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
Affiliations
Melody Chemaly
Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
David Marlevi
Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Maria-Jesus Iglesias
Science for Life Laboratory, Department of Protein Science, School of Engineering Sciences in Chemistry/Biotechnology and Health, KTH Royal Institute of Technology, 11428 Stockholm, Sweden
Mariette Lengquist
Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Malin Kronqvist
Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Daniel Bos
Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
Dianne H. K. van Dam-Nolen
Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
Anja van der Kolk
Department of Medical Imaging, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
Jeroen Hendrikse
Department of Radiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
Mohamed Kassem
Department of Radiology and Nuclear Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands
Ljubica Matic
Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Jacob Odeberg
Science for Life Laboratory, Department of Protein Science, School of Engineering Sciences in Chemistry/Biotechnology and Health, KTH Royal Institute of Technology, 11428 Stockholm, Sweden
Margreet R. de Vries
Einthoven Laboratory, Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
M. Eline Kooi
Department of Radiology and Nuclear Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands
Ulf Hedin
Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
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.
