Researchers at Inselspital, University Hospital Bern, in Switzerland, analyzed a consecutive series of 1,764 patients with acute anterior circulation ischemic stroke who underwent EVT, with or without intravenous thrombolysis, between February 2015 and March 2023. The data came from the prospectively maintained Swiss Stroke Registry, and nearly half of the patients, 48.4 percent, were women. The cohort had a median age of 76 years, making it one of the largest contemporary single-center datasets of its kind. All patients were treated at a comprehensive stroke center or transferred there through an established drip-and-ship model from referring hospitals, ensuring a standardized diagnostic and therapeutic pathway for everyone in the analysis.

The baseline picture that emerged was strikingly different between the sexes. Women were considerably older than men when they arrived, with a median age of 79.4 years compared with 73.3 years, and they more often carried atrial fibrillation, the irregular heart rhythm that predisposes to clots traveling from the heart to the brain, and chronic kidney disease. Men, by contrast, more frequently had coronary heart disease, heart failure, diabetes mellitus, and a current smoking habit. These divergent risk profiles translated directly into different stroke mechanisms: cardioembolic stroke, in which a clot originates in the heart, accounted for 46.3 percent of strokes in women versus 39.1 percent in men, whereas large artery atherosclerosis, the cholesterol-driven narrowing and rupture of vessel walls, was found in 18.1 percent of men against just 11.3 percent of women.

The pathophysiology behind this pattern is plausible, the authors argue. Advanced age and atrial fibrillation favor the formation of thrombi within the atria, which then embolize to the cerebral circulation, explaining the cardioembolic predominance in women. A heavier atherosclerotic burden in men, driven by smoking, diabetes, and coronary disease, points instead toward the artery-to-artery mechanism of large vessel atherosclerosis. Chronic kidney disease, more prevalent among women in the cohort, is itself an established cerebrovascular risk factor through chronic inflammation, endothelial dysfunction, and a prothrombotic state, and its higher prevalence may partly reflect the women’s older age.

Interestingly, when it came to the logistics of acute care, the sexes were treated almost identically. The time from last known well to hospital arrival, from door to imaging, from imaging to groin puncture, and from door to groin puncture did not differ significantly between women and men. The only workflow difference was a slightly shorter groin-puncture-to-reperfusion time in women, a gap of less than two minutes that the investigators considered unlikely to be clinically meaningful. This stands in contrast to numerous earlier studies reporting longer prehospital delays and lower rates of timely reperfusion therapy in women, disparities the Bern team attributes to well-established regional stroke pathways and standardized emergency medical services triage.

Treatment strategies did diverge in some notable ways. Men more often received bridging therapy, meaning intravenous thrombolysis before thrombectomy, at 40.8 percent versus 34.7 percent, and they more frequently underwent intracranial and extracranial stenting, procedures typically needed when atherosclerotic plaque must be propped open. These differences almost certainly reflect the higher burden of large artery disease in men rather than any preferential triage. Crucially, the core technical aspects of the procedure were equivalent: thrombectomy technique, anesthesia strategy, device selection, number of stent retriever passes, and procedural complication rates were all similar, and successful reperfusion, defined as a modified Thrombolysis in Cerebral Infarction score of 2b or higher, was achieved in 86.2 percent of all patients with no significant difference between the sexes.

Here is where the story takes its most important turn. In the raw, unadjusted data, women clearly did worse. At three months, only 37.5 percent of women had achieved a favorable functional outcome, defined as a modified Rankin Scale score of 2 or less, compared with 47.6 percent of men. Excellent outcome, a Rankin score of 1 or less, was reached by 25.6 percent of women versus 31.4 percent of men. Three-month mortality was 31.9 percent in women against 24.9 percent in men, and women were less often discharged home or to inpatient rehabilitation.

But once the researchers adjusted for the factors that actually drive recovery, including age, baseline stroke severity on the National Institutes of Health Stroke Scale, pre-stroke disability, atrial fibrillation, coronary heart disease, chronic kidney disease, occlusion site, bridging therapy, procedure duration, and calendar period, the sex gap vanished. Female sex was not independently associated with successful reperfusion, favorable outcome, excellent outcome, or mortality, with adjusted odds ratios hovering near unity and confidence intervals crossing one in every analysis. In other words, women did not do worse because they were women; they did worse because they were, on average, six years older, more disabled before their stroke, and sicker overall. Age, pre-stroke functional status, stroke severity, and comorbidity burden were far stronger predictors of outcome than sex itself.

One nuance did survive the statistical gauntlet. The team detected a sex-by-age interaction for favorable functional outcome, with the association between sex and outcome varying according to age. This exploratory finding requires confirmation in independent cohorts, and no such interaction was seen for reperfusion success, excellent outcome, or mortality, nor for effect modification by stroke etiology or bridging therapy. The authors also caution that their retrospective, single-center design limits generalizability, that the eight-year study window spanned evolving EVT techniques, and that factors such as frailty, hormonal status, clot composition, living situation, socioeconomic status, and access to rehabilitation were not captured, leaving room for residual confounding.

The clinical implications are nonetheless clear and, in their own way, reassuring. The findings support current guideline recommendations that sex alone should not influence patient selection for thrombectomy; decisions should rest on established clinical and imaging criteria applied equally to everyone. At the same time, the sharply different risk profiles argue for sex-specific prevention: intensified detection and management of atrial fibrillation in women, and aggressive control of atherosclerotic risk factors, smoking cessation, diabetes management, and lipid lowering, in men. The research team calls for future multicenter studies with predefined sex-specific analyses, better separation of sex from gender-related factors, and routine representation of women in clinical trials. For now, the message for patients and physicians alike is simple: when a large vessel occlusion strikes, the catheter lab treats both sexes with equal technical success, and it is age, disability, and comorbidity, not sex, that shape the road to recovery.

Subject of Research: Sex differences in vascular risk factors, stroke etiology, treatment characteristics, and outcomes after endovascular treatment for anterior circulation ischemic stroke

Article Title: Sex differences in risk factors, stroke etiology, treatment characteristics, and outcomes after endovascular treatment for anterior circulation ischemic stroke

Article References: Sex differences in risk factors, stroke etiology, treatment characteristics, and outcomes after endovascular treatment for anterior circulation ischemic stroke. (n.d.). https://doi.org/10.3389/fstro.2026.1946990

Image Credits: AI Generated

DOI: 10.3389/fstro.2026.1946990

Keywords: acute ischemic stroke, endovascular treatment, thrombectomy, sex differences, stroke etiology, cardioembolic stroke, large artery atherosclerosis, reperfusion, modified Rankin Scale, atrial fibrillation, stroke outcomes, Swiss Stroke Registry

G protein-coupled receptors, or GPCRs, form one of the largest receptor families in the human body, with more than 800 members. They sit in the membranes of cells throughout the cardiovascular system, including endothelial cells lining blood vessels and cardiomyocytes in the heart, and they govern everything from vascular tone to heart rate. Regulatory autoantibodies directed against these receptors can act as agonists or antagonists depending on where they bind, effectively hijacking receptor signaling. In experimental models and patient cohorts, such antibodies have been linked to pro-hypertensive and pro-atherogenic states, arrhythmias, and cardiomyopathy. Researchers have even coined the term antibodiome to describe the idea that an imbalance in these antibodies, in either direction, may influence the pathobiology of vascular disease.

The research team, led by investigators at Charité – Universitätsmedizin Berlin, measured IgG autoantibodies against seven GPCRs in serum samples collected within three to seven days of a first-ever ischemic stroke: the alpha-1, alpha-2, beta-1, and beta-2 adrenergic receptors, the angiotensin II type 2 receptor, the endothelin B receptor, and the chemokine receptor CXCR3. Measurements were performed using a sandwich ELISA developed by CellTrend GmbH, in which antibodies are detected against epitopes presented by transfected Chinese hamster ovary cells overexpressing each human receptor. Because prior work suggested that both elevated and reduced antibody levels might be pathological, the researchers deliberately avoided assuming a linear dose-response relationship. Instead, they compared patients in the lowest antibody quartile against everyone else, and separately those in the highest quartile against the lower three quartiles.

The cohort itself was drawn from a prospective, hospital-based study of incident stroke patients recruited at three Charité campuses between 2010 and 2013. The analysis focused on mild to moderate ischemic strokes, defined by a National Institutes of Health Stroke Scale score below 16, to keep the population homogeneous. The 562 patients included had a mean age of 67 years, and 38 percent were women. Four outcomes were tracked: functional outcome at one year using the modified Rankin Scale, a combined endpoint of recurrent stroke, myocardial infarction, or death over three years, cognitive outcome measured annually with a telephone-based screening test, and the burden of cerebral small vessel disease on baseline brain imaging.

The first striking result concerned stroke etiology. For every antibody tested, the distribution of stroke subtypes differed between patients with low and high antibody levels. Patients in the lowest quartile more often had strokes caused by large artery atherosclerosis, the buildup of plaque in the major vessels supplying the brain, while those in the highest quartile more often had cardioembolic strokes, in which clots formed in the heart travel to the brain. The largest discrepancies appeared for antibodies against the alpha-1 adrenergic receptor. The researchers speculate that low levels of vasodilative antibodies, such as those targeting the angiotensin II type 2 receptor, might foster a pro-atherogenic, vasoconstrictive state that promotes large artery disease, whereas elevated beta-adrenergic antibodies, previously linked to atrial fibrillation and cardiac remodeling, could contribute to the arrhythmogenic substrate underlying cardioembolic strokes.

Functional outcome at one year told a different story. Patients with high levels of alpha-2 adrenergic receptor antibodies or endothelin B receptor antibodies had significantly worse modified Rankin Scale scores than patients with lower levels, with an odds ratio of 1.49 in both cases. Mediation analyses suggested these were direct effects rather than consequences of stroke subtype: high antibody levels were associated with roughly eight percentage points lower probability of full recovery and about 2.3 percentage points higher probability of severe disability or death. A post-hoc dose-response analysis supported a graded relationship for these two antibodies. Low antibody levels, by contrast, showed no association with functional outcome in any model.

Recurrent cardiovascular risk over three years followed the opposite pattern. Among 91 patients who experienced a recurrent stroke, myocardial infarction, or death during 1,390 person-years of follow-up, the risk was elevated in patients with low levels, not high levels, of certain antibodies. Those in the lowest quartile for angiotensin II type 2 receptor antibodies had an 86 percent higher hazard of the combined endpoint, while low alpha-2 and beta-1 adrenergic receptor antibodies carried 77 percent and 58 percent higher hazards, respectively. This echoes findings from a cohort of acute coronary syndrome patients, in which low beta-1 receptor antibodies predicted early recurrent myocardial infarction and cardiovascular death, suggesting the phenomenon may generalize across diseases and age groups.

Not every hypothesis panned out. Cognitive outcome over three years showed only very small or non-significant differences between antibody groups, and cerebral small vessel disease burden, assessed with the Wahlund Score, was unrelated to antibody levels, though the authors caution that missing imaging data and low overall small vessel disease burden limit those analyses. High levels of CXCR3 antibodies, which in the large population-based Gutenberg Health Study predicted cardiac mortality, were not associated with secondary events in the overall stroke cohort, although within the subgroup with large artery atherosclerosis strokes, high CXCR3 antibody levels were linked to an almost threefold increase in recurrent event risk, consistent with the shared pathophysiology of systemic atherosclerosis.

The authors are careful to frame the study as exploratory and hypothesis-generating. Multiple statistical tests were performed without a narrow set of predefined hypotheses, raising the possibility of false-positive findings, and the results require confirmation in independent cohorts. Serum samples were collected only once, days after the stroke, so the researchers cannot determine whether the antibodies predated the event or how their levels evolved over time. Only the IgG subclass was measured, and ELISA-based quantification is sensitive to handling and environmental factors, though repeated measurements of a subset of samples showed good agreement. The restriction to mild and moderate ischemic strokes also means the findings may not extend to severe or hemorrhagic events.

Even with those caveats, the study adds a compelling new dimension to stroke prognosis. If the associations hold up, a simple blood test measuring regulatory autoantibodies in the first week after stroke could eventually help clinicians stratify patients, identifying those at heightened risk of poor recovery or recurrent vascular events and tailoring secondary prevention accordingly. The bidirectional nature of the findings, with high levels predicting worse recovery and low levels predicting relapse, underscores the antibodiome concept: immune balance, not simply more or less antibody, may be what matters. As the authors conclude, these observations warrant deeper mechanistic research into how antibodies that modulate G protein-coupled receptors participate in the pathophysiology of cerebrovascular disease.

Subject of Research: Association of GPCR-directed regulatory autoantibodies with clinical outcomes after ischemic stroke

Article Title: Autoantibodies targeting G protein-coupled receptors and clinical outcome after ischemic stroke (PROSCIS-B)

Article References: Miesenberger, A.-S., Arlt, F. A., Koschützke, L., Gebert, P., Heidecke, H., Schulze-Forster, K., Catar, R. A., Moll, G., Harms, C., Kufner, A., Liman, T., Prüss, H., Endres, M., & Sperber, P. S. (2026). Autoantibodies targeting G protein-coupled receptors and clinical outcome after ischemic stroke (PROSCIS-B). Journal of Neurology, 273(10), Article 581. https://doi.org/10.1007/s00415-026-14103-6

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14103-6

Keywords: ischemic stroke, autoantibodies, G protein-coupled receptors, regulatory autoantibodies, functional outcome, cardiovascular risk, PROSCIS-B, stroke etiology, ELISA, neurology, immunology, atherosclerosis