Novel Multiomics Profiling of Human Carotid Atherosclerotic Plaques and Plasma Reveals Biliverdin Reductase B as a Marker of Intraplaque Hemorrhage

Visual Abstract
Highlights • Multiomics profiling of gene and protein expression in carotid plaques, together with protein expression in peripheral and “local” plasma sampled around the lesion, was performed using a large cohort of patients from BiKE in discovery analyses. • BLVRB was identified as a biomarker of intraplaque hemorrhage and plaque instability in carotid atherosclerosis that was further validated in population samples. • BLVRB was characterized as a hitherto unappreciated key enzyme, functionally linked with HMOX1, in the hemoglobin catabolism under pathological conditions. • The novel translational approach applied for biomarker discovery in this study permits causal interpretation of candidates directly in relation to the underlying disease and paves the way for similar investigations in other vascular territories.
Summary Clinical tools to identify individuals with unstable atherosclerotic lesions are required to improve prevention of myocardial infarction and ischemic stroke. Here, a systems-based analysis of atherosclerotic plaques and plasma from patients undergoing carotid endarterectomy for stroke prevention was used to identify molecular signatures with a causal relationship to disease. Local plasma collected in the lesion proximity following clamping prior to arteriotomy was profiled together with matched peripheral plasma. This translational workflow identified biliverdin reductase B as a novel marker of intraplaque hemorrhage and unstable carotid atherosclerosis, which should be investigated as a potential predictive biomarker for cardiovascular events in larger cohorts.