D-dimer has emerged as a biomarker of cardiovascular event risk, yet pathophysiological factors associated with plasma D-dimer levels in stable coronary artery disease (CAD) subjects are poorly understood. In 106 stable CAD subjects undergoing intravascular ultrasound with virtual histology (IVUS-VH), we measured D-dimer, lipoprotein(a) (Lp(a)), plasminogen, biomarkers reflecting oxidation-specific epitopes (OSE) such as oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), OxPL on plasminogen (OxPL-PLG), and autoantibodies to phosphorylcholine-BSA [PC-BSA] and a malondialdehyde [MDA] mimotope. In univariate analysis, D-dimer was positively associated with Lp(a), OxPL-apoB, OxPL-PLG, and coronary artery calcium, and inversely associated with autoantibodies to OSE and plaque fibrosis. D-dimer levels > 500 ng/ml also showed positive association with plaque necrosis. After multivariate analysis, D-dimer remained significantly associated with Lp(a) and plaque calcium. While further studies are needed, results provide evidence that plasma D-dimer levels are associated with levels of OxPLs and IVUS-VH indices linked to plaque erosion and rupture.
Aims In light of recent data regarding inflammatory signalling pathways in cardiovascular disease and the recently demonstrated impact of pharmacologic inhibition of interleukin-1β (IL-1β) in heart failure, the primary aim was to assess the physiologic effects of cardiac resynchronization therapy (CRT) on the expression of systemic inflammatory, immune-modulatory, metabolic, and apoptotic genes in peripheral blood mononuclear cells (PBMCs) of patients with heart failure. Methods and results We used RNA sequencing (RNA-Seq) and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to identify gene expression changes in PBMCs in response to CRT. In total, 27 patients were analysed: 12 with heart failure undergoing CRT, 6 with heart failure undergoing standard implanted cardioverter defibrillators, and 9 with coronary artery disease but not heart failure. In CRT patients (median age 65.5 years, interquartile range 63.0–66.8 years, 33% female), RNA-Seq analysis identified 40 genes, including multiple genes associated with the IL-1β pathway, with significant correlations (false discovery rate < 0.05) with four key CRT response measures. CRT was associated with suppression of PBMC expression of IL-1β (1.80-fold decrease, P = 0.047), FOS proto-oncogene (FOS) (3.25-fold decrease, P = 0.01), dual specificity phosphatase 1 (DUSP1) (2.05-fold decrease, P = 0.001), and early growth response 1 (EGR1) (7.38-fold decrease, P = 0.03), and suppression was greater in responders vs. non-responders (P = 0.03 for IL-1β, P = 0.02 for FOS, P = 0.02 for DUSP1, and P = 0.11 for EGR1). Baseline FOS and DUSP-1 levels were greater in responders vs. non-responders (6.15-fold higher, FOS, P = 0.002; 2.60-fold higher, DUSP1, P = 0.0001). CRT responders but not non-responders showed higher baseline gene expression of FOS (P = 0.04) and DUSP1 (P = 0.06) compared with control patients without heart failure. Baseline serum high-sensitivity C-reactive protein levels were 3.47-fold higher in CRT responders vs. non-responders (P = 0.008). Conclusion Treatment of heart failure with CRT resulted in decreased PBMC expression of genes linked to inflammation. Moreover, CRT responders had higher expression of these inflammatory genes prior to CRT and greater suppression of these genes after CRT compared with non-responders.
IL-1β has emerged as a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19 and blockade of the IL-1 receptor (IL-1R) with Anakinra has entered clinical trials in COVID-19 subjects. Yet, knowledge of the specific immune cell subsets targeted by IL-1β and IL-1β-induced signaling pathways in humans is limited. Utilizing mass cytometry (CyTOF) of human peripheral blood mononuclear cells, we identified effector memory CD4 T cells and CD4 -CD8 low/-CD161 + T cells as the circulating immune subtypes with the greatest expression of p-NF-κB in response to IL-1β stimulation.Notably, CCR6 distinctly identified T cells most responsive to IL-1β. Other subsets including CD11c myeloid dendritic cells (mDCs), classical monocytes (CM), two subsets of natural killer cells (CD16 -CD56 bright CD161and CD16 -CD56 dim CD161 + ) and a population of lineage -(Lin-) cells expressing CD161 and CD25 also showed IL-1β-induced expression of p-NF-kB. The IL-1R antagonist, Anakinra significantly inhibited IL-1β-induced p-NF-kB in the CCR6 + T cells and CD11c mDCs with a trending inhibition in CD14 monocytes and Lin -CD161 + CD25 + cells. IL-1β also induced a rapid but much less robust increase in p-p38 expression as compared to p-NF-kB in the majority of these same immune cell subsets. Prolonged IL-1β stimulation greatly increased p-STAT3 and to a much lesser extent p-STAT1 and p-STAT5 in T cell subsets, monocytes, DCs and the Lin -CD161 + CD25 + cells suggesting IL-1βinduced production of downstream STAT-activating cytokines, consistent with its role in cytokine storm.Interindividual heterogeneity and inhibition of this activation by Anakinra raises the intriguing possibility that assays to measure IL-1β-induced p-NF-kB in CCR6 + T cell subtypes could identify those at higher risk of cytokine storm and those most likely to benefit from Anakinra therapy.
IL-1β is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1β blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4−CD8low/−CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1β. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16−CD56brightCD161− and CD16−CD56dimCD161+), and lineage− (Lin−) cells expressing CD161 and CD25. IL-1β also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1β stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1β–induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1β in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1β–neutralizing therapies.
Background: Oxidative stress and generation of lipid peroxidation (LPO) products are detrimental in the pathogenesis of atherosclerosis and associated acute thrombotic events. However, recent studies suggest that moderate oxidative stress and low levels of LPO products can induce adaptive immune responses and exert beneficial effects. Tissue factor (TF) is a critical initiator of coagulation and aberrant TF expression on vascular cells under inflammation triggers intravascular thrombosis. HNE, a highly reactive LPO product and TF have been shown to be associated with atherosclerosis. Recently, we demonstrated that HNE decrypts procoagulant activity of pre-existing TF on activated monocytes and endothelial cells and generates TF+ microparticles. Here, we investigated the effect of HNE on induction of TF and cell adhesion molecules in monocytes and endothelial cells that were not perturbed earlier. Methods and results: THP-1 monocytic cells and endothelial cells (HUVEC) were stimulated with LPS and TNF-α/IL1-β, respectively, in the presence of a control vehicle or varying concentrations of HNE that are pathophysiologically relevant. TF induction was measured at mRNA (by qRT-PCR), protein (by immunoblotting) and activity levels (in factor X activation assay). Pre-treating cells with HNE inhibited TNF-α/IL1-β- or LPS-stimulated TF procoagulant activity in a dose-dependent manner. THP-1 and HUVEC varied in their sensitivities to HNE (THP-1> HUVEC). HNE-mediated inhibition of TF activity correlated with lower TF mRNA and protein levels. Our results demonstrate that HNE prevents TNF-α/IL1-β- and LPS-induced IKKβ degradation and thereby inhibits NFκβ activation. In addition to inhibiting TF expression, HNE significantly reduced monocyte adhesion to endothelial cells through downregulating TNF-α/IL1-β-induced expression of endothelial adhesion molecules VCAM-1 and ICAM-1. Conclusion: HNE may play a dual role in regulating TF activity in atherosclerosis. HNE could act as a prothrombotic mediator by increasing coagulant activity of pre-existing TF through decryption process. HNE can also elicit anti-thrombotic and anti-inflammatory effect by inhibiting TF and adhesion molecules in response to stimulus by impairing the NF-ĸB pathway.
Background: Atherosclerotic plaques in mice and humans contain natural killer (NK) cells. Data on the role of NK cells in atherosclerosis using different transgenic mice models is inconsistent. Some studies showed that NK cells augment atherosclerosis through their cytotoxic potential, while others reported no effect. Evidence in humans indicates that NK cells are atherogenic. Frequency of NK cells and expression of the activating NK cell receptors are associated with severe disease and symptomatic carotid atherosclerotic plaques in humans. Hypothesis: We tested if coronary artery disease (CAD) subjects with necrotic plaques have a higher frequency of the circulating NK cells. Methods: We performed mass cytometry on peripheral blood mononuclear cells from matched CAD subjects with low and high (n=9 each) necrotic plaque content as determined by intravascular ultrasound-virtual histology. Results: CAD subjects with high necrotic plaques have significantly higher atheroburden, stenosis, calcium, fatty plaque content, and lower plaque fibrosis. Interestingly, CAD subjects with high necrotic plaques exhibited a significantly higher frequency of the CD56 bright NK cells as compared to those with low necrotic plaques (4.618 ± 0.625 vs 2.481 ± 0.37; p=0.011). Moreover, frequency of CD25 + NK cells also trended to be higher in subjects with high necrotic plaques. The frequency of the cytotoxic CD56 dim NK cells did not differ between the two groups. Correlation analyses demonstrated a significant positive association of CD56 bright NK cells with atheroburden (r=0.43; p=0.04), stenosis (r=0.58; p=0.005), plaque necrotic (r=0.71; p=0.002), calcium contents (r=0.73; p=0.0001), and a negative association with the plaque fibrous content (r=0.71; p= 0.0003). CD25 + NK cells also showed similar trending associations with burden, stenosis and plaque features. Conclusions: Our data provides yet another evidence of the atherogenic role of NK cells in humans and indicates that the CD56 bright NK cells may contribute to the development of a vulnerable plaque. CD56 bright NK cells produce proinflammatory cytokines including IFN-γ and TNF-α and cytotoxic enzymes that may contribute to increased inflammation, cell activation, and apoptosis within the plaque.
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