Role of Cardiac Biomarkers in Stroke and Cognitive Impairment.

This topical review assesses the growing role of cardiac biomarkers beyond cardiovascular health and focuses on their importance in stroke and dementia. The first part describes blood-based cardiac biomarkers in patients with stroke and highlights applications in the setting of early diagnosis, poststroke complications, outcome prediction as well as secondary prevention. Among other applications, natriuretic peptides can be helpful in differentiating stroke subtypes. They are also currently being investigated to guide prolonged ECG monitoring and secondary prevention in patients with stroke. Elevated cardiac troponin after ischemic stroke can provide information about various poststroke complications recently termed the stroke-heart syndrome. The second part focuses on the role of cardiac biomarkers in vascular cognitive impairment and dementia, emphasizing their association with structural brain lesions. These lesions such as silent brain infarcts and white matter hyperintensities often co-occur with cardiac disease and may be important mediators between cardiovascular disease and subsequent cognitive decline. ECG and echocardiogram measurements, in addition to blood-based biomarkers, show consistent associations with vascular brain changes and incident dementia, suggesting a role in indicating risk for cognitive decline. Together, the current evidence suggests that cardiac blood-based, electrophysiological, and imaging biomarkers can be used to better understand the heart and brain connection in the setting of not only stroke but also dementia.

Common and specific proteins and pathways in heart and cerebral ischemia.

OBJECTIVE: To understand the similarities and differences between acute ischemic stroke and acute myocardial infarction (AMI) to help in the development of specific or common treatment strategies. METHODS: Using an aptamer-based proteomic array, we measured and compared 1310 circulating proteins in the blood of 40 patients with AIS, 9 patients with AMI, and 31 healthy controls. Pathway enrichment analysis was performed using GSEA and g:profiler. RESULTS: Ninety-four proteins were differentially expressed in AIS, and 284 were differentially expressed in AMI. Of these, 8 were specific to cerebral ischemia, and 197 were specific to myocardial infarction. Forty-two proteins were altered in both ischemia processes. Most altered pathways in AIS could be classified as immune response, cell cycle processing, molecular transport, or signaling. Pathways altered in AMI were mostly related to lipid metabolism and transport, highlighting cholesterol metabolic processes and estrogen signaling. In both types of ischemia, we found pathways related to metabolism, specifically purine metabolism, and signaling processes, such as TNF signaling or MAPK1/3. CONCLUSIONS: The present study revealed proteins and pathways that were specifically altered in cerebral ischemia, in cardiac ischemia, or in both diseases, providing information on the similarities and differences of ischemic conditions. The role of common and specific proteins and pathways should be explored in detail to find possible therapeutic targets.

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke.

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.

Predictors of Functional Outcome After Thrombectomy in Patients With Prestroke Disability in Clinical Practice.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) in ischemic stroke patients with poor prestroke conditions remains controversial. We aimed to analyze the frequency of previously disabled patients treated with MT in clinical practice, the safety and clinical response to MT of patients with preexisting disability, and the disabled patient characteristics associated with a better response to MT. METHODS: We studied all consecutive patients with anterior circulation occlusion treated with MT from January 2017 to December 2019 included in the Codi Ictus Catalunya registry-a government-mandated, prospective, hospital-based data set. Prestroke disability was defined as modified Rankin Scale score 2 or 3. Functional outcome at 90 days was centrally assessed by a blinded evaluator of the Catalan Stroke Program. Favorable outcome (to return at least to prestroke modified Rankin Scale at 90 days) and safety and secondary outcomes were compared with patients without previous disability. Logistic regression analysis was used to assess the association between prestroke disability and outcomes and to identify a disabled patient profile with favorable outcome after MT. RESULTS: Of 2487 patients included in the study, 409 (17.1%) had prestroke disability (313 modified Rankin Scale score 2 and 96 modified Rankin Scale score 3). After adjustment for covariates, prestroke disability was not associated with a lower chance of achieving favorable outcome at 90 days (24% versus 30%; odds ratio, 0.79 [0.57-1.08]), whereas it was independently associated with a higher risk of symptomatic intracranial hemorrhage (5% versus 3%; odds ratio, 2.04 [1.11-3.72]) and long-term mortality (31% versus 18%; odds ratio, 1.74 [1.27-2.39]) compared with patients without disability. Prestroke disabled patients without diabetes, Alberta Stroke Program Early CT Score >8 and National Institutes of Health Stroke Scale score <17 showed similar safety and outcome results after MT as patients without prestroke disability. CONCLUSIONS: Despite a higher mortality and risk of symptomatic intracranial hemorrhage, prestroke-disabled patients return as often as independent patients to their prestroke level of function, especially those nondiabetic patients with favorable early ischemic signs profile. These data support a potential benefit of MT in patients with previous mild or moderate disability after large anterior vessel occlusion stroke.

Workflows and Outcomes in Patients With Suspected Large Vessel Occlusion Stroke Triaged in Urban and Nonurban Areas.

BACKGROUND: We aim to compare the outcome of patients from urban areas, where the referral center is able to perform thrombectomy, with patients from nonurban areas enrolled in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion). METHODS: Patients with suspected large vessel occlusion stroke, as evaluated by a Rapid Arterial Occlusion Evaluation score of ≥5, from urban catchment areas of thrombectomy-capable centers during RACECAT trial enrollment period were included in the Stroke Code Registry of Catalonia. Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with an ischemic stroke. Secondary outcomes included mortality at 90 days, rate of thrombolysis and thrombectomy, time from onset to thrombolysis, and thrombectomy initiation. Propensity score matching was used to assemble a cohort of patients with similar characteristics. RESULTS: The analysis included 1369 patients from nonurban areas and 2502 patients from urban areas. We matched 920 patients with an ischemic stroke from urban areas and nonurban areas based on their propensity scores. Patients with ischemic stroke from nonurban areas had higher degrees of disability at 90 days (median [interquartle range] modified Rankin Scale score, 3 [2-5] versus 3 [1-5], common odds ratio, 1.25 [95% CI, 1.06-1.48]); the observed average effect was only significant in patients with large vessel stroke (common odds ratio, 1.36 [95% CI, 1.08-1.65]). Mortality rate was similar between groups(odds ratio, 1.02 [95% CI, 0.81-1.28]). Patients from nonurban areas had higher odds of receiving thrombolysis (odds ratio, 1.36 [95% CI, 1.16-1.67]), lower odds of receiving thrombectomy(odds ratio, 0.61 [95% CI, 0.51-0.75]), and longer time from stroke onset to thrombolysis (mean difference 38 minutes [95% CI, 25-52]) and thrombectomy(mean difference 66 minutes [95% CI, 37-95]). CONCLUSIONS: In Catalonia, Spain, patients with large vessel occlusion stroke triaged in nonurban areas had worse neurological outcomes than patients from urban areas, where the referral center was able to perform thrombectomy. Interventions aimed at improving organizational practices and the development of thrombectomy capabilities in centers located in remote areas should be pursued. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02795962.

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma.

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10-5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 × 10-8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 × 10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 × 10-8; OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.

A Mouse Brain-based Multi-omics Integrative Approach Reveals Potential Blood Biomarkers for Ischemic Stroke.

Stroke remains a leading cause of death and disability worldwide. Despite continuous advances, the identification of key molecular signatures in the hyper-acute phase of ischemic stroke is still a primary interest for translational research on stroke diagnosis, prognosis, and treatment. Data integration from high-throughput -omics techniques has become crucial to unraveling key interactions among different molecular elements in complex biological contexts, such as ischemic stroke. Thus, we used advanced data integration methods for a multi-level joint analysis of transcriptomics and proteomics data sets obtained from mouse brains at 2 h after cerebral ischemia. By modeling net-like correlation structures, we identified an integrated network of genes and proteins that are differentially expressed at a very early stage after stroke. We validated 10 of these deregulated elements in acute stroke, and changes in their expression pattern over time after cerebral ischemia were described. Of these, CLDN20, GADD45G, RGS2, BAG5, and CTNND2 were next evaluated as blood biomarkers of cerebral ischemia in mice and human blood samples, which were obtained from stroke patients and patients presenting stroke-mimicking conditions. Our findings indicate that CTNND2 levels in blood might potentially be useful for distinguishing ischemic strokes from stroke-mimicking conditions in the hyper-acute phase of the disease. Furthermore, circulating GADD45G content within the first 6 h after stroke could also play a key role in predicting poor outcomes in stroke patients. For the first time, we have used an integrative biostatistical approach to elucidate key molecules in the initial stages of stroke pathophysiology and highlight new notable molecules that might be further considered as blood biomarkers of ischemic stroke.

Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.

AIMS: Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. METHODS AND RESULTS: For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48). CONCLUSION: Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease.

Evaluation and Characterization of Post-Stroke Lung Damage in a Murine Model of Cerebral Ischemia.

After stroke and other brain injuries, there is a high incidence of respiratory complications such as pneumonia or acute lung injury. The molecular mechanisms that drive the brain-lung interaction post-stroke have not yet been elucidated. We performed transient middle cerebral artery occlusion (MCAO) and sham surgery on C57BL/6J mice and collected bronchoalveolar lavage fluid (BALF), serum, brain, and lung homogenate samples 24 h after surgery. A 92 proteins-panel developed by Olink Proteomics® was used to analyze the content in BALF and lung homogenates. MCAO animals had higher protein concentration levels in BALF than sham-controls, but these levels did not correlate with the infarct volume. No alteration in alveolar-capillary barrier permeability was observed. A total of 12 and 14 proteins were differentially expressed between the groups (FDR < 0.1) in BALF and lung tissue homogenates, respectively. Of those, HGF, TGF-α, and CCL2 were identified as the most relevant to this study. Their protein expression patterns were verified by ELISA. This study confirmed that post-stroke lung damage was not associated with increased lung permeability or cerebral ischemia severity. Furthermore, the dysregulation of HGF, TGF-α, and CCL2 in BALF and lung tissue after ischemia could play an important role in the molecular mechanisms underlying stroke-induced lung damage.

Association of blood-based biomarkers with radiologic markers and cognitive decline in atrial fibrillation patients.

BACKGROUND: Atrial fibrillation (AF) has been associated with an increased risk of silent brain infarcts (SBI) and cognitive impairment, even in patients with low embolic risk. We aimed to test the association between 11 blood-biomarkers representing different AF-related pathways, and SBI, white matter hyperintensities (WMH), and cognitive decline in patients with AF and low embolic risk. METHODS: The present study followed a cross-sectional design. 70 patients with a history of AF and CHADS2 score ≤1, and 10 controls with neither AF nor SBI were included. All patients underwent a 3T brain MRI. Cortical and large subcortical ischemic lesions were considered presumed embolic origin lesions. White matter hyperintensities (WMH) were measured according to the Fazekas scale. A subset of patients underwent cognitive evaluation with the MoCA test. Circulating proteins were measured under blind conditions in a laboratory at Roche Diagnostics, Germany. RESULTS: 45 patients presented SBI in the MRI, and 25 did not. Ang-2, FGF-23, and BMP-10 were increased in patients with SBI. Ang-2 was elevated only in patients with embolic infarcts, whereas FGF-23 and BMP-10 tended to be elevated in patients with both types of infarcts. Ang-2 (OR = 1.56 [0.94-2.59], p = 0.087), and BMP-10 (OR = 4.83 [0.99-23.60], p = 0.052) were the biomarkers that showed the highest association with SBI when entered in a multivariable logistic regression model corrected by age. No biomarker was found associated with WMH or mild cognitive impairment. CONCLUSIONS: BMP-10, and Ang-2 were increased in patients with SBI. Its usefulness to detect SBI in AF patients should be further explored.

Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis: A Systematic Review.

BACKGROUND AND PURPOSE: Outcome prognostication in ischemic stroke patients remains challenging due to limited predictive properties of existing models. Blood-based biomarkers might provide additional information to established prognostic factors. We intended to identify the most promising prognostic biomarkers in ischemic stroke, their incremental prognostic value, and whether their predictive value differs among etiologies. METHODS: We searched MEDLINE (Ovid) and Institute for Scientific Information Web of Knowledge for articles reporting the predictive performance of blood-based biomarkers measured up to 7 days after ischemic stroke and reporting functional outcome or death at least 7 days after stroke. This work updates a previous systematic review (up to January 2007), follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and was registered (International Prospective Register of Systematic Reviews PROSPERO 2018; https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018094671). RESULTS: Two hundred ninety-one articles published between January 2007 and August 2018 comprising 257 different biomarkers met inclusion criteria. Median sample size was 232 (interquartile range, 110-455); 260 (89%) articles reported regression analyses with 78% adjusting for stroke severity, 82% for age, 67% for both, and 9% for none of them; 37% investigated discrimination, 5% calibration, and 11% reclassification. Including publications from a previous systematic review (1960-January 2007), natriuretic peptides, copeptin, procalcitonin, mannose-binding lectin, adipocyte fatty acid-binding protein, and cortisol were the biomarkers most consistently associated with poor outcome in higher-quality studies showing an incremental value over established prognostic factors. Other biomarkers were less consistently associated with poor outcome or were reported in lower quality studies. High heterogeneity among studies precluded the performance of a meta-analysis. CONCLUSIONS: The number of reports on prognostic blood-based biomarkers in ischemic stroke increased 3.5-fold in the period January 2007 to August 2018. Although sample size increased, methodological flaws are still common. Natriuretic peptides and markers of inflammation, atherogenesis, and stress response are the most promising prognostic biomarkers among identified studies.

External Validation of Five Scores to Predict Stroke-Associated Pneumonia and the Role of Selected Blood Biomarkers.

BACKGROUND AND PURPOSE: Several clinical scoring systems as well as biomarkers have been proposed to predict stroke-associated pneumonia (SAP). We aimed to externally and competitively validate SAP scores and hypothesized that 5 selected biomarkers would improve performance of these scores. METHODS: We pooled the clinical data of 2 acute stroke studies with identical data assessment: STRAWINSKI and PREDICT. Biomarkers (ultrasensitive procalcitonin; mid-regional proadrenomedullin; mid-regional proatrionatriuretic peptide; ultrasensitive copeptin; C-terminal proendothelin) were measured from hospital admission serum samples. A literature search was performed to identify SAP prediction scores. We then calculated multivariate regression models with the individual scores and the biomarkers. Areas under receiver operating characteristic curves were used to compare discrimination of these scores and models. RESULTS: The combined cohort consisted of 683 cases, of which 573 had available backup samples to perform the biomarker analysis. Literature search identified 9 SAP prediction scores. Our data set enabled us to calculate 5 of these scores. The scores had area under receiver operating characteristic curve of 0.543 to 0.651 for physician determined SAP, 0.574 to 0.685 for probable and 0.689 to 0.811 for definite SAP according to Pneumonia in Stroke Consensus group criteria. Multivariate models of the scores with biomarkers improved virtually all predictions, but mostly in the range of an area under receiver operating characteristic curve delta of 0.05. CONCLUSIONS: All SAP prediction scores identified patients who would develop SAP with fair to strong capabilities, with better discrimination when stricter criteria for SAP diagnosis were applied. The selected biomarkers provided only limited added predictive value, currently not warranting addition of these markers to prediction models. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01264549 and NCT01079728.

D-Dimer as Predictor of Large Vessel Occlusion in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Improving prehospital triage of large vessel occlusion (LVO) would reduce time to reperfusion therapies. We aimed to study early predictors of LVO in acute ischemic stroke to identify candidates for endovascular treatment. METHODS: The Stroke-Chip was a prospective observational study conducted at 6 Stroke Centers in Catalonia. Blood samples were obtained in the first 6 hours from symptom onset of consecutive patients. Stroke severity was evaluated with National Institutes of Health Stroke Scale (NIHSS) and LVO was assessed. Independent association of multiple blood biomarkers with LVO was evaluated using logistic regression models adjusted by covariates. Sensitivity, specificity, and predictive values were assessed for NIHSS and the combination of NIHSS and selected serum biomarkers levels. RESULTS: One thousand three hundred eight suspected strokes were enrolled for a 17-month period. LVO was not assessed in 131 patients. One thousand one hundred seventy-seven patients were selected for analysis (mean age 69.3 years, 56% men, median baseline NIHSS of 6, and median time to blood collection 2.5 hours). LVO was detected in 262 patients. LVO patients were older, had higher baseline NIHSS, history of atrial fibrillation, and lower time from stroke onset to admission. After logistic regression analysis, D-dimer remained an independent predictor of LVO (odds ratio, 1.59 [1.31-1.92]). Specificity and positive predictive value to exclude or detect LVO were higher when using combined D-dimer levels and NIHSS score assessment rather than NIHSS alone. CONCLUSIONS: Early D-dimer levels are an independent predictor of LVO and may be useful to better optimize prehospital patient transport to the appropriate stroke center.

Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome.

BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = ΔNIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. METHODS: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). RESULTS: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6-24h (R2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2=0.27), but much of the variance remained unexplained. ΔNIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24h was similarly associated with 90-day outcomes. CONCLUSIONS: The dynamic phenotype, ΔNIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.

Impact of COVID-19 Infection on the Outcome of Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: We evaluated whether stroke severity, functional outcome, and mortality are different in patients with ischemic stroke with or without coronavirus disease 2019 (COVID-19) infection. METHODS: A prospective, observational, multicentre cohort study in Catalonia, Spain. Recruitment was consecutive from mid-March to mid-May 2020. Patients had an acute ischemic stroke within 48 hours and a previous modified Rankin Scale (mRS) score of 0 to 3. We collected demographic data, vascular risk factors, prior mRS score, National Institutes of Health Stroke Scale score, rate of reperfusion therapies, logistics, and metrics. Primary end point was functional outcome at 3 months. Favourable outcome was defined depending on the previous mRS score. Secondary outcome was mortality at 3 months. We performed mRS shift and multivariable analyses. RESULTS: We evaluated 701 patients (mean age 72.3±13.3 years, 60.5% men) and 91 (13%) had COVID-19 infection. Median baseline National Institutes of Health Stroke Scale score was higher in patients with COVID-19 compared with patients without COVID-19 (8 [3-18] versus 6 [2-14], P=0.049). Proportion of patients with a favourable functional outcome was 33.7% in the COVID-19 and 47% in the non-COVID-19 group. However, after a multivariable logistic regression analysis, COVID-19 infection did not increase the probability of unfavourable functional outcome. Mortality rate was 39.3% among patients with COVID-19 and 16.1% in the non-COVID-19 group. In the multivariable logistic regression analysis, COVID-19 infection was a risk factor for mortality (hazard ratio, 3.14 [95% CI, 2.10-4.71]; P<0.001). CONCLUSIONS: Patients with ischemic stroke and COVID-19 infection have more severe strokes and a higher mortality than patients with stroke without COVID-19 infection. However, functional outcome is comparable in both groups.

Stroke-induced immunosuppression: implications for the prevention and prediction of post-stroke infections.

Stroke produces a powerful inflammatory cascade in the brain, but also a suppression of the peripheral immune system, which is also called stroke-induced immunosuppression (SIIS). The main processes that lead to SIIS are a shift from a lymphocyte phenotype T-helper (Th) 1 to a Th2 phenotype, a decrease of the lymphocyte counts and NK cells in the blood and spleen, and an impairment of the defense mechanisms of neutrophils and monocytes. The direct clinical consequence of SIIS in stroke patients is an increased susceptibility to stroke-associated infections, which is enhanced by clinical factors like dysphagia. Among these infections, stroke-associated pneumonia (SAP) is the one that accounts for the highest impact on stroke outcome, so research is focused on its early diagnosis and prevention. Biomarkers indicating modifications in SIIS pathways could have an important role in the early prediction of SAP, but currently, there are no individual biomarkers or panels of biomarkers that are accurate enough to be translated to clinical practice. Similarly, there is still no efficient therapy to prevent the onset of SAP, and clinical trials testing prophylactic antibiotic treatment and ß-blockers have failed. However, local immunomodulation could open up a new research opportunity to find a preventive therapy for SAP. Recent studies have focused on the pulmonary immune changes that could be caused by stroke similarly to other acquired brain injuries. Some of the traits observed in animal models of stroke include lung edema and inflammation, as well as inflammation of the bronchoalveolar lavage fluid.

Predictive model for atrial fibrillation in hypertensive diabetic patients.

BACKGROUND: Several scores to identify patients at high risk of suffering atrial fibrillation have been developed. Their applicability in hypertensive diabetic patients, however, remains uncertain. Our aim is to develop and validate a diagnostic predictive model to calculate the risk of developing atrial fibrillation at five years in a hypertensive diabetic population. METHODS: The derivation cohort consisted of patients with both hypertension and diabetes attended in any of the 52 primary healthcare centres of Barcelona; the validation cohort came from the 11 primary healthcare centres of Terres de l'Ebre (Catalonia South) from January 2013 to December 2017. Multivariable Cox regression identified clinical risk factors associated with the development of atrial fibrillation. The overall performance, discrimination and calibration of the model were carried out. RESULTS: The derivation data set comprised 54 575 patients. The atrial fibrillation rate incidence was 15.3 per 1000 person/year. A 5-year predictive model included age, male gender, overweight, heart failure, valvular heart disease, peripheral vascular disease, chronic kidney disease, number of antihypertensive drugs, systolic and diastolic blood pressure, heart rate, thromboembolism, stroke and previous history of myocardial infarction. The discrimination of the model was good (c-index = 0.692; 95% confidence interval, 0.684-0.700), and calibration was adequate. In the validation cohort, the discrimination was lower (c-index = 0.670). CONCLUSIONS: The model accurately predicts future atrial fibrillation in a population with both diabetes and hypertension. Early detection allows the prevention of possible complications arising from this disease.

PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, ß=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Stroke etiologies in patients with COVID-19: the SVIN COVID-19 multinational registry.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) is associated with a small but clinically significant risk of stroke, the cause of which is frequently cryptogenic. In a large multinational cohort of consecutive COVID-19 patients with stroke, we evaluated clinical predictors of cryptogenic stroke, short-term functional outcomes and in-hospital mortality among patients according to stroke etiology. METHODS: We explored clinical characteristics and short-term outcomes of consecutively evaluated patients 18 years of age or older with acute ischemic stroke (AIS) and laboratory-confirmed COVID-19 from 31 hospitals in 4 countries (3/1/20-6/16/20). RESULTS: Of the 14.483 laboratory-confirmed patients with COVID-19, 156 (1.1%) were diagnosed with AIS. Sixty-one (39.4%) were female, 84 (67.2%) white, and 88 (61.5%) were between 60 and 79 years of age. The most frequently reported etiology of AIS was cryptogenic (55/129, 42.6%), which was associated with significantly higher white blood cell count, c-reactive protein, and D-dimer levels than non-cryptogenic AIS patients (p

Searching for Atrial Fibrillation Poststroke: A White Paper of the AF-SCREEN International Collaboration.

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.