Cited by 260Atherosclerosis and Cardiovascular DiseasesLipoproteins and Cardiovascular HealthInflammasome and immune disorders

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Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis

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Ridker, Paul M·2019·Circulation Research

DOI 10.1161/circresaha.118.313129PMC PMC6386195

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Abstract

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting specific IL (interleukin) signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF [tumor necrosis factor]) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) has shown that specific targeting of IL-1β can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine-targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1β, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 contemporary trials provide proof of principle that focused cytokine inhibition, not broad-spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.

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“This result spurred the quest for developing and studying other and more accessible agents that can lower the risk of cardiovascular events by treating inflammation (12).”
Background
The Role of Inflammation in HIV-Associated Atherosclerosis—One Size May Not Fit All
Currier, J. S., & Hsue, P. Y. (2019) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiz256 · Cited by 10
STROKE DURING COVID-19 PANDEMIC
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“Another study showed that IL-6 has a role in promoting post-stroke angiogenesis (8).”
Background
Proteomics for the prediction and prevention of atherosclerotic disease
Ridker, P. M. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac036 · Cited by 10
“high residual inflammatory risk yet ultimately provided insight resulting in targeted anticytokine therapeutics for vascular disease.(2,3)”
Self-citation
Role of interleukin 6 signaling pathway in the anti-inflammatory effects of statins on coronary artery disease: Evidence from Mendelian randomization analysis
Yazdanpanah, M., Yazdanpanah, N., Chardoli, M., & Dehghan, A. (2024) · International Journal of Cardiology · doi:10.1016/j.ijcard.2024.131964 · Cited by 9
Association between interleukin-6 levels and stroke: a systematic review and meta-analysis
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“As for the treatment of stroke, Ridker 27 reported that atherosclerotic thrombosis can be treated by inhibiting the expression and activity of IL-6 using anti-cytokine drugs, thereby reducing brain tissue damage.”
Background
Proinflammatory mediators, TNFα, IFNγ, and thrombin, directly induce lymphatic capillary tube regression
Kemp, S. S., Penn, M. R., Koller, G. M., Griffin, C. T., & Davis, G. E. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.937982 · Cited by 9
“…permeability, leukocyte adhesion and transmigration, coagulation, platelet adhesion and aggregation (Ridker et al., 2000; Sainson et al., 2008; Arroyo and IruelaArispe, 2010; Rigor et al., 2012; Rigor et al., 2013; De Caterina et al., 2016; Mitoma et al., 2018; Jackson et al., 2019; Ridker, 2019).”
BackgroundInfluential
A short review on CRP synthesis inhibition in cardiovascular disease
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Changes in cerebral autoregulation, stroke‐related blood biomarkers, and autonomic regulation after patent foramen ovale closure in severe migraine patients
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Establishment and evaluation of a risk prediction model for coronary heart disease in primary Sjögren’s syndrome based on peripheral blood IL-6 and Treg percentages
Wang, X., Huang, L., Hu, B., Yang, B., Wei, R., Rong, S., & Bao, L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1440370 · Cited by 8
Polydatin combined with hawthorn flavonoids alleviate high fat diet induced atherosclerosis by remodeling the gut microbiota and glycolipid metabolism
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Targeting IL-6 in patients at high cardiovascular risk
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Impact of Systemic Inflammatory Response Syndrome on Clinical, Echocardiographic, and Computed Tomographic Outcomes Among Patients Undergoing Transcatheter Aortic Valve Implantation
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Distinct systemic cytokine networks in symptomatic and asymptomatic carotid stenosis
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Background
Pre‐Percutaneous Coronary Intervention C‐Reactive Protein Levels and In‐Stent Restenosis: A Systematic Review and Meta‐Analysis
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“…‐ Protein ‐ 3) inflammasome, in response to chronic inflammatory conditions such as diabetes and atherosclerosis also has been known to up ‐ regulate plasma CRP levels [58], via triggering a central cascade of inflammatory signaling represented by interleukin (IL) ‐ 1 β , IL ‐ 6, and CRP [59, 60].”
Atrial Myopathy and Heart Failure: Immunomolecular Mechanisms and Clinical Implications
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“Activation of PRRs triggers downstream signaling pathways that lead to the production of pro-inflammatory cytokines such as TNF-α , IL-6, IL-1 β , and TGF-β [27,86].”
From Bench to Clinic: Advances in Anti‐Inflammatory Therapies for Atherosclerotic Coronary Artery Disease
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Circulating microRNAs in Symptomatic and Asymptomatic Carotid Stenosis
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Evaluating the Causal Association between Inflammatory Bowel Disease and Risk of Atherosclerotic Cardiovascular Disease: Univariable and Multivariable Mendelian Randomization Study
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“Thus, it still cannot be ruled out that, instead of the diagnosis of IBD, the accompanied inﬂammatory mediators, such as IL-1 and IL-6, drove the increased risk of ASCVD [47].”
Background
Higher monomeric C-reactive protein levels are associated with premature coronary artery disease
Сергеевич, М. И., Kozlov, S. G., Денисович, О. С., Saburova, O., Avtaeva, Y., Kuznetsova, T., Guria, K. G., Prokofieva, L. V., Riazantseva, T. A., Ji, S., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1501125 · Cited by 7
The Interleukin 6 Protein Level as well as a Genetic Variants, (rs1800795, rs1800797) Are Associated with Adverse Cardiovascular Outcomes within 10-Years Follow-Up
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“The importance of the inﬂammasome in atherosclerosis development, in addition to its effect on interleukin 1 family, is the downstream activation of the central signaling cytokine interleukin 6 (IL-6), which is associated with the enhanced release of C-reactive protein [5].”
Background
Jack of all trades inhibits inflammation (in sober people)
Schmidt, F. I., & Latz, E. (2020) · Nature Immunology · doi:10.1038/s41590-020-0693-6 · Cited by 7
Interleukin-6 Modulates the Expression and Function of HCN Channels: A Link Between Inflammation and Atrial Electrogenesis
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TAX1BP1/A20 inhibited TLR2-NF-κB activation to induce tolerant expression of IL-6 in endothelial cells
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Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies
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“It has become apparent that RIR and RCR are two elements of atherosclerosis treatment that must be targeted in a combinatorial manner (Aday and Ridker, 2019).”
BackgroundInfluential
Hepatitis B virus-mediated sodium influx contributes to hepatic inflammation via synergism with intrahepatic danger signals
Wang, J., Liu, Q., Zhou, Y., Cao, C., Chen, P., Meng, G., Zhang, J., Xin, X.-J., Huang, G., & Wu, Y. (2023) · iScience · doi:10.1016/j.isci.2023.108723 · Cited by 6
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Background
Neuroimaging Features of Cytokine-related Diseases
Kurokawa, M., Kurokawa, R., Baba, A., Gomi, T., Cho, S., Yoshioka, K., Harada, T., Kim, J., Pinarbasi, E. S., Abe, O., et al. (2024) · Radiographics · doi:10.1148/rg.230069 · Cited by 5
The EGR3 gene modulates CRP and VCAM-1 expression to promote the development of atherosclerosis
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The potential targets in immunotherapy of atherosclerosis
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Background
RETRACTED ARTICLE: Emerging insights into the role of IL-1 inhibitors and colchicine for inflammation control in type 2 diabetes
Guan, J., Abudouaini, H., Lin, K., & Yang, K. (2024) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-024-01369-x · Cited by 6
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Background
Retracted
Management of Acute Stroke During COVID-19 Global Pandemic
Pandian, J. D., & Sebastian, I. A. (2020) · Journal of Stroke Medicine · doi:10.1177/2516608520934639 · Cited by 5
Incidence and pathophysiologic mechanisms of stroke in the COVID-19 pandemic: the dilemma
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“While high levels of serum markers for thrombosis and inflammation have been reported in COVID-19-affected patients, as well as increased levels of inflammatory cytokines (interleukin [IL]-2R, IL-6, and tumor necrosis factor-α) [8].”
Background
Identifying and Validating New Drug Targets for Stroke and Beyond
Plump, A. S., & Smith, G. D. (2019) · Circulation · doi:10.1161/circulationaha.119.042005 · Cited by 4
Platelet Implication in Atherosclerosis Pathogenesis
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IL-36 antagonism blunts the proliferation and migration of oral squamous cell carcinoma cells
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Effects of Pemafibrate in Patients with Stroke and Hypertriglyceridemia: Baseline Cerebral Artery Diseases and 3-Month Laboratory Outcomes
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The Synthetic Flavonoid Hidrosmin Improves Endothelial Dysfunction and Atherosclerotic Lesions in Diabetic Mice
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“Since inflammation plays an important role in the development and progression of atherosclerosis, there is a tremendous interest in the evaluation of anti-inflammatory agents as an additional therapy for atherothrombosis prevention and treatment [14], as shown in the recent Canakinumab Anti-inflammatory Thrombosis Out…”
Result
Interleukin-receptor antagonist and tumour necrosis factor inhibitors for the primary and secondary prevention of atherosclerotic cardiovascular diseases
Martí-Carvajal, A. J., Gemmato-Valecillos, M. A., Martín, D. M., Dayer, M., Alegría‐Barrero, E., Sanctis, J. B. D., Parise-Vasco, J. M., Lizardo, R. J. R., Nicola, S., Martí-Amarista, C. E., et al. (2024) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd014741.pub2 · Cited by 3
Growing evidence for a role for acyl-CoA synthetase 1 in immunometabolism
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Authors: Ridker, P. M.
Affiliations: Brigham and Women's Hospital (US)
Corresponding author: Ridker, Paul M
ORCID: Ridker, Paul M
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2019-02
Volume: 124
Issue: 3
Pages: 437-450
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/circresaha.118.313129
PMC: PMC6386195
OpenAlex: W2914237180
Cited by: 260
References: 148
Citations by year: 2026: 15 · 2025: 30 · 2024: 30 · 2023: 38 · 2022: 42 · 2021: 40 · 2020: 37 · 2019: 28
FWCI: 3.17
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (U01HL101422)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: anti-cytokine therapy, atherosclerosis, cytokines, IL-1β, interleukin-6, TNF-α, CANTOS trial, methotrexate, cardiovascular inflammation, high-sensitivity C-reactive protein, residual inflammatory risk, atheroprotection, cardiovascular disease prevention
MeSH terms: NLR Family, Pyrin Domain-Containing 3 Protein, Triggering Receptor Expressed on Myeloid Cells-1, Interleukin-6 Inhibitors, Animals, Antibodies, Monoclonal, C-Reactive Protein, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Disease Models, Animal, Hematopoiesis, Humans, Methotrexate, Thrombosis, Signal Transduction, Randomized Controlled Trials as Topic, CD40 Antigens, Interleukin-18, Stroke, CD40 Ligand, Atherosclerosis, Mice, Renal Insufficiency, Chronic, Interleukin-1beta, Inflammasomes, Antibodies, Monoclonal, Humanized

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Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis

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