Ischemic Stroke Subtypes Research Articles

Longitudinal Changes in Iron and Myelination Within Ischemic Lesions Associate With Neurological Outcomes: A Pilot Study.

Combined quantitative susceptibility mapping and R2* relaxometry can distinguish iron and myelin components in ischemic lesions. We aimed to investigate whether longitudinal changes in magnetic susceptibility and R2* values within ischemic lesions were associated with neurological outcomes. In this single-center prospective study, we included patients, 20 to 90 years of age, who were consecutively admitted to the stroke care unit between August 2020 and March 2022 due to acute ischemic stroke. The participants underwent 2 instances of quantitative susceptibility mapping and R2* relaxometry scanning before and after stroke rehabilitation. We compared the changes in these quantitative measures across different subtypes of acute ischemic stroke. Multiple linear regression models were used to investigate the associations between the National Institutes of Health Stroke Scale scores and the mean magnetic susceptibility and R2* values in ischemic lesions. Among a total of 112 patients with acute ischemic stroke, 32 participants (aged 73.3±9.4 years; 20 men and 12 women) were evaluated. The median time from stroke onset to the first imaging was 5 days and that to the second imaging was 102 days. The changes in magnetic susceptibility values of branch atheromatous disease were higher than those of cardioembolism (mean difference, 0.018 [95% CI, 0.009-0.027] ppm; P<0.001) and lacunar (mean difference, 0.013 [95% CI, 0.005-0.020] ppm; P=0.004). Across all patients, the changes in National Institutes of Health Stroke Scale scores were associated with those of magnetic susceptibility values (coefficient, 0.311 [95% CI, 0.098-0.520]; P=0.017) but not with R2* values (coefficient, 0.114 [95% CI, -0.127 to 0.345]; P=0.291). The longitudinal changes in the magnetic susceptibility values within ischemic lesions were associated with neurological outcomes during the restorative stages poststroke in patients experiencing acute ischemic stroke. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000050719.

Etiologic subtypes of first and recurrent ischemic stroke in young patients using A-S-C-O and TOAST classification criteria: A retrospective follow-up study.

Scarce data exist on the etiology of recurrent ischemic strokes (ISs) among young adults. We analyzed the etiology of first-ever and recurrent events and the differences between them. Patients aged 15-49 years with a first-ever IS in 1994-2007 were included in the Helsinki Young Stroke Registry. In this retrospective cohort study, data on recurrent ISs were identified from Care Register for Health Care until the end of 2017 and Causes of Death Register and from patient records until the end of 2020. All first-ever and recurrent ISs were classified using Atherosclerosis-Small vessel disease-Cardioembolism-Other Cause (A-S-C-O) and Trial of Org 10172 in Acute Stroke Treatment (TOAST) classifications. A total of 970 patients were included (median age at index IS 46 years, interquartile range 43-48, 33% women), of which 155 (16.0%) patients had recurrent IS, with 8 (5.2%) fatal cases and 5 (3.2%) unverifiable cases. The median follow-up was 17.4 (IQR 13.9-21.7) years. Median time from the index event to the first recurrent event was 4.5 (interquartile range [IQR] 1.6-10.2) years. Recurrence was more often due to definite cardioembolism (10.7% vs 18.0%, p = 0.013), while the proportion of other definite A-S-C-O subgroups remained the same. With TOAST classification, the proportion of true cryptogenic ISs decreased (16.7% vs 6.7%, p = 0.003), while those with incomplete evaluation increased (9.3% vs 19.3%, p = 0.015). Other TOAST phenotypes remained the same. The proportion of definite cardioembolism increased at recurrence using the A-S-C-O classification and the number of cryptogenic ISs decreased using the TOAST classification, while cases with incomplete evaluation increased. Most etiologies remained the same.

Genetically predicted high serum sex hormone-binding globulin levels are associated with lower ischemic stroke risk: A sex-stratified Mendelian randomization study

ObjectiveCross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke. MethodsSingle-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders. ResultsInverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003). ConclusionOur findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.

TOAST stroke subtype classification in clinical practice: implications for the Get With The Guidelines-Stroke nationwide registry.

The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) is the most commonly used ischemic stroke subtype classification system worldwide and a required field in the US National Get With The Guidelines-Stroke (GWTG-Stroke) registry. However, stroke diagnostics have advanced substantially since the TOAST classification was designed 30 years ago, potentially making it difficult to apply reliably. In this prospective diagnostic accuracy study, we analyzed consecutive ischemic stroke patients admitted to a Comprehensive Stroke Center between July-October 2021. Clinical practice TOAST classification diagnoses rendered by the stroke team in the electronic medical record (EMR) at discharge were retrieved from GWTG-Stroke registry and compared to a reference ("gold") standard diagnosis derived from agreement between two expert raters after review of the EMR and patient imaging. Among 49 patients; age was 72.3 years (±12.1), 53% female, and presenting NIHSS median 3 (IQR 1-11). Work-up included: brain imaging in 100%; cardiac rhythm assessment in 100%; cervical/cerebral vessel imaging in 98%; TTE ± TEE in 92%; and TCD emboli evaluation in 51%. Reference standard diagnoses were: LAA-6%, SVD-14%, CE-39%, OTH-10%, UND-M (more than one cause)-20%, and UND-C (cryptogenic)-10%. GWTG-Stroke TOAST diagnoses agreed with reference standard diagnoses in 30/49 (61%). Among the 6 subtype diagnoses, specificity was generally high (84.8%-97.7%), but sensitivity suboptimal for LAA (33%), OTH (60%), UND-M (10%), and UND-C (20%). Positive predictive value was suboptimal for 5 of the 6 subtypes: LAA (13%), SVD (58%), OTH (75%), UND-M (50%), and UND-C (50%). Clinical practice TOAST classification subtype diagnoses entered into the GWTG-Stroke registry were accurate in only 61% of patients, a performance rate that, if similarly present at other centers, would hamper the ability of the national registry to provide dependable insights into subtype-related care. Development of an updated ischemic stroke subtype classification system, with algorithmic logic embedded in electronic medical records, is desirable.

Variants in 3p24.3 predicts the risk of early neurological deterioration in large artery atherosclerotic stroke

The rate of early neurological deterioration (END) differs in different subtypes of ischaemic stroke. Previous studies showed PLCL2 gene is a novel susceptibility locus for the occurrence of atherosclerosis and thrombotic events. The objective of this research is to examine the efficacy that PLCL2 may have on the risk of END in large artery atherosclerotic (LAA) stroke. Tagged single nucleotide polymorphisms (SNPs) were identified by a strategy of fine-mapping. The genotyping of the selected SNPs was performed by SNPscan. The impact of PLCL2 on indicating the susceptibility of END in LAA patients was evaluated by binary logistic regression. The SNP–SNP interactions of PLCL2 for END was assessed by generalized multifactor dimensionality reduction (GMDR). A total of 1527 LAA stroke patients were recruited, 582 patients (38 %) experienced END. Compared to participants without END, participants experienced END were much older (P = 0.018), more likely to suffer pre-existing diabetes mellitus (P = 0.036), higher frequent in active tobacco users (P = 0.022) and had much higher median NIHSS on admission (P < 0.001). Rs4685423 was identified to be a predictor to the risk of END: the frequency of END in AA genotype patients is lower than that in AC or CC genotype patients (multivariate-adjusted, OR 0.63; 95 % CI 0.49–0.80; P < 0.001). The SNP-SNP interactions analysis indicates rs4685423 has the greatest impacton the risk of END for LAA patients. The time from admission diagnosis to END onset in AA genotype patients is much later than that in CA or CC genotype patients (log-rank, P = 0.005). In summary, the PLCL2 rs4685423 SNP is probably associated with the END risk in LAA stroke patients.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case–control study

Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Considering Context-Specific microRNAs in Ischemic Stroke with Three "W": Where, When, and What.

MicroRNAs are short non-coding RNA molecules that function as critical regulators of various biological processes through negative regulation of gene expression post-transcriptionally. Recent studies have indicated that microRNAs are potential biomarkers for ischemic stroke. In this review, we first illustrate the pathogenesis of ischemic stroke and demonstrate the biogenesis and transportation of microRNAs from cells. We then discuss several promising microRNA biomarkers in ischemic stroke in a context-specific manner from three dimensions: biofluids selection for microRNA extraction (Where), the timing of sample collection after ischemic stroke onset (When), and the clinical application of the differential-expressed microRNAs during stroke pathophysiology (What). We show that microRNAs have the utilities in ischemic stroke diagnosis, risk stratification, subtype classification, prognosis prediction, and treatment response monitoring. However, there are also obstacles in microRNA biomarker research, and this review will discuss the possible ways to improve microRNA biomarkers. Overall, microRNAs have the potential to assist clinical treatment, and developing microRNA panels for clinical application is worthwhile.

Procoagulant Phospholipid Activity and MPV Values in Acute Ischemic Stroke

Ischemic stroke can be caused by atherothrombosis or embolism. Atherothrombosis occurs due to the rupture of an atherosclerotic plaque causing platelet activation. There are several markers of platelet activation, including platelet microparticles. The levels of platelet microparticles can be measured by examining procoagulant phospholipid (PPL) activity. It is not yet known exactly what activates thrombopoiesis, which can be assessed by an increase in Mean Platelet Volume (MPV). This study aimed to know whether there is an increase in PPL activity and MPV values in acute ischemic stroke, whether platelet activation is influenced by differences in ischemic stroke subtypes, and whether there is a relationship between PPL activity and MPV values in acute ischemic stroke. The study design was cross-sectional and involved 60 subjects. PPL activity in acute ischemic stroke (65.14±13.35 seconds) tends to be higher (shorter clotting time) than in healthy individuals (68.59±8.56 seconds), however, this difference was not statistically and clinically significant. The MPV value in acute ischemic stroke (9.83±0.72 fL) compared to healthy individuals (9.65±0.86 fL) however this difference was not statistically significant. PPL activity in the SAO subtype (61.66±1.31 seconds) tends to be higher than LAA (68.62±14.57 seconds), however, this difference was also not statistically significant. There was a weak correlation between PPL activity (seconds) and MPV value (fL) in acute ischemic stroke (r =0.34, p-value=0.03).

Risk factors, susceptibility vessel sign and thrombosis pathology for prognosis inpatients with different subtypes of acute ischemic stroke treated with mechanical thrombectomy

Abstract Purpose This study highlights the relationship between stroke subtypes, thrombosis pathology, and SVS and identifies probable risk factors affecting recanalization and outcomes in endovascular treatment. Methods A prospective study was conducted in which 53 AIS patients received intravenous thrombolysis and mechanical thrombectomy (MT) from January 2017 to December 2019 in a native Hospital. The recanalization was evaluated using modified cerebral infarction thrombolysis grade and prognosis at 3 months using modified rankin Scale (mRS). The risk factors were identified using univariate and multivariate logistic regression analyses. The thrombus samples were stained to determine their composition. Magnetic SWI was used to determine SVS. Results Age, locations of occlusion, and treatments were significantly different of TOAST subtypes (P &amp;lt; 0.05). The time from door to puncture (TDP) and time of operation (TO) were significantly lower in the successful recanalization group (P &amp;lt; 0.05). National Institutes of Health Stroke Scale (NIHSS), MT, TDP, time from onset to recanalization (TOR), and TO have significant differences between the two groups of mRS ≤ 2 and &amp;gt; 3. The occurrence of symptomatic intracranial hemorrhage (sICH) significantly affected the mRS score. The red and mixed thrombi were common in patients with positive SVS whereas the white thrombi were associated with the negative SVS. Conclusion Improved recanalization and prognosis was observed in early MT and when endovascular operations time was reduced.

Does Inclement Weather Increase the Risk of Cardioembolic Stroke in Kashmir Valley?

Background Cardioembolic strokes are a common cause of mortality and morbidity because they are usually big and multiple. Despite extensive advances in the determination and management of modifiable risk factors of these strokes, a significant proportion are attributed to non-modifiable factors. We wanted to test the hypothesis that cardioembolic strokes and no other subtypes of ischemic stroke are associated with inclement weather in Kashmir Valley where winter seasons have harsh weather. Results A total of 540 ischemic stroke patients were included in the study of which cardioembolic strokes were most common. Cardioembolic strokes were more common in the winter season and associated with lower minimum and maximum temperatures. Conclusion Evaluation and management of cardioembolic strokes during winter months may demand more attention, particularly in elderly individuals and those with risk factors for atrial fibrillation.

Remnant cholesterol traits and risk of stroke: A multivariable Mendelian randomization study.

Observational epidemiological studies have reported a relationship between remnant cholesterol and stroke. However, the results are inconclusive, and causality remains unclear due to confounding or reverse causality. Our objective in this study was to investigate the causal relevance of remnant cholesterol and the risk of stroke and its subtypes using the Mendelian randomization (MR) approach. Genome-wide association studies (GWASs) including 115,082 European individuals (UK Biobank) were used to identify instruments for remnant cholesterol, including intermediate-density lipoprotein (IDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol. Summary-level data for total stroke, intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke (IS), and IS subtypes were obtained from GWAS meta-analyses conducted by the MEGASTROKE consortium. Univariable and multivariable MR analyses were performed. The GWAS identified multiple single-nucleotide polymorphisms after clumping for remnant cholesterol (n = 52), IDL cholesterol (n = 62), and VLDL cholesterol (n = 67). Assessed individually using MR, remnant cholesterol (weighted median: odds ratio [OR] 1.32 per 1-SD higher trait; 95% CI: 1.04-1.67; P = 0.024) had effect estimates consistent with a higher risk of LAS-IS, driven by IDL cholesterol (OR 1.32; 95% CI: 1.04-1.68; P = 0.022). In multivariable MR, IDL cholesterol (OR 1.46; 95% CI: 1.10-1.93; P = 0.009) retained a robust effect on LAS-IS after controlling for VLDL cholesterol and high-density lipoprotein cholesterol. The MR analysis did not indicate causal associations between remnant cholesterol and other stroke subtypes. This study suggests that remnant cholesterol is causally associated with the risk of LAS-IS driven by IDL cholesterol.

Abstract 72: Association Between Stroke Subtype and Post-Stroke Cognitive Decline: A Pooled Cohort Analysis of Four Cohorts

Introduction: Associations between stroke subtype and post-stroke cognitive decline are unclear. We determined if post-stroke cognitive trajectories differed between 1) hemorrhagic vs. ischemic stroke and 2) ischemic stroke subtypes. Methods: We identified 1,150 eligible dementia-free individuals with incident stroke (93% ischemic, 7% hemorrhagic, 50% women, 31% Black, median age, 65) from 4 cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Offspring Study, and Reasons for Geographic and Racial Differences in Stroke. Of the ischemic strokes, 22% were small-vessel occlusion, 8% large artery atherosclerosis, 21% cardioembolic, and 49% cryptogenic/other determined etiology. Linear mixed-effects models were used to estimate longitudinal changes in cognition after incident stroke. Global cognition (primary outcome), executive function, and memory were harmonized across studies and standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median (IQR) follow-up was 5.9 (3.2, 9.2) years. Results: Survivors of ischemic stroke had significant declines in global cognition, executive function, and memory (Table). For example, global cognition declined -0.35 points/year (95%CI, -0.43, -0.26); P &lt;0.001. Initial post-stroke cognitive scores and post-stroke cognitive trajectories did not differ between hemorrhagic and ischemic stroke, except for lower initial post-stroke memory scores (adjusted difference, -1.39 points; 95% CI, -2.77, -0.01; P =0.049). Survivors of small-vessel occlusions had significant declines in global cognition, executive function, and memory (Table). Initial post-stroke cognitive scores and post-stroke cognitive trajectories did not differ by ischemic stroke subtype. Conclusions: Our results suggest that stroke survivors experience long-term post-stroke cognitive decline regardless of subtype.

Abstract 133: Associations of Genetically Predicted Iron Status and Ischemic Stroke Subtypes: A Mendelian Randomization Study

Mendelian randomization (MR) studies suggest a causal effect of Fe status on ischemic stroke (IS). It is currently unknown if these associations are confounded by pleiotropic effects of the instrumental variables (IV) on cardiovascular disease (CVD) risk factors, such as low-density lipoprotein cholesterol (LDL), diastolic blood pressure (DBP), and body mass index (BMI). We aimed to investigate the effect of iron (Fe) status on risk of IS subtypes (cardioembolic (CES), small vessel (SVS), and large artery atherosclerotic (LAS)) controlling for CVD risk factors. Fe biomarker IVs (total Fe binding capacity (TIBC), transferrin saturation (TSAT), serum Fe (SI), serum ferritin (SF)) were selected from a European GWAS (n=198K-258K) and filtered based on genome-wide significance ( P &lt;5e -8 ), F-statistic&gt;10, R 2 &lt;0.001, minor allele frequency &gt;1%, and consistent effect direction for all Fe traits. We performed univariate two-sample MR of each Fe trait on IS subtypes from MEGASTROKE (n cases: CES=7,193; SVS =5,386; LAS= 4,373) and implemented multivariate MR conditioning on LDL, DBP, and BMI from the UK Biobank. Estimates are expressed as odds ratio [95%CI] per SD unit increase in Fe. Univariate MR showed a detrimental effect of higher Fe status on CES, no effect on SVS, and a protective effect on LAS across all Fe markers ( Figure 1 ). The negative effect of Fe status on CES persisted when conditioning on LDL (TSAT: 1.17 [1.03-1.34]; TIBC: 0.84 [0.71-0.98]), DBP (TSAT: 1.15 [1.01-1.31]; TIBC: 0.82 [0.70-0.96]), or BMI (TSAT: 1.18 [1.04-1.34]; TIBC: 0.82 [0.70-0.95]) (all P &lt;0.05). However, the apparent positive effect of Fe status on LAS disappeared when conditioning on CVD risk factors ( Figure 1 ), particularly LDL (all P &lt;0.05). Higher Fe status is associated with a greater risk of CES independent of CVD risk factors. These findings support the role of Fe status as a modifiable risk factor for CES. Future studies are needed to assess the mechanisms mediating this effect.

Abstract TMP99: Risk of Stroke Recurrence and Silent Myocardial Infarction

Background: Prior data suggest that unrecognized or silent myocardial infarction (MI) detected on routine ECG is associated with first-ever stroke, but the impact on stroke recurrence is unknown. We aimed to determine the association of silent MI with stroke recurrence in patients with recent ischemic stroke. Methods: We included all subjects with an index stroke and available baseline ECG enrolled in the Insulin Resistance in Ischemic Stroke (IRIS) trial. Clinical MI was defined as a prior hospitalization for MI. Silent MI was defined as ECG evidence of MI (Q wave or equivalent patterns) without prior hospitalization for MI. The primary outcome was recurrent stroke. Ischemic stroke and ischemic stroke subtype were assessed as secondary outcomes. Multivariate cox regression adjusted for age, sex, race, pioglitazone, and vascular risk factors was performed for analysis. Results: Of 2285 participants analyzed, prior clinical and silent MI were identified in 164 (7.2%) and 94 (4.1%) patients respectively. Over an average of 4.5 years, 209 recurrent strokes occurred with 191 classified as ischemic. In the fully adjusted model, silent MI was associated with stroke (HR 2.27, CI 1.33-3.88) and ischemic stroke (HR 2.08, CI 1.17-3.68) recurrence. Clinical MI was associated with stroke and ischemic stroke recurrence in the unadjusted analysis; however, the association was no longer significant after adjustment (all stroke: HR 1.31, CI 0.81-2.11; ischemic stroke: HR 1.42, CI 0.87-2.32). No association between silent MI and stroke subtype was significant. Discussion: Among patients with a recent ischemic stroke, silent MI is associated with stroke recurrence. Tailored secondary stroke prevention strategies in this population require future investigation.

Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial.

Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence. Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression). A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P=0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ2, 4.33, P=0.23). In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Modifiable risk factors mediate the effect of gastroesophageal reflux disease on stroke and subtypes: A Mendelian randomization study

ObjectivesPrevious observational studies have suggested that gastroesophageal reflux disease (GERD) increases the risk of stroke, but the specific underlying mechanisms are unclear. We investigated the causal associations of GERD with stroke and its subtypes using Mendelian randomization (MR), and evaluated the potential mediating effects of modifiable stroke risk factors in the causal pathway. MethodsGenetic instrumental variables for GERD were extracted from the latest genome-wide association study (GWAS) summary level data. We initially performed two-sample MR to examine the association of GERD with stroke and its subtypes, including ischemic stroke, intracranial hemorrhage, and the major subtypes of ischemic stroke. Two-step MR was further employed to investigate the mediating effect of 15 risk factors in the causal pathway. ResultsWe found significant causal associations of genetically predicted GERD with increased risk of stroke (OR: 1.22 95% CI: 1.126–1.322), ischemic stroke (OR: 1.19 95% CI: 1.098–1.299), and large-artery stroke (OR: 1.49 95% CI: 1.214–1.836). Replication and sensitivity analyses yielded consistent effect directions and similar estimates. Further mediation analyses indicated that hypertension (HTN), systolic blood pressure (SBP), and type 2 diabetes (T2D) mediated 36.0%, 9.0%, and 15.8% of the effect of GERD on stroke; 42.9%, 10.8%, and 21.4% for ischemic stroke, and 23.3%; 7.9%, and 18.7% for large-artery stroke, respectively. ConclusionsThis study supports that GERD increases susceptibility to stroke, ischemic stroke, and large-artery stroke, and is partially mediated by HTN, SBP, and T2D.

Adipokines and stroke: A systematic review and meta-analysis of disease risk and patient outcomes.

Obesity is reported to increase stroke risk, with adipocyte-derived cytokines or adipokines implicated as mediators. However, the relationship between adipokines and stroke is not well clarified. Thus, we aimed to evaluate the association of adipokines with stroke using fully adjusted risk estimates that incorporated body mass index in a meta-analysis. Data from 52 studies (62,428 patients) were pooled in a random-effects meta-analysis. Adiponectin was independently associated with a lower risk of pre-existing stroke (adjusted odds ratio: 0.64 [95% confidence interval: 0.46-0.88], p < 0.01), whereas leptin (1.08 [1.00-1.17], p = 0.04), resistin (1.06 [1.04-1.08], p < 0.01) and visfatin (1.04 [1.01-1.07], p = 0.01) are associated with a higher risk of stroke, but none with incident stroke. Adipokines independently associated with an ischaemic stroke subtype were adiponectin (0.48 [0.30-0.77], p < 0.01), leptin (1.10 [1.01-1.20], p = 0.04), and resistin (1.06 [1.04-1.08], p < 0.01). Fatty acid-binding protein-4 (FABP-4) independently predicted 6-month poor functional outcomes in stroke patients (adjusted hazard ratio: 1.09 [1.06-1.12], p < 0.01); whereas both FABP-4 (1.17 [1.03-1.34], p = 0.01) and visfatin (1.24 [1.00-1.55], p = 0.05) were predictive of 6-month mortality. Adipokines are associated with a greater risk of pre-existing stroke, but not with the relationship with incident stroke. Adipokines, such as FABP-4 and visfatin, may serve as biomarkers of stroke severity and worsening of stroke outcomes.

Exploring clinical indicator variations in stroke patients with multiple risk factors: focus on hypertension and inflammatory reactions

BackgroundStroke stands as the second leading cause of death worldwide. Currently, extensive research has been conducted on stroke risk factors. However, when stroke patients contend with multiple risk factors, the impact on clinical indicators remains uncertain.ObjectivesThis study seeks to investigate potential significant variations among distinct ranges of clinical indicators in instances where stroke patients experience multiple risk factors and various ischemic stroke subtypes.Material and methodsThe research encompassed 440 stroke patients admitted to the First People's Hospital of Wenling City, Zhejiang Province, China. These patients were classified based on the type and quantity of risk factors and subtypes of ischemic stroke they presented. The χ2 test was employed to assess the relationship between the risk of comorbid diseases and clinical indicators in stroke patients.ResultsThe results of our study have underscored a significant correlation between various comorbid risk factors in stroke patients and the patients' age (P < 0.010). Furthermore, we observed noteworthy disparities in the plasma levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and INF-γ between patients devoid of risk factors and those presenting with comorbid risk factors associated with stroke. Significant differences in INF-γ were observed between the two subtypes of ischemic stroke, namely lacunar infarction and cardioembolic stroke.ConclusionAge is correlated with an elevated risk of stroke. Individuals exhibiting multiple stroke risk factors and diverse ischemic stroke subtypes commonly present with abnormal lipid levels and imbalances in Th1/Th2 cytokines. These factors significantly contribute to the onset and progression of stroke. Furthermore, inflammatory responses, particularly those induced by atherosclerosis, play a pivotal role in the genesis of stroke and exert a substantial influence on its prognosis.

Predictors for unfavorable prognosis after stroke with perforator artery disease.

Perforator artery disease (PAD) is an important subtype of ischemic stroke. The risk factors affecting the prognosis of patients with PAD are unclear. This study aimed to investigate the risk factors affecting the unfavorable prognosis of PAD. Patients with PAD were enrolled from Dushu Lake Hospital Affiliated to Soochow University and diagnosed as stroke with PAD during the period from September 2021 to July 2023 and followed up with a modified Rankin Scale (mRS) after 90 days, defining the mRS of 0-2 as a group with favorable prognosis, and 3-6 as a group with unfavorable functional outcome. Logistic regression was used to identify predictors for PAD. Multiple logistic regression analysis and receiver operating characteristics (ROC) were used to identify predictors of unfavorable prognosis. Of the 181 enrolled patients, 48 (26.5%) were identified with unfavorable prognosis. On multivariate analysis, increased age (OR = 1.076, 95% CI: 1.012 ~ 1.144, p = 0.019), higher National Institutes of Health Stroke Scale (NIHSS) score at admission (OR = 2.930, 95% CI: 1. 905 ~ 4.508, p < 0.001), and increased neutrophil-to-lymphocyte ratio (NLR) (OR = 3.028, 95% CI: 1.615 ~ 5.675, p = 0.001) were independent risk factors for unfavorable prognosis in patients with PAD, and the area under the receiver operating characteristic curve was 0.590, 0.905, and 0.798, and the multi-factor diagnostic model (Model 2) showed reliable diagnostic specificity and sensitivity (area under the curve = 0.956, p < 0.001, specificity 0.805, sensitivity 0.958, accuracy 0.845). Increased baseline NLR and NIHSS score and aging may be independent risk factors for unfavorable prognosis of patients with PAD. NLR can be used as a potential biological indicator to predict the prognosis of stroke with PAD.

Seasonal Variations in Stroke and a Comparison of the Predictors of Unfavorable Outcomes among Patients with Acute Ischemic Stroke and Cardioembolic Stroke.

We investigated the seasonal variations in stroke in 4040 retrospectively enrolled patients with acute ischemic stroke (AIS) admitted between January 2011 and December 2022, particularly those with cardioembolic (CE) stroke, and compared predictors of unfavorable outcomes between AIS patients and CE stroke patients. The classification of stroke subtypes was based on the Trial of ORG 10172 in Acute Stroke Treatment. Stroke occurrence was stratified by seasons and weekdays or holidays. Of all AIS cases, 18% were of CE stroke. Of all five ischemic stroke subtypes, CE stroke patients were the oldest; received the most thrombolysis and thrombectomy; had the highest initial National Institutes of Stroke Scale (NIHSS) and discharge modified Rankin Scale (mRS) scores; and had the highest rate of in-hospital complications, unfavorable outcomes (mRS > 2), and mortality. The highest CE stroke prevalence was noted in patients aged ≥ 85 years (30.9%); moreover, CE stroke prevalence increased from 14.9% in summer to 23.0% in winter. The main predictors of death in patients with CE stroke were age > 86 years, heart rate > 79 beats/min, initial NIHSS score > 16, neutrophil-to-lymphocyte ratio (NLR) > 6.4, glucose > 159 mg/dL, cancer history, in-hospital complications, and neurological deterioration (ND). The three most dominant factors influencing death, noted in not only patients with AIS but also those with CE stroke, are high initial NIHSS score, ND, and high NLR. We selected the most significant factors to establish nomograms for predicting fatal outcomes. Effective heart rhythm monitoring, particularly in older patients and during winter, may help develop stroke prevention strategies and facilitate early AF detection.