Increased leukocyte activity as a predictor for flow-limiting coronary lesions in patients with angina pectoris

Takeshita, Satoshi; Hashimoto, Hideki; Ono, Yasuo; Ochiai, Masahiko; Yokoyama, Naoyuki; Terakura, Moriyuki; Sato, Tomohide; Isshiki, Takaaki

doi:10.1016/s0021-9150(01)00463-4

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…This does not exclude local activation of T cells within the vulnerable arterial plaque, or it may imply that plaque rupture is not mediated by an Ag-driven Th1-type immune response. Although controversial, other investigators have also failed to find systemic signs of adaptive immune responses in patients with unstable angina despite evidence of inflammation and activation of innate immunity (17)(18)(19). Our findings substantiate the extensive experimental data on the role of the IFN-␥ axis in the pathogenesis of atherosclerosis.…”

Section: Discussionsupporting

confidence: 81%

An Inflammatory Pathway of IFN-γ Production in Coronary Atherosclerosis

Ranjbaran¹,

Sokol²,

Gallo³

et al. 2007

The Journal of Immunology

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Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN-γ-related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN-γ and IFN-γ-inducible chemokines, defining an IFN-γ axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN-γ axis, but not that of IL-18. Activation of the IFN-γ axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN-γ and IFN-γ-inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN-γ in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN-γ secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.

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Section: Discussionsupporting

confidence: 81%

An Inflammatory Pathway of IFN-γ Production in Coronary Atherosclerosis

Ranjbaran¹,

Sokol²,

Gallo³

et al. 2007

The Journal of Immunology

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“…Mounting evidence, however, points toward a critical role for inflammatory processes. [5][6][7][8] Macrophages serve as the dominant cell type in the immediate site of both plaque ruptures and superficial erosions in subjects who experience acute coronary thrombosis, 8 and recent clinical investigations reveal important associations between leukocytes, 9,10 their enzymes, [11][12][13] and their activation, 14,15 in subjects with unstable angina and acute coronary syndromes. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Sugiyama and colleagues significantly extend our knowledge of potential pathophysiologic inflammatory processes within vulnerable atheroma.…”

Section: Inflammation and The Vulnerable Plaquementioning

confidence: 99%

Myeloperoxidase and Plaque Vulnerability

Hazen

2004

ATVB

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Inflammation and the Vulnerable PlaqueSudden cardiac death remains the leading cause of mortality in industrialized societies, outpacing all cancer related deaths combined. The majority of sudden cardiac deaths arise from acute myocardial infarction secondary to intracoronary artery thromboses. Remarkably, the culprit lesions involved are typically not flow-limiting stenoses, 1,2 but rather inflamed lipid-laden lesions. 3,4 Whereas plaque fissuring or rupture, which exposes the intensely prothrombogenic lipid core, occurs in a majority of cases, fully 40% of intracoronary artery thromboses arise at sites of superficial erosions, where endothelial cell (EC) loss and denudation occurs. 3 The mechanisms responsible for plaque vulnerability leading to acute coronary artery thrombosis remain poorly understood. Mounting evidence, however, points toward a critical role for inflammatory processes. [5][6][7][8] Macrophages serve as the dominant cell type in the immediate site of both plaque ruptures and superficial erosions in subjects who experience acute coronary thrombosis, 8 and recent clinical investigations reveal important associations between leukocytes, 9,10 their enzymes, [11][12][13] and their activation, 14,15 in subjects with unstable angina and acute coronary syndromes. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Sugiyama and colleagues significantly extend our knowledge of potential pathophysiologic inflammatory processes within vulnerable atheroma. 16 Using a combination of biochemical, cellular, and immunohistologic studies, they describe unifying mechanistic links between the activity of the leukocyte enzyme myeloperoxidase (MPO) and two cardinal features of vulnerable plaque: EC loss/denudation and development of a prothrombotic phenotype. See page 1309 Myeloperoxidase: an Inflammatory Mediator of AtherosclerosisFirst identified within human atherosclerotic plaque nearly a decade ago, 17 MPO has emerged as an important potential participant in the atherosclerotic process. MPO, a member of the heme peroxidase superfamily, generates reactive oxidants and diffusible radical species as part of its normal function in innate host defenses. 18 A unique activity of MPO is its ability to use the halide chloride as cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid (HOCl), a potent antimicrobicidal agent. [18][19][20]17,21 and specific chlorinated protein 20 and lipid 22 oxidation products, are all markedly enriched within human atheroma. Leukocytes use MPO to generate oxidants capable of initiating lipid peroxidation both in model systems 23,24 and in vivo, 25 including conversion of low density lipoprotein into an atherogenic form recognized by macrophage scavenger receptors. 26 MPO may also contribute to the atherosclerotic process by promoting endothelial dysfunction, by virtue of its capacity to catalytically consume nitric oxide as a substrate in vitro 27 and in vivo, 28 resulting in formation of nitric oxidederived oxidants. 29 -31 Inde...

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“…Leukocyte count is associated with several traditional CHD risk factors like smoking, dyslipidemia, and insulin resistance (13)(14)(15). In atherosclerotic patients, increased activation of leukocytes as determined by measurement of oxidative stress generation (16,17), surface antigen expression (18), and plasma levels of soluble activation markers has been described (19). Counteracting these processes at different levels reduced myocardial ischemia-reperfusion injury in animal models (20).…”

mentioning

confidence: 99%

Postprandial recruitment of neutrophils may contribute to endothelial dysfunction

Oostrom

Sijmonsma

Verseyden

et al. 2003

Journal of Lipid Research

227

170

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Atherosclerosis is a low-grade inflammatory disease involving leukocytes, lipids, and glucose leading to endothelial dysfunction. Since activation of neutrophils by triglycerides and glucose has been described in vitro, we hypothesized that the postprandial phase is an inflammatory state affecting leukocytes, possibly contributing to endothelial dysfunction. We measured postprandial blood leukocyte counts, cytokines, hydroperoxides (HPOs), and flow-mediated vasodilation (FMD) in eight healthy males (age 23 ؎ 2 years) after a FAT (50 g/m 2 ) and GLUCOSE challenge (37.5 g/m 2 ), a combination of both (MIXED test), and after WATER. All tests, except WATER, resulted in significantly impaired FMD (10% reduction) between t ‫؍‬ 1 h and t ‫؍‬ 3 h, accompanied by a significant increase of neutrophils (59% after FAT and 28% after GLUCOSE and MIXED), total plasma HPOs (15 to 31% increase), and plasma interleukin-8 (IL-8) (50-130% increase). WATER did not affect FMD, neutrophils, HPOs, or IL-8. Lymphocytes increased gradually in all tests (40-70% increase at t ‫؍‬ 10 h compared with t ‫؍‬ 0; P Ͻ 0.005), paralleling a gradual 3-to 5-fold interleukin-6 increase. Monocyte and erythrocyte counts did not change in any test. In conclusion, the neutrophil increment during postprandial lipemia and glycemia with concomitant IL-8 and HPO increases may contribute to endothelial dysfunction. Lymphocyte increment is a nonspecific diurnal process. Postprandial intravascular inflammatory changes may be relevant for the pathogenesis of atherosclerosis. -van Oostrom, A.

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Increased leukocyte activity as a predictor for flow-limiting coronary lesions in patients with angina pectoris

Cited by 4 publications

References 29 publications

An Inflammatory Pathway of IFN-γ Production in Coronary Atherosclerosis

An Inflammatory Pathway of IFN-γ Production in Coronary Atherosclerosis

Myeloperoxidase and Plaque Vulnerability

Postprandial recruitment of neutrophils may contribute to endothelial dysfunction

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