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Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis
Open accessAbstract
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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“particularly inhibition of the central interleukin-1β to interleukin-6 to C-reactive protein pathway of innate immunity that is important for atherosclerosis development 4,5”
From Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy (2022) · cites this paper as [5]
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Systematic Review and Meta-Analysis of Methotrexate Use and Risk of Cardiovascular Disease
Micha, R., Imamura, F., von Ballmoos, M. C. W., Solomon, D. H., Hernán, M. Á., Ridker, P. M., & Mozaffarian, D. (2011) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2011.06.054 · Cited by 542 · cited 1×
“As with biologics, observational data also suggested that inflammatory patients treated with LDM have reduced vascular event rates.(38) To formally test this possibility, CIRT randomly allocated 4786 North American patients with known atherosclerosis and either diabetes mellitus or metabolic syndrome to aggressive sta…”
BackgroundSelf-citationRidker, P. M., Howard, C. P., Walter, V., Everett, B., Libby, P., Hensen, J., & Thuren, T. (2012) · Circulation · doi:10.1161/circulationaha.112.122556 · Cited by 530
Self-citationInhibition of Tumor Necrosis Factor-α Reduces Atherosclerosis in Apolipoprotein E Knockout Mice
Brånén, L., Hovgaard, L., Nitulescu, M., Bengtsson, E., Nilsson, J. Å., & Jovinge, S. V. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000143933.20616.1b · Cited by 506 · cited 1×
“As critical examples, when compared with control animals, TNF-α ApoE double-knockout mice have less atherosclerosis and reduced endothelial adhesion(13)—an effect replicated in ApoE mice treated with agents that reduce TNF-α activity.(14,15) Similarly, early data indicated that lack of IL-1β decreases the severity of…”
BackgroundCytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets
Ramji, D. P., & Davies, T. S. (2015) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2015.04.003 · Cited by 492
Inflammatory cytokines in atherosclerosis: current therapeutic approaches
Tousoulis, D., Oikonomou, E. K., Economou, E. K., Crea, F., & Kaski, J. C. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehv759 · Cited by 465
O’Donoghue, M. L., Braunwald, E., White, H. D., Steen, D. P., Lukas, M. A., Tarka, E., Steg, P. G., Hochman, J. S., Bode, C., Maggioni, A. P., et al. (2014) · JAMA · doi:10.1001/jama.2014.11061 · Cited by 456
Ridker, P. M. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.11.037 · Cited by 414 · cited 1×
“From a clinical perspective, assessment of low-grade systemic inflammation with hsCRP remains the gold standard.(40)”
BackgroundSelf-citationMallat, Z., Corbaz, A., Scoazec, A., Graber, P., Alouani, S., Esposito, B., Humbert, Y., Chvatchko, Y., & Tedgui, A. (2001) · Circulation Research · doi:10.1161/hh1901.098735 · Cited by 404 · cited 1×
“IL-18 may promote atherosclerosis and increase lesion size in ApoE-deficient mice,(20,21) whereas reduced atherosclerosis has been observed in IL-18–deficient ApoE knockout mice.(22,23)”
BackgroundKleveland, O., Kunszt, G., Bratlie, M., Ueland, T., Broch, K., Holte, E., Michelsen, A. E., Bendz, B., Amundsen, B. H., Espevik, T., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw171 · Cited by 403 · cited 1×
“In a small randomized trial of patients with ST-segment–elevation myocardial infarction, tocilizumab reduced troponin levels suggesting smaller infarct size.(120) This observation is being corroborated in the ongoing ASSAIL (Assessing the Effect of Anti–IL-6 Treatment in Myocardial Infarction Study; NCT03004703).”
Abbate, A., Tassell, B. W. V., Biondi‐Zoccai, G., Kontos, M. C., Grizzard, J. D., Spillman, D., Oddi, C., Roberts, C. S., Melchior, R. D., Mueller, G. H., et al. (2013) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2013.01.287 · Cited by 402
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“provements in left ventricular structure and function and a trend toward improved functional status.(56)”
BackgroundInterleukin-18 Enhances Atherosclerosis in Apolipoprotein E −/− Mice Through Release of Interferon-γ
Whitman, S. C., Ravisankar, P., & Daugherty, A. (2002) · Circulation Research · doi:10.1161/hh0202.105292 · Cited by 386
Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice
Elhage, R. (2003) · Cardiovascular Research · doi:10.1016/s0008-6363(03)00343-2 · Cited by 378 · cited 1×
“IL-18 may promote atherosclerosis and increase lesion size in ApoE-deficient mice,(20,21) whereas reduced atherosclerosis has been observed in IL-18–deficient ApoE knockout mice.(22,23)”
BackgroundBarnabe, C. C. M., Martin, B., & Ghali, W. A. (2010) · Arthritis Care & Research · doi:10.1002/acr.20371 · Cited by 372
Everett, B. M., Pradhan, A. D., Solomon, D. H., Paynter, N., MacFadyen, J., Zaharris, E., Gupta, M., Clearfield, M., Libby, P., Hasan, A. A. K., et al. (2013) · American Heart Journal · doi:10.1016/j.ahj.2013.03.018 · Cited by 368 · cited 1×
“By contrast, the National Heart, Lung, and Blood Institute–funded CIRT was designed to address whether an alternative broad-spectrum anti-inflammatory approach using LDM might also reduce vascular event rates.(5,79) LDM is Figure 4.”
BackgroundSelf-citationAbbate, A., Salloum, F. N., Vecile, E., Das, A., Hoke, N. N., Straino, S., Biondi‐Zoccai, G., Houser, J.-E., Qureshi, I., Ownby, E. D., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.740233 · Cited by 364 · cited 1×
“among patients with heart failure.(59,60) Further, recent findings”
BackgroundMorton, A. C., Rothman, A. M. K., Greenwood, J. P., Gunn, J. P., Chase, A. J., Clarke, B., Hall, A. S., Fox, K. A. A., Foley, C. E., BANYA, W. A. S., et al. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu272 · Cited by 363
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van der Heijden, T., Kritikou, E., Venema, W., van Duijn, J., van Santbrink, P. J., Slütter, B., Foks, A. C., Bot, I., & Kuiper, J. (2017) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.117.309575 · Cited by 348 · cited 1×
“In ApoE-deficient mice, the selective NLRP3 inhibitor MCC950 has shown reduced development of atherosclerotic lesions, as well as ICAM and VCAM mRNA expression.(118) MCC950 also reduces infarct size and preserves ventricular function in pig models of myocardial infarction and has shown efficacy in the treatment of inf…”
BackgroundOhta, H., Wada, H., Niwa, T., Kirii, H., Iwamoto, N., Fujii, H., Saito, K., Sekikawa, K., & Seishima, M. (2005) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2004.11.016 · Cited by 346
Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes
Everett, B. M., Donath, M. Y., Pradhan, A. D., Thuren, T. Y., Pais, P. S., Nicolau, J. C., Glynn, R. J., Libby, P., & Ridker, P. M. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.03.002 · Cited by 345 · cited 1×
“Affirming earlier work, baseline IL-6 and hsCRP levels in CANTOS associated with incident type 2 diabetes mellitus.(102) Further, random allocation to canakinumab reduced major cardiovascular events with similar efficacy among those with prevalent diabetes mellitus, prediabetes, and normoglycemia.”
BackgroundSelf-citationBohula, E. A., Giugliano, R. P., Cannon, C. P., Zhou, J., Murphy, S. A., White, J. A., Tershakovec, A. M., Blazing, M. A., & Braunwald, E. (2015) · Circulation · doi:10.1161/circulationaha.115.018381 · Cited by 340
van Hout, G. P. J., Bosch, L., Ellenbroek, G. H. J. M., de Haan, J. J., van Solinge, W. W., Cooper, M. A., Arslan, F., de Jager, S. C. A., Robertson, A. A. B., Pasterkamp, G., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw247 · Cited by 334 · cited 1×
“MCC950 also reduces infarct size and preserves ventricular function in pig models of myocardial infarction and has shown efficacy in the treatment of inflammatory disorders in man.(119) Of recent interest, NLRP3 inhibition may have benefits in nonalcoholic steatohepatitis.”
BackgroundRidker, P. M., MacFadyen, J. G., Glynn, R. J., Köenig, W., Libby, P., Everett, B. M., Lefkowitz, M. P., Thuren, T. Y., & Cornel, J. H. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.03.490 · Cited by 324
Self-citationBarreto, D. V., Barreto, F. C., Liabeuf, S., Temmar, M., Lemke, H., Tribouilloy, C. M., Choukroun, G. J., Vanholder, R. C., & Massy, Z. A. (2009) · Kidney International · doi:10.1038/ki.2009.503 · Cited by 321
Targeting Interleukin-1 in Heart Disease
Tassell, B. W. V., Toldo, S. A., Mezzaroma, E., & Abbate, A. (2013) · Circulation · doi:10.1161/circulationaha.113.003199 · Cited by 321
Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin
Ridker, P. M. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw024 · Cited by 316
Self-citationShimokawa, H., Itô, A., Fukumoto, Y., Kadokami, T., Nakaike, R., Sakata, M., Takayanagi, T., Egashira, K., & Takeshita, A. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118476 · Cited by 292 · cited 1×
“By contrast, exposure to exogenous IL-1β increases intimal medial thickening.(18,19) In parallel work, administration of either IL-6 or”
BackgroundWhy not treat human cancer with interleukin-1 blockade?
Dinarello, C. A. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9229-0 · Cited by 287
Inflammatory and Cholesterol Risk in the FOURIER Trial
Bohula, E. A., Giugliano, R. P., Leiter, L. A., Verma, S., Park, J.-G., Sever, P. S., Lira Pineda, A., Honarpour, N., Wang, H., Murphy, S. A., et al. (2018) · Circulation · doi:10.1161/circulationaha.118.034032 · Cited by 280
Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice
Gomez, D. A., Baylis, R. A., Durgin, B. G., Newman, A. A. C., Alencar, G. F., Mahan, S., Hilaire, C. S., Müller, W., Waisman, A., Francis, S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0124-5 · Cited by 260 · cited 1×
“Yet, other recent murine work has suggested that IL-1α and IL-1β may have contrarian atheroprotective effects in advanced lesions in ApoE mice.(24,25)”
BackgroundResidual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy
Pradhan, A. D., Aday, A. W., Rose, L. M., & Ridker, P. M. (2018) · Circulation · doi:10.1161/circulationaha.118.034645 · Cited by 258 · cited 1×
“Third, as recently presented in the SPIRE-1, SPIRE-2, and FOURIER trials, there is substantial residual inflammatory risk among patients already treated with a PCSK9 inhibitor.(146,147) In FOURIER, absolute risk among patients with on-treatment LDL-C <30 mg/dL but elevated hsCRP exceeds that of patients with LDL-C lev…”
MethodSelf-citationTargeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction
Sager, H. B., Heidt, T., Hulsmans, M., Dutta, P., Courties, G., Sebas, M., Wojtkiewicz, G. R., Tricot, B., Iwamoto, Y., Sun, Y., et al. (2015) · Circulation · doi:10.1161/circulationaha.115.016160 · Cited by 255 · cited 1×
“Activation of the IL-1–associated NRLP3 inflammasome thus seems to be linked closely to clonal hematopoiesis—a finding consistent with parabiotic mouse models that implicate IL-1β as a central cytokine linking atherosclerosis to bone marrow and splenic function.(109) DNMT3A and JAK2 also play significant roles for inf…”
BackgroundSalicylate (Salsalate) in Patients With Type 2 Diabetes: A Randomized Trial
Goldfine, A. B., Fonseca, V., Jablonski, K. A., Chen, Y.-D. I., Tipton, L., Staten, M. A., & Shoelson, S. E. (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-159-1-201307020-00003 · Cited by 251
Lutgens, E., Lievens, D., Beckers, L., Wijnands, E., Soehnlein, O., Zernecke, A., Seijkens, T. T. P., Engel, D. A., Cleutjens, J. P. M., Keller, A. M., et al. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20091293 · Cited by 251 · cited 1×
“Inhibition of CD40 signaling reduces atherosclerosis in mice,(125) and CD40-CD40L binding leads to recruitment of TRAFs (TNF receptor-associated factors) of which CD40-TRAF6 is involved in atherogenesis.(126) Smallmolecule inhibitors of CD40-TRAF6 have been developed that have the ability to reduce atherosclerosis and…”
BackgroundBlamire, A. M., Anthony, D. C., Rajagopalan, B., Sibson, N. R., Perry, V. H., & Styles, P. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-21-08153.2000 · Cited by 249 · cited 1×
“Cytokine Blockade and Stroke In parallel with evidence for coronary atherosclerosis, preclinical data implicate IL-1 inhibition in animal models of stroke including critical findings that IL-1β plays a role in bloodbrain barrier permeability; this nonatherosclerotic effect alters poststroke edema and hence could reduc…”
BackgroundO’Donoghue, M. L., Glaser, R., Cavender, M. A., Aylward, P. E., Bonaca, M. P., Budaj, A., Davies, R. Y., Dellborg, M., Fox, K. A. A., Gutierrez, J. A. T., et al. (2016) · JAMA · doi:10.1001/jama.2016.3609 · Cited by 249
Inflammation and Cardiovascular Disease
Fearon, W. F., & Fearon, D. T. (2008) · Circulation · doi:10.1161/circulationaha.108.772491 · Cited by 241 · cited 6×
“As critical components of the innate immune system, inflammasomes comprise macromolecular protein complexes capable of recognizing a variety of immune stimuli, including microbial and nonmicrobial pathogens, exogenous crystalline structures, and cell degradation products, such as pathogen-associated molecular patterns…”
BackgroundInfluentialThe NLRP3 inflammasome in kidney disease and autoimmunity
Hutton, H., Ooi, J. D., Holdsworth, S. R., & Kitching, A. R. (2016) · Nephrology · doi:10.1111/nep.12785 · Cited by 237 · cited 1×
“Abundant work implicates the NLRP3 inflammasome in renal failure, and experimental work has suggested benefit from IL-1 inhibition in several models of renal failure.(90,91) However, data from early clinical trials targeting inflammation in kidney disease have been neutral.”
BackgroundAlexander, M. R., Moehle, C. W., Johnson, J. L., Yang, Z., Lee, J. K., Jackson, C. L., & Owens, G. K. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43713 · Cited by 223 · cited 1×
“Yet, other recent murine work has suggested that IL-1α and IL-1β may have contrarian atheroprotective effects in advanced lesions in ApoE mice.(24,25)”
BackgroundGiles, J., Sattar, N., Gabriel, S., Ridker, P., Gay, S., Warne, C., Musselman, D., Brockwell, L., Shittu, E., Klearman, M., et al. (2019) · Arthritis & Rheumatology · doi:10.1002/art.41095 · Cited by 208
Self-citationRelton, J. K., Martin, D. A., Thompson, R. C., & Russell, D. A. (1996) · Experimental Neurology · doi:10.1006/exnr.1996.0059 · Cited by 206 · cited 1×
“Cytokine Blockade and Stroke In parallel with evidence for coronary atherosclerosis, preclinical data implicate IL-1 inhibition in animal models of stroke including critical findings that IL-1β plays a role in bloodbrain barrier permeability; this nonatherosclerotic effect alters poststroke edema and hence could reduc…”
BackgroundHow Common Is Residual Inflammatory Risk?
Ridker, P. M. (2017) · Circulation Research · doi:10.1161/circresaha.116.310527 · Cited by 201 · cited 1×
“thal condition more prevalent in contemporary patients than its counterpart residual cholesterol risk.(3) Within the past 18”
BackgroundSelf-citationMerhi‐Soussi, F., Kwak, B. R., Magne, D., Chadjichristos, C. E., Berti, M., Pelli, G., James, R. W., Mach, F., & Gabay, C. (2005) · Cardiovascular Research · doi:10.1016/j.cardiores.2005.01.008 · Cited by 200 · cited 1×
“Similarly, early data indicated that lack of IL-1β decreases the severity of atherosclerosis in ApoE-deficient mice,(16) and antibodies targeting mouse IL-1 have resulted in reduced atherogenesis.(17) By contrast, exposure to exogenous IL-1β increases intimal medial thickening.”
BackgroundSCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke)
Smith, C. J., Hulme, S., Vail, A., Heal, C., Parry‐Jones, A., Scarth, S., Hopkins, K., Hoadley, M. E., Allan, S. M., Rothwell, N. J., et al. (2018) · Stroke · doi:10.1161/strokeaha.118.020750 · Cited by 200
Targeting CD40-induced TRAF6 signaling in macrophages reduces atherosclerosis
Seijkens, T. T. P., van Tiel, C. M., Kusters, P. J. H., Atzler, D., Soehnlein, O., Zarzycka, B., Aarts, S. A. B. M., Lameijer, M., Gijbels, M. J., Beckers, L., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.11.055 · Cited by 195 · cited 1×
“Smallmolecule inhibitors of CD40-TRAF6 have been developed that have the ability to reduce atherosclerosis and markedly slow plaque progression in ApoE mice without inducing major immune suppression or thromboembolic events.(127) Whether these effects are independent of IL-1 inhibition and can translate to human ather…”
BackgroundBlockade of Interleukin-12 Function by Protein Vaccination Attenuates Atherosclerosis
Hauer, A. D., Uyttenhove, C., de Vos, P., Stroobant, V., Renauld, J., van Berkel, T. J. C., Snick, J. V., & Kuiper, J. (2005) · Circulation · doi:10.1161/circulationaha.104.533463 · Cited by 182 · cited 1×
“In an early preclinical trial, blockade of IL-12 function through protein vaccination lead to attenuation of atherosclerosis in LDLr mice.(141) More recent murine evidence with erlotinib— a selective inhibitor of the epidermal growth factor receptor— also suggests reductions in experimental atherosclerosis.”
BackgroundTherapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk
Goldfine, A. B., & Shoelson, S. E. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88884 · Cited by 176 · cited 1×
“It has thus long been hypothesized that inflammation inhibition could play a major role in diabetes mellitus management.(99) Anakinra—an IL-1 receptor antagonist—has been shown to improve β-cell function and modestly lower glycosylated hemoglobin,(100) effects similar to that of gevokizumab, a therapeutic antibody tar…”
BackgroundTREM-1 Mediates Inflammatory Injury and Cardiac Remodeling Following Myocardial Infarction
Boufenzer, A., Lemarie, J., Simon, T., Derive, M., Bouazza, Y., Tran, N., Maskali, F., Groubatch, F., Bonnin, P., Bastien, C., et al. (2015) · Circulation Research · doi:10.1161/circresaha.116.305628 · Cited by 163 · cited 1×
“Further translational work is also needed for investigations of TREM-1 (triggering receptor expressed on myeloid cells 1), which has been shown to stimulate the inflammatory response after acute coronary ischemia.(129) Supporting this concept, genetic variants in TREM1 may be associated with human coronary disease—an…”
BackgroundInflammation and Atherosclerosis
Hansson, G. K. (2017) · Circulation · doi:10.1161/circulationaha.117.030484 · Cited by 149
CD40 and Its Ligand in Atherosclerosis
Lutgens, E., Lievens, D., Beckers, L., Donners, M. M. P. C., & Daemen, M. J. A. P. (2007) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2007.02.004 · Cited by 135 · cited 1×
“The costimulatory CD40-CD40L receptor-ligand signaling dyad represents an additional inflammatory pathway relevant for atherothrombosis.(123,124) Inhibition of CD40 signaling reduces atherosclerosis in mice,(125) and CD40-CD40L binding leads to recruitment of TRAFs (TNF receptor-associated factors) of which CD40-TRAF6…”
BackgroundSobowale, O. A., Parry‐Jones, A., Smith, C. J., Tyrrell, P. J., Rothwell, N. J., & Allan, S. M. (2016) · Stroke · doi:10.1161/strokeaha.115.010001 · Cited by 131 · cited 1×
“As reviewed elsewhere, a series of small clinical trials testing IL-1Ra in acute stroke have been conducted, which generally show safety, reductions in IL-6 and CRP, and nonsignificant trends toward improved outcomes.(85) Cytokine reductions in cerebrospinal fluid have also been reported after IL-1Ra therapy in the se…”
BackgroundGalea, J. P., Ogungbenro, K., Hulme, S., Patel, H. C., Scarth, S., Hoadley, M. E., Illingworth, K., McMahon, C. J., Tzerakis, N., King, A. T., et al. (2017) · Journal of neurosurgery · doi:10.3171/2016.9.jns16615 · Cited by 128 · cited 1×
“Cytokine reductions in cerebrospinal fluid have also been reported after IL-1Ra therapy in the setting of aneurysmal subarachnoid hemorrhage.(86) No stroke study to date has been adequately powered to address efficacy of IL-1Ra on hard clinical end points; however, in the recently reported SCIL-STROKE trial (Subcutane…”
BackgroundJoffre, J., Potteaux, S., Zeboudj, L., Loyer, X., Boufenzer, A., Laurans, L., Esposito, B., Vandestienne, M., de Jager, S. C. A., Hénique, C., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.10.015 · Cited by 117 · cited 1×
“Recently, inhibition of TREM-1 has been shown to reduce atherosclerosis progression and vascular inflammation in LDLr-deficient and ApoE-deficient mice.(131,132)”
BackgroundCai, T., Zhang, Y., Ho, Y.-L. A., Link, N., Sun, J., Huang, J., Cai, T. A., Damrauer, S. M., Ahuja, Y., Honerlaw, J. P., et al. (2018) · JAMA Cardiology · doi:10.1001/jamacardio.2018.2287 · Cited by 114
Glynn, R. J., MacFadyen, J. G., & Ridker, P. M. (2008) · Clinical Chemistry · doi:10.1373/clinchem.2008.120642 · Cited by 107 · cited 1×
“identical to that of LDL (low-density lipoprotein) cholesterol (LDL-C) and superior to that of blood pressure.(41) hsCRP fur-”
BackgroundSelf-citationThe NLRP3 inflammasome contributes to sarcopenia and lower muscle glycolytic potential in old mice
McBride, M. J., Foley, K. P., D’Souza, D. M., Li, Y. E., Lau, T. C., Hawke, T. J., & Schertzer, J. D. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00060.2017 · Cited by 103 · cited 1×
“The NLRP3 inflammasome also provides linkage between chronic inflammation and functional decline in aging, thymic immunosenescence, and sarcopenia.(114,115) Crystalline structures that can activate the inflammasome include urate crystals (the triggering agent in gout) and cholesterol crystals.”
BackgroundThe Emerging Role of the Inflammasome in Kidney Diseases
Chang, A., Ko, K., & Clark, M. (2014) · Current opinion in nephrology and hypertension · doi:10.1097/01.mnh.0000444814.49755.90 · Cited by 100 · cited 1×
“Abundant work implicates the NLRP3 inflammasome in renal failure, and experimental work has suggested benefit from IL-1 inhibition in several models of renal failure.(90,91) However, data from early clinical trials targeting inflammation in kidney disease have been neutral.”
BackgroundShah, P. K., Chyu, K., Dimayuga, P. C., & Nilsson, J. Å. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.10.018 · Cited by 98
Baylis, R. A., Gomez, D. A., Mallat, Z., Pasterkamp, G., & Owens, G. K. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.310097 · Cited by 94
Canault, M. (2003) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2003.10.004 · Cited by 92 · cited 1×
“As critical examples, when compared with control animals, TNF-α ApoE double-knockout mice have less atherosclerosis and reduced endothelial adhesion(13)—an effect replicated in ApoE mice treated with agents that reduce TNF-α activity.(14,15) Similarly, early data indicated that lack of IL-1β decreases the severity of…”
BackgroundSelective EGF-Receptor Inhibition in CD4+ T Cells Induces Anergy and Limits Atherosclerosis
Zeboudj, L., Maître, M., Guyonnet, L., Laurans, L., Joffre, J., Lemarie, J., Bourcier, S., Nour‐Eldine, W., Guérin, C. L., Friard, J., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.10.084 · Cited by 73 · cited 1×
“More recent murine evidence with erlotinib— a selective inhibitor of the epidermal growth factor receptor— also suggests reductions in experimental atherosclerosis.(142,143)”
BackgroundCANTOS Trial Validates the Inflammatory Pathogenesis of Atherosclerosis
Weber, C., & von Hundelshausen, P. (2017) · Circulation Research · doi:10.1161/circresaha.117.311984 · Cited by 69
Vaccination to modulate atherosclerosis
Kimura, T., Tse, K. Y., Sette, A., & Ley, K. F. (2015) · Autoimmunity · doi:10.3109/08916934.2014.1003641 · Cited by 67
Головкин, А. С., Ponasenko, A. V., Khutornaya, M. V., Кутихин, А. Г., Ринатович, С. Р., Yuzhalin, A. E., Игоревна, Ж. И., Барбараш, О. Л., & Barbarash, L. S. (2014) · Gene · doi:10.1016/j.gene.2014.08.022 · Cited by 59
Taming Immune and Inflammatory Responses to Treat Atherosclerosis
Libby, P., & Hansson, G. K. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.10.081 · Cited by 58 · cited 1×
“More recent murine evidence with erlotinib— a selective inhibitor of the epidermal growth factor receptor— also suggests reductions in experimental atherosclerosis.(142,143)”
BackgroundLiberale, L., Diaz-Canestro, C., Bonetti, N., Paneni, F., Akhmedov, A., Beer, J., Montecucco, F., Lüscher, T., & Camici, G. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy286 · Cited by 56 · cited 1×
“In provocative recent work, postischemic administration of a murine canakinumab analog modestly improved outcomes in experimental stroke; in mice subjected to transient middle cerebral artery occlusion and reperfusion, cerebral infarct volume was reduced, ipsilateral edema declined, and reduced MMP-2 expression and ne…”
BackgroundMORTON, A., Arnold, N., GUNN, J., Varcoe, R. W., Francis, S., Dower, S., & Crossman, D. C. (2005) · Cardiovascular Research · doi:10.1016/j.cardiores.2005.06.026 · Cited by 48 · cited 1×
“By contrast, exposure to exogenous IL-1β increases intimal medial thickening.(18,19) In parallel work, administration of either IL-6 or”
BackgroundIbáñez, B., & Fuster, V. (2017) · Circulation Research · doi:10.1161/circresaha.117.312200 · Cited by 44
Vaccines against atherosclerosis
Nilsson, J. Å., Wigren, M., & Shah, P. K. (2013) · Expert Review of Vaccines · doi:10.1586/erv.13.4 · Cited by 35
Hartman, O., Kovanen, P. T., Lehtonen, J. Y. A., Eklund, K. K., & Sinisalo, J. P. (2016) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvw035 · Cited by 33 · cited 1×
“In parallel to the CIRT trial of LDM, a trial of hydroxychloroquine to prevent recurrent events after myocardial infarction has been initiated.(122) Hydroxychloroquine is an antimalarial with anti-inflammatory properties used as secondline therapy in rheumatoid arthritis and lupus.”
BackgroundCANTOS Ushers in a New Calculus of Inflammasome Targeting for Vascular Protection—and Maybe More
Verma, S., Leiter, L. A., & Bhatt, D. L. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.022 · Cited by 29
Demonstration of a human pyrogen-inducing factor during mixed leukocyte reactions.
Dinarello, C. A. (1981) · The Journal of Experimental Medicine · doi:10.1084/jem.153.5.1215 · Cited by 28 · cited 1×
“Critical early discoveries of cytokine function were made in the field of fever research where the first between white blood cell signaling molecule or IL-1 was described.(11) The cytokine family includes >30 subsequently identified ILs, as well as TNFs (tumor necrosis factors), interferons, chemokines, colony-stimula…”
BackgroundInflammation Revisited: Atherosclerosis in The Post-CANTOS Era
Köenig, W., & Deutsches Herzzentrum München, T. U. M. (2017) · European Cardiology Review · doi:10.15420/ecr.2017:18:1 · Cited by 26
Addressing Acute Coronary Syndromes
Crea, F., & Liuzzo, G. (2018) · Circulation · doi:10.1161/circulationaha.117.032178 · Cited by 22
Targeting Inflammation in the Prevention and Treatment of Type 2 Diabetes
Verma, S., Mathew, V., & Farkouh, M. E. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.03.480 · Cited by 21 · cited 1×
“Yet, although IL-1β inhibition in CANTOS modestly reduced HbA1c (hemoglobin A1c) during the first 6 to 9 months of treatment, no long-term benefits on glucose levels were observed nor was there a significant reduction in incident diabetes mellitus.(103)”
BackgroundCardiovascular Risk Reduction in Patients With Chronic Kidney Disease
Cherney, D. Z. I., Lytvyn, Y., & McCullough, P. A. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.04.008 · Cited by 15 · cited 1×
“Thus, extension of these IL signaling data into the setting of severe renal failure is a promising direction.(95) The renal subgroup data from CANTOS are hypothesis generating and require direct testing.”
BackgroundWhy the CANTOS Is a Game Changer in Cardiovascular Medicine
Abbate, A. (2017) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000546 · Cited by 14
Targeting Inflammation in Atherosclerosis ∗
Bentzon, J. F. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.11.005 · Cited by 12 · cited 1×
“Recently, inhibition of TREM-1 has been shown to reduce atherosclerosis progression and vascular inflammation in LDLr-deficient and ApoE-deficient mice.(131,132)”
BackgroundInterleukin-1 inhibition and ischaemic stroke: has the time for a major outcomes trial arrived?
Ridker, P. M. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy360 · Cited by 10 · cited 1×
“The above data support consideration for a major outcomes trial of IL-1β inhibition in acute stroke.(89) In CANTOS—a trial of patients with postmyocardial infarction, the incidence rate for stroke was 0.”
ResultSelf-citationSTOP the TRAFfic and Reduce the Plaque
Arditi, M., & Shah, P. K. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.12.023 · Cited by 4 · cited 1×
“Whether these effects are independent of IL-1 inhibition and can translate to human atherosclerosis requires further investigation.(128) Further translational work is also needed for investigations of TREM-1 (triggering receptor expressed on myeloid cells 1), which has been shown to stimulate the inflammatory response…”
Background
Research works printed but not linked: 1
- Svennson, EC, Madar, A, Campbell, CD, He, Y, Sultan, M, Healey, ML, D’Aco, K, Fernandez, A, Wache-Mainier, C, Ridker, PM, Beste, MT, Basson, CT. TET-2-driven clonal hematopoiesis predicts response to canakinumab in the CANTOS trials: an exploratory analysis. Abstract presented at American Heart Association Scientific Session, November 12, 2018.
Cited by
Sorted by citations
Ridker, P. M., Devalaraja, M., Baeres, F. M. M., Engelmann, M. D. M., Hovingh, G. K., Ivkovic, M., Lo, L., Kling, D. F., Pérgola, P. E., Raj, D. S., et al. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00520-1 · Cited by 802
Self-citationInterleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease
Ridker, P. M., & Rane, M. A. (2021) · Circulation Research · doi:10.1161/circresaha.121.319077 · Cited by 743
Self-citationTargeting cardiovascular inflammation: next steps in clinical translation
Lawler, P. R., Bhatt, D. L., Godoy, L. C., Lüscher, T. F., Bonow, R. O., Verma, S., & Ridker, P. M. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa099 · Cited by 463
Self-citationTherapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?
Engelen, S. E., Robinson, A., Zurke, Y.-X., & Monaco, C. G. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00668-4 · Cited by 455
Dziedzic, E. A., Gąsior, J. S., Tuzimek, A., Paleczny, J., Junka, A., Dąbrowski, M., & Jankowski, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179553 · Cited by 345
Metadata
- Authors
- Ridker, P. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Ridker, Paul M
- ORCID
- Ridker, Paul M
- Venue
- Circulation Research
- Published
- 2019-02
- Volume
- 124
- Issue
- 3
- Pages
- 437-450
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- 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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