Circadian Misalignment May Modify Infarct Volume Impact After Stroke Thrombectomy

In an observational investigation of patients undergoing mechanical reperfusion for acute ischemic stroke caused by large vessel occlusion, researchers found that social-biological time misalignment did not directly dictate clinical recovery on its own, but instead acted as a state-dependent effect modifier altering the relationship between final infarct volume and ninety-day functional outcomes. Endovascular thrombectomy has established itself as a transformative standard of care, routinely achieving complete or near-complete arterial recanalization in specialized centers worldwide. Despite these high procedural success rates, only twenty to forty percent of treated individuals ultimately regain functional independence. Traditional prognostic indicators, which focus almost exclusively on initial neurological severity scores, baseline ischemic core dimensions, and the technical degree of recanalization, have largely plateaued in their predictive accuracy. This persistent gap between anatomical restoration of blood flow and actual neurological recovery indicates that underlying biological and physiological states modulate how brain tissue responds to acute ischemic damage and subsequent reperfusion.

To explore this divergence, investigators from Liaoyang Central Hospital and Jinzhou Medical University focused on endogenous chronobiology, drawing upon foundational laboratory evidence demonstrating that circadian rhythms tightly govern critical cellular and vascular processes in the brain. Experimental models have documented marked daily oscillations in blood-brain barrier permeability, endothelial nitric oxide synthase activity, reactive oxygen species generation, and neutrophil extracellular trap formation during acute cerebral ischemia. When internal circadian rhythms are experimentally disrupted in animal studies, cerebral edema and tissue infarction become noticeably exacerbated, whereas targeted genetic modulation of molecular clock components provides neuroprotection. Although prior clinical cohort studies have attempted to link the clock time of stroke onset or shift work status to patient outcomes, their findings have remained largely inconsistent and conflicting, with some groups reporting increased morbidity during nighttime hours while others observed no discernible effect at all.

The research team hypothesized that these historical contradictions arose because earlier studies treated onset time or occupational shift schedules as simple independent risk factors, presuming that disrupted circadian timing exerts an identical, direct causal insult across all patients regardless of injury burden. Drawing from conceptual models in vascular biology where the endogenous timing system acts primarily as a disease modifier rather than a primary initiator of pathology, the authors formulated the state-structure interaction hypothesis. Within this theoretical framework, social-biological time misalignment represents an internal biological state that alters tissue vulnerability and physiological resilience, thereby modifying the prognostic influence exerted by structural injury, specifically the final volume of infarcted brain tissue. Mechanical thrombectomy offered a well-controlled clinical setting to test this premise because final infarct volume provides an objective continuous measure of structural damage, treatment delivery is standardized, and long-term disability can be systematically evaluated using established functional rating scales.

The study analyzed a consecutive retrospective cohort of one hundred sixty adult patients admitted to the Stroke Center of Liaoyang Central Hospital between January 2022 and September 2025 who underwent endovascular thrombectomy for acute large vessel occlusion. To isolate biological and structural interactions cleanly, the analytic cohort was restricted to individuals who achieved complete reperfusion, defined as modified Treatment in Cerebral Infarction grade 3, ensuring that procedural failure or residual macrovascular occlusion would not confound downstream recovery. Patients were excluded if they lacked ninety-day functional follow-up, had substantial pre-stroke neurological disability defined as a modified Rankin Scale score greater than two, or possessed incomplete documentation regarding occupational routines or precise symptom onset. The primary clinical endpoint was favorable functional outcome at ninety days, defined as achieving a modified Rankin Scale score between zero and two, representing functional independence in daily living activities.

To rigorously measure circadian disruption without relying solely on hospital arrival time, the investigators developed a composite Social-Biological Time Misalignment Score integrating chronic occupational rhythm strain and acute biological onset phase. Occupational histories were independently reviewed by investigators blinded to patient outcomes and classified into three ordinal tiers: low constraint representing regular daytime work, retirement, or unemployment; moderate constraint involving partially flexible schedules or occasional night shifts; and high constraint encompassing rotating night shifts or high-stress round-the-clock vocations such as commercial long-distance driving or emergency healthcare. Acute biological phase was categorized based on confirmed symptom onset, classifying cases occurring between 18:00 and 06:00 as nighttime onsets marking the physiological rest phase. The resulting composite score allocated one point for high occupational constraint and one point for nighttime symptom onset, classifying sixty percent of the cohort as aligned with zero points, thirty-three point eight percent with single misalignment, and six point two percent with double misalignment.

Within the overall study cohort, the median age was sixty-two years and seventy-one point two percent were male, presenting with an initial median National Institutes of Health Stroke Scale score of thirteen. Consistent with high baseline stroke severity, final infarct volumes measured on follow-up neuroimaging were substantial, exhibiting a median volume of twenty-nine point five milliliters, with over half the cohort exceeding twenty-five milliliters. Patients characterized by social-biological misalignment were significantly younger, with a median age of fifty-seven years compared to sixty-five years among aligned individuals, and presented with lower median baseline stroke severity scores of twelve versus fifteen. At the ninety-day evaluation, thirty-one patients, representing nineteen point four percent of the total cohort, attained a favorable functional outcome, while twenty patients died, reflecting the substantial severity of large vessel infarctions managed in regional neurocritical care centers.

Multivariable logistic regression revealed that social-biological misalignment score did not have a statistically significant independent association with ninety-day functional recovery in a standard main-effects model, yielding an odds ratio of zero point eighty-one. Conversely, standardized final infarct volume demonstrated a pronounced inverse association with favorable recovery, corresponding to an odds ratio of zero point zero four. However, when the multiplicative interaction term between standardized misalignment and standardized final infarct volume was incorporated into the regression model, a statistically significant interaction emerged, with an odds ratio of nine point seventy and a likelihood ratio test p-value of zero point zero zero eight. Adding this interaction term significantly improved overall model fit, decreasing the Akaike Information Criterion from 124.35 to 119.38 and elevating Nagelkerke pseudo R-squared from 0.435 to 0.483, with the final model demonstrating strong discriminative ability and an area under the receiver operating characteristic curve of 0.894.

Clinical interpretation of this interaction revealed that the adverse prognostic influence of accumulating infarct volume was most pronounced among patients whose daily social activities aligned with biological rest schedules, whereas this inverse relationship was markedly attenuated in misaligned patients. Stratified simple slope evaluations demonstrated that every ten-milliliter enlargement of final infarct volume substantially reduced the odds of favorable recovery among aligned patients, producing an odds ratio of zero point fifty-six, and among mildly misaligned patients, with an odds ratio of zero point forty-one. Exploratory threshold modeling further suggested a potential inflection point at a standardized infarct volume of negative zero point forty-three standard deviations, translating to an anatomical volume of approximately twenty-five milliliters. The authors noted that this approximate boundary aligns with independent clinical-diffusion mismatch criteria in ischemic stroke literature, where core volumes under twenty-five milliliters typically delineate substantial salvageable penumbral tissue.

To evaluate whether this statistical interaction represented a robust biological signal rather than an artifact of modest sample size or sparse-event separation, the researchers executed a comprehensive battery of sensitivity analyses. The core interaction remained statistically significant following Benjamini-Hochberg false discovery rate correction with an adjusted q-value of zero point zero thirty-four. Profile likelihood estimation confirmed an odds ratio range between 1.84 and 69.72, while Firth penalized likelihood regression yielded an adjusted odds ratio of six point eighty-four with a p-value of zero point zero zero nine. Inverse probability of treatment weighting produced a concordant interaction odds ratio of five point sixty-six, and extended multivariable adjustments incorporating onset-to-reperfusion latency, occlusion territory, lesion laterality, and TOAST ischemic stroke etiology maintained stable interaction estimates ranging from 9.35 to 11.48 without statistical attenuation.

In contrast, standard non-parametric bootstrapping techniques yielded extremely wide confidence intervals that crossed the null value, an expected instability attributed directly to quasi-complete data separation when repeatedly resampling small numbers of binary outcome events across multi-parameter regression models. Evaluation of an unmeasured confounding metric yielded an E-value of 18.89, indicating that an unobserved confounder would require an odds ratio exceeding eighteen to explain away the observed interaction. Furthermore, a pre-specified negative control interaction between biological sex and final infarct volume failed to achieve statistical significance. Exploring alternative structural endpoints demonstrated that substituting infarct progression burden for final infarct volume preserved the significant interaction pattern, while testing varied nocturnal time windows showed that broad overnight intervals yielded more consistent associations than narrow dawn windows.

The investigators emphasized several methodological and biological limitations that necessitate cautious interpretation of these findings. As a single-center retrospective study involving one hundred sixty patients and thirty-one favorable outcome events, the effective ratio of events per predictor variable was approximately three point four, falling below conventional modeling recommendations and prompting reliance on penalized likelihood methods. The nocturnal timing classification of 18:00 to 06:00 served merely as an operational proxy for biological night, lacking direct biomarker validation such as endogenous melatonin profiles, continuous core body temperature monitoring, or prolonged actigraphy recordings. In addition, neuroimaging metrics such as collateral vessel status and Alberta Stroke Program Early CT Scores were unrecorded, and because all enrolled patients achieved complete mTICI 3 reperfusion, the findings cannot be generalized to individuals experiencing partial or failed recanalization.

Ultimately, the researchers concluded that social-biological time misalignment acts not as an independent, universal determinant of disability following acute ischemic stroke, but rather as a state-dependent modifier that alters the clinical consequences of structural brain injury following mechanical thrombectomy. These findings reconcile historical discrepancies in chronobiological stroke research by demonstrating that the clinical impact of circadian disruption is inherently context-dependent and coupled to underlying lesion magnitude. Because this investigation was retrospective and single-center in design, the observed threshold inflection point and interaction estimates remain strictly hypothesis-generating. Future prospective multicenter cohorts incorporating physiological circadian monitoring, comprehensive hemodynamic profiling, and diverse reperfusion grades will be essential to validate this state-structure paradigm before chronobiological timing can directly inform acute stroke triage and neuroprotective interventions.

Subject of Research: Interaction between circadian misalignment and infarct volume on stroke recovery

Article Title: Social-biological misalignment modulates the prognostic impact of infarct volume after endovascular thrombectomy

Article References: Liu, Y., Chen, C., & Yang, C. (2026). Social-biological misalignment modulates the prognostic impact of infarct volume after endovascular thrombectomy. Frontiers in Neurology, 17, Article 1985723. https://doi.org/10.3389/fneur.2026.1985723

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1985723

Keywords: acute ischemic stroke, endovascular thrombectomy, circadian rhythm, social-biological misalignment, infarct volume, functional outcome, modified Rankin Scale, large vessel occlusion, neurocritical care, recanalization, effect modification, logistic regression, Firth penalized regression, reperfusion injury, chronobiology, clinical neurology