Elevated Risk Of Stroke Research Articles

Association between plasma trimethylamine N-oxide and cerebral white matter hyperintensity: a cross-sectional study

BackgroundCerebral white matter hyperintensity (WMH) is a pivotal imaging feature of cerebral small vessel disease (CSVD), closely correlated with an elevated risk of ischemic stroke (IS). Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is increasingly associated with IS and atherosclerosis. However, the intricate relationship between TMAO and WMH remains ambiguous. This study aimed to study the connection between plasma TMAO and WMH. Furthermore, it assessed the potential of TMAO as a risk evaluation instrument for WMH.MethodsIn this cross-sectional study, we categorized WMH into periventricular WMH (P-WMH) and deep WMH (D-WMH), based on its locations. The severity of WMH was assessed and grouped according to the Fazekas scale. Plasma TMAO levels were quantitatively determined. We established the correlation between plasma TMAO levels and WMH severity using a Logistic regression model. Additionally, we employed ROC curves to evaluate the diagnostic efficacy of plasma TMAO concentration in distinguishing the severity of WMH.ResultsA higher plasma TMAO tertile was significantly linked to a higher Fazekas score, encompassing the overall score, P-WMH score, and D-WMH score (p < 0.001). A logical regression analysis revealed that plasma TMAO levels were independently associated with overall moderate and severe WMH, compared to overall non-mild WMH, in the unadjusted model (OR = 1.373, 95%CI 1.183–1.594 for moderate; OR = 1.384, 95%CI 1.192–1.607 for severe), the adjusted model a (OR = 1.436, 95%CI 1.214–1.669 for moderate; OR = 1.446, 95%CI 1.222–1.711 for severe) and the adjusted model b (OR = 1.490, 95%CI 1.234–1.800 for moderate; OR = 1.494, 95%CI 1.237–1.805 for severe). The analysis also showed an independent correlation between plasma TMAO levels and WMH severity, irrespective of the unadjusted model, adjusted model a, or adjusted model b, when considering P-WMH and D-WMH severity. The ROC indicated that, in overall WMH and P-WMH, the area under curve (AUC) for non-mild and severe WMH were both>0.5, while the AUC for moderate WMH was<0.5. In contrast, in D-WMH, the AUC for non-mild, moderate, and severe WMH were all>0.5.ConclusionPlasma TMAO levels exhibited a significant correlation with both overall and region-specific WMH severity. Furthermore, the plasma TMAO levels displayed robust predictive capability for D-WMH.

Decoding the Nexus: Cellular and Molecular Mechanisms Linking Stroke and Neurotoxic Microenvironments in Brain Cancer Patients

Abstract: Stroke is an often underrecognized albeit significant complication in patients with brain cancer, arising from the intricate interplay between cancer biology and cerebrovascular health. This review delves into the multifactorial pathophysiological framework linking brain cancer to elevated stroke risk, with particular emphasis on the crucial role of the neurotoxic microenvironment (NTME). The NTME, characterized by oxidative stress, neuroinflammation, and blood–brain barrier (BBB) disruption, creates a milieu that promotes and sustains vascular and neuronal injury. Key pathogenic factors driving brain cancer-related stroke include cancer-related hypercoagulability, inflammatory and immunological mechanisms, and other tumor-associated processes, including direct tumor compression, infection-related sequelae, and treatment-related complications. Recent advances in genomic and proteomic profiling present promising opportunities for personalized medicine, enabling the identification of biomarkers—such as oncogenes and tumor suppressor genes—that predict stroke susceptibility and inform individualized therapeutic strategies. Targeting the NTME through antioxidants to alleviate oxidative stress, anti-inflammatory agents to mitigate neuroinflammation, and therapies aimed at reinforcing the BBB could pave the way for more effective stroke prevention and management strategies. This integrative approach holds the potential to reduce both the incidence and severity of stroke, ultimately improving clinical outcomes and quality of life for brain cancer patients. Further research and well-designed clinical trials are essential to validate these strategies and integrate them into routine clinical practice, thereby redefining the management of stroke risk in brain cancer patients.

Abstract 4143227: Incidence of Hemorrhagic Stroke in Hypertrophic Cardiomyopathy

Background: Individuals with hypertrophic cardiomyopathy (HCM) have an elevated risk of ischemic stroke, primarily driven by the increased risk of atrial fibrillation (AF) development in this patient population. This risk remains elevated regardless of CHADS2VASC score; thus, anticoagulation is recommended for all HCM patients with AF. Given the known association between anticoagulant medications and hemorrhagic events, there is likely an assumed risk of hemorrhagic stroke in these individuals. Currently, the incidence of hemorrhagic stroke in HCM and its relationship to AF and anticoagulation has not been well-established in the literature. The goal of this study was to establish the presence of and risk factors for hemorrhagic stroke in individuals with HCM. Methods: A retrospective review of all HCM patients ages 18 and older in our institution’s health system was performed from 2019-2023. ICD 10 codes were used to identify individuals with hemorrhagic stroke. Patient charts were reviewed for additional data including demographics, comorbid conditions, anticoagulant prescription, and other inciting factors prior to the hemorrhagic event. Results: The study cohort comprised 343 HCM patients, of which 47.1% were female and 72.7% were Caucasian. Concurrently, 30% (n=103) had a diagnosis of AF. The overall incidence of hemorrhagic stroke was 2.9% (5.8%, n=6 in those with AF vs 1.7%, n=4 in those without AF); furthermore, AF was associated with a non-statistically significant increased risk of hemorrhagic stroke (RR = 3.36, 95% CI 0.97-11.7). Anticoagulant use at the time of hemorrhagic event was observed in 4 individuals (67%) with AF and 1 individual (25%) without AF. Head trauma and falls were frequently observed as precipitating events prior to hospital admission for hemorrhagic stroke, occurring in 83% (n = 5) of patients with AF and 50% (n = 2) of those without AF. Conclusions: While ischemic stroke and anticoagulant use are commonly studied in those with HCM, the incidence of hemorrhagic stroke in this population is not negligible. Risk of hemorrhagic events in HCM appears largely influenced by anticoagulant use, particularly in those with concurrent AF, and by head trauma. Given the known benefits of anticoagulation on ischemic stroke risk in the HCM population, appropriate counseling and careful attention to individual patient factors may be warranted in the administration of anticoagulants.

Stroke Risk Following Nonarteritic Anterior Ischemic Optic Neuropathy

The association between nonarteritic anterior ischemic optic neuropathy (NAION) and an increased risk of stroke has been a subject of debate. However, multinational studies on this topic are scarce. To evaluate the short-term and long-term stroke risk after NAION compared with a matched control group. This global, retrospective, population-based cohort study used aggregated electronic health records from January 1, 2004, through March 19, 2024, sourced from the Global Collaborative Network of TriNetX, which includes data from over 152 million patients across 17 countries. Patients in the study were followed up for a maximum duration of 10 years. Patients with NAION and age-related cataract were included in the analysis. Those with stroke before the diagnosis of NAION and age-related cataract were excluded. Propensity score matching was applied to balance age, sex, race, ethnicity, comorbidities, and medication use. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis code for NAION or age-related cataract. The primary outcome was the relative risk (RR) of stroke (ICD-10 code I60-63) in the NAION cohort vs the matched controls. Multivariable logistic regression analyses were applied to identify potential clinical factors associated with stroke within the NAION cohort. A total of 89 811 patients were identified in both the NAION (mean [SD] age, 57.2 [18.5] years; 38 678 men [43.1%]) and control (mean [SD] age, 57.0 [17.9] years; 40 014 men [44.6%]) cohorts after matching. The NAION cohort demonstrated a significantly higher all-stroke risk at all time points: 1 month (RR, 5.04; 95% CI, 4.41-5.78), 3 months (RR, 3.79; 95% CI, 3.40-4.21), 1 year (RR, 2.50; 95% CI, 2.32-2.70), 5 years (RR, 1.54; 95% CI, 1.45-1.63), and 10 years (RR, 1.33; 95% CI, 1.23-1.43). Sensitivity analysis in patients without comorbidities similarly revealed a significantly increased all-stroke risk across all intervals: 1 month (RR, 7.55; 95% CI, 4.74-12.03), 3 months (RR, 6.70; 95% CI, 4.48-10.04), 1 year (RR, 3.96; 95% CI, 2.94-5.34), 5 years (RR, 2.85; 95% CI, 2.18-3.72), and 10 years (RR, 1.68; 95% CI, 1.25-2.26). Among all the clinical factors of interest, only hypertension was consistently associated with all subtypes of stroke following NAION. This cohort study of patients with NAION found a significantly elevated risk of stroke compared with matched controls, independently of comorbidities. These findings underscore the importance of regular stroke workups following the onset of NAION.

Menstruation: An Important Indicator for Assessing Stroke Risk and Its Outcomes.

In recent years, stroke incidence in older adults has declined strikingly, but stroke in younger women has become more common. Abnormalities of menstruation, the shedding of the uterine lining at the beginning of each menstrual cycle, may offer clues about stroke risk in young and midlife women. Endometrial and structural uterine abnormalities are associated with anemia and may be associated with hypercoagulability, possibly increasing stroke risk. Patient factors that influence both menstruation and stroke risk include coagulopathies, polycystic ovarian syndrome, endometriosis, migraine, and other systemic disorders, in addition to menopause. Environmental and iatrogenic factors that influence both menstruation and stroke risk include hormonal contraceptives, nicotine, xenoestrogens, phytoestrogens, oophorectomy, and hysterectomy. Importantly, secondary stroke prevention can affect menstruation. Our current review presents literature supporting the idea that abnormal menstruation may indicate elevated stroke risk in premenopausal women.

Plasma metabolites, systolic blood pressure, lifestyle, and stroke risk: A prospective cohort study.

To estimate the associations of stroke risk with plasma metabolites, metabolic risk score (MRS), the combinations of MRS with hypertension or lifestyle, and lifestyle-related metabolic signature. To assess the improvement of the stroke risk prediction model through the incorporation of MRS. A total of 77,315 participants from the UK Biobank were included in this study. Xgboost and LASSO-Cox regression were used to select metabolites and construct MRS. Elastic net regression was utilized to construct the lifestyle-related metabolic signature. Multivariate Cox regression was used to estimate the associations between metabolites, MRS, the combinations of MRS with hypertension or lifestyle, lifestyle-related metabolic signature, and stroke risk. We identified 48, 63, 39, and 4 metabolites associated with the risk of stroke, ischemic stroke (IS), subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH), respectively. High MRS significantly increased the risk of stroke (HR = 2.65 (95% confidence interval (CI): 2.09-3.35)), IS (HR = 2.45 (95% CI: 1.89-3.17)), ICH (HR = 2.74 (95% CI: 1.55-4.85)), and SAH (HR = 4.64 (95% CI: 2.25-9.56)). In the combination analyses, compared with normal systolic blood pressure (SBP) and low MRS, normal/high SBP, and high MRS significantly increased stroke risk (HR = 5.80 (95% CI: 2.75-12.27)/6.37 (95% CI: 3.22-12.62)). A favorable/unfavorable lifestyle and high MRS also significantly increased stroke risk (HR = 2.38 (95% CI: 1.73-3.28)/3.86 (95% CI: 2.63-5.67)) compared with a favorable lifestyle and low MRS. Incorporating MRS into the 15-year stroke and IS risk prediction model increased the areas under the curves (AUCs) from 0.746 to 0.766 and from 0.771 to 0.811, respectively. The metabolic signature was correlated with adherence to a healthy lifestyle (r = 0.414; P = 2.22e-16) and inversely associated with stroke risk (HR = 0.80 (95% CI: 0.73-0.86)). Various metabolites and MRS were significantly associated with the risk of stroke, IS, ICH, and SAH. Individuals with a high MRS may face an elevated stroke risk among populations with high SBP or unhealthy lifestyle, even those with normal SBP or healthy lifestyle. MRS provided modest improvement to the stroke risk prediction model. The lifestyle-related metabolic signature could reduce 20% stroke risk.

Decision Support Intervention and Anticoagulation for Emergency Department Atrial Fibrillation

Oral anticoagulation for adults with atrial fibrillation or atrial flutter (AFF) who are at elevated stroke risk reduces the incidence of ischemic stroke but remains underused. Efforts to increase anticoagulation initiation on emergency department (ED) discharge have yielded conflicting results. To evaluate the effectiveness of a multipronged intervention supporting anticoagulation initiation for eligible adult ED patients. The Clinical Decision Support to Optimize Care of Patients With Atrial Fibrillation or Flutter in the Emergency Department (O'CAFÉ) pragmatic, stepped-wedge cluster randomized clinical trial was conducted from July 1, 2021, through April 30, 2023, at 13 community medical centers (in 9 clusters) of an integrated health system in Northern California. The study included adult ED patients with primary AFF eligible for anticoagulation initiation when discharged home. Clusters were randomly assigned to staggered dates for 1-way crossover from the control phase (usual care) to the intervention phase. Physician education, facility-specific audit and feedback, and access to decision support, which identified eligible patients and recommended shared decision-making, anticoagulation initiation (if suitable), and timely follow-up. The main outcome was a composite of anticoagulation on discharge or within 30 days. A primary intention-to-treat analysis (decision support access regardless of use) and a secondary per-protocol analysis (decision support use) were performed. Multivariable analyses adjusted for intervention and exposure months with random effects, accounting for clustering by facility and patient. A total of 3388 eligible patients with atrial fibrillation were discharged home: 2185 (64.5%) were receiving pre-ED arrival anticoagulation and 1203 (35.5%) were eligible for anticoagulation. Among the 1203 patients with an initiation-eligible encounter, the median age was 74.0 (IQR, 68.0-82.0) years and approximately half (618 [51.4%]) were men. Among the 387 patients with an initiation-eligible control encounter, 244 (63.0%) received anticoagulation (190 [49.0%] at discharge and 54 [14.0%] within 30 days). Among the 816 patients with an initiation-eligible intervention encounter, 558 (68.4%) received anticoagulation (428 [52.5%] on discharge and 130 [15.9%] within 30 days). There was no statistically significant change in initiation of anticoagulation associated with the intervention (adjusted odds ratio, 1.33 [95% CI, 0.75-2.35]; P = .13). Decision support was used for 217 eligible case patients (26.6%) (per protocol) and was associated with a statistically significant change in anticoagulation initiation when compared with 599 patients for whom decision support was not used (164 [75.6%] vs 394 [65.8%]; P = .008). In this trial, a multipronged intervention to facilitate thromboprophylaxis among eligible ED patients with AFF did not significantly increase anticoagulation initiation. Opportunities exist to further improve stroke prevention among ED patients with primary AFF. ClinicalTrials.gov Identifier: NCT05009225.

Association between dementia and left atrial appendage occlusion in patients with atrial fibrillation: A TriNetX-based retrospective cohort study with target trial emulation

BackgroundAtrial fibrillation (AF) is a common cardiac arrhythmia linked to an elevated risk of stroke and dementia. Emerging observational evidence suggests that left atrial appendage occlusion (LAAO) may reduce dementia risk in AF patients; however, further research is required to confirm this potential benefit. ObjectiveThis study aimed to compare the effectiveness of LAAO versus direct oral anticoagulants (DOACs) in reducing the risk of dementia among patients with AF. MethodsWe conducted a target trial emulation using data from the TriNetX research network. Patients with AF were allocated into two cohorts (2,270 patients in each one), either treated with LAAO or with DOACs, and balanced with propensity score-matching. The primary endpoints were composite dementia, vascular dementia, and Alzheimer's disease. Secondary endpoints included mortality, ischemic stroke, intracranial hemorrhage, and major adverse cardiovascular events. Follow-up was conducted over three years. ResultsAt 3-year follow-up, the risk of composite dementia was lower in the LAAO group compared to the DOAC group (HR 0.57, 95% CI 0.38-0.85). Subgroup analyses showed consistent results trending toward the LAAO group. No significant differences were found in the incidences of secondary outcomes. ConclusionThis real-world study suggests that LAAO is associated with a lower risk of dementia in AF patients compared to DOACs. Further prospective research with long-term follow-up is needed to validate our finding in the AF population.

Incidence and outcomes of transient new-onset atrial fibrillation complicating acute coronary syndromes: results from a systematic review and meta-analysis

Abstract Background The overall risk of long-term adverse events of a transient episode of new-onset atrial fibrillation (AF) in patients with acute coronary syndrome (ACS) remains uncertain. This meta-analysis aimed to assess the prognostic impact of transient new-onset AF complicating ACS. Methods and results Cohort studies examining the risk of adverse events in patients with transient new-onset AF compared to those in sinus rhythm after ACS were identified through a comprehensive search of MEDLINE, Scopus, Cochrane, and Google Scholar Library. Studies reporting the incidence of ischaemic stroke events, recurrent AF, or all-cause mortality at the longest follow-up were included. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CI) were synthesized using inverse variance-weighted random-effects meta-analysis. In the seven observational studies included, comprising 151 735 patients, 6 597 (4.3%) experienced transient new-onset AF, which was associated with an increased risk of ischaemic stroke, recurrent AF, or all-cause mortality (HR: 2.24, 95% CI: 1.75–2.85; P < 0.0001; I2 = 30.76%; seven studies). The results remained consistent across each individual endpoint, including ischaemic stroke (HR 2.38, 95% CI: 1.64–3.44; P < 0.01; I2 = 50.2%; five studies), recurrent AF (HR 4.68, 95% CI: 2.07–10.59; P = 0.0002; I2 = 50.2%; four studies), and all-cause mortality (HR 1.36, 95% CI: 1.08–1.71; P = 0.0089; I2 = 53.25%; four studies). Meta-regression analyses revealed a significant increase in these adverse events associated with ST-elevation myocardial infarction (P = 0.001), while there was a tendency for their decrease associated with oral anticoagulant prescription at discharge (P = 0.07). Conclusions The occurrence of transient new-onset AF is associated with an elevated long-term risk of stroke, recurrent AF, and all-cause mortality in patients with ACS. Consequently, these data urge randomized clinical trials to assess the best antithrombotic regimen while potentially helping the current treatment decision-making process for these patients.

Elevated risk for stroke in genetically predisposed bicuspid aortic valve disease: evidences from a mendelian randomization study

Abstract Background Patients with bicuspid aortic valve (BAV) have been recognized to have an elevated risk for stroke. However, the exact causal association between BAV and stroke remains elusive due to stroke-related comorbidities, residual confounding bias and sample size limitations of observational studies. Purpose To identify the causal relationship between genetically predisposed BAV and 15 cardiovascular diseases (CVDs), and whether calcific aortic valve stenosis (CAVS) or atrial fibrillation (AF) could serve as the mediator on the pathway from BAV to stroke by mendelian randomization (MR) approach. Methods Uncorrelated (r² < 0.001) and genome-wide significant (P < 5×10^-8) single nucleotide polymorphisms were extracted from the largest genome-wide association study statistics (2,236 patients and 11,604 controls) of BAV by Gehlen et al. Summary-level statistics for 15 CVDs were obtained from the UK Biobank study, FinnGen study, HERMES consortium, CARDIoGRAMplusC4D consortium and GIGASTROKE consortium. We used 2-sample MR to estimate the causal association between BAV and 15 CVDs, evaluated 12 potential mediators and mediated proportions within 2-step MR framework. Inverse variance weighted was utilized as primary MR analyses method. Results for each outcome from different sources were pooled using the random effect meta-analysis. False discovery rate (FDR) was calculated by Benjamini-Hochberg method to account for multiple comparisons. Results Genetically predicted per log-odds liability increase of BAV was significantly associated with aortic aneurysm (OR, 1.26; 95% CI, 1.13-1.40; FDR-adjusted P = 3.54 × 10^-4), any stroke (OR, 1.06; 95% CI, 1.02-1.09; FDR-adjusted P = 0.004), ischemic stroke (IS) (OR, 1.17; 95% CI, 1.03-1.11; FDR-adjusted P = 0.001) and cardioembolic stroke (CES) (OR, 1.15; 95% CI, 1.06-1.25; FDR-adjusted P = 0.004). No significant association were observed between BAV and another 11 CVD outcomes. Instead of CAVS, genetic liability to AF mediated the total effect of BAV on any stroke (proportion mediated = 13.2% [95% CI, 3.1% - 23.2%]), IS (proportion mediated = 10.8% [95% CI, 2.5% - 19.1%]) and CES (proportion mediated = 21.5% [95% CI, 5.3% - 37.7%]). Conclusions Genetically predisposed BAV is associated with a higher risk of any stroke, IS and CES, which could be mediated by AF. This study implies the pathophysiological processes from BAV towards stroke and highlights the clinical significance of AF intervention in reducing the incidence of stroke for BAV patients.Causal association between BAV and CVDs

Long-Term Impact of Infertility and Assisted Reproductive Technology on Cardio-Renal Health in Sweden

Abstract Background The use of Assisted Reproductive Technology (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), is rising in Europe. These treatments involve high doses of hormones to increase oocyte collection. While most safety studies in women have focused on cancer risks, the association with cardio-renal diseases remains under-explored. This study examines whether the use of ART is linked to coronary ischemic disease (CHD), stroke, brain hemorrhage, other cerebrovascular diseases, chronic kidney disease, and aortic aneurysm/dissection, while also exploring the association between infertility and these conditions. Methods A nationwide cohort study was conducted using Swedish national registries, following all nulliparous women who gave birth between 1982 and 2002 until the end of 2017. Descriptive statistics and inverse probability weighted Kaplan-Meier curves to adjust for body mass index, maternal age, country of origin, smoking, and year of delivery, were used to compare 1) women who conceived with or without ART, 2) women who used IVF or ICSI respectively to women with known infertility that conceived without ART, and 3) women with and without known infertility. Results Compared to all other women, women undergoing ART were at elevated risk for CHD, stroke, and other cerebrovascular diseases, but after adjustment for underlying risk factors, including infertility, no substantial differences were seen. As a group, women with known infertility were at elevated risk of CHD and stroke, also after adjustment for known background factors. Conclusions Data suggest that the use of ART does not increase the long-term risk of cardio-renal diseases. Nonetheless, infertility itself is associated with a higher risk of CHD and stroke. Key messages • Infertility, more so than the use of ART, is linked to elevated risks of CHD and stroke. • Preventive measures for these conditions should be considered for women with infertility.

Hypertensive disorders of pregnancy and stroke: a univariate and multivariate Mendelian randomization study.

Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of stroke later in life in multiparous women. However, causality of these associations remains unclear. This study employed 2-sample univariate and multivariate Mendelian randomization (MR) to assess the causal connection between HDP and stroke. Genetic variants for HDP and two subtypes were identified from recent large-scale genome-wide association studies and the FinnGen consortium. Stroke summary data were obtained from the MEGASTROKE consortium. The primary analytical approach for univariate MR was the inverse variance weighting method. Sensitivity analyses incorporated methods such as MR-Egger regression, weighted median, and maximum likelihood to ascertain the robustness of the results. Additionally, multivariable MR analyses were conducted to account for potential associative effects of hypertension and type 2 diabetes. Genetically predicted HDP was associated with a high risk of large artery atherosclerosis (odds ratio [OR]=1.50, 95% confidence interval [CI]: 1.17-1.91, P=1.13×10-3) and small vessel stroke (OR=1.29, 95% CI: 1.20-1.50, P=1.52×10-3). HDP may also correlate with ischemic stroke (OR=1.13, 95% CI: 1.04-1.23, P=4.99×10-3) and stroke (OR=1.11, 95% CI: 1.03-1.20, P=8.85×10-3). An elevated risk of small vessel stroke (OR=1.20, 95% CI: 1.01-1.43, P=3.74×10-2) and large artery atherosclerosis (OR=1.22, 95% CI: 1.01-1.47, P=4.07×10-2) may be related with genetically predicted susceptibility to gestational hypertension. Genetically predicted susceptibility to preeclampsia or eclampsia may be associated with an increased risk of stroke (OR = 1.10, 95% CI: 1.02-1.19, P = 1.16×10-2) and ischemic stroke (OR = 1.10, 95% CI: 1.02-1.20, P = 1.84×10-2). Type 2 diabetes mellitus and hypertension were identified as significant factors contributing to the association between HDP and stroke. This study provides genetic evidence supporting an association between HDP and increased stroke risk bolstering HDP as a cerebrovascular risk factor.

Dissecting Causal Relationships Between Dietary Habits and Diverse Subtypes of Stroke: Mendelian Randomization Study

Background: Understanding the causal relations between dietary habits and stroke is crucial for prioritizing public health interventions and developing effective health strategies. This study utilized Mendelian randomization (MR) analysis to examine the causal associations between 20 dietary habits and various stroke subtypes, aiming to identify potential mediators and evaluate the proportions of mediation. Methods: A two-sample MR analysis was conducted to examine the causal relationships between dietary habits and stroke incidence. Mediation analysis, two-step MR (TSMR), and multivariable MR (MVMR) were employed to identify potential mediators. Genetic data pertaining to dietary habits and stroke were obtained from extensive genome-wide association study (GWAS) consortia. The inverse variance-weighted (IVW) method served as the primary analytical approach, with the additional scrutiny of significant correlations conducted through the Egger regression, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and weighted median techniques. Results: Our analyses indicated that genetically predicted intakes of dried fruits, cheese, cereal, oily fish, and hot drink temperatures were protective against stroke, whereas higher intakes of lamb/mutton, poultry, and added salt significantly elevated stroke risk. Specifically, dried fruit consumption demonstrated a protective effect against total stroke (β = −0.009, p = 0.013), ischemic stroke (β = −0.475, p = 0.003), and small-vessel ischemic stroke (β = −0.682, p = 0.033) through reductions in BMI levels, accounting for mediated proportions of 3.2%, 17.1%, and 8.5%, respectively. Furthermore, cheese intake provided a protective effect against ischemic stroke (β = −0.275, p = 0.003) by decreasing BMI and increasing HDL-C levels, with mediated proportions of 30.5% and 6.5%. Together, BMI and HDL-C accounted for 34.9% of the beneficial effect of cheese intake on reducing the risk of ischemic stroke. In contrast, an increased salt intake exhibited a positive association with large-artery ischemic stroke (β = 0.432, p = 0.033) through BMI elevation, with a mediated proportion of 10.9%. Conclusions: Our findings provide compelling evidence supporting causal relationships between dietary habits and stroke subtypes, while identifying mediators and evaluating the proportions of mediation. Adhering to a low-calorie, nutrient-dense diet enriched with dried fruits, cheese, and cereal, along with reduced salt and poultry consumption, could potentially mitigate stroke risk.

Risk of Intestinal Complications, Extraintestinal Morbidity, and Mortality in Patients with Crohn’s Disease and Ocular Involvement

ABSTRACT Purpose Patients with Crohn’s disease (CD) and subsequent ocular manifestations may have worse outcomes when compared to matched patients with CD without ocular disease. Methods In this retrospective cohort study, an aggregated electronic health records research network, TriNetX (Cambridge, MA, USA), was used to identify patients diagnosed with CD stratified by the presence or absence of ocular involvement with at least 1 year of follow-up. Propensity score matching (PSM) was performed to control for baseline demographics and medical comorbidities. Results Patients with CD with ocular disease showed a greater risk of undergoing bowel resections (RR: 2.06, 95% CI: 1.48–2.85, p < 0.001), developing other CD-related gastrointestinal complications (RR: 1.31, CI: 1.15–1.49, p < 0.001), or acquiring Clostridioides difficile infections (RR: 2.19, CI: 1.89–2.54, p < 0.001). Further, patients with CD with ocular sequelae had a greater risk of developing NASH (RR: 1.43, CI: 1.31–1.56, p < 0.001), CD-related nutrient deficiencies (RR: 1.38, CI: 1.29–1.49, p < 0.001), iron deficiency anemia (RR: 1.41, CI: 1.33–1.50, p < 0.001), CD-related dermatological disease (RR: 1.84, CI: 1.65–2.05, p < 0.001), osteoporosis (RR: 1.49, CI: 1.37–1.64, p < 0.001) and primary sclerosing cholangitis (RR: 1.63, CI: 1.11–2.38, p = 0.011). Among patients with CD with ocular involvement, there was an elevated risk of MI (RR: 1.36, CI: 1.14–1.63, p < 0.001), stroke (RR: 1.42, CI: 1.18–1.70, p < 0.001), VTE (RR: 1.37, CI: 1.22–1.54, p < 0.001), and sepsis (RR: 1.53, CI: 1.37–1.71, p < 0.001). Conclusions Patients who have CD and subsequent ocular involvement have an increased risk of local intestinal complications, extraintestinal morbidity, and cardiovascular complications when compared to patients with CD without ocular involvement.

Loss of function in protein Z (PROZ) is associated with increased risk of ischemic stroke in the UK Biobank

BackgroundThe vitamin K–dependent coagulation factor protein Z (PZ), encoded by the PROZ gene, is canonically considered to have anticoagulant effects through negative regulation of factor Xa. Paradoxically, higher circulating PZ concentrations have repeatedly been associated with an elevated risk of acute ischemic stroke. ObjectivesWe performed a large-scale genetic association study to examine the relationship between germline genetic variants in PROZ and the risk of ischemic stroke. MethodsUsing whole-exome sequencing and clinical data for 416 711 participants in the UK Biobank (UKB), we identified individuals with rare (minor allele frequency ≤0.1%) putatively function-altering variants in PROZ. Using Firth’s logistic regression and controlling for known stroke risk factors, we evaluated the association between variant carrier status and noncardioembolic ischemic stroke (NCEIS). Additionally, we evaluated differences in the plasma levels of 1472 proteins between PROZ variant carriers and noncarriers in a subset of 48 893 UKB participants. ResultsAfter accounting for missing data, qualifying variants in PROZ were identified in 414 UKB participants (99.0% heterozygous). Variant carriers had a significantly increased risk of NCEIS (odds ratio, 2.34; 95% CI, 1.15-4.13; P = .02) but not of venous thromboembolism, myocardial infarction, or peripheral artery disease. Plasma proteomics analysis revealed that PROZ variant carriers had significantly elevated levels of 2 proteins related to the response to cerebral ischemia, peroxiredoxins 1 and 6 (PRDX1: fold change, 1.83; P = 1.3 × 10−5; PRDX6: fold change, 1.78; P = 9.6 × 10−10). ConclusionLifelong exposure to decreased PZ levels confers a significantly increased risk of NCEIS, consistent with the role of PZ as an anticoagulant factor.

Changes in Type 1 Diabetes-Associated Gut Microbiota Aggravate Brain Ischemia Injury by Affecting Microglial Polarization Via the Butyrate-MyD88 Pathway in Mice.

People with type 1 diabetes (T1D) have a significantly elevated risk of stroke, but the mechanism through which T1D worsens ischemic stroke remains unclear. This study was aimed at investigating the roles of T1D-associated changes in the gut microbiota in aggravating ischemic stroke and the underlying mechanism. Fecal 16SrRNA sequencing indicated that T1D mice and mice with transplantation of T1D mouse gut microbiota had lower relative abundance of butyric acid producers, f_Erysipelotrichaceae and g_Allobaculum, and lower content of butyric acid in feces. After middle cerebral artery occlusion (MCAO), these mice had poorer neurological outcomes and more severe inflammation, but higher expression of myeloid differentiation factor 88 (MyD88) in the ischemic penumbra; moreover, the microglia were inclined to polarize toward the pro-inflammatory type. Administration of butyrate to T1D mice in the drinking water alleviated the neurological damage after MCAO. Butyrate influenced the response and polarization of BV2 and decreased the production of inflammatory cytokines via MyD88 after oxygen-glucose deprivation/reoxygenation. Knocking down MyD88 in the brain alleviated neurological outcomes and decreased the concentrations of inflammatory cytokines in the brain after stroke in mice with transplantation of T1D mouse gut microbiota. Poor neurological outcomes and aggravated inflammatory responses of T1D mice after ischemic stroke may be partly due to differences in microglial polarization mediated by the gut microbiota-butyrate-MyD88 pathway. These findings provide new ideas and potential intervention targets for alleviating neurological damage after ischemic stroke in T1D.

Exploring the Long-Term Effect of Artificial Sweeteners on Metabolic Health.

Artificial sweeteners (ASs) are widely used as low-calorie sugar substitutes for managing conditions like diabetes and obesity, but recent evidence suggests their health effects may be more complex than previously understood. High consumption has been associated with increased risks of metabolic disorders, cardiovascular diseases, certain cancers, and, somewhat paradoxically, weight gain, adverse pregnancy outcomes, and potential risks for individuals with low seizure thresholds. Studies, including the Women's Health Initiative, have linked artificially sweetened beverages to an elevated risk of stroke, coronary heart disease, and mortality, independent of established risk factors. Concerns extend to gut health, where ASs like saccharin have been linked to inflammatory bowel diseases, gut microbiota disruption, increased intestinal permeability, and dysbiosis, leading to metabolic disturbances such as impaired glucose tolerance, insulin resistance, and heightened systemic inflammation. These disruptions reduce the production of short-chain fatty acids crucial for insulin sensitivity, further contributing to the development of metabolic disorders like type 2 diabetes mellitus. Given these potential health risks, this review underscores the need for cautious use, informed consumer choices, and stringent regulatory oversight, while emphasizing the necessity for further research to elucidate long-term health effects and develop strategies to mitigate these risks.

Percutaneous or surgical LAAO for stroke prevention in patients with atrial fibrillation: A network meta-analysis

BackgroundStroke, which is mainly caused by thrombus formation in the left atrial appendage, represents the most prevalent complication of atrial fibrillation (AF). Both percutaneous left atrial appendage occlusion (p-LAAO) and surgical LAAO (s-LAAO) are used to treat AF and prevent stroke events. However, no head-to-head randomized controlled trials (RCTs) compared these strategies. ObjectiveTo examine the efficacy and safety of diverse strategies for reducing stroke risk using a network meta-analysis (NMA). MethodsPubMed, EMBASE, and Cochrane repositories were explored to identify RCTs involving p-LAAO or s-LAAO, and five were included for NMA. This investigation adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses. The NMA was pooled using the Bayesian random effect framework. All findings were expressed as odds ratios accompanied by a 95 % confidence interval.The primary efficacy endpoint was any stroke (AS), and the secondary efficacy endpoint was combined AS and systematic embolism (AS/SE). The primary and secondary safety endpoints were major bleeding (MB) and all-cause death (ACD), respectively. ResultsOur meta-analysis incorporated 6337 individuals diagnosed with AF. The NMA demonstrated a reducing trend in AS and AS/SE for s-LAAO versus p-LAAO, while p-LAAO showed a benefit in reducing MB and ACD. Conclusionsand Relevance: s-LAAO could potentially benefit individuals at elevated risk for stroke, whereas p-LAAO may be linked to a reduced likelihood of bleeding.

Incidence and Predictors of Stroke in Australian Adults With Congenital Heart Disease (2000-2017).

Adults with congenital heart disease (CHD) are at increased risk of stroke but high-quality population level data on stroke incidence in these patients are scant. A retrospective whole-population Western Australian cohort of adultpatients with CHD aged 18 to 64 years was created and followed from January 2000 to December 2017 using linked hospital data. Stroke incidence rates within the adult cohort with CHD were calculated and compared with the general population via direct standardization. A nested case-control design assessed predictors of ischemic and hemorrhagic stroke within the cohort. Among 7916 adults with CHD, 249 (3.1%) incident strokes occurred at a median age of 47 years; 186 (2.3%) ischemic, 33 (0.4%) hemorrhagic and 30 (0.4%) unspecified strokes. Ischemic and hemorrhagic stroke incidence was, respectively, 9 and 3 times higher in adults with CHD than the general population. Absolute risk was low with annual rates of 0.26% (ischemic) and 0.05% (hemorrhagic). Highest rates were observed in adults with shunt and left-sided lesions. Predictors of ischemic stroke in adults with CHD included recent cardiac surgery, left-sided valve repair/replacements, shunt lesions, and traditional risk factors (hypertension, infective endocarditis, peripheral vascular disease, and tobacco use). Mental health disorders and increasing Charlson's comorbidity scores were strongly associated with higher risk of ischemic and hemorrhagic stroke. The CHA2DS2VASc score was associated with ischemic stroke incidence. This study provides the first population-based stroke incidence estimates for adults with CHD in Australia, showing elevated stroke risk across different CHD lesions. It highlights the potential clinical importance of managing comorbidities, especially mental health.

Elevated Risk of Stroke in Young Adults After Traumatic Brain Injury: A Nationwide Study of 1 Million Individuals.

Although stroke is commonly perceived as occurring in older adults, traumatic brain injury, one of the risk factors for stroke, is a leading cause of death in the younger adults. This study evaluated stroke risk in young-to-middle-aged adults based on traumatic brain injury severity and stroke subtypes. For this retrospective, population-based, cohort study, data of adults aged 18 to 49 years who were diagnosed with traumatic brain injury were obtained from the Korean National Health Insurance Service between 2010 and 2017. Traumatic brain injury history was measured based on the International Classification of Diseases, Tenth Revision (ICD-10), codes. Posttraumatic brain injury stroke risk was analyzed using a time-dependent Cox regression model. At baseline, 518423 patients with traumatic brain injury and 518 423 age- and sex-matched controls were included. The stroke incidence rate per 1000 person-years was 3.82 in patients with traumatic brain injury and 1.61 in controls. Stroke risk was approximately 1.89 times as high in patients with traumatic brain injury (hazard ratio, 1.89 [95% CI, 1.84-1.95]). After excluding stroke cases that occurred within 12 months following traumatic brain injury, these significant associations remained. In the subgroup analysis, patients with brain injury other than concussion had an approximately 9.34-fold risk of intracerebral hemorrhage than did the controls. Stroke prevention should be a priority even in young-to-middle-aged adult patients with traumatic brain injury. Managing stroke risk factors through regular health checkups and modifying health-related behaviors is necessary to prevent stroke.