Tumor Necrosis Factor Antagonism With Etanercept Improves Systemic Endothelial Vasoreactivity in Patients With Advanced Heart Failure

Fichtlscherer, Stephan; Rössig, Lothar; Breuer, Susanne; Vasa, Mariuca; Dimmeler, Stefanie; Zeiher, Andreas M.

doi:10.1161/hc5001.101749

Cited by 132 publications

(67 citation statements)

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“…In particular, TNF-␣ presumably produced by activated macrophages and vascular endothelial cells has been shown to aggravate the hemodynamics of CHF (14,16). As has been mentioned, clinical studies have demonstrated that targeted anti-TNF-␣ therapy with recombinant TNF-␣ receptor improves the functional status of patients with CHF (18). In this context, the role of ANP in cytokine regulation should be taken into consideration.…”

Section: Discussionmentioning

confidence: 99%

“…TNF-␣ in particular has been shown experimentally to depress systemic endothelial vasodilator function and thus aggravates CHF (17). In fact, recent clinical studies have demonstrated that targeted anti-TNF-␣ therapy with etanercept, a recombinant TNF-␣ receptor that binds to and functionally inactivates TNF-␣, improves the functional status of patients with CHF (18). On the other hand, anti-inflammatory cytokines including IL-10 have been speculated to counteract the effects of TNF-␣ (19).…”

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confidence: 99%

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Atrial Natriuretic Peptide Polarizes Human Dendritic Cells Toward a Th2-Promoting Phenotype Through Its Receptor Guanylyl Cyclase-Coupled Receptor A

Morita

Ukyo

Furuya

et al. 2003

The Journal of Immunology

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Atrial natriuretic peptide (ANP) is a cardiovascular hormone secreted mainly by the cardiac atria and regulates the volume-pressure homeostasis. The action of ANP is mediated by its receptor, guanylyl cyclase-coupled receptor A (GC-A). In this study, we explored the possibility that ANP and GC-A may play a role in the dendritic cell (DC)-mediated immune regulation. We first examined the expression of GC-A in human monocyte-derived DCs in comparison with monocytes and found that DCs but not monocytes express GC-A at both the mRNA and protein levels. DCs responded to ANP with an increase in intracellular cGMP in a dose-dependent manner, indicating that GC-A expressed on DCs is functional. Furthermore, treatment of DCs with ANP decreased production of IL-12 and TNF-α and conversely increased that of IL-10 upon stimulation with LPS. In accordance with this change of cytokine production, DCs treated with ANP plus LPS promoted differentiation of naive CD4+ T cells into a Th2 phenotype. Finally, we presented evidence that ANP affected cytokine production of fresh whole blood stimulated with LPS in line with the above-mentioned results. These results indicate that ANP polarizes human DCs toward a Th2-promoting phenotype through GC-A and thus can regulate immune responses.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Atrial Natriuretic Peptide Polarizes Human Dendritic Cells Toward a Th2-Promoting Phenotype Through Its Receptor Guanylyl Cyclase-Coupled Receptor A

Morita

Ukyo

Furuya

et al. 2003

The Journal of Immunology

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“…On this basis, investigators have argued that the beneficial effects of statins on endothelial function in patients might also be attributable to pleiotropic anti-inflammatory effects (Bonetti et al 2003). More specific interventions, including drugs that bind TNF-α, have also been shown to improve endothelial function in patients with heart failure (Fichtlscherer et al 2001) or rheumatoid arthritis, (Hurlimann et al 2002), and it would be interesting to observe the effects of these or more specific interventions in patients with atherosclerosis.…”

Section: Human Studies Of Systemic Inflammation and Endothelial Dysfumentioning

confidence: 99%

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Huang

Vita

2006

Trends in Cardiovascular Medicine

118

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The importance of inflammation in the pathogenesis of atherosclerosis is well established. The vascular endothelium contributes to and is affected by the inflammatory process. For example, a variety of cytokines have the ability to "activate" the endothelium and thereby promote expression of adhesion molecules and chemotactic factors that accelerate the inflammatory process and direct accumulation of leukocytes to specific sites in the arterial tree. In experimental systems, activation of endothelial cells is also associated with a loss of the biologic activity of endothelium-derived nitric oxide, an effect that accelerates the inflammatory process and also promotes local thrombosis and impairs local control of vasomotor tone. Consistent with these experimental studies, recent studies have provided evidence that inflammation is associated with an impairment of nitric oxide-dependent responses in human subjects. This article will review the experimental and clinical studies that support the relevance of inflammation to nitric oxide bioactivity in human atherosclerosis.It is now well recognized that atherosclerosis is an inflammatory disease (Ross 1999). Systemic risk factors induce a state of inflammation that contributes to all stages of atherosclerosis from the initiating events in lesion formation to the latest phase when plaques rupture, thrombose, and produce clinical syndromes such as myocardial infarction or stroke (Libby et al. 2002). The importance of inflammation in atherosclerosis is supported by recent studies showing that elevated levels of inflammatory markers identify individuals with increased risk for cardiovascular events (Pearson et al. 2003). In particular, the acute phase reactant C-reactive protein (CRP) shows promise as a clinically useful marker of cardiovascular risk (Ridker 2003).The vascular endothelium is both affected by and contributes to the inflammatory process that leads to atherosclerosis. For example, proinflammatory factors "activate" endothelial cells to promote an atherogenic phenotype. The activated endothelium, in turn, expresses adhesion molecules and chemotactic factors that accelerate and localize the inflammatory process. An important consequence of endothelial activation is loss of the biologic activity of endotheliumderived nitric oxide. Investigators have argued that a broad alteration of endothelial function, including loss of nitric oxide under proinflammatory conditions, might be a critical mechanism that links systemic states of inflammation to atherosclerosis (Vallance et al. 1997). This article will review the recent studies that support the relevance of systemic inflammation to nitric oxide bioactivity in human subjects. The Endothelium as a Regulator of Vascular HomeostasisThe endothelium regulates vasomotor tone, blood fluidity, growth of vascular smooth muscle cells, and local inflammation by elaborating a number of paracrine factors, including nitric oxide (Widlansky et al. 2003a). Endothelium-derived nitric oxide is a potent vasodilator and acts ...

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“…Functionally, endothelial inflammatory activation is associated with a profound impairment in endothelium-dependent vasodilator function. [12][13][14] As such, endothelial function may be regarded as an integral index of all inflammatory mediators present in an individual and thus may represent the vascular phenotype of an inflamed patient. Therefore, we tested the hypothesis that assessment of systemic endothelial vasodilator function provides prognostic information in patients suffering from an acute coronary syndrome and is capable of identifying the vulnerable patient who is prone to experience recurrence of instability.…”

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confidence: 99%

Prognostic Value of Systemic Endothelial Dysfunction in Patients With Acute Coronary Syndromes

2004

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Background-Endothelial vasodilator dysfunction may serve as a marker integrating the vascular risk of an individual; however, whether systemic vasodilator function predicts disease progression and cardiovascular event rates in patients with manifest acute coronary syndromes (ACS) is unknown. Methods and Results-In 198 patients with angiographically documented ACS, forearm blood flow (FBF) responses to acetylcholine (ACH; 10 to 50 g/min) and sodium nitroprusside (SNP; 2 to 8 g/min) were measured by venous occlusion plethysmography before hospital discharge within 5 days of an episode of an ACS. Cardiovascular events (cardiovascular death, myocardial infarction, and ischemic stroke) served as outcome variables over a mean follow-up period of 47.7Ϯ15.1 months. Patients who experienced cardiovascular events during follow-up (nϭ31) had a significantly reduced vasodilator response to ACH (PϽ0.05) and SNP (PϽ0.05). By multivariate analysis, vasodilator response to ACH and elevated troponin T serum levels were the only significant (PϽ0.05) independent predictors of a poor prognosis, even after adjustment for traditional cardiovascular risk factors, concurrent medication, invasive treatment strategy, and C-reactive protein serum levels. Recovery of endothelium-dependent vasoreactivity as assessed by repeated FBF assessment 8 weeks after the index measurement after the ACS predicted further event-free survival in a subset of 78 patients. Conclusions-Systemic endothelium-dependent vasoreactivity predicts recurrence of instability and cardiovascular event rates in patients with ACS. Furthermore, the recovery of systemic endothelial function is associated with event-free survival. Assessment of systemic vasoreactivity, measured by a minimally invasive test, provides important prognostic information in addition to that derived from traditional risk factor assessment in patients with ACS.

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Tumor Necrosis Factor Antagonism With Etanercept Improves Systemic Endothelial Vasoreactivity in Patients With Advanced Heart Failure

Cited by 132 publications

References 25 publications

Atrial Natriuretic Peptide Polarizes Human Dendritic Cells Toward a Th2-Promoting Phenotype Through Its Receptor Guanylyl Cyclase-Coupled Receptor A

Atrial Natriuretic Peptide Polarizes Human Dendritic Cells Toward a Th2-Promoting Phenotype Through Its Receptor Guanylyl Cyclase-Coupled Receptor A

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Prognostic Value of Systemic Endothelial Dysfunction in Patients With Acute Coronary Syndromes

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