Exploring Sex Differences in Stroke Outcomes: A Comprehensive Analysis From the SPAN 1 Trial

Anjali Chauhan; Eunyoung Angela Lee; Rakesh B Patel; Mariia Kumskova; Enrique C Leira; Anil Chauhan; Yanrong Shi; Suyi Cao; Raymond C Koehler; Krishnan M Dhandapani; Mohammad Badruzzaman Khan; Pradip K Kamat; Ali Arbab; David C Hess; Alison L Herman; Ligia Boisserand; Lauren H Sansing; Andreia Morais; Xuyan Jin; Sanem Aykan; Takahiko Imai; Cenk Ayata; Karisma A Nagarkatti; Jessica Lamb; Márcio A Diniz; Patrick D Lyden; Jaroslaw Aronowski; Louise D McCullough

doi:10.1161/JAHA.125.043220

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Exploring Sex Differences in Stroke Outcomes: A Comprehensive Analysis From the SPAN 1 Trial

Journal article

Open access

Peer reviewed

Exploring Sex Differences in Stroke Outcomes: A Comprehensive Analysis From the SPAN 1 Trial

Anjali Chauhan, Eunyoung Angela Lee, Rakesh B Patel, Mariia Kumskova, Enrique C Leira, Anil Chauhan, Yanrong Shi, Suyi Cao, Raymond C Koehler, Krishnan M Dhandapani, …

Journal of the American Heart Association, Vol.15(4), e043220

02/17/2026

DOI: 10.1161/JAHA.125.043220

PMCID: PMC13055782

PMID: 41631765

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Abstract

Stroke is a sexually dimorphic disease, with different risk factors, incidence, outcomes, and treatment responses in men and women. While sex differences have been documented in preclinical studies, these findings often come from single-site studies with small sample sizes and require validation across diverse research settings. We used data from the SPAN (Stroke Preclinical Assessment Network), a randomized, placebo-controlled, blinded, multilaboratory trial, to determine if sex differences in neurological outcomes are present in preclinical stroke models. We analyzed data from 665 stroke animals treated with saline, including young mice, diet-induced obese mice, aging mice, young rats, and spontaneously hypertensive rats. We compared the corner test index and brain morphology between the sexes using linear random effect models and assessed the mortality rate using Cox proportional hazard regression models. No significant sex differences were found in neurological outcome measured with the corner test on either day 7 or day 30 after stroke, regardless of the mouse or rat stroke model used. Additionally, female and male mice exhibited similar infarct sizes on day 2 magnetic resonance imaging and on brain atrophy measures on day 30 after stroke, indicating a lack of sex differences in brain injury. Similarly, no sex differences were observed in acute or chronic sensorimotor or tissue outcomes in young rats. In 1 subanalysis, sex differences were seen in the spontaneously hypertensive rats cohort. Female rats exhibited a higher corner test index on day 30 than males, indicating more severe sensorimotor injury. In this multicenter preclinical study, we did not detect sex differences in stroke outcomes in mice, although sex differences in behavioral outcomes were observed in spontaneously hypertensive rats. These findings highlight that sex differences may be model-specific and subtle, emphasizing the need for methodological consistency and thoughtful inclusion of diverse animal models in translational stroke research to better understand if sex-specific responses contribute to stroke outcomes.

Magnetic Resonance Imaging

Animals

Brain - diagnostic imaging

Brain - pathology

Disease Models, Animal

Female

Male

Mice

Mice, Inbred C57BL

Rats

Rats, Inbred SHR

Sex Factors

Stroke - mortality

Stroke - physiopathology

Details

Title: Subtitle: Exploring Sex Differences in Stroke Outcomes: A Comprehensive Analysis From the SPAN 1 Trial
Creators: Anjali Chauhan - University of Iowa
Eunyoung Angela Lee - University of Iowa
Rakesh B Patel - The University of Texas Health Science Center
Mariia Kumskova - University of Iowa
Enrique C Leira - University of Iowa
Anil Chauhan - University of Iowa
Yanrong Shi - University of Iowa
Suyi Cao - University of Iowa
Raymond C Koehler - Johns Hopkins University
Krishnan M Dhandapani - Johns Hopkins University
Mohammad Badruzzaman Khan - Johns Hopkins University
Pradip K Kamat - Augusta University
Ali Arbab - Augusta University
David C Hess - Augusta University
Alison L Herman - Augusta University
Ligia Boisserand - Augusta University
Lauren H Sansing - Yale University
Andreia Morais - Yale University
Xuyan Jin - Yale University
Sanem Aykan - Harvard University
Takahiko Imai - Harvard University
Cenk Ayata - Harvard University
Karisma A Nagarkatti - Harvard University
Jessica Lamb - Harvard University
Márcio A Diniz - Keck Hospital of USC
Patrick D Lyden - Keck Hospital of USC
Jaroslaw Aronowski - Icahn School of Medicine at Mount Sinai
Louise D McCullough - Keck Hospital of USC
Resource Type: Journal article
Publication Details: Journal of the American Heart Association, Vol.15(4), e043220
DOI: 10.1161/JAHA.125.043220
PMID: 41631765
PMCID: PMC13055782
NLM abbreviation: J Am Heart Assoc
ISSN: 2047-9980
eISSN: 2047-9980
Publisher: American Heart Association
Grant note: National Institutes of Health funding to Massachusetts General Hospital: U01NS113443 Yale University: U01NS113445 University of Texas: U01NS113451, R35NS132265 University of Southern California: U24NS113452 Johns Hopkins University: U01NS113444, R01NS102583, R01NS105894 University of Iowa: U01NS113388, R35HL139926 Augusta University: R01 NS099455, RF1NS122863, U01NS113356 Laboratory of Neuro Imaging Resource at the University of Southern California: P41EB015922
National Institutes of Health funding to Massachusetts General Hospital (U01NS113443, Dr Ayata), Yale University (U01NS113445, Dr Sansing), University of Texas (U01NS113451, Dr Aronowski, R35NS132265, Dr McCullough), the University of Southern California (U24NS113452, Dr Lyden), Johns Hopkins University (U01NS113444, R01NS102583, and R01NS105894), University of Iowa (U01NS113388, Drs Chauhan and Leira; R35HL139926, Dr Chauhan), Augusta University (R01 NS099455; RF1NS122863 and U01NS113356, Dr Hess), and the Laboratory of Neuro Imaging Resource at the University of Southern California (P41EB015922).
Language: English
Date published: 02/17/2026
Academic Unit: Neurology; Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
Record Identifier: 9985139299402771

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