Stroke

BackgroundAcute basilar artery occlusion (BAO) causes devastating strokes. Despite the benefit of endovascular treatment, the optimal management remains sometimes controversial, such as for patients with mild deficits, and would benefit from robust prognostic tools. Given the dense white matter networks within the posterior fossa, we tested whether quantifying disconnections from acute diffusion-weighted imaging (DWI) could improve outcome prediction and responders to recanalization compared with conventional metrics. MethodsWe conducted a secondary analysis from a prospective multicenter stroke registry, including consecutive patients (2017-2024) with BAO and admission MRI. Ultra-high-resolution diffusion MRI was acquired in healthy participants to build normative tractograms with optimized posterior fossa quality. Patient infarcts delineated on DWI were projected onto these tractograms to estimate disconnected fiber volume. The primary outcome was 90-day modified Rankin Scale (mRS) 0-3 vs 4-6. Predictive performance of disconnected fiber volume was compared with baseline NIHSS, infarct volume, and posterior circulation ASPECTS (pc-ASPECTS) using logistic regressions and areas under receiver operating characteristic curves (AUC). Ordinal regressions tested associations across the full mRS spectrum, stratified by recanalization status. Analyses were repeated in patients with NIHSS [&le;]10. ResultsAmong 201 patients (median age 70; NIHSS 10), 97 (48.3%) had poor outcome. Despite small median infarct volume (4.75 mL), disconnected fiber volume was substantial (median 25.15 mL). Disconnected fiber volume achieved an AUC of 0.84, outperforming NIHSS (0.67; p<0.0001), infarct volume (0.75; p=0.00059), and pc-ASPECTS (0.76; p=0.0127). Low disconnected fiber volume predicted better outcomes across the full mRS (OR=0.12 [95% CI, 0.065-0.204]) and greater benefit from successful recanalization (OR=0.33 [95% CI, 0.15-0.70]). In patients with NIHSS [&le;]10 (n=102), disconnected fiber volume remained the strongest predictor (AUC=0.83). ConclusionsDisconnected fiber volume derived indirectly is a robust prognostic marker of BAO outcomes that outperforms conventional predictors and may support future treatment decisions. Registrationhttps://clinicaltrials.gov - NCT03776877.

Abstract Objective: To compare the safety and efficacy of bridging intravenous thrombolysis (IVT) plus endovascular thrombectomy (EVT) versus direct EVT in patients with acute ischemic stroke (AIS) due to anterior circulation large vessel occlusion (LVO) treated within the 6- to 24-hour time window. Methods: This is a retrospective analysis of prospective EVT registry from 10 comprehensive stroke centers in China and Singapore between 2019 and 2024. Eligible patients had anterior circulation LVO, underwent EVT within 6-24 hours of onset, had ASPECTS 6, NIHSS 6, and pre-stroke mRS 2. Patients were stratified into bridging IVT + EVT (IVT group) versus direct EVT alone (non-IVT group). Propensity score matching (1:2 ratio) was performed to balance baseline covariates. The primary outcome was 3-month favorable functional outcome (mRS 0-2). Secondary outcomes included successful recanalization (mTICI 2b-3), symptomatic intracranial hemorrhage (sICH), hemorrhagic transformation (HT) and 3-month mortality. In the matched cohort, binary outcomes were compared using the Cochran-Mantel-Haenszel test. Results: Of 772 included patients, 110 (14.2%) received bridging IVT and 662 (85.8%) received direct EVT. After propensity score matching, 202 non-IVT patients were matched to 101 IVT patients, with all covariates well-balanced (absolute SMD <0.10). In the matched cohort, bridging IVT was not associated with a significant difference in 3-month favorable outcome (44.55% vs. 47.03%; common OR 0.91; 95% CI 0.56-1.46), successful recanalization (91.09% vs. 90.10%; OR 1.11; 0.51-2.44), sICH (5.94% vs. 9.41%; OR 0.61; 0.24-1.58), HT (23.76% vs. 23.27%; OR 1.03; 0.57-1.85), or 3-month mortality (15.84% vs. 13.37%; OR 1.22; 0.62-2.37). Conclusion: In this large multicenter propensity score-matched analysis, bridging intravenous thrombolysis before endovascular thrombectomy in the 6- to 24-hour time window was not significantly associated with improved efficacy or increased safety risks compared with direct endovascular therapy alone.

Background Outcome after stroke varies according to stroke subtype by location, but healthcare systems data studies do not include subtyping information. We linked natural language processing (NLP) of brain imaging reports to routinely collected data to estimate risk of death and other outcomes after stroke subtypes in a nationwide dataset. Methods We applied a previously validated NLP algorithm to all CT and MRI head scan reports in Scotland between 2010 and 2018. We linked the reports to hospital readmissions, prescriptions and death data to identify and characterize people with stroke, and to categorize into deep and cortical ischemic stroke, deep and lobar intracerebral hemorrhage (ICH), subarachnoid hemorrhage, and subdural hemorrhage. We used a matched cohort design, and age- and sex-matched four controls per case who never had a stroke. By subtype, we estimated rehospitalization with stroke, myocardial infarction (MI), cancer, dementia, epilepsy and death, accounting for confounders and competing risk of death. Results From 785,331 people with a head scan, we identified 64,219 with clinical stroke phenotypes (mean age 73.4yrs, 49.5% male), and subtyped 12,616 with deep ischaemic stroke; 14,103 with cortical ischaemic stroke; 1,814 with deep ICH; and 1,456 with lobar ICH. There was higher absolute rate of 1-year hospital readmission for lobar compared with deep ICH (4.9% [95%CI 3.9% - 6.1%] vs 3.4% [2.6% - 4.3%]), higher risk of dementia beyond 6 months after lobar ICH compared to controls than for other stroke subtypes (aHR 3.5 [2.3-5.3]); and higher risk of MI within 6 months of cortical ischemic stroke than for other stroke subtypes (aHR 4.6 [3.4-6.3]). Conclusions NLP of free-text reports linked to coded data successfully subtyped stroke at scale, and we estimated risk of clinically relevant outcomes. Future work should use free text to enable large-scale audit and epidemiology of people with stroke.

ObjectiveLevetiracetam is commonly prescribed for seizure prophylaxis after acute ischemic stroke (AIS) and often continued beyond discharge. While its short-term effectiveness for preventing post-stroke seizures is established, it is unclear whether prolonged use improves survival, particularly in older adults. We estimated the effect of continued levetiracetam use on 90-day mortality among Medicare beneficiaries after AIS. MethodsUsing Traditional Medicare claims data (2008-2021), we identified beneficiaries aged [&ge;]66 years hospitalized for AIS who initiated outpatient levetiracetam within 90 days of discharge. After one month of continued post-stroke use of levetiracetam (start of follow-up), we compared 90-day mortality between patients with a new levetiracetam dispensation within a 14-day grace period post-follow up and those without one. We performed cloning, censoring and weighting to address immortal time bias and estimated standardized mortality risks, risk differences, and 95% confidence intervals (CI). ResultsAmong 3,212 eligible beneficiaries, 1,779 (55.4%) received a new levetiracetam dispensation within the 14-day grace period. Median age was 76 years (IQR 70-83); 57.8% were female. After adjustment for demographics, hospitalization characteristics, timing of initiation, and comorbidities, continued use was associated with lower 90-day mortality than discontinuation (53 vs 62 deaths per 1,000; risk difference -9 per 1,000; 95% CI: (-12,-5)). The reduction was observed primarily among patients aged [&ge;]75 years. SignificanceAmong older Medicare beneficiaries who initiated levetiracetam after AIS, continued outpatient use was associated with modestly lower 90-day mortality, particularly in those aged [&ge;]75 years. These findings suggest potential benefits of levetiracetam continuation beyond the immediate post-stroke period.

Sex specific differences in stroke are recognized. Whether differences in incident stroke risk persists in recent periods needs further elucidation to aid public health preventive efforts. Aim: To determine long-term sex specific trends in stroke and stroke risk factors at different epochs among Framingham Heart Study participants. Methods: We examined age-adjusted 10-year stroke incidence using Cox regression in women and men in five epochs: 1962-1969 (epoch 1, reference), 1971-1976 (epoch 2), 1987-1991 (epoch 3), 1998-2005 (epoch 4), 2015-2021 (epoch 5). We compared stroke incidence by sex across epochs, estimated decade-wise linear trends overall and by sex. We compared risk factors in successive epochs to the first, and estimated sex-specific trends in risk factors. Interactions between baseline risk factors with epoch and trends were assessed by sex. Secondary analyses were repeated in participants <60 years old. Results: Incident stroke occurred in 4.5% (178/3996) in epoch 1, 3.9% (227/5786) in epoch 2, 3.9% (199/5137) in epoch 3, 2.7% (207/7642) in epoch 4, 2.2% (119/5534) in epoch 5. Men had higher risk of incident stroke in each epoch with significant difference in epochs 2 (HR 1.41, 95% CI [1.08, 1.84]) and 4 (HR 1.46, 95% CI [1.11, 1.91]) overall, and in epoch 4 (HR 2.13, 95% CI [1.17, 3.87]) among those <60 years. Stroke incidence declined by 16% per decade in men (HR 0.84, 95% CI [0.79, 0.89]) and 19% per decade in women (HR 0.81, 95% CI [0.76, 0.86]). Among those <60 years, stroke incidence declined by 22% per decade in women (HR 0.78, 95% CI [0.67, 0.95]). Hypertension declined by 8% per decade in women only ([OR] 0.92, 95% CI [0.90, 0.94]), while Atrial fibrillation and diabetes increased in both. Conclusion: Stroke incidence continues to decline in recent periods for women and men. Among participants <60 years, decline was observed only in women, possibly related to decline in hypertension in women.

Post-stroke cognitive recovery is difficult to predict using focal lesion characteristics alone. The brain's capacity to maintain cognitive function depends also on structural integrity of the whole brain. One way to measure brain health is through the severity of cerebral small vessel disease (CSVD) markers, which reflect aging-related pathologies that erode structural integrity. Here, we propose a composite measure of CSVD (cCSVD) integrating three independently validated biomarkers automatically quantified using T1-weighted MRIs: white matter hyperintensity volume (WMH; representing vascular injury), perivascular space count (PVS; putative glymphatic clearance), and brain-predicted age difference (brain-PAD; structural atrophy). We hypothesize that cCSVD, which captures the shared variance across these CSVD biomarkers, will be a robust indicator of whole-brain structural integrity and predict cognitive changes 3 months after stroke. We analyzed 65 early subacute stroke survivors with assessments within 21 days (baseline) and at 90 days (follow-up) post-stroke. WMH volume, PVS count, and brain-PAD were quantified from baseline T1-weighted MRIs, and then residualized for age, sex, days since stroke, and intracranial volume. Principal component analysis (PCA) of the residualized biomarkers was used to derive cCSVD. Beta regression with stability selection using LASSO was used to model three outcomes: baseline Montreal Cognitive Assessment (MoCA) scores, follow-up MoCA scores, and longitudinal change (follow-up score adjusted for baseline score). Logistic regression was used to test if baseline cCSVD predicted improvement in those with baseline cognitive impairment (MoCA < 26). The PCA revealed that the first principal component (PC1) explained 43.1% of the total variance among WMH volume, PVS count, and brain-PAD. The three biomarkers contributed nearly equally to PC1, which was subsequently used as the baseline cCSVD score. Lower baseline cCSVD was significantly associated with better MoCA scores at follow-up ({beta} = -0.19, p = 0.009), even after adjusting for baseline MoCA ({beta} = -0.12, p = 0.042), and, importantly, outperformed all individual biomarkers. Furthermore, lower cCSVD at baseline significantly increased the likelihood of improving to cognitively unimpaired status at three months (OR = 0.34, p = 0.036), independent of age and education. The composite CSVD captures the additive impact of vascular injury, glymphatic dysfunction, and structural atrophy on recovery in a way that individual measures do not. cCSVD accounts for shared variance across these domains, reflecting a patient's latent capacity for cognitive recovery, where relative integrity in one CSVD domain may mitigate effects of another. This automated, T1-based framework offers a scalable tool for predicting post-stroke recovery.

Abstract Background: Acute ischemic stroke (AIS) remains a significant cause of disability worldwide. Current treatments, primarily intravenous thrombolysis (IVT), are limited by narrow time windows and reperfusion injury, leading to suboptimal outcomes for many patients. Chuanzhi Tongluo (CZTL), a traditional Chinese medicine, has been preliminarily recognized as a novel cerebral protection agent in animal models. Objectives: This trial investigates the efficacy and safety of CZTL capsule in patients with AIS who are not eligible for IVT or who experience early neurological deterioration after IVT. Methods and design: The CONCERN trial is an investigator-initiated, prospective, multicenter, double-blind, parallel-control, randomized clinical study in China. An estimated 1,208 eligible participants will be consecutively randomized to receive CZTL capsule therapy or placebo in 1:1 ratio across approximately 70 stroke centers in China. All enrolled patients are orally administered 2 capsules of CZTL or placebo 3 times a day together with antiplatelet agents for 3 months. Outcomes: The primary endpoint is an excellent functional outcome, defined as a score of 0 or 1 on the mRS at 90 days. Lead safety endpoints included 90-day mortality and symptomatic intracranial hemorrhage within 48 hours. Conclusions: Results of CONCERN trial will determine the clinical efficacy and safety of the traditional Chinese medicine CZTL capsule in the treatment of AIS patients. Trial registry number: ChiCTR2300074147 (www.chictr.org.cn).

Background: Type 2 diabetes mellitus (T2DM) has long been considered a risk factor for cerebral small vessel disease (cSVD), yet the exact relationship between glycemic markers and cSVD remains unclear. This study explores the genetic overlap and causal associations between T2DM, glycemic indices, and cSVD phenotypes using genome-wide association studies (GWAS). Methods: Using large consortium-based GWAS data, we examined relationships between T2DM, glycemic indicators (glycated hemoglobin, fasting glucose, 2-hour glucose after oral challenge, and fasting insulin), and cSVD phenotypes (white matter hyperintensity volume, lacunar stroke, cerebral microbleeds, and enlarged perivascular spaces). Our multi-level genomic strategy included: 1) identifying pleiotropic single nucleotide polymorphisms (SNPs) through PLEIO and eQTL analysis, 2) assessing genome-wide genetic correlations using LDSC and GNOVA, and 3) determining causal relationships with two-sample and multivariable Mendelian randomization analyses. Results: We identified 14 pleiotropic SNPs with significant shared associations among T2DM, glycemic indicators, and cSVD phenotypes. Notably, MICB gene expression was elevated in brain, vascular, and pancreatic tissues, while three HLA genes (HLA-DQA1, HLA-DRB1 and HLA-DRB5) showed reduced expression. Genetic correlation analysis revealed positive correlations between T2DM, fasting glucose, and postprandial glucose with multiple cSVD phenotypes including WMH, lacunar stroke, and perivascular spaces. Mendelian randomization demonstrated that T2DM, 2-hour glucose, and HbA1c level causally increased lacunar stroke risk (OR 1.16 [1.09-1.23], OR 1.46 [1.20-1.77], OR 1.52 [1.04-2.23], respectively). Multivariable Mendelian randomization analysis confirmed that T2DM and postprandial glucose maintained a robust direct effect on lacunar stroke independent of other cSVD phenotypes, while HbA1c did not retain significance after conditioning on cSVD imaging markers. Conclusions: Our multi-level genomic analysis reveals links between T2DM, glycemic traits, and cSVD through specific genetic variants, genome-wide correlations, and causal relationships. The involvement of immune-related genes suggests potential biological mechanisms. The causal effect of postprandial glucose on lacunar stroke suggests that impaired glucose tolerance may be a relevant therapeutic target for lacunar stroke prevention.

BackgroundGlobal cerebral anoxia is a leading cause of death and resuscitated patients often remained persistently affected by neurological deficits. While previous studies suggest that brain-heart electrophysiological interactions may predict severity and prognosis after hypoxic brain injury coma, little is known about the brain-heart dynamics at near-death. Gaining insight into these mechanisms is crucial for developing targeted interventions in critical conditions. ResultsUsing a rodent model of reversible systemic anoxia (n=29, male and female rats), we investigated whether brain-heart interactions during the asphyxia onset could predict the return of brain electrical activities after resuscitation. Electrophysiological recordings confirmed that cerebral activity declines following asphyxia, coinciding with increased heart rate variability. Notably, the strong coupling between cardiac parasympathetic activity and high-frequency brain activity in the somatosensory cortex and hippocampus serves as a key predictor of a favorable outcome. ConclusionOur study underscores the involvement of the brain-heart axis mechanisms in the physiology of dying and the potential prognostic significance of these mechanisms, paving the way for translational research into critical care, based on new characterizations of cardiac reflexes and brain-heart interactions.

BackgroundTheory of Mind (ToM) deficits are well-documented in right-hemisphere stroke but remain understudied in post-stroke aphasia. Prior work suggests that performance on tasks assessing ToM may be relatively preserved in aphasia and dissociable from language impairment, but these findings are based largely on small studies. This study examined performance on nonverbal false-belief tasks in post-stroke aphasia, its relationship with aphasia severity, and whether vascular brain health, operationalized using cerebral small vessel disease (CSVD) markers, contributed to variability in performance. MethodsForty-four individuals with aphasia completed two nonverbal belief-reasoning tasks assessing spontaneous perspective-taking and self-perspective inhibition. Task accuracy served as the primary outcome. Linear regression models examined associations between task performance, aphasia severity (Western Aphasia Battery-Revised Aphasia Quotient), and CSVD markers, including white matter hyperintensities, cerebral microbleeds, lacunes and enlarged perivascular spaces in the basal ganglia and centrum semiovale. ResultsPerformance was heterogeneous across tasks, with reduced performance observed in 23% of participants on the Reality-Unknown task and 36% on the Reality-Known task. Aphasia severity was not associated with task accuracy. Greater cerebral microbleed count was associated with lower accuracy on both tasks, while greater basal ganglia enlarged perivascular spaces burden showed a more selective association with lower performance. ConclusionsPerformance on nonverbal false-belief tasks in aphasia is variable and not explained by aphasia severity alone. These findings suggest that apparent ToM-related difficulties in aphasia may be shaped by broader vascular brain health, supporting a more multidimensional framework for interpreting social-cognitive task performance after stroke.

A prominent radiological manifestation of cerebral amyloid angiopathy (CAA) is enlargement of perivascular spaces (EPVS), which is suggested to result from fluid stagnation due to impaired perivascular clearance. Here, we report a novel observation of hypointense rims in cerebral white matter surrounding EPVS near haemorrhages on in vivo 7T Gradient Echo MRI. We hypothesised that the observed black rim pattern denotes iron accumulation that may be caused by incomplete clearance following bleeding. We investigated the occurrence and localisation of this marker on in vivo and ex vivo MRI and examined its histopathological correlates. From MRI data of the prospective longitudinal natural history study of hereditary Dutch-type CAA (D-CAA) at Leiden University Medical Centre, we selected the first 20 consecutive patients who underwent 7T imaging and assessed the presence of black rims on MRI. Post-mortem material was available from one donor with black rims on in vivo scans. Formalin-fixed coronal brain slabs were scanned at 7T MRI, including a high-resolution T2*-weighted sequence. Guided by ex vivo MRI, tissue blocks from representative areas with black rims were sampled for histopathological analysis. Serial sections were stained for iron, calcium, myelin, and general tissue morphology. On in vivo 7T MRI, 9 out of 20 participants exhibited one or several black rims, all located close to a haemorrhage. In the D-CAA donor, ex vivo MRI signal loss matched the in vivo contrast changes. Thirty-six vessels with ex vivo-observed black rims were retrieved and histopathologically examined, showing iron accumulation surrounding perivascular spaces, but the pattern and severity of iron deposition varied. Across groups, vessels displayed microvascular degeneration, including hyaline vessel wall thickening, adventitial fibrosis, and perivascular inflammation. We identified black rims on in vivo 7T MRI and confirmed their correspondence on ex vivo imaging. Iron deposition was determined as the underlying correlate of black rims, but the histopathology appears heterogeneous. The preferential deposition of iron around EPVS may indicate incomplete clearance of iron-positive blood-breakdown products after bleeding. The varied pattern of iron accumulation and microvascular alterations may reflect different pathophysiological mechanisms related to the formation and maintenance of black rims in D-CAA.

BackgroundHypertension is the leading modifiable risk factor for ischemic stroke, yet the adequacy of preventative hypertension care in routine clinical practice remains suboptimal. Whether gaps in hypertension management represent missed opportunities for stroke prevention remains unclear. ObjectiveTo evaluate the association between hypertension care delivery and the risk of incident ischemic stroke. MethodsWe conducted a retrospective, matched, nested case-control study among adults with hypertension using electronic health record data from a large regional health system (2010-2024). Patients with a first-ever ischemic stroke were matched 1:2 to controls on age, sex, race and ethnicity, and calendar time. Three care metrics were assessed during follow-up: (1) outpatient visits with blood pressure (BP) measurement per year; (2) number of antihypertensive medication ingredients; and (3) medication intensification score. Conditional logistic regression estimated adjusted odds ratios (aORs). ResultsThe study included 13,476 cases and 26,952 matched controls (N = 40,428). Mean (SD) age was 64.8 (12.2) years, 54.1% were female, and mean follow-up was 2,497 (1,308) days. Cases had fewer BP visits per year (median, 2.50 vs. 3.01; p < 0.001), similar number of medication ingredients (2.00 vs 2.00), and lower treatment intensification scores (-0.211 vs - 0.125). In adjusted models, >5 BP visits per year was associated with lower stroke odds (aOR, 0.55; 95% CI, 0.51-0.59) compared with [&le;]1 visit. Use of 2-3 medication ingredients (vs 0) was also associated with reduced stroke odds (aOR, 0.80; 95% CI, 0.75-0.86), whereas >3 ingredients was not significant. The highest quartile of treatment intensification showed the strongest association (aOR, 0.47; 95% CI, 0.44-0.51). Findings were consistent across subgroup and sensitivity analyses, including strata defined by baseline SBP and follow-up SBP. ConclusionsGreater engagement in hypertension care was associated with lower odds of ischemic stroke, suggesting that gaps in routine management may represent missed opportunities for prevention.

Background: Elevated lipoprotein(a) [Lp(a)] is a known risk factor for several cardiovascular-related diseases established from multiple genetic and observational studies. However, the underlying mechanisms mediating the effects of Lp(a) levels on cardiovascular disease risk and major adverse cardiovascular events (MACE) are unclear. The aim of this study was to identify proteins downstream of Lp(a) using mendelian randomization (MR) - a genetic causal inference approach. Methods: A two-sample MR was performed by initially identifying Lp(a) genetic instruments based on data from genome wide association studies (GWAS) of Lp(a) blood concentrations. These instruments were then tested for association with proteins from proteomic pQTL data (Olink from UK Biobank, 2940 proteins and SomaScan from deCODE, 4907 proteins). Results: A total of 521 proteins associated with Lp(a) were identified. Using pathway enrichment analysis, the following MACE-relevant pathways were identified comprising a total of 91 Lp(a) downstream proteins: oxidized phospholipid-related, chemotaxis of immune cells and endothelial cell activation, pro-inflammatory monocyte activation, neutrophil activity, coagulation, and lipid metabolism. Conclusion: The results suggest that the influence of Lp(a) treatments is primarily through modifying inflammation rather than lipid-lowering, thus providing insight into the mechanistic framework which mediates the effects of elevated Lp(a) on atherosclerotic cardiovascular disease.

Abstract Background Spontaneous coronary artery dissection (SCAD) is a well-recognised cause of acute coronary syndrome particularly among women without conventional cardiovascular risk factors. Increasing evidence indicates a genetic contribution; however, the underlying genetic architecture of SCAD remains insufficiently understood. Objective The aim of this study was to assess the prevalence of rare variants in previously reported SCAD associated genes and to explore the potential presence of novel genetic alterations in well-characterised Swedish patients with SCAD. Methods The study comprised 201 patients enrolled in SweSCAD, a national project examining the clinical characteristics, aetiology, and outcomes of SCAD. All individuals had a confirmed diagnosis based on invasive coronary angiography. Comprehensive exome sequencing was performed to identify rare variants contributing to disease susceptibility. Results Genetic variants that have been associated with SCAD according to current clinical genetics practice for variant reporting were identified in approximately 4 % of patients. In addition, rare potentially relevant variants were detected in almost 60 % of patients in genes associated with vascular integrity and vascular remodelling. Conclusion This study supports SCAD as a genetically complex arteriopathy, driven by rare high?impact variants together with broader polygenic susceptibility. Variants in collagen, vascular extracellular matrix, and oestrogen?responsive pathways provide biologically plausible links to female?predominant disease. Although the diagnostic yield of clearly actionable variants is modest, these findings support broader genomic evaluation beyond overt syndromic presentations and highlight the need for larger integrative genomic and functional studies to refine risk stratification and management.

Introduction: Accurate stratification of hard atherosclerotic cardiovascular disease (ASCVD) risk remains challenging despite advances in prevention. Liver function biomarkers (LFBs), particularly gamma - glutamyl transferase (GGT), have been linked to cardiovascular outcomes, yet their contribution to hard ASCVD risk prediction is not well defined. Methods: This study analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2005 - 2018) to assess cross - sectional associations between LFBs and 10 - year hard ASCVD risk estimated by the ACC/AHA Pooled Cohort Equations. Multivariable regression, restricted cubic splines, and mediation analyses were applied to examine independent and dose - response relationships. External validation was performed in the China Health and Retirement Longitudinal Study (CHARLS) and NHANES using machine learning models (CoxBoost, Naive Bayes and Random Forest). Results: Among 5,731 NHANES participants, GGT showed an independent linear association with hard ASCVD risk (P - trend = 0.003), partly mediated by systolic blood pressure (44.8%), HbA1c (19.0%), and high density lipoprotein cholesterol (13.4%). Machine learning (ML) models incorporating GGT, alkaline phosphatase (ALP), and globulin alongside traditional risk factors improved predictive accuracy, with Naive Bayes achieving an AUC of 0.751 in NHANES validation. Conclusions: GGT is an independent and biologically plausible biomarker of hard ASCVD risk, acting through cardiometabolic pathways. Incorporating LFBs into risk prediction models, particularly with machine learning, enhances risk stratification and may facilitate early identification of high - risk individuals.

Background: Even for experienced operators, endovascular treatment of unruptured intracranial aneurysms involves intraoperative uncertainty that may lead to adjustments in strategy, prolong the procedure, and potentially cause inefficiency and device waste. This study aimed to evaluate whether pre-procedural testing (PPT) of endovascular treatment using patient-specific models was associated with increased operator confidence and perceived clinical utility, including improvements in procedural efficiency and reduced resource waste. Methods: We enrolled a cohort of patients who underwent PPT before endovascular treatment for complex unruptured intracranial aneurysms and compared their outcomes with a control group treated without PPT. The primary outcome was the Training Fidelity Score, a composite of three operator-reported Likert items defined a priori. Secondary outcomes included perceived clinical utility, intraoperative strategy changes, procedural time, radiation exposure, device waste and safety. Results: A total of 85 patients met the inclusion criteria (PPT=40; control=45). The Training Fidelity Score was high across the PPT group (median, 4.33/5). Perceived clinical utility was high and further increased significantly after the procedure. A significant reduction was observed in intraoperative strategy changes, with no changes recorded in the PPT group, compared to 6/45 in the control group (RR 0.09; p=0.027). Reductions in treatment time, radiation exposure and device waste were also noted. Conclusion: PPT using patient-specific models was associated with increased operator confidence, fewer intraoperative strategy changes, improved procedural efficiency, and reduced device waste without compromising safety. These findings support its use in pre-interventional preparation, but require prospective multicenter validation.

This research demonstrates that the trans-aqueduct approach is a feasible, minimally invasive access pathway to the third ventricle, offering a potential route to the deep brain for therapeutic technologies. Further pre-clinical investigation is required to thoroughly evaluate physiological tolerance, trauma risk, and the long-term implications of intraventricular implantation. The third ventricle is a high-value site for neuromodulation due to its proximity to deep-brain targets, including the subthalamic nucleus (STN) and globus pallidus internus (GPi). This study defined the anatomical pathway; and evaluated the technical feasibility of retrograde access to the third ventricle via the cerebral aqueduct using minimally invasive interventional techniques. Evaluation was conducted in three phases using human MRI datasets (n=16; mean age 48.4 years) and cadaveric specimens (n=6; mean age 88.2 years). Phase 1 involved morphometric MRI analysis of the aqueduct and ventricles. Phase 2 tested trans-aqueduct access on cadaver specimens via fluoroscopically guided guidewires and catheters. Phase 3 utilized direct anatomical dissections on cadaver specimens (n=3) to morphometrically measure the third ventricular cavity and its relationship to deep-brain nuclei. Measurements across the sample groups showed a mean aqueduct diameter of 1.6 mm (SD=0.14). Third ventricle dimensions averaged 27.6 mm (ventral-dorsal), 19.9 mm (caudal-cranial), and 5.7 mm (lateral). Successful access to the third ventricle was achieved in 83% (5/6) of cadaveric specimens. The optimal technical configuration utilized a 0.018'' angled-tip guidewire and 5-6 Fr catheters; the aqueduct accommodated diameters up to 2.0 mm with minimal resistance. The STN and GPi were localized within 5-20 mm of the ventricular volumetric centroid. The trans-aqueduct approach is a technically feasible, minimally invasive pathway for accessing the third ventricle. This route offers a potential alternative for the delivery of therapeutic neurotechnologies. Further research is required to assess physiological tolerance, trauma risk, and the long-term safety of intraventricular implantation.

BackgroundGenetic studies using cardiac magnetic resonance (CMR) imaging have identified loci related to cardiac shape, but most focus on static morphology. The value of a dynamic cardiac shape atlas capturing both shape and function remains unknown. MethodsA dynamic shape atlas comprising CMR-derived shape models at end-diastole and end-systole was combined with genetic and outcome data in 36,992 UK Biobank participants. Dynamic shape principal components (PCs) describing >1% of variance were characterized, and tested for associations with prevalent and incident cardiometabolic diseases, including ischemic heart disease (IHD), heart failure (HF), significant atrioventricular block (AVB), and atrial fibrillation (AF), and independent predictive power alongside standard CMR measures. Genome-wide association studies (GWAS) were performed to identify candidate genes and biological pathways, and polygenic risk scores (PRS) were assessed for disease associations. Mendelian randomization (MR) was performed to test causality of observed disease associations. ResultsWe identified 14 dynamic cardiac shape PCs capturing 83.3% of total dynamic cardiac shape variance. These PCs captured distinct functional remodeling patterns such as variation in annular plane systolic excursion, while remaining only modestly correlated with standard CMR measures. All 14 PCs were associated with at least one incident cardiometabolic disease, with the strongest associations observed for incident IHD, HF, and AVB. Notably, incorporating dynamic shape PCs improved the prediction of incident IHD beyond standard CMR measures. GWAS identified 75 genetic loci associated with dynamic shape, including 14 variants previously unreported for cardiac traits, and candidate genes demonstrated enrichment in pathways related to cardiac development and contractile function. PRS derived from dynamic shape loci were significantly associated with multiple outcomes, most prominently HF. MR identified significant causal relationships between several PCs and cardiometabolic disease. ConclusionsDynamic cardiac shape features capture aspects of cardiac structure and function not fully represented by standard CMR measures. These features are strongly associated with incident cardiometabolic disease and provide new insights into the genetic architecture of cardiac remodeling. Clinical perspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIGenetic and outcome relationships with a dynamic statistical shape model capturing both left and right ventricles at end-diastole and end-systole. C_LIO_LIDemonstration of incremental value over existing cardiac shape models, through capture of functional remodeling not represented by standard imaging measures. C_LIO_LIIdentification of genetic susceptibility loci for dynamic cardiac shape, including 14 variants not previously reported for cardiac traits. C_LI What are the clinical implications?O_LIThe results enhance our understanding of the genetic architecture of dynamic cardiac shape and function in the general population and clarify their relationships with other cardiovascular endophenotypes and incident cardiometabolic diseases. C_LIO_LINewly identified candidate genes expand the biological pathways implicated in cardiac remodeling and provide targets for future functional and mechanistic studies. C_LIO_LIThe improved prediction of incident cardiometabolic disease, particularly ischemic heart disease, achieved by adding dynamic shape PCs to traditional CMR measures suggests potential value for their inclusion in evaluation of patients. C_LI

Introduction: Spontaneous coronary artery dissection (SCAD) is frequently accompanied by persistent symptoms of unknown pathogenesis after the index event. Autonomic dysfunction is a plausible mechanism for these but has not been systematically characterized. We quantified antecedent and contemporary autonomic symptoms in survivors of SCAD and examined their associations with cardiac and extra-cardiac symptoms and health-related quality of life. Methods: This cross-sectional study recruited 227 volunteers from multiple countries with a self-reported history of SCAD. Participants completed validated patient-reported measures, including the Composite Autonomic Symptom Score-31 (COMPASS-31), Anxiety Sensitivity Index-3 (ASI-3), and EuroQol-5 Dimension-5L (EQ-5D-5L). They also completed an internally derived retrospective autonomic predisposition score assessing symptoms during adolescence and early adulthood. Results: Participants were predominantly female (97.8%), median age 53 (47-58) years, and were surveyed a median of 3 (1-5) years after their index SCAD event. 21.6% reported SCAD recurrence. Moderate autonomic symptom burden (COMPASS-31 20) was present in 56.4% and severe burden (40) in 16.3%. History of antecedent autonomic symptoms was the strongest independent predictor of contemporary autonomic symptom burden after adjustment for demographic and clinical covariates (=0.514; P <0.001). Greater autonomic symptom burden independently predicted lower EQ-5D health utility (=0.150; P=0.029) and was associated with the ASI-3 physical concerns (=0.232; P <0.001), but not social concerns domain. Autonomic symptoms were not associated with SCAD recurrence. Conclusion: Symptoms of autonomic dysregulation are common in survivors of SCAD and are associated with reduced quality of life. Their association with antecedent dysautonomic features during adolescence and early adulthood suggests a longstanding predisposition, the significance of which warrants further evaluation.

Background: Acute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. Methods: We conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. Findings: The RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.