Journal article
Determinants of Outcome After Endovascular Middle Cerebral Artery Occlusion in Rats in the SPAN Trial
Stroke (1970), Vol.56(9), pp.2734-2747
09/2025
DOI: 10.1161/STROKEAHA.125.051235
PMCID: PMC12353655
PMID: 40396268
Abstract
The SPAN (Stroke Preclinical Assessment Network) is a confirmatory trial platform to test the efficacy and safety of candidate cerebroprotective interventions in acute stroke. As the largest multicenter preclinical stroke trial to date, the SPAN1 trial (first SPAN) prospectively captured many biological and procedural variables, revealing a high degree of heterogeneity introduced by the multicenter approach that may impact stroke outcomes. Here, we examined the biological and procedural predictors of tissue and neurological outcomes after focal cerebral ischemic stroke in rats.
SPAN1 enrolled and randomized 698 rats to various active treatment arms or controls. Rats were subjected to transient middle cerebral artery occlusion for 60 (spontaneously hypertensive rats) or 120 minutes (young, healthy Sprague-Dawley rats) and followed for 1 month. Nine biological and procedural independent variables (sex, weight, strain, intervention arm, site, endovascular filament silicone tip coating characteristics, anesthesia duration, and intervention protocol) and 5 dependent outcome variables (weight loss, 4-point neuroscore, corner test, infarct volume, and mortality) were captured. Multivariable regression was used to identify independent predictors of each outcome readout and determine their effect sizes.
Spontaneously hypertensive rats exhibited larger infarcts than Sprague-Dawley rats, particularly among females. Neuroscores were also worse in spontaneously hypertensive rats. Prolonged anesthesia exposure was associated with smaller cortical and hippocampal infarcts. Filament thickness and length showed a complex association with different regional infarct volumes, neuroscores, weight loss, and corner test outcomes. Mortality was worse among females. Bivariate analysis of dependent variables revealed moderate correlations among the tissue and neurological outcomes.
Using the large and multicenter, prospective SPAN1 dataset, our multivariable analyses identified several predictors influencing rat middle cerebral artery occlusion outcomes and refuted others previously reported. Investigators should consider whether biological and procedural predictors identified herein should be standardized, accounted for, or stratified during subject allocation to decrease variability and avoid confounders in future multicenter preclinical trials.
Details
- Title: Subtitle
- Determinants of Outcome After Endovascular Middle Cerebral Artery Occlusion in Rats in the SPAN Trial
- Creators
- Xuyan Jin - Massachusetts General HospitalAndreia Morais - Massachusetts General HospitalTakahiko Imai - Massachusetts General HospitalJessica Lamb - Keck Hospital of USCKarisma Nagarkatti - Keck Hospital of USCLigia S B Boisserand - Yale UniversityHannah Beatty - Yale UniversityLauren H Sansing - Yale UniversityMohammad B Khan - Augusta UniversityKrishnan Dhandapani - Augusta UniversityPradip Kamat - Augusta UniversityDavid C Hess - Augusta UniversityRakesh B Patel - University of IowaMariia Kumskova - University of IowaAnil K Chauhan - University of IowaLouise D McCullough - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (L.D.M., J.A.)Jaroslaw Aronowski - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (L.D.M., J.A.)Enrique C Leira - University of IowaYanrong Shi - Johns Hopkins UniversityBrooklyn D Avery - Johns Hopkins UniversityRaymond C Koehler - Johns Hopkins UniversityPatrick D Lyden - Keck Hospital of USCCenk Ayata - Massachusetts General Hospital
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.56(9), pp.2734-2747
- DOI
- 10.1161/STROKEAHA.125.051235
- PMID
- 40396268
- PMCID
- PMC12353655
- NLM abbreviation
- Stroke
- ISSN
- 1524-4628
- eISSN
- 1524-4628
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Grant note
- National Institutes of Health: U01NS113388, R35HL139926 University of Southern California: U24NS113452 Yale University School of Medicine: U01NS113445 Johns Hopkins University: U01NS113444, R01NS102583, R01NS105894 Augusta University: R01NS099455, U01NS113356, R01NS112511 Massachusetts General Hospital: U01NS113443 University of Texas: U01NS113451
Supported by the National Institutes of Health funding to the University of Iowa (U01NS113388, R35HL139926, Dr Chauhan and U01NS113388, Dr Leira), the University of Southern California (U24NS113452, Dr Lyden), the Yale University School of Medicine (U01NS113445, Dr Sansing), the Johns Hopkins University (U01NS113444, R01NS102583, and R01NS105894, Dr Koehler), the Augusta University (R01NS099455, U01NS113356, and R01NS112511, Dr Hess), the Massachusetts General Hospital (U01NS113443, Dr Ayata), the University of Texas (U01NS113451, Dr McCullough and Dr Aronowski).
- Language
- English
- Electronic publication date
- 05/21/2025
- Date published
- 09/2025
- Academic Unit
- Neurology; Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
- Record Identifier
- 9984824288502771
Metrics
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