Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

Francesco Arba^{1

2}, Alessio Giannini¹, Benedetta Piccardi^{1

2}, Silvia Biagini¹, Vanessa Palumbo², Betti Giusti³, Patrizia Nencini², Anna Maria Gori³, Mascia Nesi², Giovanni Pracucci¹, Giorgio Bono⁴, Paolo Bovi⁵, Enrico Fainardi⁶, Domenico Consoli⁷, Antonia Nucera⁸, Francesca Massaro⁹, Giovanni Orlandi¹⁰, Francesco Perini¹¹, Rossana Tassi¹², Maria Sessa¹³, Danilo Toni¹⁴, Rosanna Abbate¹⁵, Domenico Inzitari^{1

6}

Affiliations

¹ Department of NEUROFARBA, Neuroscience Section, University of Florence, Florence, Italy.
² Stroke Unit, AOU Careggi, University of Florence, Florence, Italy.
³ Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence, Florence, Italy.
⁴ Stroke Unit, Department of Neurology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy.
⁵ SSO Stroke Unit, Department of Neurosciences, Azienda Ospedaliera Integrata, Verona, Italy.
⁶ Department of Neuroradiology, Careggi University Hospital, Florence, Italy.
⁷ U.O. Neurologia, G. Jazzolino Hospital, Vibo Valentia, Italy.
⁸ Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, Canada.
⁹ Neurology Unit, Santo Stefano Hospital, Prato, Italy.
¹⁰ Department of Neurosciences, Neurological Clinic, University of Pisa, Pisa, Italy.
¹¹ UOC di Neurologia e Stroke Unit, Ospedale San Bortolo, Vicenza, Italy.
¹² U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e Neurosensoriali, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
¹³ U.O. Neurologia, Istituti Ospitalieri di Cremona, Cremona, Italy.
¹⁴ Emergency Department Stroke Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
¹⁵ Centro Studi Medicina Avanzata (CESMAV) Florence, Italy.

PMID: 31259260
PMCID: PMC6591766
DOI: 10.1177/2396987318805905

Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

Francesco Arba et al. Eur Stroke J. 2019 Jun.

. 2019 Jun;4(2):119-126.

doi: 10.1177/2396987318805905. Epub 2018 Oct 22.

Authors

Affiliations

¹ Department of NEUROFARBA, Neuroscience Section, University of Florence, Florence, Italy.
² Stroke Unit, AOU Careggi, University of Florence, Florence, Italy.
³ Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence, Florence, Italy.
⁴ Stroke Unit, Department of Neurology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy.
⁵ SSO Stroke Unit, Department of Neurosciences, Azienda Ospedaliera Integrata, Verona, Italy.
⁶ Department of Neuroradiology, Careggi University Hospital, Florence, Italy.
⁷ U.O. Neurologia, G. Jazzolino Hospital, Vibo Valentia, Italy.
⁸ Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, Canada.
⁹ Neurology Unit, Santo Stefano Hospital, Prato, Italy.
¹⁰ Department of Neurosciences, Neurological Clinic, University of Pisa, Pisa, Italy.
¹¹ UOC di Neurologia e Stroke Unit, Ospedale San Bortolo, Vicenza, Italy.
¹² U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e Neurosensoriali, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
¹³ U.O. Neurologia, Istituti Ospitalieri di Cremona, Cremona, Italy.
¹⁴ Emergency Department Stroke Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
¹⁵ Centro Studi Medicina Avanzata (CESMAV) Florence, Italy.

PMID: 31259260
PMCID: PMC6591766
DOI: 10.1177/2396987318805905

Abstract

Introduction: Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this cross-sectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients.

Patients and methods: In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke.

Results: A total of 263 patients were available for the analysis. Mean age (±SD) was 69 (±13) years, 154 (59%) patients were male. We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesion molecule-1 (β = 0.21; p = 0.016) and vascular cell adhesion molecule-1 (β = 0.22; p = 0.009), and lacunes were associated with vascular endothelial growth factor levels (β = 0.21; p = 0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (β = 0.26; p = 0.006).

Discussion: Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease.

Conclusions: Small vessel disease features and total burden were associated with endothelial dysfunction 90 days after the stroke, whereas there was no relation during the acute phase. Our results suggest that endothelial dysfunction, particularly vascular endothelial growth factor, is involved in pathological process of small vessel disease.

Keywords: Small vessel disease; acute stroke; endothelial dysfunction; intercellular adhesion molecule; vascular cell adhesion molecule; vascular endothelial growth factor.

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Figures

**Figure 1.**
Associations between SVD score and markers of endothelial dysfunction at 90 days. Data are means (95% confidence interval).

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Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

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Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

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