From Vulnerable Plaque to Vulnerable Patient

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients

Vaccination against atherosclerosis? Induction of atheroprotective immunity

Atherosclerosis involves the formation of inflammatory arterial lesions and is one of the most common causes of death globally. It has been evident for more than 20 years that adaptive immunity regulates the magnitude of the atherogenic proinflammatory response. T cells may also influence the stability of the atherosclerotic lesion and thus the propensity for thrombus formation and the clinical outcome of disease. Immunization of hypercholesterolemic animals with low-density lipoprotein preparations reduces atherosclerosis, suggesting that vaccination may represent a useful strategy for disease prevention or modulation. This review summarizes our current understanding of the role immunity in atherosclerosis and outlines strategies for antigen-specific prevention of this disease

Interferon-oy Inhibits Scavenger Receptor Expression and Foam Cell Formation in Human Monocyte-derived Macrophages

The scavenger receptor (ScR) mediates uptake of chemically modified low density lipoprotein (LDL) by human monocytederived macrophages. It is not down-regulated by high intracellular cholesterol levels, and exposure of macrophages to acetylated or oxidized LDL therefore leads to foam cell development. The hypothesis that this represents an important mechanism for intracellular cholesterol accumulation in atherosclerosis is supported by the finding of ScR expression in foam cells of atherosclerotic plaques. T lymphocytes are also present in such plaques and it is known that T cell products regulate macrophage activation. We have therefore studied the effect of interferon-'y (IFN'y), a lymphokine secreted by activated T lymphocytes, on the expression of ScR in human monocytederived macrophages. Binding and uptake of acetylated LDL were significantly reduced in macrophages exposed to recombinant IFNy or IFN-y-containing lymphocyte-conditioned media. Competition experiments showed that the IFNy-regulated binding and uptake of acetylated LDL was mediated via ScR. IFN'y exerted its effect on the saturable binding of acetylated LDL by reducing the number of cell surface binding sites without significantly affecting the affinity between acetylated LDL and its receptor. Northern analysis revealed that the type I ScR mRNA was significantly reduced in IFNy-treated cells. Finally, IFN'y treatment reduced intracellular cholesteryl ester accumulation and inhibited the development of foam cells in the cultures. In conclusion, our data show that IFNy blocks the development of macrophage-derived foam cells by inhibiting expression of ScR. This suggests that macrophage-T lymphocyte interactions may reduce intracellular cholesterol accumulation in the atherosclerotic plaque. (J. Clin. Invest. 1992. 89:1322-1330.) Key words: atherosclerosis * cholesterol * low density lipoprotein * lipoprotein receptors * lymphokine

Burden of Treatment-Induced Peripheral Neuropathy in Patients with Multiple Myeloma in Sweden

Introduction: Treatment-induced peripheral neuropathy (TIPN) is a complication of multiple myeloma (MM) treatment. Objective: This real-world, retrospective study used electronic medical record (EMR) data from 3 Swedish clinics to assess the occurrence and economic burden of TIPN in patients with MM. Methods: Eligible patients had an MM diagnosis in the Swedish Cancer Registry between 2006 and 2015 and initiated treatment during that period. Follow-up was until last EMR visit, death, or study end (April 2017). The current analyses included patients receiving bortezomib, lenalidomide, carfilzomib, or thalidomide at any treatment line. To discern healthcare resource utilization (HCRU) and costs associated with TIPN from other causes, patients with TIPN were matched with those without on baseline characteristics, treatment, and line of therapy. All analyses were descriptive. Results: Overall, 457 patients were included; 102 (22%) experienced TIPN. Patients experiencing TIPN during first-line treatment mostly received bortezomib-based regimens (n = 48/57 [84%]); those with TIPN during second- and third/fourth-line treatment mostly received lenalidomide/thalidomide-based regimens (19/31 [61%], 8/14 [57%], respectively). Patients with TIPN had higher HCRU/costs than those without TIPN (mean differences in hospital outpatient visits: 5.2, p = 0.0031; total costs per patient-year: EUR 17,183, p = 0.0007). Conclusions: Effective MM treatments associated with a reduced incidence of TIPN could result in decreased healthcare expenditure

Identification of a Danger-Associated Peptide From Apolipoprotein B100 (ApoBDS-1) That Triggers Innate Proatherogenic Responses

Background-Subendothelial deposited low-density lipoprotein particles are a known inflammatory factor in atherosclerosis. However, the causal components derived from low-density lipoprotein are still poorly defined. Apolipoprotein B100 (ApoB100) is the unexchangeable protein component of low-density lipoprotein, and the progression of atherosclerosis is associated with immune responses to ApoB100-derived peptides. In this study, we analyzed the proinflammatory activity of ApoB100 peptides in atherosclerosis. Methods and Results-By screening a peptide library of ApoB100, we identified a distinct native peptide referred to as ApoB100 danger-associated signal 1 (ApoBDS-1), which shows sequence-specific bioactivity in stimulation of interleukin-8, CCL2, and interleukin-6. ApoBDS-1 activates mitogen-activated protein kinase and calcium signaling, thereby effecting the expression of interleukin-8 in innate immune cells. Ex vivo stimulation of carotid plaques with ApoBDS-1 enhances interleukin-8 and prostaglandin E(2) release. Furthermore, we demonstrated that ApoBDS-1-positive peptide fragments are present in atherosclerotic lesions using immunoassays and that low-molecular-weight fractions isolated from plaque show ApoBDS-1 activity inducing interleukin-8 production. Conclusions-Our data show that ApoBDS-1 is a previously unrecognized peptide with robust proinflammatory activity, contributing to the disease-promoting effects of low-density lipoprotein in the pathogenesis of atherosclerosis. (Circulation. 2011; 124: 2433-2443.

NOD2-Mediated Innate Immune Signaling Regulates the Eicosanoids in Atherosclerosis

<p>Objective-The activity of eicosanoid pathways is critical to the inflammatory and immune responses that are associated with the progression of atherosclerosis. Yet, the signals that regulate these pathways are poorly understood. Here, we address whether the innate immune signals of nucleotide-binding oligomerization domain-containing protein (NOD) 2 affect eicosanoids metabolism in atherosclerosis.</p><p>Approach and Results-Analysis of human carotid plaques revealed that NOD2 was abundantly expressed at both mRNA and protein levels by endothelial cells and macrophages. Stimulation of NOD2 in ex vivo-cultured carotid plaques by muramyl dipeptide, an extrinsic ligand of NOD2, led to release of prostaglandin E-2, upregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, and to downregulation of cyclooxygenase-1. NOD2 was coexpressed with cyclooxygenase-2 in lesional macrophages. NOD2-induced cyclooxygenase-2 expression in macrophages was dependent on p38 mitogen-activated protein kinase activation and was mediated by interleukin-1 beta and tumor necrosis factor-alpha. Selective lipidomic analysis of the eicosanoids released by the carotid plaques characterized the metabolites of 12-, 5-, and 15-lipoxygenase as the predominant eicosanoids that were produced by the atherosclerotic lesion in the absence of additional stimuli. Unlike the prostaglandin E-2 pathway, metabolic activity of the lipoxygenase pathways was not altered on the short-term activation of NOD2 in carotid plaques.</p><p>Conclusions-These results suggest that atherosclerosis may involve enhanced NOD2-mediated innate immunity. Activation of NOD2 preferentially upregulates the prostaglandin E-2 pathway. Nevertheless, lipoxygenase pathways, such as 12-lipoxygenase, predominate the basal synthesis and metabolism of eicosanoids in atherosclerotic plaques. These findings provide new insights into the regulation of eicosanoids in atherosclerosis.</p>

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

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. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation