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

Biomolecules. 2023 May 24;13(6):882. doi: 10.3390/biom13060882.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Carotid Artery Diseases* / blood
  • Carotid Artery Diseases* / complications
  • Hemorrhage / blood
  • Hemorrhage / diagnostic imaging
  • Hemorrhage / etiology
  • Humans
  • Ischemic Stroke* / blood
  • Ischemic Stroke* / etiology
  • Mice
  • Plaque, Atherosclerotic* / blood
  • Plaque, Atherosclerotic* / diagnostic imaging
  • Plaque, Atherosclerotic* / pathology
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • biliverdin reductase
  • Biomarkers
  • Vascular Endothelial Growth Factor A

Grants and funding

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.