Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis

Melody Chemaly; David Marlevi; Maria-Jesus Iglesias; Mariette Lengquist; Malin Kronqvist; Daniel Bos; Dianne H K van Dam-Nolen; Anja van der Kolk; Jeroen Hendrikse; Mohamed Kassem; Ljubica Matic; Jacob Odeberg; Margreet R de Vries; M Eline Kooi; Ulf Hedin

doi:10.3390/biom13060882

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis

Melody Chemaly^*, David Marlevi, Maria-Jesus Iglesias, Mariette Lengquist, Malin Kronqvist, Daniel Bos, Dianne H K van Dam-Nolen, Anja van der Kolk, Jeroen Hendrikse, Mohamed Kassem, Ljubica Matic, Jacob Odeberg, Margreet R de Vries, M Eline Kooi, Ulf Hedin

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

7 Downloads (Pure)

Abstract

BACKGROUND: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH.

OBJECTIVE: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting.

METHODS: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study ( n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2).

RESULTS: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004).

CONCLUSIONS: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

Original language	English
Article number	882
Number of pages	16
Journal	Biomolecules
Volume	13
Issue number	6
DOIs	https://doi.org/10.3390/biom13060882
Publication status	Published - Jun 2023

Keywords

antiangiogenic therapy
biliverdin reductase B
intraplaque hemorrhage
ischemic stroke
magnetic resonance imaging
vulnerable atherosclerotic plaque

Access to Document

10.3390/biom13060882Licence: CC BY

biomolecules-13-00882Final published version, 3.18 MBLicence: CC BY

Cite this

Chemaly, M., Marlevi, D., Iglesias, M.-J., Lengquist, M., Kronqvist, M., Bos, D., van Dam-Nolen, D. H. K., van der Kolk, A., Hendrikse, J., Kassem, M., Matic, L., Odeberg, J., de Vries, M. R., Kooi, M. E., & Hedin, U. (2023). Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis. Biomolecules, 13(6), Article 882. https://doi.org/10.3390/biom13060882

@article{031cd6e23b8a47e1bbffbf2a418c7f88,

title = "Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis",

abstract = "BACKGROUND: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH.OBJECTIVE: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting.METHODS: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study ( n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). RESULTS: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). CONCLUSIONS: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.",

keywords = "antiangiogenic therapy, biliverdin reductase B, intraplaque hemorrhage, ischemic stroke, magnetic resonance imaging, vulnerable atherosclerotic plaque",

author = "Melody Chemaly and David Marlevi and Maria-Jesus Iglesias and Mariette Lengquist and Malin Kronqvist and Daniel Bos and {van Dam-Nolen}, {Dianne H K} and {van der Kolk}, Anja and Jeroen Hendrikse and Mohamed Kassem and Ljubica Matic and Jacob Odeberg and {de Vries}, {Margreet R} and Kooi, {M Eline} and Ulf Hedin",

note = "Funding Information: This research was funded by Stockholm County (HMT 20180867, 20170842), the Swedish Heart–Lung Foundation (20180036, 20170584, 20180244, 201602877, 20180247), the Swedish Research Council (2017-01070, 2019-02027), HelseNord (HNF1544-20), Karolinska Institutet, and the King Gustav Vth and Queen Victorias Foundation. The PARISK study was supported by the Center for Translational Molecular Medicine (www.ctmm.nl), project PARISK (grant 01C-202), and the Netherlands Heart Foundation. M.E. Kooi is supported by an Aspasia Grant 2018/SGw/00460457 from Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO). Mohamed Kassem is supported by NWO, grant agreement VidW.1154.18.02L7637. Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = jun,

doi = "10.3390/biom13060882",

language = "English",

volume = "13",

number = "6",

}

Chemaly, M, Marlevi, D, Iglesias, M-J, Lengquist, M, Kronqvist, M, Bos, D, van Dam-Nolen, DHK, van der Kolk, A, Hendrikse, J, Kassem, M, Matic, L, Odeberg, J, de Vries, MR, Kooi, ME & Hedin, U 2023, 'Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis', Biomolecules, vol. 13, no. 6, 882. https://doi.org/10.3390/biom13060882

TY - JOUR

T1 - Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis

AU - Chemaly, Melody

AU - Marlevi, David

AU - Iglesias, Maria-Jesus

AU - Lengquist, Mariette

AU - Kronqvist, Malin

AU - Bos, Daniel

AU - van Dam-Nolen, Dianne H K

AU - van der Kolk, Anja

AU - Hendrikse, Jeroen

AU - Kassem, Mohamed

AU - Matic, Ljubica

AU - Odeberg, Jacob

AU - de Vries, Margreet R

AU - Kooi, M Eline

AU - Hedin, Ulf

N1 - Funding Information: This research was funded by Stockholm County (HMT 20180867, 20170842), the Swedish Heart–Lung Foundation (20180036, 20170584, 20180244, 201602877, 20180247), the Swedish Research Council (2017-01070, 2019-02027), HelseNord (HNF1544-20), Karolinska Institutet, and the King Gustav Vth and Queen Victorias Foundation. The PARISK study was supported by the Center for Translational Molecular Medicine (www.ctmm.nl), project PARISK (grant 01C-202), and the Netherlands Heart Foundation. M.E. Kooi is supported by an Aspasia Grant 2018/SGw/00460457 from Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO). Mohamed Kassem is supported by NWO, grant agreement VidW.1154.18.02L7637. Publisher Copyright: © 2023 by the authors.

PY - 2023/6

Y1 - 2023/6

N2 - BACKGROUND: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH.OBJECTIVE: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting.METHODS: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study ( n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). RESULTS: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). CONCLUSIONS: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

AB - BACKGROUND: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH.OBJECTIVE: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting.METHODS: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study ( n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). RESULTS: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). CONCLUSIONS: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

KW - antiangiogenic therapy

KW - biliverdin reductase B

KW - intraplaque hemorrhage

KW - ischemic stroke

KW - magnetic resonance imaging

KW - vulnerable atherosclerotic plaque

UR - http://www.scopus.com/inward/record.url?scp=85163599043&partnerID=8YFLogxK

U2 - 10.3390/biom13060882

DO - 10.3390/biom13060882

M3 - Article

C2 - 37371462

SN - 2218-273X

VL - 13

JO - Biomolecules

JF - Biomolecules

IS - 6

M1 - 882

ER -

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this