Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.

Autor:	Morais A; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (A.M., T.I., X.J., K.v.L., C.A.)., Imai T; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (A.M., T.I., X.J., K.v.L., C.A.)., Jin X; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (A.M., T.I., X.J., K.v.L., C.A.)., Locascio JJ; Harvard Catalyst Biostatistical Consulting Unit, Department of Biostatistics, Harvard Medical School, Boston, MA (J.J.L.).; Department of Neurology, Massachusetts General Hospital, Boston, Harvard Medical School (J.J.L., W.T.K., C.A.)., Boisserand L; Department of Neurology (L.B., A.L.H., L.H.S.), Yale University School of Medicine, New Haven, CT.; Department of Immunobiology (L.B., A.L.H., L.H.S.), Yale University School of Medicine, New Haven, CT., Herman AL; Department of Neurology (L.B., A.L.H., L.H.S.), Yale University School of Medicine, New Haven, CT.; Department of Immunobiology (L.B., A.L.H., L.H.S.), Yale University School of Medicine, New Haven, CT., Chauhan A; Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A.C., J.A.)., Lamb J; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (J.L., K.N., P.D.L.).; Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA (J.L., K.N., P.D.L.)., Nagarkatti K; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (J.L., K.N., P.D.L.).; Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA (J.L., K.N., P.D.L.)., Diniz MA; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York (M.A.D.)., Kumskova M; Department of Internal Medicine, Carver College of Medicine (M.K., N.D., R.B.P., B.S., A.K.C.), University of Iowa, Iowa City., Dhanesha N; Department of Internal Medicine, Carver College of Medicine (M.K., N.D., R.B.P., B.S., A.K.C.), University of Iowa, Iowa City.; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport (N.D., M.B.K.)., Kamat PK; Department of Neurology (P.K.K., D.C.H.), Medical College of Georgia, Augusta University., Badruzzaman Khan M; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport (N.D., M.B.K.)., Dhandapani KM; Department of Neurosurgery (K.M.D.), Medical College of Georgia, Augusta University., Patel RB; Department of Internal Medicine, Carver College of Medicine (M.K., N.D., R.B.P., B.S., A.K.C.), University of Iowa, Iowa City., Sutariya B; Department of Internal Medicine, Carver College of Medicine (M.K., N.D., R.B.P., B.S., A.K.C.), University of Iowa, Iowa City., Shi Y; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore (Y.S., R.C.K.)., van Leyen K; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (A.M., T.I., X.J., K.v.L., C.A.)., Kimberly WT; Department of Neurology, Massachusetts General Hospital, Boston, Harvard Medical School (J.J.L., W.T.K., C.A.)., Hess DC; Department of Neurology (P.K.K., D.C.H.), Medical College of Georgia, Augusta University., Aronowski J; Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A.C., J.A.)., Leira EC; Departments of Neurology, Neurosurgery, Carver College of Medicine, and Epidemiology, College of Public Health (E.C.L.), University of Iowa, Iowa City., Koehler RC; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore (Y.S., R.C.K.)., Chauhan AK; Department of Internal Medicine, Carver College of Medicine (M.K., N.D., R.B.P., B.S., A.K.C.), University of Iowa, Iowa City., Sansing LH; Department of Neurology (L.B., A.L.H., L.H.S.), Yale University School of Medicine, New Haven, CT.; Department of Immunobiology (L.B., A.L.H., L.H.S.), Yale University School of Medicine, New Haven, CT., Lyden PD; Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Los Angeles, CA (J.L., K.N., P.D.L.).; Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA (J.L., K.N., P.D.L.)., Ayata C; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (A.M., T.I., X.J., K.v.L., C.A.).; Department of Neurology, Massachusetts General Hospital, Boston, Harvard Medical School (J.J.L., W.T.K., C.A.).
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2024 Aug 16; Vol. 135 (5), pp. 575-592. Date of Electronic Publication: 2024 Jul 22.
DOI:	10.1161/CIRCRESAHA.123.324139
Abstrakt:	Background: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo. Methods: The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes. Results: Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes. Conclusions: Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivariable model, and the large sample size, we think this is the most definitive analysis of the predictors of preclinical stroke outcome to date. Future multicenter experimental stroke trials should standardize or at least ensure a balanced representation of the biological and procedural variables identified herein as potential confounders. Competing Interests: P.D. Lyden reports compensation from the National Institutes of Health Clinical Center for other services, and compensation from Apex Innovations and EMD Serono for consultant services. C. Ayata reports compensation from Neurelis Inc for other services.
Databáze:	MEDLINE
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