MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in context
Summary: Background: Matrix metalloproteinases (MMPs) are implied in blood–brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collate...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-05-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424001300 |
| _version_ | 1827292118740107264 |
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| author | Alexander M. Kollikowski Mirko Pham Alexander G. März Jörn Feick Marius L. Vogt Yanyan Xiong Marc Strinitz Christoph Vollmuth Fabian Essig Hermann Neugebauer Karl Georg Haeusler Christian Hametner Lena Zimmermann Guido Stoll Michael K. Schuhmann |
| author_facet | Alexander M. Kollikowski Mirko Pham Alexander G. März Jörn Feick Marius L. Vogt Yanyan Xiong Marc Strinitz Christoph Vollmuth Fabian Essig Hermann Neugebauer Karl Georg Haeusler Christian Hametner Lena Zimmermann Guido Stoll Michael K. Schuhmann |
| author_sort | Alexander M. Kollikowski |
| collection | DOAJ |
| description | Summary: Background: Matrix metalloproteinases (MMPs) are implied in blood–brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). Methods: We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. Findings: Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40–94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4–569.6] vs 441 [IQR 223.4–731.5] ng/ml, p < 0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007–5086] vs 3078 [IQR 1108–7963], p = 0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c–3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5 at hospital discharge) by 2.33 times per 1000 ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. Interpretation: Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. Funding: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg. |
| first_indexed | 2024-04-24T12:51:07Z |
| format | Article |
| id | doaj.art-6cbc00f3ba454381a890f3ccf41b2636 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-24T12:51:07Z |
| publishDate | 2024-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6cbc00f3ba454381a890f3ccf41b26362024-04-06T04:40:02ZengElsevierEBioMedicine2352-39642024-05-01103105095MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in contextAlexander M. Kollikowski0Mirko Pham1Alexander G. März2Jörn Feick3Marius L. Vogt4Yanyan Xiong5Marc Strinitz6Christoph Vollmuth7Fabian Essig8Hermann Neugebauer9Karl Georg Haeusler10Christian Hametner11Lena Zimmermann12Guido Stoll13Michael K. Schuhmann14Department of Neuroradiology, University Hospital Würzburg, Würzburg, Germany; Corresponding author. Department of Neuroradiology, University Hospital Würzburg, Josef-Schneider-Str.11, 97080, Würzburg, Germany.Department of Neuroradiology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neuroradiology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neuroradiology, University Hospital Würzburg, Würzburg, Germany; Department of Radiology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neuroradiology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neuroradiology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neuroradiology, University Hospital Würzburg, Würzburg, Germany; Department of Neuroradiology, Rechts der Isar Hospital, Technical University Munich, Munich, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, Germany; Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, GermanyDepartment of Neurology, University Hospital Würzburg, Würzburg, Germany; Corresponding author. Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str.11, 97080, Würzburg, Germany.Summary: Background: Matrix metalloproteinases (MMPs) are implied in blood–brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). Methods: We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. Findings: Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40–94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4–569.6] vs 441 [IQR 223.4–731.5] ng/ml, p < 0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007–5086] vs 3078 [IQR 1108–7963], p = 0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c–3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5 at hospital discharge) by 2.33 times per 1000 ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. Interpretation: Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. Funding: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.http://www.sciencedirect.com/science/article/pii/S2352396424001300StrokeIschaemic strokeLarge-vessel occlusionMatrix metalloproteinasesMMP-9MMP-2 |
| spellingShingle | Alexander M. Kollikowski Mirko Pham Alexander G. März Jörn Feick Marius L. Vogt Yanyan Xiong Marc Strinitz Christoph Vollmuth Fabian Essig Hermann Neugebauer Karl Georg Haeusler Christian Hametner Lena Zimmermann Guido Stoll Michael K. Schuhmann MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in context EBioMedicine Stroke Ischaemic stroke Large-vessel occlusion Matrix metalloproteinases MMP-9 MMP-2 |
| title | MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in context |
| title_full | MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in context |
| title_fullStr | MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in context |
| title_full_unstemmed | MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in context |
| title_short | MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept studyResearch in context |
| title_sort | mmp 9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke a proof of concept studyresearch in context |
| topic | Stroke Ischaemic stroke Large-vessel occlusion Matrix metalloproteinases MMP-9 MMP-2 |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424001300 |
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