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

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

Impact of the lockdown on acute stroke treatments during the first surge of the COVID-19 outbreak in the Netherlands

INTRODUCTION: We investigated the impact of the Corona Virus Disease 2019 (COVID-19) pandemic and the resulting lockdown on reperfusion treatments and door-to-treatment times during the first surge in Dutch comprehensive stroke centers. Furthermore, we studied the association between COVID-19-status and treatment times. METHODS: We included all patients receiving reperfusion treatment in 17 Dutch stroke centers from May 11th, 2017, until May 11th, 2020. We collected baseline characteristics, National Institutes of Health Stroke Scale (NIHSS) at admission, onset-to-door time (ODT), door-to-needle time (DNT), door-to-groin time (DGT) and COVID-19-status at admission. Parameters during the lockdown (March 15th, 2020 until May 11th, 2020) were compared with those in the same period in 2019, and between groups stratified by COVID-19-status. We used nationwide data and extrapolated our findings to the increasing trend of EVT numbers since May 2017. RESULTS: A decline of 14% was seen in reperfusion treatments during lockdown, with a decline in both IVT and EVT delivery. DGT increased by 12 min (50 to 62 min, p-value of < 0.001). Furthermore, median NIHSS-scores were higher in COVID-19 - suspected or positive patients (7 to 11, p-value of 0.004), door-to-treatment times did not differ significantly when stratified for COVID-19-status. CONCLUSIONS: During the first surge of the COVID-19 pandemic, a decline in acute reperfusion treatments and a delay in DGT was seen, which indicates a target for attention. It also appeared that COVID-19-positive or -suspected patients had more severe neurologic symptoms, whereas their EVT-workflow was not affected. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-021-02539-4

Circulatory markers of immunity and carotid atherosclerotic plaque

Background and aims : We aimed to determine the association of circulatory markers of innate and adaptive immunity with carotid atherosclerotic plaque characteristics. Methods : In 1602 participants from the population-based Rotterdam Study with subclinicalcarotid atherosclerosis, blood sampling was performed to determine granulocyte, platelet, monocyte (innate immunity) and lymphocyte (adaptive immunity) counts, from which the granulocyte-to-lymphocyte ratio [GLR], platelet-to-lymphocyte ratio [PLR], monocyte-to-lymphocyte ratio [MLR] and systemic immune-inflammation index [SII] were calculated. All participants underwent carotid MRI for evaluation of plaque characteristics. Plaque size (stenosis >30%, maximum plaque thickness) and plaque composition (presence of intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], and calcification) were assessed. Using linear and logistic regression models, the association of innate and adaptive immunity markers with plaque size and plaque components, adjusting for relevant confounders, was assessed. Results : Higher levels of granulocytes were significantly associated with larger plaque thickness (mean difference [Ln (mm)] per Ln increase granulocyte count [95% CI]: 0.06 [0.02; 0.10]). Conversely, more lymphocytes related with smaller maximum plaque thickness (mean difference [Ln (mm)] per Ln increase lymphocyte count: 0.09 [-0.14;-0.04]) and a lower prevalence of IPH (odds ratio per Ln increase lymphocyte count: 0.60 [0.37; 0.97]). Moreover, all ratio measures were associated with larger plaque thickness, of which the MLR also associated with more frequent LRNC (odds ratio per Ln increase MLR: 1.26 [1.02; 1.56]). Conclusions : The innate immunity links to larger plaques, whilst the adaptive immunity seems to relate to smaller plaques and a lower frequency of IPH. These results suggest that an imbalance in innate and adaptive immunity may play a role in the vulnerability of carotid atherosclerotic plaques

Advances in multimodality carotid plaque imaging: AJR expert panel narrative review

Contemporary imaging methods provide detailed visualization of carotid atherosclerotic plaque, enabling a major evolution of in vivo carotid plaque imaging evaluation. The degree of luminal stenosis in the carotid artery bifurcation, as assessed by ultrasound, has historically served as the primary imaging feature for determining ischemic stroke risk and the potential need for surgery. However, stroke risk may be more strongly driven by the presence of specific characteristics of vulnerable plaque, as visualized on CT and MRI, than by traditional ultrasound-based assessment of luminal narrowing. This review highlights six promising imaging-based plaque characteristics that harbor unique information regarding plaque vulnerability: maximum plaque thickness and volume, calcification, ulceration, intraplaque hemorrhage, lipid-rich necrotic core, and thin or ruptured fibrous cap. Increasing evidence supports the association of these plaque characteristics with risk of ischemic stroke, although these characteristics have varying suitability for clinical implementation. Key aspects of CT and MRI protocols for carotid plaque imaging are also considered. Practical next steps and hurdles are explored for implementing routine imaging assessment of these plaque characteristics in addition to, or even as replacement for, traditional assessment of the degree of vascular stenosis on ultrasound, in the identification of individuals at high risk of ischemic stroke

Dolichoarteriopathies of the extracranial internal carotid artery

Background and purpose: Dolichoarteriopathies of the extracranial part of the internal carotid artery (ICA) are associated with cerebrovascular events, yet information on their prevalence and risk factors remains limited. The aim of the present study therefore was to study the prevalence and risk factors of dolichoarteriopathies in a sample of patients with cerebrovascular symptoms from the Plaque At RISK (PARISK) study. Methods: In a random sample of 100 patients from the PARISK study, multidetector computed tomography angiography (MDCTA) was performed as part of clinical workup. On MDCTA, we evaluated the extracranial trajectory of the ICA by measuring the length (in millimeters), the tortuosity index (TI; defined as the ICA length divided by the shortest possible distance from bifurcation to skull base), and dolichoarteriopathy type (tortuosity, coiling or kinking). Next, we investigated the association between cardiovascular risk factors and these measurements using linear and logistic regression analyses. Results: The mean (standard deviation) length of the ICA was 93 (± 14) mm, with a median (interquartile range) TI of 1.2 (1.1–1.3). The overall prevalence of dolichoarteriopathies was 69%, with tortuosity being the most common (72%), followed by coiling (20%), and kinking (8%). We found that age and obesity were associated with a higher TI: difference per 10-year increase in age: 0.05 (95% confidence interval [CI] 0.02–0.08) and 0.16 (95% CI 0.07–0.25) for obesity. Obesity and hypercholesterolemia were associated with a more severe type of dolichoarteriopathy (odds ratio [OR] 2.07 [95% CI 1.04–4.12] and OR 2.17 [95% CI 1.02–4.63], respectively). Conclusion: Dolichoarteriopathies in the extracranial ICA are common in patients with cerebrovascular symptoms, and age, obesity and hypercholesterolemia may play an important role in the pathophysiology of these abnormalities.</p

Lipoprotein(a) levels and atherosclerotic plaque characteristics in the carotid artery

Background and aims: Lipoprotein(a) is an independent risk factor for cardiovascular disease and recurrent ischemic stroke. Lipoprotein(a) levels are known to be associated with carotid artery stenosis, but the relation of lipoprotein(a) levels to carotid atherosclerotic plaque composition and morphology is less known. We hypothesize that higher lipoprotein(a) levels and lipoprotein(a)-related SNPs are associated with a more vulnerable carotid plaque and that this effect is sex-specific. Methods: In 182 patients of the Plaque At RISK study we determined lipoprotein(a) concentrations, apo(a) KIV-2 repeats and LPA SNPs. Imaging characteristics of carotid atherosclerosis were determined by MDCTA (n = 161) and/or MRI (n = 171). Regressions analyses were used to investigate sex-stratified associations between lipoprotein(a) levels, apo(a) KIV-2 repeats, and LPA SNPs and imaging characteristics. Results: Lipoprotein(a) was associated with presence of lipid-rich necrotic core (LRNC) (aOR = 1.07, 95% CI: 1.00; 1.15), thin-or-ruptured fibrous cap (TRFC) (aOR = 1.07, 95% CI: 1.01; 1.14), and degree of stenosis (β = 0.44, 95% CI: 0.00; 0.88). In women, lipoprotein(a) was associated with presence of intraplaque hemorrhage (IPH) (aOR = 1.25, 95% CI: 1.06; 1.61). In men, lipoprotein(a) was associated with degree of stenosis (β = 0.58, 95% CI: 0.04; 1.12). Rs10455872 was significantly associated with increased calcification volume (β = 1.07, 95% CI: 0.25; 1.89) and absence of plaque ulceration (aOR = 0.25, 95% CI: 0.04; 0.93). T3888P was associated with absence of LRNC (aOR = 0.36, 95% CI: 0.16; 0.78) and smaller maximum vessel wall area (β = -10.24, 95%CI: -19.03; -1.44). Conclusions: In patients with symptomatic carotid artery stenosis, increased lipoprotein(a) levels were associated with degree of stenosis, and IPH, LRNC, and TRFC, known as vulnerable plaque characteristics, in the carotid artery. T3888P was associated with lower LRNC prevalence and smaller maximum vessel wall area. Further research in larger study populations is needed to confirm these results.</p