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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The interleukin-1β to interleukin-6 to C-reactive protein pathway of innate immunity is important for atherosclerosis development.
“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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“As described above, in CANTOS, much of the benefit of IL-1β inhibition was mediated through modulation of IL-6 (Figure 5).(65) Thus, direct targeting of IL-6 with agents that either block IL-6 binding (such as tocilizumab) or that alter IL-6 receptor activity (such as sarilumab) merit consideration for atheroprotectio…”
BackgroundSelf-citationInterleukin-6 Exacerbates Early Atherosclerosis in Mice
Huber, S. A., Sakkinen, P. A., Conze, D. B., Hardin, N. J., & Tracy, R. P. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.10.2364 · Cited by 549 · see citing works
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 535 · cited 1× · see citing works
“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 · see citing works
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 495 · cited 1× · see citing works
“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 469 · see citing works
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 460 · see citing works
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 · see citing works
Ridker, P. M. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.11.037 · Cited by 414 · cited 1× · see citing works
“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× · see citing works
“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× · see citing works
“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 398 · see citing works
Bozkurt, B., Torre‐Amione, G., Warren, M. S., Whitmore, J. B., Soran, O. Z., Feldman, A. M., & Mann, D. L. (2001) · Circulation · doi:10.1161/01.cir.103.8.1044 · Cited by 388 · cited 1× · see citing works
“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 · see citing works
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 374 · cited 1× · see citing works
“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 · see citing works
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× · see citing works
“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. Z., Ownby, E. D., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.740233 · Cited by 359 · cited 1× · see citing works
“among patients with heart failure.(59,60) Further, recent findings”
BackgroundWestlake, S. L., Colebatch, A. N., Baird, J., Kiely, P., Quinn, M., Choy, E., Ostor, A. J. K., & Edwards, C. J. (2010) · Rheumatology · doi:10.1093/rheumatology/kep366 · Cited by 357 · see citing works
Morton, 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 353 · see citing works
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× · see citing works
“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…”
BackgroundBohula, 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 · see citing works
Ohta, 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 334 · see citing works
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 332 · cited 1× · see citing works
“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.”
BackgroundAnti-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 328 · cited 1× · see citing works
“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-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 311 · see citing works
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 309 · see citing works
Self-citationTargeting 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 306 · see citing works
Ridker, 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 298 · see citing works
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× · see citing works
“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 280 · see citing works
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 · see citing works
Residual 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× · see citing works
“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-citationInterleukin-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 256 · cited 1× · see citing works
“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)”
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 · see citing works
Targeting 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 250 · cited 1× · see citing works
“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…”
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 · see citing works
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 247 · cited 1× · see citing works
“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 245 · cited 1× · see citing works
“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…”
BackgroundInflammation and Cardiovascular Disease
Fearon, W. F., & Fearon, D. T. (2008) · Circulation · doi:10.1161/circulationaha.108.772491 · Cited by 241 · cited 6× · see citing works
“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 232 · cited 1× · see citing works
“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 218 · cited 1× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“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 172 · cited 1× · see citing works
“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 154 · cited 1× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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…”
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 110 · see citing works
Joffre, 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 108 · cited 1× · see citing works
“Recently, inhibition of TREM-1 has been shown to reduce atherosclerosis progression and vascular inflammation in LDLr-deficient and ApoE-deficient mice.(131,132)”
BackgroundGlynn, R. J., MacFadyen, J. G., & Ridker, P. M. (2008) · Clinical Chemistry · doi:10.1373/clinchem.2008.120642 · Cited by 107 · cited 1× · see citing works
“identical to that of LDL (low-density lipoprotein) cholesterol (LDL-C) and superior to that of blood pressure.(41) hsCRP fur-”
BackgroundSelf-citationThe 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× · see citing works
“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.”
BackgroundThe 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 99 · cited 1× · see citing works
“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.”
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 · see citing works
Canault, M. (2003) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2003.10.004 · Cited by 92 · cited 1× · see citing works
“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…”
BackgroundBaylis, 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 92 · see citing works
Selective 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 72 · cited 1× · see citing works
“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 70 · see citing works
Vaccination to modulate atherosclerosis
Kimura, T., Tse, K. Y., Sette, A., & Ley, K. F. (2015) · Autoimmunity · doi:10.3109/08916934.2014.1003641 · Cited by 68 · see citing works
Liberale, L., Díaz-Cañestro, C., Bonetti, N. R., Paneni, F., Akhmedov, A. T., Beer, J. H., Montecucco, F., Lüscher, T. F., & Camici, G. G. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy286 · Cited by 60 · cited 1× · see citing works
“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…”
BackgroundГоловкин, 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 · see citing works
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× · see citing works
“More recent murine evidence with erlotinib— a selective inhibitor of the epidermal growth factor receptor— also suggests reductions in experimental atherosclerosis.(142,143)”
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“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 · see citing works
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 · see citing works
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“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 · see citing works
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× · see citing works
“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 · see citing works
Addressing Acute Coronary Syndromes
Crea, F., & Liuzzo, G. (2018) · Circulation · doi:10.1161/circulationaha.117.032178 · Cited by 22 · see citing works
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 20 · cited 1× · see citing works
“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× · see citing works
“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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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…”
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- [65]Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ on behalf of the CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomized controlled trial. Lancet 2018; 391: 319– 28. 29146124
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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 750 · see citing works
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 715 · see citing works
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 445 · see citing works
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 442 · see citing works
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Neuroinflammation across neurological diseases
Shi, F., & Yong, V. W. (2025) · Science · doi:10.1126/science.adx0043 · Cited by 312 · see citing works
Ridker, P. M., MacFadyen, J. G., Thuren, T. Y., & Libby, P. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz542 · Cited by 241 · see citing works
Self-citationLivshits, G., & Kalinkovich, A. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100980 · Cited by 239 · see citing works
Zaki, N., Alashwal, H., & Ibrahim, S. (2020) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2020.07.005 · Cited by 240 · see citing works
Lipoprotein‐associated phospholipase A2: The story continues
Huang, F., Wang, K., & Shen, J. (2020) · Medicinal Research Reviews · doi:10.1002/med.21597 · Cited by 212 · see citing works
“Furthermore, the possibility that Lp‐PLA2 might not be a suitable target to address the residual inflammatory risk could not be excluded, based on the observation that broad‐spectrum anti‐inflammatory therapy by methotrexate failed to reduce cardiovascular events while specific cytokine inhibition by canakinumab could…”
BackgroundWhite Blood Cells and Blood Pressure
Siedliński, M., Józefczuk, E., Xu, X., Teumer, A., Εvangelou, Ε., Schnabel, R. B., Welsh, P. I., Maffia, P., Erdmann, J., Tomaszewski, M., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.045102 · Cited by 203 · see citing works
The Baffling Case of Ischemic Stroke Disappearance from the Casualty Department in the COVID-19 Era
Morelli, N., Rota, E., Terracciano, C., Immovilli, P., Spallazzi, M., Colombi, D., Zaino, D., Michieletti, E., & Guidetti, D. (2020) · European Neurology · doi:10.1159/000507666 · Cited by 191 · see citing works
“Indeed, although high IL-6 levels have been reported to have a negative effect on brain infarct volume and long-term outcome [10] , conversely, in ischemic stroke, there is also experimental evidence that IL-6 has a protective effect and helps in the improvement of poststroke angiogenesis [11] .”
BackgroundTargeting the CCL2–CCR2 axis for atheroprotection
Georgakis, M. K., Bernhagen, J., Heitman, L. H., Weber, C., & Dichgans, M. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac094 · Cited by 173 · see citing works
Ridker, P. M., MacFadyen, J. G., Glynn, R. J., Bradwin, G., Hasan, A., & Rifai, N. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa160 · Cited by 162 · see citing works
Self-citationRidker, P. M. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab231 · Cited by 156 · see citing works
“Yet, cardiologists and vascular biologists now have hard evidence that inhibition of the NLRP3 to IL-1b to IL-6 to C-reactive protein (CRP) pathway of innate immunity is also a potent target for atheroprotection.(1) This proof-of-principle derives from the 10 000 participant multi-national CANTOS trial presented in 20…”
BackgroundSelf-citationChallenges and advances in the management of inflammation in atherosclerosis
Xing, Y., & Lin, X. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.06.016 · Cited by 142 · see citing works
“Notably, IL-10 is known for its atheroprotective effects, adding complexity to the role of Th17 cells in atherogenesis [54,55].”
Endothelial shear stress signal transduction and atherogenesis: From mechanisms to therapeutics
He, L., Zhang, C., Chen, Q., Wang, L., & Huang, Y. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108152 · Cited by 137 · see citing works
Ridker, P. M., Rifai, N., MacFadyen, J., Glynn, R. J., Jiao, L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Tardif, J.-C., et al. (2022) · Circulation · doi:10.1161/circulationaha.122.059410 · Cited by 131 · see citing works
Self-citationPCSK9 inhibition and inflammation: A narrative review
Ruscica, M., Tokgözoğlu, L. S., Corsini, A., & Sirtori, C. R. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.07.015 · Cited by 130 · see citing works
“with a 2X2 factorial design, with aggressive LDL-C-lowering and anti-inflammatory therapies are eagerly awaited [140].”
MethodRossi, J., Lu, Z. Y., Massart, C., & Levón, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.595722 · Cited by 138 · see citing works
“Dynamic analysis of the inflammatory biomarkers may contribute to a more personalized immune medicine, monitoring both the risks associated to vaccine and the therapies needed, aiming to reduce inflammation by using anti-cytokine targeting IL-1, TNFa, or IL-6, or to amplify an immune response by using immune adjuvants…”
BackgroundInflammation drives residual risk in chronic kidney disease: a CANTOS substudy
Ridker, P. M., Tuttle, K. R., Perkovic, V., Libby, P., & MacFadyen, J. G. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac444 · Cited by 117 · see citing works
Self-citationRidker, P. M. (2020) · Circulation · doi:10.1161/circulationaha.119.045256 · Cited by 111 · see citing works
Self-citationCirculating Monocyte Chemoattractant Protein-1 and Risk of Stroke
Georgakis, M. K., Malik, R., Björkbacka, H., Pana, T. A., Demissie, S., Ayers, C. R., Elhadad, M. A., Fornage, M., Beiser, A., Benjamin, E. J., et al. (2019) · Circulation Research · doi:10.1161/circresaha.119.315380 · Cited by 109 · see citing works
Georgakis, M. K., van der Laan, S. W., Asare, Y., Mekke, J. M., Haitjema, S., Schoneveld, A. H., de Jager, S. C. A., Nurmohamed, N. S., Kroon, J., Stroes, E. S. G., et al. (2021) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.121.316091 · Cited by 109 · see citing works
Wang, H., Liu, Z., Shao, J., Lin, L., Jiang, M., Wang, L., Lu, X.-C., Zhang, H. S., Chen, Y., & Zhang, R. (2020) · Journal of Immunology Research · doi:10.1155/2020/4904217 · Cited by 105 · see citing works
“…showed a reduced level of troponin and in fl am-matory markers in the ASSessing the E ff ect of Anti-IL-6 Treatment in MI (ASSAIL-MI) trial [16, 69, 70], which was designed to assess the e ff ects of tocilizumab on ischemia reperfusion injury in patients with ST-elevation myocardial…”
InfluentialHasselbalch, H. C., Elvers, M., & Schafer, A. I. (2021) · Blood · doi:10.1182/blood.2020008109 · Cited by 102 · see citing works
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Roles and Mechanisms of Hawthorn and Its Extracts on Atherosclerosis: A Review
Wu, M., Liu, L., Xing, Y., Yang, S., Li, H., & Cao, Y. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00118 · Cited by 103 · see citing works
“The hyper-activated inflammatory response can lead to Frontiers in Pharmacology | www.frontiersin.org 6 acute coronary syndromes (Gimbrone and García-Cardeña, 2016; Ferrucci and Fabbri, 2018; Ridker, 2019).”
BackgroundTocchetti, C. G., Farmakis, D. T., Koop, Y., Andrés, M. S., Couch, L. S., Formisano, L., Ciardiello, F., Pane, F., Au, L., Emmerich, M., et al. (2024) · European Journal of Heart Failure · doi:10.1002/ejhf.3340 · Cited by 98 · see citing works
D’Alessandro, E., Becker, C., Bergmeier, W., Bode, C., Bourne, J. H., Brown, H. C., Buller, H. R., ten Cate‐Hoek, A. J., ten Cate, V., van Cauteren, Y. J. M., et al. (2020) · Thrombosis and Haemostasis · doi:10.1055/s-0040-1708035 · Cited by 90 · see citing works
Inflammation and Cardiovascular Disease: The Future
Arnold, N., Lechner, K., Waldeyer, C., Shapiro, M. D., & Köenig, W. (2021) · European Cardiology Review · doi:10.15420/ecr.2020.50 · Cited by 89 · see citing works
Sex Differences in Proatherogenic Cytokine Levels
Bernardi, S., Toffoli, B., Tonon, F., Francica, M., Campagnolo, E., Ferretti, T., Comar, S., Giudici, F., Stenner, E., & Fabris, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113861 · Cited by 85 · see citing works
“IL-1β, IL-6, and TNF-α are soluble low-molecular-weight-proteins that mediate crosstalk between immune and nonimmune cells and have been implicated in atherosclerosis development and progression [26].”
BackgroundCupido, A. J., Asselbergs, F. W., Natarajan, P., CHARGE Inflammation Working Group, Ridker, P. M., Hovingh, G. K., & Schmidt, A. F. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.15191 · Cited by 83 · see citing works
Self-citationAnticytokine Immune Therapy and Atherothrombotic Cardiovascular Risk
Ait‐Oufella, H., Libby, P., & Tedgui, A. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.311998 · Cited by 80 · see citing works
The ABCA1-efferocytosis axis: A new strategy to protect against atherosclerosis
Chen, W., Li, L., Wang, J., Zhang, R., Zhang, T., Wu, Y., Wang, S., & Xing, D. (2021) · Clinica Chimica Acta · doi:10.1016/j.cca.2021.02.025 · Cited by 84 · see citing works
Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases
Potere, N., Bonaventura, A., & Abbate, A. (2024) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.124.319980 · Cited by 78 · see citing works
Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis
Lorey, M. B., Öörni, K., & Kovanen, P. T. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.841545 · Cited by 80 · see citing works
Wada, Y., Jensen, C., Meyer, A., Zonoozi, A. A. M., & Honda, H. (2023) · Journal of Cardiology · doi:10.1016/j.jjcc.2023.05.006 · Cited by 77 · see citing works
Georgakis, M. K., Malik, R., Björkbacka, H., Pana, T. A., Demissie, S., Ayers, C. R., Elhadad, M. A., Fornage, M., Beiser, A., Benjamin, E. J., et al. (2019) · PubMed · doi:10.17863/cam.43602 · Cited by 74 · see citing works
Identification of HMOX1 as a Critical Ferroptosis-Related Gene in Atherosclerosis
Wu, D., Hu, Q., Wang, Y., Jin, M., Tao, Z., & Wan, J. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.833642 · Cited by 75 · see citing works
Cytokines as key players in obesity low grade inflammation and related complications
Uti, D. E., Atangwho, I. J., Omang, W. A., Alum, E. U., Obeten, U. N., Udeozor, P. A., Agada, S. A., Bawa, I., & Ogbu, C. O. (2025) · Obesity Medicine · doi:10.1016/j.obmed.2025.100585 · Cited by 107 · see citing works
Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes
Herder, C., Maalmi, H., Straßburger, K., Zaharia, O., Ratter, J. M., Karusheva, Y., Elhadad, M. A., Bódis, K. B., Bongaerts, B. W. C., Rathmann, W., et al. (2021) · Diabetes · doi:10.2337/db20-1054 · Cited by 73 · see citing works
Li, J., Lin, J., Pan, Y., Wang, M., Meng, X., Li, H., Wang, Y., Zhao, X., 秦海强, Liu, L., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02467-1 · Cited by 72 · see citing works
Atherosclerosis: Insights into Vascular Pathobiology and Outlook to Novel Treatments
Wolf, M., & Hunziker, P. (2020) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-020-09961-y · Cited by 71 · see citing works
“Cytokine blockade therapy has become an important option in the treatment of autoimmune and auto-inflammatory diseases and is considered for treatment of atherosclerosis [151].”
BackgroundBallerini, P., Contursi, A., Bruno, A., Mucci, M., Tacconelli, S., & Patrignani, P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.838079 · Cited by 69 · see citing works
“Chronic inflammation promotes many pathological conditions, including atherothrombosis (Libby et al., 2009; Ridker 2019), tissue fibrosis (Wynn and Ramalingam 2012), aberrant angiogenesis (Jackson et al., 1997), and neoplasia (Coussens and Werb, 2002; Grivennikov et al., 2010; Hanahan and Weinberg…”
BackgroundRidker, P. M., Baeres, F. M. M., Hvelplund, A., Engelmann, M. D. M., Hovingh, G. K., Lincoff, A. M., Marx, N., Návar, A. M., Sattar, N. A., Tuttle, K. R., et al. (2025) · JAMA Cardiology · doi:10.1001/jamacardio.2025.4491 · Cited by 71 · see citing works
Self-citationEffects of Interleukin-1β Inhibition on Incident Anemia
Vallurupalli, M., MacFadyen, J. G., Glynn, R. J., Thuren, T. Y., Libby, P., Berliner, N., & Ridker, P. M. (2020) · Annals of Internal Medicine · doi:10.7326/m19-2945 · Cited by 68 · see citing works
“Earlier analyses from CANTOS revealed that canakinumab treatment modifies several disease processes involving inflammasome signaling (22).”
BackgroundSelf-citationAdvances in biological therapies for dyslipidemias and atherosclerosis
Valanti, E.-K., Dalakoura-Karagkouni, K., Siasos, G., Kardassis, D., Eliopoulos, A. G., & Sanoudou, D. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154461 · Cited by 68 · see citing works
Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism
Lin, W., Song, H., Shen, J., Wang, J., Yang, Y., Yang, Y., Cao, J., Xue, L., Zhao, F., Xiao, T., et al. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1110926 · Cited by 67 · see citing works
“Among thousands of cytokines, NOD-, LRR-, and pyrin domaincontaining protein 3 (NLRP3), C-reactive protein (CRP), IL-1, and IL-6 were involved in atherosclerosis pathogenesis (Ridker, 2016; Lutgens et al., 2019; Ridker, 2019).”
BackgroundNLRP3 inflammasome in cardiovascular diseases: an update
Mo, B., Ding, Y., & Ji, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1550226 · Cited by 67 · see citing works
“Numerous studies have been conducted to investigate potential treatment approaches that target the in fl ammatory response since the function of the NLRP3 in fl ammasome in cardiovascular diseases has been increasingly validated (195).”
Immunomodulation Strategies for the Successful Regeneration of a Tissue‐Engineered Vascular Graft
Zhang, F., & King, M. W. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202200045 · Cited by 67 · see citing works
Molecular and cellular mechanisms of inflammation in atherosclerosis
Popa‐Fotea, N., Ferdoschi, C., & Micheu, M.-M. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1200341 · Cited by 63 · see citing works
Wei, X., Zhang, Z., Wei, J., & Luo, C. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1248655 · Cited by 64 · see citing works
Decoding inflammation, its causes, genomic responses, and emerging countermeasures
Hawiger, J., & Zienkiewicz, J. (2019) · Scandinavian Journal of Immunology · doi:10.1111/sji.12812 · Cited by 62 · see citing works
Koshino, A., Schechter, M., Sen, T., Vart, P., Neuen, B. L., Neal, B. C., Arnott, C. G., Perkovic, V., Ridker, P. M., Tuttle, K. R., et al. (2022) · Diabetes Care · doi:10.2337/dc22-0866 · Cited by 63 · see citing works
Self-citationTargeting Inflammation After Acute Myocardial Infarction
Imbesi, A., Greco, A., Spagnolo, M., Laudani, C., Raffo, C., Finocchiaro, S., Mazzone, P. M., Landolina, D., Mauro, M. S., Cutore, L., et al. (2025) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2025.07.064 · Cited by 66 · see citing works
Growth Factors as Immunotherapeutic Targets in Cardiovascular Disease
Mindur, J. E., & Świrski, F. K. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.311994 · Cited by 57 · see citing works
Koller, G. M., Schafer, C. M., Kemp, S. S., Aguera, K. N., Lin, P. K., Forgy, J. C., Griffin, C. T., & Davis, G. E. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.313536 · Cited by 57 · see citing works
Advances in the treatment of atherosclerosis with ligand‐modified nanocarriers
Deng, X., Wang, J., Yu, S., Tan, S., Yu, T., Xu, Q., Chen, N., Zhang, S., Zhang, M., Hu, K., et al. (2023) · Exploration · doi:10.1002/exp.20230090 · Cited by 56 · see citing works
Advances in Atherosclerosis Theranostics Harnessing Iron Oxide‐Based Nanoparticles
Wang, S., He, H., Mao, Y., Zhang, Y., & Gu, N. (2024) · Advanced Science · doi:10.1002/advs.202308298 · Cited by 53 · see citing works
Hoffmann, J., Mas‐Peiró, S., Berkowitsch, A., Boeckling, F., Rasper, T., Pieszko, K., Rosa, R. D., Hiczkiewicz, J., Burchardt, P., Fichtlscherer, S., et al. (2020) · ESC Heart Failure · doi:10.1002/ehf2.12837 · Cited by 53 · see citing works
“The era of anti-inflammatory therapies in cardiovascular disease and heart failure has just begun.(41) A recent subgroup”
BackgroundMonomeric C-Reactive Protein in Atherosclerotic Cardiovascular Disease: Advances and Perspectives
Сергеевич, М. И., Kozlov, S. G., Saburova, O., Avtaeva, Y., Guria, K. G., & Ахнафович, Г. З. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032079 · Cited by 51 · see citing works
“Moreover, the mechanism of the anti-inflammatory action of methotrexate does not affect the NLRP3 inflammasome and IL-1β/IL-6/CRP axis [36].”
BackgroundInfluentialQuagliariello, V., Passariello, M., Mauro, A. D., Cipullo, C., Paccone, A., Barbieri, A., Palma, G., Luciano, A., Buccolo, S., Bisceglia, I., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.930797 · Cited by 49 · see citing works
“Moreover, the results of this study warrant further preclinical cardioprotective trials with anti-cytokine (52, 53), anti-NLRP3 (54–56) or anti-MyD88 (57, 58) therapies in primary or secondary prevention of ICIs-related cardiotoxicity.”
ResultImmunomodulatory hybrid micro-nanofiber scaffolds enhance vascular regeneration
Liu, S. M., Yao, L., Wang, Y., Li, Y., Jia, Y., Yang, Y., Li, N., Hu, Y., Kong, D., Dong, X., et al. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.08.018 · Cited by 49 · see citing works
“IL-1β triggered the secretion of various pro-inflammatory cytokines related to the level of stenosis and athetosis [50,51].”
BackgroundDziedzic, E. A., Gąsior, J. S., Tuzimek, A., Dąbrowski, M., & Jankowski, P. (2022) · Nutrients · doi:10.3390/nu14194212 · Cited by 49 · see citing works
Alisma orientalis Beverage Treats Atherosclerosis by Regulating Gut Microbiota in ApoE-/- Mice
Zhu, B., Zhai, Y., Ji, M., Wei, Y., Wu, J., Xue, W., Tao, W. W., & Wu, H. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.570555 · Cited by 48 · see citing works
“Under constant stimulation of chronic systemic inflammation and high blood lipid levels, the arteries will suffer corresponding damage and produce atherosclerotic lesions (Fatkhullina et al., 2018; Komaroff, 2018; Ridker, 2019).”
BackgroundGeorgakis, M. K., Malik, R., Burgess, S., & Dichgans, M. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.121.023277 · Cited by 48 · see citing works
“10 Here, we use large-scale data to test whether there is genetic support for this hypothesis before investing in a clinical trial.”
Reflections on Atherosclerosis: Lesson from the Past and Future Research Directions
Minelli, S., Minelli, P., & Montinari, M. R. (2020) · Journal of Multidisciplinary Healthcare · doi:10.2147/jmdh.s254016 · Cited by 48 · see citing works
Gu, H., Yang, K., Lin, J., Jing, J., Zhao, X., Wang, Y., Liu, L., Meng, X., Jiang, Y., Li, H., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104054 · Cited by 47 · see citing works
Li, X., Yang, Y., Wang, Z., Jiang, S., Meng, Y., Song, X., Zhao, L., Zou, L., Li, M., & Yu, T. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.62506 · Cited by 47 · see citing works
“In patients with AS, activated NLRP3 inflammasomes produce IL-1β and IL-18 [77, 78], which up-regulate VCAM to induce T-cell differentiation and promote a downstream inflammatory response, thus leading to plaque progression [79, 80].”
BackgroundDongoran, R. A., Lin, T., Byekyet, A., Tang, S., Yang, J., & Liu, C. (2020) · Biomolecules · doi:10.3390/biom10121689 · Cited by 46 · see citing works
Yin, T., Li, Y., Ren, Y., Fuad, A. R. M., Hu, F., Du, R., Wang, Y., Wang, Y., & Wang, Y. (2021) · Journal of Nanobiotechnology · doi:10.1186/s12951-021-00863-y · Cited by 41 · see citing works
Role of the adaptive immune system in atherosclerosis
Ley, K. F. (2020) · Biochemical Society Transactions · doi:10.1042/bst20200602 · Cited by 40 · see citing works
Hafiane, A., & Daskalopoulou, S. S. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106157 · Cited by 40 · see citing works
Sánchez-Azofra, A., Gu, W., Masso-Silva, J. A., Sánz-Rubio, D., Marín‐Oto, M., Cubero, P., Gil, A. V., Moya, E. A., Barnes, L. A., Mesarwi, O. A., et al. (2023) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.10600 · Cited by 39 · see citing works
Yang, L., Yue, Q., Fang, F., Zhang, Y., Liu, P., Zhang, Z., Wang, G., Chen, S., Wu, S., & Yang, X. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-01826-3 · Cited by 39 · see citing works
“OxLDL-C can also increase the expression of hs-CRP [31], which can activate the complement system to form atherosclerotic plaque [32, 33].”
BackgroundStrategies to Overcome Residual Risk During Statins Era
Cho, K. I., Yu, J., Hayashi, T., Han, S. H., & Koh, K. K. (2019) · Circulation Journal · doi:10.1253/circj.cj-19-0624 · Cited by 38 · see citing works
Effects of Bilberry Supplementation on Metabolic and Cardiovascular Disease Risk
Chan, S. W., & Tomlinson, B. (2020) · Molecules · doi:10.3390/molecules25071653 · Cited by 40 · see citing works
“Furthermore, data from the recent Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) and Cardiovascular Inflammation Reduction Trial (CIRT) provide clinical support of the benefit of anti-cytokine therapies, but not weaker broad-spectrum antiinflammatory therapy, in atherosclerosis treatment [65,66].”
ResultNon-stenotic Carotid Plaques in Embolic Stroke of Unknown Source
Tatuene, J. K., Nomani, A. Z., Falcione, S. R., Munsterman, D., Sykes, G. P., Joy, T., Spronk, E., Vargas, M. I., & Jickling, G. C. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.719329 · Cited by 39 · see citing works
Mullis, C. E., & Swartz, T. H. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00095 · Cited by 39 · see citing works
New evidence on the role of inflammation in CVD risk
Lorenzatti, A. J., & Servato, L. (2019) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000625 · Cited by 37 · see citing works
Atherothrombosis and the NLRP3 inflammasome – endogenous mechanisms of inhibition
Satish, M., & Agrawal, D. K. (2019) · Translational research · doi:10.1016/j.trsl.2019.08.003 · Cited by 37 · see citing works
Sun, L., Yuan, J., Chen, Q.-C., Xiao, W.-K., Ma, G., Liang, J., Chen, X., Wang, S., Zhou, X., Wu, H. M., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.996467 · Cited by 39 · see citing works
Georgakis, M. K., Malik, R., Gill, D., Franceschini, N., Sudlow, C. L. M., & Dichgans, M. (2019) · medRxiv · doi:10.1101/19007682 · Cited by 36 · see citing works
Gallucci, G., Turazza, F. M., Inno, A., Canale, M. L., Silvestris, N., Farì, R., Navazio, A., Pinto, C., & Tarantini, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25084232 · Cited by 35 · see citing works
“The remarkable inflammatory features of atherosclerosis explain the beneficial effect of drugs that target the inflammasome pathway, but a “focused” cytokine inhibition is necessary, as Ridker states, to yield an effective atheroprotective effect [87,88].”
BackgroundDing, E., Deng, F., Fang, J., Liu, J., Yan, W., Yao, Q., Miao, K., Wang, Y., Sun, P., Li, C., et al. (2024) · Environmental Health Perspectives · doi:10.1289/ehp13864 · Cited by 33 · see citing works
“88 Epidemiological studies have also supported the fi ndings of our pathway analysis.”
ResultRole of Periodontal Infection, Inflammation and Immunity in Atherosclerosis
Choi, H., Dey, A. K., Priyamvara, A., Aksentijevich, M., Bandyopadhyay, D., Dey, D. K., Dani, S. S., Guha, A., Nambiar, P. H., Nasir, K., et al. (2020) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2020.100638 · Cited by 33 · see citing works
Ma, J., & Chen, X. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.631398 · Cited by 32 · see citing works
Fang, Q., Li, X., Wang, M., Qiao, X., Huang, F., Hu, C., Xue, Y., Zhao, S., & Lin, Y. (2022) · Food & Function · doi:10.1039/d2fo00012a · Cited by 31 · see citing works
Clemens, D. L., Duryee, M. J., Hall, J. H., Thiele, G. M., Mikuls, T. R., Klassen, L. W., Zimmerman, M. C., & Anderson, D. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107413 · Cited by 30 · see citing works
Radionuclide Image-Guided Repair of the Heart
Hess, A., Thackeray, J. T., Wollert, K. C., & Bengel, F. M. (2019) · JACC. Cardiovascular imaging · doi:10.1016/j.jcmg.2019.11.007 · Cited by 30 · see citing works
Bugueno, I. M., Zobairi, F., Batool, F., Itawi, H. E., Anglés‐Cano, E., Benkirane-Jessel, N., Toti, F., & Huck, O. (2020) · Scientific Reports · doi:10.1038/s41598-020-58374-z · Cited by 30 · see citing works
Colchicine – new horizons for an ancient drug. Review based on the highest hierarchy of evidence
Schattner, A. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.10.002 · Cited by 30 · see citing works
Macrophage Dysfunction in Autoimmune Rheumatic Diseases and Atherosclerosis
Владимировна, Г. Е., Попкова, Т. В., Gerasimova, D. A., & Kirichenko, T. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094513 · Cited by 30 · see citing works
“CIRT [96], and COLCOT studies [97], several new anti-inflammatory and anticytokine agents are expected to be developed for the treatment of atherosclerosis [98].”
BackgroundEverett, B. M. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.02.056 · Cited by 30 · see citing works
“Novel therapies directed at the NLRP3 inflammasome and its downstream signaling cascade—including IL-1b and -6—are in development (2).”
BackgroundHigh l -Carnitine Ingestion Impairs Liver Function by Disordering Gut Bacteria Composition in Mice
Wu, Q., Zhang, X., Zhao, Y., & Yang, X. (2020) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b08313 · Cited by 29 · see citing works
Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques
Harber, K. J., Neele, A. E., van Roomen, C. P. A. A., Gijbels, M. J., Beckers, L., den Toom, M., Schomakers, B. V., Heister, D., Willemsen, L., Griffith, G. R., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103054 · Cited by 28 · see citing works
Nordeng, J., Schandiz, H., Solheim, S., Åkra, S., Hoffman, P., Roald, B., Bendz, B., Arnesen, H., Helseth, R., & Seljeflot, I. (2021) · Mediators of Inflammation · doi:10.1155/2021/5525917 · Cited by 28 · see citing works
“Further downstream C-Reactive-Protein (CRP), produced in the liver as a response to IL-6, has been demonstrated to be a sustainable clinical marker of cardiovascular disease [19, 20].”
BackgroundFifty years of research on antithrombotic therapy: Achievements and disappointments
Hirsh, J., Eikelboom, J. W., & Chan, N. (2019) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2019.10.023 · Cited by 27 · see citing works
Anti-inflammatory Therapies for Coronary Heart Disease: A Systematic Review and Meta-Analysis
Wang, H., Jiang, M., Li, X., Zhao, Y., Shao, J., Liu, Z., Lin, L., Xu, Q., Wang, L., Lu, X.-C., et al. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.726341 · Cited by 27 · see citing works
“Current Evidence of Anti-inflammatory Therapy for CHD The attainment of cardiovascular benefits is compromised by the limitations of available treatment for CHD (1, 2, 8, 28).”
Background
- 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 › Surgery › 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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