Strategies for detecting cardiac sources of embolism after ischemic stroke

Detecting the probable cause of ischemic stroke is one of the main goals of the diagnostic evaluation of ischemic stroke patients. Various causes of stroke require specific treatment changes that can lower the risk of recurrent stroke. However, after the first in-hospital analysis, no cause of stroke is detected in about 25% of patients. Because several cardiac diseases can be a cause of ischemic stroke, this group of patients undergoes additional cardiac evaluation. This thesis aims to evaluate the use of routine cardiac investigations for the detection of major cardiac sources of embolism (CSE) in patients with ischemic stroke or TIA of undetermined cause, and to find possibilities for improvement of the current strategy. Part one focuses on the detection of atrial fibrillation (AF). We show that the use of an automated detection algorithm for AF during in-hospital heart rhythm monitoring improves AF detection in stroke patients. After hospital discharge, ambulatory heart rhythm monitoring further increases the rate of AF detection. In addition, longer monitoring duration leads to higher detection rates. These results support extending the current guideline-recommended monitoring period of three days to at least seven days. Part two concentrates on the detection of structural CSEs with transthoracic echocardiography (TTE). Currently, in the Netherlands, the availability of TTE is limited due to shortage of experienced echocardiographers. When combining data from our systematic review and meta-analysis, retrospective single-center study, and prospective multicenter study, we can conclude that routine TTE in patients with ischemic stroke or TIA of undetermined cause infrequently detects a major CSE, in about 1% of patients. The majority of these patients also had major abnormalities on their electrocardiogram (ECG). Results of a subsequent cost-effectiveness analysis show that the strategy of only selecting patients with such ECG-abnormalities for TTE is cost-effective compared to performing TTE in all patients with ischemic stroke or no patients. Thus, a strategy that only selects patients with major ECG-abnormalities to undergo TTE would therefore be more efficient, reduce the amount of unnecessary TTE examinations and consequently reduce pressure on the Dutch healthcare system.<br/

CX3C chemokine receptor 1 deficiency modulates microglia morphology but does not affect lesion size and short-term deficits after experimental stroke

Background: The fractalkine/CX3C chemokine receptor 1 (CX3CR1) pathway has been identified to play an essential role in the chemotaxis of microglia, leukocyte trafficking and microglia/macrophage recruitment. It has also been shown to be important in the regulation of the inflammatory response in the early phase after experimental stroke. The present study was performed to investigate if CX3CR1 deficiency affects microglia during the first 14days with consequences for tissue damage after experimental stroke. Results: CX3CR1 deficiency significantly increased the number of intersections of GFP positive microglia in the proximal peri-infarct area at 2, 7 and 14days following tMCAO compared to heterozygous and wildtype littermates. In addition, the length of microglial branches increased until day 7 in CX3CR1 knockout mice while the presence of a functional CX3CR1 allele resulted in a gradual reduction of their length following tMCAO. After stroke, wildtype, heterozygous and CX3CR1 deficient mice did not show differences in the composite neuroscore and assessment of infarct volumes from CX3CR1 wildtype, heterozygous and deficient mice revealed no differences between the genotypes 7 and 14days after stroke. Conclusion: Results demonstrate that CX3CR1 deficiency affects the morphology of GFP positive microglia located in the proximal peri-infarct region during the first 14days after tMCAO. Our data also indicate that CX3CR1 deficiency does not affect definite infarct volumes. Modulation of the CX3CR1 pathway may have implication for microglia function contributing to mechanisms of tissue reorganization in the post-ischemic brain

CX3C chemokine receptor 1 deficiency modulates microglia morphology but does not affect lesion size and short-term deficits after experimental stroke

Background: The fractalkine/CX3C chemokine receptor 1 (CX3CR1) pathway has been identified to play an essential role in the chemotaxis of microglia, leukocyte trafficking and microglia/macrophage recruitment. It has also been shown to be important in the regulation of the inflammatory response in the early phase after experimental stroke. The present study was performed to investigate if CX3CR1 deficiency affects microglia during the first 14days with consequences for tissue damage after experimental stroke. Results: CX3CR1 deficiency significantly increased the number of intersections of GFP positive microglia in the proximal peri-infarct area at 2, 7 and 14days following tMCAO compared to heterozygous and wildtype littermates. In addition, the length of microglial branches increased until day 7 in CX3CR1 knockout mice while the presence of a functional CX3CR1 allele resulted in a gradual reduction of their length following tMCAO. After stroke, wildtype, heterozygous and CX3CR1 deficient mice did not show differences in the composite neuroscore and assessment of infarct volumes from CX3CR1 wildtype, heterozygous and deficient mice revealed no differences between the genotypes 7 and 14days after stroke. Conclusion: Results demonstrate that CX3CR1 deficiency affects the morphology of GFP positive microglia located in the proximal peri-infarct region during the first 14days after tMCAO. Our data also indicate that CX3CR1 deficiency does not affect definite infarct volumes. Modulation of the CX3CR1 pathway may have implication for microglia function contributing to mechanisms of tissue reorganization in the post-ischemic brain

Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke

Background: Recovery of lost neurological function after stroke is limited and dependent on multiple mechanisms including inflammatory processes. Selective pharmacological modulation of inflammation might be a promising approach to improve stroke outcome. Methods: We used 1,1'-[1,4-phenylenebis(methylene)] bis[1,4,8,11-tetraazacyclotetradecane] (AMD3100), an antagonist to the C-X-C chemokine receptor type 4 (CXCR4) and potential allosteric agonist to CXCR7, administered to mice twice daily from day 2 after induction of photothrombosis (PT). In addition to functional outcome, the dynamics of post-stroke microglia response were monitored in vivo by 2-photon-laser-microscopy in heterozygous transgenic CX(3)CR1-green fluorescent protein (GFP) mice (CX(3)CR1(GFP/+)) and complemented with analyses for fractalkine (FKN) and pro-inflammatory cytokines. Results: We found a significantly enhanced recovery and modified microglia activation without affecting infarct size in mice treated with AMD3100 after PT. AMD3100 treatment significantly reduced the number of microglia in the peri-infarct area accompanied by stabilization of soma size and ramified cell morphology. Within the ischemic infarct core of AMD3100 treated wild-type mice we obtained significantly reduced levels of the endogenous CX(3)CR1 ligand FKN and the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-6. Interestingly, in CX(3)CR1-deficient mice (homozygous transgenic CX(3)CR1-GFP mice) subjected to PT, the levels of FKN were significantly lower compared to their wild-type littermates. Moreover, AMD3100 treatment did not induce any relevant changes of cytokine levels in CX(3)CR1 deficient mice. Conclusion: After AMD3100 treatment, attenuation of microglia activation contributes to enhanced recovery of lost neurological function in experimental stroke possibly due to a depression of FKN levels in the brain. We further hypothesize that this mechanism is dependent on a functional receptor CX(3)CR1

Cardiac imaging in ischemic stroke or transient ischemic attack of undetermined cause: Systematic review & meta-analysis

Background: Patients with ischemic stroke or transient ischemic attack (TIA) of undetermined cause often undergo cardiac imaging in search of a cardioembolic source. As the choice of the most appropriate imaging approach is controversial and therapeutic implications have changed over time, we aimed to identify in patients with “cryptogenic stroke or TIA” the yield of transthoracic or transesophageal echocardiography (TTE or TEE) and cardiac computed tomography (CT). Methods and results: We performed a systematic review and meta-analysis according to the PRISMA guidelines. Included were studies that assessed consecutive patients with ischemic stroke or TIA of undetermined cause to evaluate the yield of TTE, TEE, or cardiac CT for detecting cardioembolic sources. For each type of cardioembolic source the pooled prevalence was calculated. Only six out of 1458 studies fulfilled the inclusion criteria (1022 patients). One study reported the yield of TTE, four of TEE, and one of both TTE and TEE; no study assessed cardiac CT. Mean patient age ranged from 44.3–71.2 years, 49.2–59.7% were male. TTE detected 43 cardioembolic sources in 316 patients (4 (1.3%) major, 39 (12.3%) minor), and TEE 248 in 937 patients (55 (5.9%) major, 193 (20.6%) minor). The most prevalent major cardioembolic source was left atrial appendage thrombus, yet results were heterogeneous among studies. Conclusions: TTE and TEE infrequently detect major cardioembolic sources that require a change of therapy. Findings should be interpreted with caution due to the limited number of studies. A large-sized prospective clinical trial is warranted to support evidence-based decision-making

Detection of major cardioembolic sources in real-world patients with ischemic stroke or transient ischemic attack of undetermined cause

Background/Aim: Current guidelines recommend transthoracic echocardiography (TTE) and ambulatory rhythm monitoring following ischemic stroke or transient ischemic attack (TIA) of undetermined cause for identifying cardioembolic sources (CES). Due to ongoing controversies about this routine strategy, we evaluated its yield in a real-world setting. Methods: In a tertiary medical center, we retrospectively evaluated consecutive patients with ischemic stroke or TIA of undetermined cause, who (after standard work-up) underwent TTE, ambulatory rhythm monitoring, or both. CES were classified as major if probably related to ischemic events and warranting a change of therapy. Results: Between January 2014 and December 2017, 674 patients had ischemic stroke or TIA of undetermined cause. Of all 484 patients (71.8%) who underwent TTE, 9 (1.9%) had a major CES. However, 7 of them had already been identified for cardiac evaluation due to new major electrocardiographic abnormalities or cardiac symptoms. Thus, only 2 patients (0.4%) truly benefitted from unselected TTE screening. Ambulatory rhythm monitoring was performed in 411 patients (61.0%) and revealed AF in 10 patients (2.4%). Conclusion: Detecting a major CES is essential because appropriate treatment lowers the risk of recurrent stroke. Nonetheless, in this real-world study that aimed at routine use of TTE and ambulatory rhythm monitoring in patients with ischemic stroke or TIA of undetermined cause, the prevalence of major CES was low. Most patients with major CES on TTE already had an indication for referral to a cardiologist, suggesting that major CES might also have been identified with a much more selective use of TTE