Biliverdin Reductase B Is A Plasma Biomarker For Intraplaque Hemorrhage And A Predictor Of Ischemic Stroke In Symptomatic Carotid Stenosis

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 plaque 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 symptomatic patients from the PARISK study (n=177, 5-year follow-up) with and without IPH upon MRI quantification. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following anti-angiogenic 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), with no association to baseline clinical and biological parameters. Baseline plasma BLVRB levels were 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 is a viable biomarker for IPH based on its 1) association with carotid plaque IPH, 2) higher levels in patients with recurrent ischemic stroke, and 3) capacity to monitor the efficacy of pharmacotherapy aimed for IPH reduction. This gives strong evidence to the utility of plasma BLVRB as a future biomarker for plaque instability.