TY - JOUR
T1 - Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome
AU - Heitsch, Laura
AU - Ibanez, Laura
AU - Carrera, Caty
AU - Binkley, Michael M.
AU - Strbian, Daniel
AU - Tatlisumak, Turgut
AU - Bustamante, Alejandro
AU - Ribó, Marc
AU - Molina, Carlos
AU - Dávalos, Antoni
AU - López-Cancio, Elena
AU - Muñoz-Narbona, Lucia
AU - Soriano-Tárraga, Carol
AU - Giralt-Steinhauer, Eva
AU - Obach, Victor
AU - Slowik, Agnieszka
AU - Pera, Joanna
AU - Lapicka-Bodzioch, Katarzyna
AU - Derbisz, Justyna
AU - Sobrino, Tomás
AU - Castillo, José
AU - Campos, Francisco
AU - Rodríguez-Castro, Emilio
AU - Arias-Rivas, Susana
AU - Segura, Tomas
AU - Serrano-Heras, Gemma
AU - Vives-Bauza, Cristófol
AU - Díaz-Navarro, Rosa
AU - Tur, Silva
AU - Jimenez, Carmen
AU - Martí-Fàbregas, Joan
AU - Delgado-Mederos, Raquel
AU - Arenillas, Juan
AU - Krupinski, Jerzy
AU - Cullell, Natalia
AU - Torres-Aguila, Nuria P.
AU - Muiño, Elena
AU - Cárcel-Márquez, Jara
AU - Moniche, Francisco
AU - Cabezas, Juan A.
AU - Ford, Andria L.
AU - Dhar, Rajat
AU - Roquer, Jaume
AU - Khatri, Pooja
AU - Jiménez-Conde, Jordi
AU - Fernandez-Cadenas, Israel
AU - Montaner, Joan
AU - Rosand, Jonathan
AU - Cruchaga, Carlos
AU - Lee, Jin Moo
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) R01NS085419 (Dr Lee, Dr Montaner, and C.Cruchaga); NIH K23 NS099487 (Dr Heitsch); Emergency Medicine Foundation (Dr Heitsch); American Heart Association National Committee for Responsive PhilanthropyMentored Clinical and Population Research (14CRP18860027; Dr Heitsch); NIH U24NS107230 (Dr Lee); Barnes-Jewish Hospital Foundation (Dr Lee); Biogen (C.Cruchaga, and Dr Lee); R01NIH National Heart, Lung, and Blood Institute R01HL129241 (Dr Ford); NIH K23NS099440 (Dr Dhar); Helsinki University Central Hospital (Finland government subsidiary funds; Drs Tatlisumak and Strbian); Finnish Medical Foundation (Drs Tatlisumak and Strbian); Finnish Academy of Sciences (Dr Tatlisumak); Sigrid Juselius Foundation (Dr Tatlisumak); University of Gothenburg grant (Dr Tatlisumak); Sahlgrenska University Hospital grant (Dr Tatlisumak); and Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (Generación Project and Maestro project [Dr Fernandez-Cadenas]); grants Registro BASICMAR Funding for Research in Health (PI051737; Dr Jiménez-Conde), GWALA project from Fondos de Investigación Sanitaria ISC III (PI10/02064), (PI12/01238), and (PI15/00451; Dr Jiménez-Conde); Juan Rodés research contract (JR16/00008; Dr Bustamante); grant PI17/01103 (Dr Campos); Miguel Servet Program grant CPII17/00027 (Dr Sobrino) and CP14/00154 (Dr Campos) and (Dr Fernandez-Cadenas). Le Fonds Européen de Développement Regional/European Regional Development Fund Red de Investigación Cardiovascular (RD12/0042/0020; Dr Jiménez-Conde). Fundació la Marató TV3 (Epigenisis project [Dr Fernan-dez-Cadenas]; GOD’s Project [Dr Jiménez-Conde]); Genestroke Consortium (76/C/2011; Dr Jiménez-Conde); Generación Project (Dr Jiménez-Conde); and Recercaixa’13 (JJ086116; Dr Jiménez-Conde). Agència de Gestió d’Ajuts Uni-versitaris i de Recerca (2019_FI_B 00853; J. Cárcel-Márquez); Spanish Ministry of Economy and Competitiveness (SAF2017-84267-R [Dr Contaner]); Xunta de Galicia (IN607A2018/3 [Dr Contaner]); Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS PLUS (RD16/0019 [most of Spanish groups]); and European Union Le Fonds Européen de Développement Regional (FEDER) program.
Funding Information:
Dr Tatlisumak reports grants and personal fees from Bayer, grants and personal fees from Boehringer Ingelheim, personal fees from Bristol Myers Squibb, personal fees from Lumosa Pharm, and grants and personal fees from Portola Pharm outside the submitted work. Dr Arenillas reports having received honoraria as speaker/consultant for the following companies: Boehringer Ingelheim, Pfizer, Daiichi, Bayer, Amgen, and Medtronic. Dr Krupinski reports consultancy fees from Boehringer Ingelheim, Ferrer and Bayer. Dr Khatri reports grants from Cerenovus, grants from Nervive, consulting fees from Lumosa, and compensation for PI effort from Bayer outside the submitted work. Dr Rosand reports grants from OneMind for Research and the American Heart Association as well as consulting fees from Boehringer Ingelheim, all of which are outside the scope of the submitted work. Dr Cruchaga receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr Cruchaga is also a member of the advisory board of Vivid genetics, Halia Therapeutics, and ADx Healthcare. Dr Lee reports research support from Biogen and personal fees from Regenera. The other authors report no conflicts.
Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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 ΔNIHSS6-24hwas examined. Finally, the association of ΔNIHSS6-24hwith 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 ΔNIHSS6-24hwas 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. ΔNIHSS6-24hhad a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24hwas 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, ΔNIHSS6-24hpromises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.
AB - 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 ΔNIHSS6-24hwas examined. Finally, the association of ΔNIHSS6-24hwith 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 ΔNIHSS6-24hwas 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. ΔNIHSS6-24hhad a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24hwas 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, ΔNIHSS6-24hpromises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.
KW - genome-wide association study
KW - phenotype
KW - population
KW - stroke, ischemic
UR - http://www.scopus.com/inward/record.url?scp=85099034710&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.119.028687
DO - 10.1161/STROKEAHA.119.028687
M3 - Article
C2 - 33317415
AN - SCOPUS:85099034710
SN - 0039-2499
VL - 52
SP - 132
EP - 141
JO - Stroke
JF - Stroke
IS - 1
ER -