Large vessel cardioembolic stroke and embolic stroke of undetermined source share a common profile of matrix metalloproteinase-9 level and susceptibility vessel sign length
Hanan Alhazmi
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Resources (lead), Writing - original draft (lead), Writing - review & editing (supporting)
Search for more papers by this authorAlexandre Bani-Sadr
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Data curation (supporting), Resources (supporting), Writing - review & editing (supporting)
Search for more papers by this authorThomas Bochaton
Cardiac Intensive Care Unit, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Formal analysis (supporting), Resources (supporting), Writing - original draft (supporting)
Search for more papers by this authorAlexandre Paccalet
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Validation (supporting)
Search for more papers by this authorClaire Crola Da Silva
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Validation (supporting)
Search for more papers by this authorMarielle Buisson
Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Formal analysis (lead), Investigation (lead), Resources (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCamille Amaz
Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Formal analysis (lead), Investigation (lead), Resources (supporting)
Search for more papers by this authorRoxana Ameli
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Formal analysis (supporting), Resources (supporting), Supervision (supporting)
Search for more papers by this authorYves Berthezene
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CREATIS, CNRS UMR 5220, INSERM U1044, University Lyon 1, Lyon, France
Contribution: Supervision (supporting), Validation (supporting)
Search for more papers by this authorOmer Faruk Eker
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CREATIS, CNRS UMR 5220, INSERM U1044, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Validation (supporting)
Search for more papers by this authorMichel Ovize
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Methodology (supporting), Validation (supporting)
Search for more papers by this authorTae-Hee Cho
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Supervision (supporting), Validation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorNorbert Nighoghossian
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Supervision (lead), Validation (lead), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Laura Mechtouff
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Correspondence
Laura Mechtouff, Stroke Department, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677 Bron, France.
Email: [email protected]
Contribution: Resources (lead), Supervision (lead), Validation (lead), Writing - review & editing (lead)
Search for more papers by this authorHanan Alhazmi
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Resources (lead), Writing - original draft (lead), Writing - review & editing (supporting)
Search for more papers by this authorAlexandre Bani-Sadr
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Data curation (supporting), Resources (supporting), Writing - review & editing (supporting)
Search for more papers by this authorThomas Bochaton
Cardiac Intensive Care Unit, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Formal analysis (supporting), Resources (supporting), Writing - original draft (supporting)
Search for more papers by this authorAlexandre Paccalet
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Validation (supporting)
Search for more papers by this authorClaire Crola Da Silva
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Validation (supporting)
Search for more papers by this authorMarielle Buisson
Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Formal analysis (lead), Investigation (lead), Resources (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCamille Amaz
Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Formal analysis (lead), Investigation (lead), Resources (supporting)
Search for more papers by this authorRoxana Ameli
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Formal analysis (supporting), Resources (supporting), Supervision (supporting)
Search for more papers by this authorYves Berthezene
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CREATIS, CNRS UMR 5220, INSERM U1044, University Lyon 1, Lyon, France
Contribution: Supervision (supporting), Validation (supporting)
Search for more papers by this authorOmer Faruk Eker
Neuroradiology Department, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CREATIS, CNRS UMR 5220, INSERM U1044, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Validation (supporting)
Search for more papers by this authorMichel Ovize
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Clinical Investigation Center, INSERM 1407, Louis Pradel Hospital, Hospices Civils de Lyon, Bron, France
Contribution: Methodology (supporting), Validation (supporting)
Search for more papers by this authorTae-Hee Cho
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Resources (supporting), Supervision (supporting), Validation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorNorbert Nighoghossian
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Contribution: Supervision (lead), Validation (lead), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Laura Mechtouff
Stroke Center, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Bron, France
CarMeN, INSERM U.1060/Université Lyon1/INRA U.1397/INSA Lyon/Hospices Civils Lyon, University Lyon 1, Lyon, France
Correspondence
Laura Mechtouff, Stroke Department, Hospices Civils de Lyon, 59 Boulevard Pinel, 69677 Bron, France.
Email: [email protected]
Contribution: Resources (lead), Supervision (lead), Validation (lead), Writing - review & editing (lead)
Search for more papers by this authorFunding information
This work has been supported by the RHU MARVELOUS (ANR-16-RHUS-0009) of Université Claude Bernard Lyon-1 (UCBL), within the program "Investissements d'Avenir” operated by the French National Research Agency (ANR; Agence Nationale de la Recherche) and the CASDEN prize from CASDEN/Fondation de l’Avenir.
Abstract
Background
Embolic stroke of undetermined source (ESUS) accounts for up to 25% of ischemic strokes. Identification of biomarkers that could improve the prediction of stroke subtype and subsequently of stroke prevention still remains a major issue.
Methods
The HIBISCUS-STROKE cohort includes ischemic stroke patients with large vessel occlusion treated with mechanical thrombectomy following admission magnetic resonance imaging. Presence and length of susceptibility vessel sign (SVS) were assessed by gradient-recalled echo T2*-weighted imaging. Matrix metalloproteinase-9 (MMP-9) was measured on sera collected at admission. A multiple logistic regression model was performed to detect independent markers distinguishing cardioembolic (CE) from large-artery atherosclerosis (LAA) subtype.
Results
A total of 147 patients were included, of them the etiology was distributed as follows: 86 (58.5%) CE, 26 (17.7%) LAA, and 35 (23.8%) ESUS. The optimal cutoff for differentiating CE from LAA subtype was 14.5 mm for SVS length (sensitivity, 79.7%; specificity, 72.7%) and 1110 ng/ml for admission MMP-9 level (sensitivity, 85.3%; specificity, 52.2%). Multivariate analysis revealed that current smoking (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.01–0.93), tandem occlusion (OR 0.01, 95% CI 0.01–0.21), SVS length (OR 0.78, 95% CI 0.63–0.97), and admission MMP-9 level (OR 0.99, 95% CI 0.99–1.00) were inversely associated with CE subtype. SVS length and MMP-9 level did not differ between ESUS and CE subtypes.
Conclusion
SVS length and admission MMP-9 level may improve the prediction of CE subtype whose profile is close to ESUS, thus suggesting a common cardiac embolic source.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author on reasonable request.
REFERENCES
- 1Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50(12): https://doi.org/10.1161/STR.0000000000000211
- 2Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke. 2017; 48(4): 867-872.
- 3Rovira A, Orellana P, Alvarez-Sabín J, et al. Hyperacute ischemic stroke: middle cerebral artery susceptibility sign at echo-planar gradient-echo MR imaging. Radiology. 2004; 232(2): 466-473.
- 4Flacke S, Urbach H, Keller E, et al. Middle cerebral artery (MCA) susceptibility sign at susceptibility-based perfusion MR imaging: clinical importance and comparison with hyperdense MCA sign at CT. Radiology. 2000; 215(2): 476-482.
- 5Cho K-H, Kim JS, Kwon SU, Cho A-H, Kang D-W. Significance of susceptibility vessel sign on T2*-weighted gradient echo imaging for identification of stroke subtypes. Stroke. 2005; 36(11): 2379-2383.
- 6Kang D-W, Jeong H-G, Kim DY, Yang W, Lee S-H. Prediction of stroke subtype and recanalization using susceptibility vessel sign on susceptibility-weighted magnetic resonance imaging. Stroke. 2017; 48(6): 1554-1559.
- 7Horie N, Tateishi Y, Morikawa M, et al. Acute stroke with major intracranial vessel occlusion: characteristics of cardioembolism and atherosclerosis-related in situ stenosis/occlusion. J Clin Neurosci. 2016; 32: 24-29.
- 8Zhang R, Zhou Y, Liu C, et al. Overestimation of susceptibility vessel sign: a predictive marker of stroke cause. Stroke. 2017; 48(7): 1993-1996.
- 9Yamamoto N, Satomi J, Tada Y, et al. Two-layered susceptibility vessel sign on 3-Tesla T2*-weighted imaging is a predictive biomarker of stroke subtype. Stroke. 2015; 46(1): 269-271.
- 10Pfefferkorn T, Rosenberg GA. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke. 2003; 34(8): 2025-2030.
- 11Montaner J, Molina CA, Monasterio J, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003; 107(4): 598-603.
- 12Tan C, Liu Y, Li W, et al. Associations of matrix metalloproteinase-9 and monocyte chemoattractant protein-1 concentrations with carotid atherosclerosis, based on measurements of plaque and intima–media thickness. Atherosclerosis. 2014; 232(1): 199-203.
- 13Loftus IM, Naylor AR, Goodall S, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques: a potential role in acute plaque disruption. Stroke. 2000; 31(1): 40-47.
- 14Heo SH, Cho C-H, Kim HO, et al. Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: involvement of matrix metalloproteinases 2 and 9. J Clin Neurol. 2011; 7(2): 69.
- 15Olejarz W, Łacheta D, Kubiak-Tomaszewska G. Matrix metalloproteinases as biomarkers of atherosclerotic plaque instability. Int J Mol Sci. 2020; 21(11): 3946.
- 16Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24(1): 35-41.
- 17Hart RG, Diener H-C, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014; 13(4): 429-438.
- 18Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. The Lancet. 2000; 355(9216): 1670-1674.
- 19Naggara O, Raymond J, Domingo Ayllon M, et al. T2* “susceptibility vessel sign” demonstrates clot location and length in acute ischemic stroke. PLoS One. 2013; 8(10):e76727.
- 20Higashida RT, Furlan AJ. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003; 34(8): https://doi.org/10.1161/01.STR.0000082721.62796.09
- 21Boodt N, Compagne KCJ, Dutra BG, et al. Stroke etiology and thrombus computed tomography characteristics in patients with acute ischemic stroke: a MR CLEAN Registry Substudy. Stroke. 2020; 51(6): 1727-1735.
- 22Vanacker P, Lambrou D, Eskandari A, et al. Improving the prediction of spontaneous and post-thrombolytic recanalization in ischemic stroke patients. J Stroke Cerebrovasc Dis. 2015; 24(8): 1781-1786.
- 23Qazi EM, Sohn SI, Mishra S, et al. Thrombus characteristics are related to collaterals and angioarchitecture in acute stroke. Can J Neurol Sci J Can Sci Neurol. 2015; 42(6): 381-388.
- 24Hathcock JJ. Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol. 2006; 26(8): 1729-1737.
- 25Kreisel SH, Stroick M, Griebe M, et al. True effects or bias? MMP-2 and MMP-9 serum concentrations after acute stroke. Cerebrovasc Dis. 2016; 42(5–6): 352-360.
- 26Lehmann MF, Kallaur AP, Oliveira SR, et al. Inflammatory and metabolic markers and short-time outcome in patients with acute ischemic stroke in relation to TOAST subtypes. Metab Brain Dis. 2015; 30(6): 1417-1428.
- 27Zhou Z, Li X, Yang B, Jiang D. Relationship between lysophosphatidic acid and matrix metalloproteinase-9 plasma concentrations and carotid atheromatous plaque stability in patients with cerebral infarction. J Int Med Res. 2014; 42(3): 669-676.
- 28Montaner J, Perea-Gainza M, Delgado P, et al. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke. 2008; 39(8): 2280-2287.
- 29Baek BH, Kim HS, Yoon W, et al. Inflammatory mediator expression within retrieved clots in acute ischemic stroke. Ann Clin Transl Neurol. 2018; 5(3): 273-279.
- 30Sporns PB, Hanning U, Schwindt W, et al. Ischemic stroke: what does the histological composition tell us about the origin of the thrombus? Stroke. 2017; 48(8): 2206-2210.
- 31Ntaios G, Perlepe K, Lambrou D, et al. Prevalence and overlap of potential embolic sources in patients with embolic stroke of undetermined source. J Am Heart Assoc. 2019; 8(15): https://doi.org/10.1161/JAHA.119.012858
- 32Bourcier R, Détraz L, Serfaty JM, et al. MRI interscanner agreement of the association between the susceptibility vessel sign and histologic composition of thrombi: inter-MRI agreement of the susceptibility vessel sign. J Neuroimaging. 2017; 27(6): 577-582.
