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February 09, 2021; 96 (6) Article

Endothelial and Leukocyte-Derived Microvesicles and Cardiovascular Risk After Stroke

PROSCIS-B

View ORCID ProfileShufan Huo, Nicolle Kränkel, Alexander Heinrich Nave, View ORCID ProfilePia Sophie Sperber, View ORCID ProfileJessica Lee Rohmann, View ORCID ProfileSophie Käthe Piper, Peter Ulrich Heuschmann, View ORCID ProfileUlf Landmesser, Matthias Endres, View ORCID ProfileBob Siegerink, Thomas Günter Liman
First published November 12, 2020, DOI: https://doi.org/10.1212/WNL.0000000000011223
Shufan Huo
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Nicolle Kränkel
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Alexander Heinrich Nave
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Pia Sophie Sperber
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Jessica Lee Rohmann
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Sophie Käthe Piper
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Peter Ulrich Heuschmann
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Ulf Landmesser
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Matthias Endres
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Bob Siegerink
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Thomas Günter Liman
From the Center for Stroke Research Berlin CSB (S.H., A.H.N., P.S.S., J.L.R., M.E., B.S., T.G.L.), Klinik für Neurologie (S.H., A.H.N., M.E., T.G.L.), Institute of Public Health (J.L.R.), Institute of Biometry and Clinical Epidemiology (S.K.P.), Campus Benjamin Franklin (N.K., U.L.), Department of Cardiology, and Excellence Cluster Neurocure (M.E.), Charité-Universitätsmedizin Berlin; DZHK (German Centre for Cardiovascular Research), partner site Berlin (S.H., N.K., A.H.N., P.S.S., U.L., M.E., T.G.L.); Berlin Institute of Health (A.H.N., S.K.P.); Institute of Clinical Epidemiology and Biometry (P.H.), University of Würzburg; Clinical Trial Center Würzburg (P.H., U.L.), University Hospital Würzburg; and DZNE (German Center for Neurodegenerative Disease) Partner Site Berlin (M.E.), Germany.
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Citation
Endothelial and Leukocyte-Derived Microvesicles and Cardiovascular Risk After Stroke
PROSCIS-B
Shufan Huo, Nicolle Kränkel, Alexander Heinrich Nave, Pia Sophie Sperber, Jessica Lee Rohmann, Sophie Käthe Piper, Peter Ulrich Heuschmann, Ulf Landmesser, Matthias Endres, Bob Siegerink, Thomas Günter Liman
Neurology Feb 2021, 96 (6) e937-e946; DOI: 10.1212/WNL.0000000000011223

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Abstract

Objective To determine the role of circulating microvesicles (MV) on long-term cardiovascular outcomes after stroke, we measured them in patients with first-ever stroke with a 3-year follow-up.

Methods In the Prospective Cohort With Incident Stroke Berlin (PROSCIS-B), patients with first-ever ischemic stroke were followed up for 3 years. The primary combined endpoint consisted of recurrent stroke, myocardial infarction, and all-cause mortality. Citrate-blood levels of endothelial MV (EMV), leukocyte-derived MV (LMV), monocytic MV (MMV), and platelet-derived MV (PMV) were measured with flow cytometry. Kaplan-Meier curves and adjusted Cox proportional hazards models were used to estimate the effect of MV levels on the combined endpoint.

Results Five hundred seventy-one patients were recruited (median age 69 years, 39% female, median NIH Stroke Scale score 2, interquartile range 1–4), and 95 endpoints occurred. Patients with levels of EMV (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.2–4.9) or LMV (HR 3.1, 95% CI 1.4–6.8) in the highest quartile were more likely to experience an event than participants with lower levels with the lowest quartile used as the reference category. The association was less pronounced for PMV (HR 1.7, 95% CI 0.9–3.2) and absent for MMV (HR 1.1, 95% CI 0.6–1.8).

Conclusion High levels of EMV and LMV after stroke were associated with worse cardiovascular outcome within 3 years. These results reinforce that endothelial dysfunction and vascular inflammation affect the long-term prognosis after stroke. EMV and LMV might play a role in risk prediction for stroke patients.

ClinicalTrials.gov Identifier NCT01363856.

Classification of Evidence This study provides Class II evidence of the effect of MV levels on subsequent stroke, myocardial infarction, or all-cause mortality in survivors of mild stroke.

Glossary

AV=
annexin V;
CAD=
coronary artery disease;
CI=
confidence interval;
ED=
endothelial dysfunction;
EMV=
endothelial MV;
HR=
hazard ratio;
IQR=
interquartile range;
LAA=
large artery atherosclerotic;
LMV=
leukocyte-derived MV;
MI=
myocardial infarction;
MMV=
monocytic MV;
MV=
microvesicles;
NIHSS=
NIH Stroke Scale;
PMV=
platelet-derived MV;
PROCIS-B=
Prospective Cohort with Incident Stroke Berlin;
py=
person-years;
rcf=
relative centrifugal force;
TOAST=
Trial of ORG 10172 in Acute Stroke Treatment

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Class of Evidence: NPub.org/coe

  • Received January 22, 2020.
  • Accepted in final form October 5, 2020.
  • © 2020 American Academy of Neurology
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