Matthew J Feinstein1, Petra Buzkova2, Nels C Olson3, Margaret F Doyle3, Colleen M Sitlani2, Alison E Fohner2, Sally A Huber3, James Floyd2, Arjun Sinha4, Edward B Thorp5, Alan Landay6, Matthew S Freiberg7, William T Longstreth8, Russell P Tracy3, Bruce M Psaty9, Joseph Ac Delaney10. 1. Division of Cardiology in the Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Clinical and Translational Immunocardiology Program, Northwestern Medicine Bluhm Cardiovascular Institute, Chicago, IL, USA. Electronic address: matthewjfeinstein@northwestern.edu. 2. University of Washington, Seattle, WA, USA. 3. University of Vermont, Burlington, VT, USA. 4. Division of Cardiology in the Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Clinical and Translational Immunocardiology Program, Northwestern Medicine Bluhm Cardiovascular Institute, Chicago, IL, USA. 5. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Clinical and Translational Immunocardiology Program, Northwestern Medicine Bluhm Cardiovascular Institute, Chicago, IL, USA. 6. Rush University Medical Center, Chicago, IL, USA. 7. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. 8. University of Washington, Seattle, WA, USA; Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, USA. 9. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA. 10. University of Manitoba, Winnipeg, Manitoba, Canada.
Abstract
BACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke. METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models. RESULTS: We observed associations of intermediate monocytes, early-activated CD4+ T cells, and both CD4+ and CD8+ T cells producing interleukin-4 after cytokine stimulation (Th2 and Tc2, respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women. CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.
BACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke. METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models. RESULTS: We observed associations of intermediate monocytes, early-activated CD4+ T cells, and both CD4+ and CD8+ T cells producing interleukin-4 after cytokine stimulation (Th2 and Tc2, respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women. CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.
Authors: John Danesh; Sarah Lewington; Simon G Thompson; Gordon D O Lowe; Rory Collins; J B Kostis; A C Wilson; A R Folsom; K Wu; M Benderly; U Goldbourt; J Willeit; S Kiechl; J W G Yarnell; P M Sweetnam; P C Elwood; M Cushman; B M Psaty; R P Tracy; A Tybjaerg-Hansen; F Haverkate; M P M de Maat; F G R Fowkes; A J Lee; F B Smith; V Salomaa; K Harald; R Rasi; E Vahtera; P Jousilahti; J Pekkanen; R D'Agostino; W B Kannel; P W F Wilson; G Tofler; C L Arocha-Piñango; A Rodriguez-Larralde; E Nagy; M Mijares; R Espinosa; E Rodriquez-Roa; E Ryder; M P Diez-Ewald; G Campos; V Fernandez; E Torres; R Marchioli; F Valagussa; A Rosengren; L Wilhelmsen; G Lappas; H Eriksson; P Cremer; D Nagel; J D Curb; B Rodriguez; K Yano; J T Salonen; K Nyyssönen; T-P Tuomainen; B Hedblad; P Lind; H Loewel; W Koenig; T W Meade; J A Cooper; B De Stavola; C Knottenbelt; G J Miller; J A Cooper; K A Bauer; R D Rosenberg; S Sato; A Kitamura; Y Naito; T Palosuo; P Ducimetiere; P Amouyel; D Arveiler; A E Evans; J Ferrieres; I Juhan-Vague; A Bingham; H Schulte; G Assmann; B Cantin; B Lamarche; J-P Després; G R Dagenais; H Tunstall-Pedoe; M Woodward; Y Ben-Shlomo; G Davey Smith; V Palmieri; J L Yeh; A Rudnicka; P Ridker; F Rodeghiero; A Tosetto; J Shepherd; I Ford; M Robertson; E Brunner; M Shipley; E J M Feskens; D Kromhout; A Dickinson; B Ireland; K Juzwishin; S Kaptoge; S Lewington; A Memon; N Sarwar; M Walker; J Wheeler; I White; A Wood Journal: JAMA Date: 2005-10-12 Impact factor: 56.272
Authors: Christopher C Patterson; Anne E Smith; John W G Yarnell; Ann Rumley; Yoav Ben-Shlomo; Gordon D O Lowe Journal: Atherosclerosis Date: 2009-09-27 Impact factor: 5.162
Authors: Sanne Willems; Aryan Vink; Ilze Bot; Paul H A Quax; Gert Jan de Borst; Jean-Paul P M de Vries; Sander M van de Weg; Frans L Moll; Johan Kuiper; Petri T Kovanen; Dominique P V de Kleijn; Imo E Hoefer; Gerard Pasterkamp Journal: Eur Heart J Date: 2013-06-11 Impact factor: 29.983