Laura Heitsch1,2, Laura Ibanez3, Caty Carrera4,5, Michael M Binkley1, Daniel Strbian6, Turgut Tatlisumak6,7, Alejandro Bustamante4,5, Marc Ribó5, Carlos Molina5, Antoni Dávalos8, Elena López-Cancio9, Lucia Muñoz-Narbona10, Carol Soriano-Tárraga10, Eva Giralt-Steinhauer10,11, Victor Obach12, Agnieszka Slowik13, Joanna Pera13, Katarzyna Lapicka-Bodzioch14, Justyna Derbisz13, Tomás Sobrino15,16, José Castillo15, Francisco Campos15, Emilio Rodríguez-Castro15, Susana Arias-Rivas15, Tomas Segura15,16, Gemma Serrano-Heras16, Cristófol Vives-Bauza17, Rosa Díaz-Navarro17, Silva Tur17, Carmen Jimenez17, Joan Martí-Fàbregas18, Raquel Delgado-Mederos18, Juan Arenillas19, Jerzy Krupinski20,21, Natalia Cullell22,23, Nuria P Torres-Aguila23, Elena Muiño22,23, Jara Cárcel-Márquez22,23, Francisco Moniche24, Juan A Cabezas24, Andria L Ford2, Rajat Dhar2, Jaume Roquer10,11,25, Pooja Khatri26, Jordi Jiménez-Conde10,11, Israel Fernandez-Cadenas4,20,22, Joan Montaner4,27, Jonathan Rosand10,11,25, Carlos Cruchaga3, Jin-Moo Lee2. 1. Division of Emergency Medicine (L.H.), Washington University School of Medicine, St Louis, MO. 2. Department of Neurology (L.H., M.M.B., A.L.F., R.D., J.-M.L.), Washington University School of Medicine, St Louis, MO. 3. Department of Psychiatry (L.I., C. Cruchaga), Washington University School of Medicine, St Louis, MO. 4. Neurovascular Research Laboratory and Neurovascular Unit, Vall d'Hebron Institute of Research (VHIR) (C. Carrera, A.B., I.F.-C., J.M.), Universitat Autonoma de Barcelona, Spain. 5. Department of Neurology, Hospital Universitari Vall d"Hebron (C. Carrera, A.B., M.R., C.M.), Universitat Autonoma de Barcelona, Spain. 6. Department of Neurology, Helsinki University Hospital, Finland (D.S., T.T.). 7. Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg and Department of Neurology, Sahlgrenska University Hospital, Sweden (T.T.). 8. Department of Neurology, Hospital Universitari Germans Trias I Pujol, Badalona, Spain (A.D.). 9. Department of Neurology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain (E.L.-C.). 10. Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Spain (L.M.-N., C.S.-T., E.G.-S., J.R., J.J.-C.). 11. Department of Neurology, Hospital de Mar, Barcelona, Spain (E.G.-S., J.R., J.J.-C.). 12. Department of Neuroscience, Hospital Clinic, University of Barcelona and August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain (V.O.). 13. Department of Neurology (A.S., J.P., J.D.), Jagiellonian University Medical College, Krakow, Poland. 14. Department of Neurogenetics (K.L.-B.), Jagiellonian University Medical College, Krakow, Poland. 15. Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela, Hospital Clinico Universitario, Universidade de Santiago de Compostela, Spain (T.S., J.C., F.C., E.R.-C., S.A.-R.). 16. Department of Neurology, Hospital Universitario de Albacete, Spain (T.S., G.S.-H.). 17. Department of Neurology, Son Espases University Hospital, IdISBa, Palma de Mallorca, Spain (C.V.-B., R.D.-N., S.T., C.J.). 18. Department of Neurology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain (J.M.-F., R.D.-M.). 19. Department of Neurology, Hospital Clinico Universitario de Valladolid, Spain (J.A.). 20. Department of Neurology, Hospital Mutua de Terrassa, Spain (J.K., I.F.-C.). 21. School of Life Sciences, Centre for Biosciences, Manchester Met University, United Kingdom (J.K.). 22. Stroke Pharmacogenomics and Genetics, Fundacio Docencia I Recerca Mutua de Terrassa, Spain (N.C., E.M., J.C.-M., I.F.-C.). 23. Stroke Pharmacogenomics and Genetics, Sant Pau Institute of Research, Sant Pau Hospital, Barcelona, Spain (N.C., N.P.T.-A., E.M., J.C.-M.). 24. Department of Neurology, Hospital Universitario Virgen del Rocio, Sevilla, Spain (F.M., J.A.C.). 25. Henry and Alison Center for Brain Health, Center for Genomic Medicine, Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (J.R.). 26. Department of Neurology, University of Cincinnati, OH (P.K.). 27. Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville and Department of Neurology, Hospital Universitario Virgen Macarena (J.M.).
Abstract
BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = ΔNIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. METHODS: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). RESULTS: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6-24h (R2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2=0.27), but much of the variance remained unexplained. ΔNIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24h was similarly associated with 90-day outcomes. CONCLUSIONS: The dynamic phenotype, ΔNIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.
BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = ΔNIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. METHODS: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). RESULTS: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6-24h (R2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2=0.27), but much of the variance remained unexplained. ΔNIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24h was similarly associated with 90-day outcomes. CONCLUSIONS: The dynamic phenotype, ΔNIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.
Entities:
Keywords:
genome-wide association study; phenotype; population; stroke, ischemic
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