: medication adherence did not differ in one randomized controlled trial (p = 0.089). Mortality was reported in one study and was significantly (p < 0.001) higher in patients non-participating in a web-based intervention. Four studies assessed blood pressure in a comparable way that allowed calculation of a meta-analysis. In that, telemedical intervention had a significant blood-pressure lowering effect compared to the control group (mean difference −6.14 (95% confidence interval −10.41, −1.87), p = 0.005). Conclusions: Telemedical-supported secondary prevention in cerebrovascular diseases might be effective but larger trials with standardized interventions and outcome measures including clinical endpoints are needed.