A Novel Pathway of Platelet Activation in ACS Mediated by LL-37 Immunoglobulin G Autoantibody Immune Complexes.

The cathelicidin antimicrobial peptide LL-37 is a self-antigen in neutrophil extracellular traps that provokes autoantibody responses in autoimmune/autoinflammatory conditions. LL-37 immunoglobulin (Ig) G autoantibody levels were measured in subjects with and without atherosclerotic cardiovascular disease assessed using the coronary artery calcium score, in patients who had a future myocardial infarction and in a cohort of acute coronary syndrome (ACS) patients. LL-37 IgG levels were not associated with coronary artery calcium score, but future myocardial infarction patients had significantly higher LL-37 IgG at baseline.

Differentiation between descending thoracic aortic diseases using machine learning and plasma proteomic signatures.

Background: Descending thoracic aortic aneurysms and dissections can go undetected until severe and catastrophic, and few clinical indices exist to screen for aneurysms or predict risk of dissection.

Methods: This study generated a plasma proteomic dataset from 75 patients with descending type B dissection (Type B) and 62 patients with descending thoracic aortic aneurysm (DTAA). Standard statistical approaches were compared to supervised machine learning (ML) algorithms to distinguish Type B from DTAA cases.

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome.

Background: LL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients.

Methods And Results: The activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls.

Electrocardiograms in Critical Care Cardiology.

Patients with critical illness may present with electrocardiogram (ECG) findings with bizarre QRS morphology or abnormal amplitude. This article provides ECG examples from such clinical scenarios and discusses their clinical characteristics and significance. ().

ECGs in Critical Care Cardiology: Do Not Miss That Myocardial Infarction.

This paper provides clinical cases of acute myocardial infarction that do not show ST-segment elevation on 12-lead electrocardiogram, but should be clinically treated as ST-segment elevation myocardial infarction with early diagnostic coronary angiogram followed by appropriate strategy of revascularization. ().

Electrocardiograms in Critical Care Cardiology: Is it Acute Coronary Syndrome?

Patients with critical illness may present with electrocardiogram (ECG) findings difficult for physicians to distinguish them from acute coronary syndrome. This article provides three cases of such clinical scenarios. Examples of ECGs and their clinical characteristics and significance are discussed.

Immunization using ApoB-100 peptide-linked nanoparticles reduces atherosclerosis.

Active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has been used clinically. We first characterized the responses of T cells to P210 using PBMCs from patients with atherosclerotic cardiovascular disease (ASCVD).

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification.

The human cationic anti-microbial peptide LL-37 is a T cell self-antigen in patients with psoriasis, who have increased risk of cardiovascular events. However, the role of LL-37 as a T cell self-antigen in the context of atherosclerosis remains unclear. The objective of this study was to test for the presence of T cells reactive to LL-37 in patients with acute coronary syndrome (ACS).

Immunogenetics of Atherosclerosis-Link between Lipids, Immunity, and Genes.

Purpose Of Review: Atherosclerosis is a complex disease process with lipid as a traditional modifiable risk factor and therapeutic target in treating atherosclerotic cardiovascular disease (ACVD). Recent evidence indicates that genetic influence and host immune response also are vital in this process. How these elements interact and modify each other and if immune response may emerge as a novel modifiable target remain poorly understood.

Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics.

A significant body of work implicates the adaptive immune response in atherosclerosis, the main underlying cause of coronary artery disease (CAD), yet specific antigens involved remain to be fully identified. The pathobiology of CAD is influenced by sex with many factors that may be involved in the underlying mechanisms. Given the reported sexual dimorphic nature of immune-inflammatory responses, we investigated the influence of sex on potential CAD self-antigens from acute coronary syndrome (ACS) patients using immune-precipitation of soluble HLA Class-I/peptide complexes and mass spectrometry.

IL-7R blockade reduces post-myocardial infarction-induced atherosclerotic plaque inflammation in ApoE mice.

Modulating inflammation by targeting IL-1β reduces recurrent athero-thrombotic cardiovascular events without lipid lowering. This presents an opportunity to explore other pathways associated with the IL-1β signaling cascade to modulate the inflammatory response post-myocardial infarction (MI). IL-7 is a mediator of the inflammatory pathway involved in monocyte trafficking into atherosclerotic plaques and levels of IL-7 have been shown to be elevated in patients with acute MI.

Keratin 8 is a potential self-antigen in the coronary artery disease immunopeptidome: A translational approach.

Background: Inflammation is an important risk factor in atherosclerosis, the underlying cause of coronary artery disease (CAD). Unresolved inflammation may result in maladaptive immune responses and lead to immune reactivity to self-antigens. We hypothesized that inflammation in CAD patients would manifest in immune reactivity to self-antigens detectable in soluble HLA-I/peptide complexes in the plasma.

The cathelicidin protein CRAMP is a potential atherosclerosis self-antigen in ApoE(-/-) mice.

Auto-immunity is believed to contribute to inflammation in atherosclerosis. The antimicrobial peptide LL-37, a fragment of the cathelicidin protein precursor hCAP18, was previously identified as an autoantigen in psoriasis. Given the reported link between psoriasis and coronary artery disease, the biological relevance of the autoantigen to atherosclerosis was tested in vitro using a truncated (t) form of the mouse homolog of hCAP18, CRAMP, on splenocytes from athero-prone ApoE(-/-) mice.

Identification of apoB-100 Peptide-Specific CD8+ T Cells in Atherosclerosis.

Background: T cells are found in atherosclerotic plaques, with evidence supporting a potential role for CD8+ T cells in atherogenesis. Prior studies provide evidence of low-density lipoprotein and apoB-100 reactive T cells, yet specific epitopes relevant to the disease remain to be defined. The current study was undertaken to identify and characterize endogenous, antigen-specific CD8+ T cells in atherosclerosis.

Vaccine against arteriosclerosis: an update.

Substantial data from experimental and clinical investigation support the role of immune-mediated mechanisms in atherogenesis, with immune systems responding to many endogenous and exogenous antigens that play either proatherogenic or atheroprotective roles. An active immunization strategy against many of these antigens could potentially alter the natural history of atherosclerosis. This review mainly focuses on the important studies on the search for antigens that have been tested in vaccine formulations to reduce atherosclerosis in preclinical models.

HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis.

The HDL hypothesis stating that simply raising HDL cholesterol (HDL-C) may produce cardiovascular benefits has been questioned recently based on several randomized clinical trials using CETP inhibitors or niacin to raise HDL-C levels. However, extensive pre-clinical data support the vascular protective effects of administration of exogenous ApoA-1 containing preβ-HDL like particles. Several small proof-of-concept clinical trials using such HDL/ApoA-1 infusion therapy have shown encouraging results but definitive proof of efficacy must await large scale clinical trials.

ApoB-100-related peptide vaccine protects against angiotensin II-induced aortic aneurysm formation and rupture.

Background: T cells and macrophages are implicated in the pathogenesis of aortic aneurysm (AA) and atherosclerosis. We recently demonstrated that a vaccine using an apoB-100-related peptide p210 reduces atherosclerosis with favorable modulation of CD8+ T cells in apolipoprotein E-deficient (apoE-/-) mice.

Objectives: This study hypothesized that a p210 vaccine could reduce AA formation in the angiotensin II (Ang II)-induced AA model.

Vaccine for atherosclerosis.

Atherosclerosis is an immune-mediated inflammatory disease of the arterial wall, with both the innate and adaptive immune systems responding to many endogenous and exogenous antigens. Both proatherogenic as well as atheroprotective roles have been identified for the immune system in atherosclerosis. Hence, it is conceivable that an immunomodulatory strategy via active immunization against many of these antigens could potentially alter the natural history of atherosclerosis.

Advances in immune-modulating therapies to treat atherosclerotic cardiovascular diseases.

In addition to hypercholesterolemia, innate and adaptive immune mechanisms play a critical role in atherogenesis, thus making immune-modulation therapy a potentially attractive way of managing atherosclerotic cardiovascular disease. These immune-modulation strategies include both active and passive immunization and confer beneficial reduction in atherosclerosis. Preclinical studies have demonstrated promising results and we review current knowledge on the complex role of the immune system and the potential for immunization as an immune-modulation therapy for atherosclerosis.

Cholesterol lowering modulates T cell function in vivo and in vitro.

Background: The lipid milleu exacerbates the inflammatory response in atherosclerosis but its effect on T cell mediated immune response has not been fully elucidated. We hypothesized that lipid lowering would modulate T cell mediated immune function.

Methods And Results: T cells isolated from human PBMC or splenic T cells from apoE-/- mouse had higher proliferative response to T cell receptor (TCR) ligation in medium supplemented with 10% fetal bovine serum (FBS) compared to medium with 10% delipidated FBS.

CD8(+)CD25(+) T cells reduce atherosclerosis in apoE(-/-) mice.

Background: It is increasingly evident that CD8(+) T cells are involved in atherosclerosis but the specific subtypes have yet to be defined. CD8(+)CD25(+) T cells exert suppressive effects on immune signaling and modulate experimental autoimmune disorders but their role in atherosclerosis remains to be determined. The phenotype and functional role of CD8(+)CD25(+) T cells in experimental atherosclerosis were investigated in this study.