Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1β in non-ST-elevation myocardial infarction

Kleveland, Ola; Ueland, Thor; Kunszt, Gabor; Bratlie, Marte; Yndestad, Arne; Broch, Kaspar; Holte, Espen; Ryan, Liv; Amundsen, Brage H.; Bendz, Bjørn; Aakhus, Svend; Espevik, Terje; Halvorsen, Bente; Mollnes, Tom Eirik; Wiseth, Rune; Gullestad, Lars; Aukrust, Pål; Damås, Jan Kristian

doi:10.1016/j.ijcard.2018.04.136

Cited by 31 publications

(15 citation statements)

References 25 publications

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“…In non-ST elevation myocardial infarction (non-STEMI) patients, a single dose of tocilizumab administered prior to coronary angiography was safe and attenuated troponin T release and systemic inflammation [110]. Although IL-6 blockade reduced serum CRP, levels of the chemokines CXCL10 and CCL4 were increased, highlighting the complexity of IL-6 actions on inflammatory cascades [111].…”

Section: Targeting Il-6 In Human Heart Failurementioning

confidence: 99%

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Hanna

Frangogiannis

2020

Cardiovasc Drugs Ther

248

170

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Heart failure exhibits remarkable pathophysiologic heterogeneity. A large body of evidence suggests that regardless of the underlying etiology, heart failure is associated with induction of cytokines and chemokines that may contribute to the pathogenesis of adverse remodeling, and systolic and diastolic dysfunction. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 have been extensively implicated in the pathogenesis of heart failure. Inflammatory cytokines modulate phenotype and function of all myocardial cells, suppressing contractile function in cardiomyocytes, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrixdegrading phenotype in fibroblasts. Moreover, cytokine-induced growth factor synthesis may exert chronic fibrogenic actions contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In addition to their role in adverse cardiac remodeling, some inflammatory cytokines may also exert protective actions on cardiomyocytes under conditions of stress. Chemokines, such as CCL2, are also upregulated in failing hearts and may stimulate recruitment of pro-inflammatory leukocytes, promoting myocardial injury, fibrotic remodeling, and dysfunction. Although experimental evidence suggests that cytokine and chemokine targeting may hold therapeutic promise in heart failure, clinical translation remains challenging. This review manuscript summarizes our knowledge on the role of TNF-α, IL-1, IL-6, and CCL2 in the pathogenesis of heart failure, and discusses the promises and challenges of targeted anti-cytokine therapy. Dissection of protective and maladaptive cellular actions of cytokines in the failing heart, and identification of patient subsets with overactive or dysregulated myocardial inflammatory responses are required for design of successful therapeutic approaches.

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Section: Targeting Il-6 In Human Heart Failurementioning

confidence: 99%

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Hanna

Frangogiannis

2020

Cardiovasc Drugs Ther

248

170

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“…It is given by injection intravenously and/or subcutaneously [104] and has undergone limited evaluation for efficacy in CVD. A recently completed phase II clinical trial examined its ability to reduce acute vascular inflammation in nonS/T-elevation myocardial infarction (NSTEMI) patients; however, the anticipated cardioprotective effect was not clear-cut, with tocilizumab causing a selective upregulation of inflammatory mediators interferon gamma-inducible protein 10 (IP-10) and macrophage inflammatory protein-1 β (MIP-1 β ) [105]. Given that many patients undergoing CVD interventions already suffer from underlying chronic inflammation observed in conditions such as T2DM, this potential proinflammatory effect may limit its usefulness in the clinic.…”

Section: Opportunities For Therapeutic Applicationsmentioning

confidence: 99%

“…Given that many patients undergoing CVD interventions already suffer from underlying chronic inflammation observed in conditions such as T2DM, this potential proinflammatory effect may limit its usefulness in the clinic. Furthermore, this clinical trial was not able to fully recapitulate the effects of tocilizumab that were evident in vitro [105].…”

Section: Opportunities For Therapeutic Applicationsmentioning

confidence: 99%

Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus

Moshapa

Riches-Suman

Palmer

2019

Cardiology Research and Practice

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Type 2 diabetes mellitus (T2DM) is increasing worldwide, and it is associated with increased risk of coronary artery disease (CAD). For T2DM patients, the main surgical intervention for CAD is autologous saphenous vein grafting. However, T2DM patients have increased risk of saphenous vein graft failure (SVGF). While the mechanisms underlying increased risk of vascular disease in T2DM are not fully understood, hyperglycaemia, insulin resistance, and hyperinsulinaemia have been shown to contribute to microvascular damage, whereas clinical trials have reported limited effects of intensive glycaemic control in the management of macrovascular complications. This suggests that factors other than glucose exposure may be responsible for the macrovascular complications observed in T2DM. SVGF is characterised by neointimal hyperplasia (NIH) arising from endothelial cell (EC) dysfunction and uncontrolled migration and proliferation of vascular smooth muscle cells (SMCs). This is driven in part by proinflammatory cytokines released from the activated ECs and SMCs, particularly interleukin 6 (IL-6). IL-6 stimulation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) pathway is a key mechanism through which EC inflammation, SMC migration, and proliferation are controlled and whose activation might therefore be enhanced in patients with T2DM. In this review, we investigate how proinflammatory cytokines, particularly IL-6, contribute to vascular damage resulting in SVGF and how suppression of proinflammatory cytokine responses via targeting the JAK/STAT pathway could be exploited as a potential therapeutic strategy. These include the targeting of suppressor of cytokine signalling (SOCS3), which appears to play a key role in suppressing unwanted vascular inflammation, SMC migration, and proliferation.

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“…As previously described, the use of IL6-RA in NSTEMI patients, at a dosage considerably lesser than in the present trial, reduced hsCRP and troponin levels [ 21 ], as well as altered cytokine levels [ 30 ]. The degree of systemic inflammation in these NSTEMI patients was much lesser than observed after OHCA and likely the effects of IL-6RA will be of a different magnitude in the present trial; likewise, a substantial proportion of OHCA patients in this trial will present with STEMI, again leading to higher levels of myocardial injury and troponin release.…”

Section: Discussionmentioning

confidence: 78%

Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial

Meyer

Wiberg

Grand

et al. 2020

Trials

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Background Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose at admission are at high risk of morbidity and mortality. This has been attributed to the post-cardiac arrest syndrome (PCAS) which encompasses multiple interacting components, including systemic inflammation. Elevated levels of circulating interleukin-6 (IL-6), a pro-inflammatory cytokine, is associated with worse outcomes in OHCA patients, including higher vasopressor requirements and higher mortality rates. In this study, we aim to reduce systemic inflammation after OHCA by administering a single infusion of tocilizumab, an IL-6 receptor antibody approved for use for other indications. Methods Investigator-initiated, double-blinded, placebo-controlled, single-center, randomized clinical trial in comatose OHCA patients admitted to an intensive cardiac care unit. Brief inclusion criteria: OHCA of presumed cardiac cause, persistent unconsciousness, age ≥ 18 years. Intervention: 80 patients will be randomized in a 1:1 ratio to a single 1-h intravenous infusion of either tocilizumab or placebo (NaCl). During the study period, patients will receive standard of care, including sedation and targeted temperature management of 36 ° for at least 24 h, vasopressors and/or inotropes as/if needed, prophylactic antibiotics, and any additional treatment at the discretion of the treating physician. Blood samples are drawn for measurements of biomarkers included in the primary and secondary endpoints during the initial 72 h. Primary endpoint: reduction in C-reactive protein (CRP). Secondary endpoints (abbreviated): cytokine levels, markers of brain, cardiac, kidney and liver damage, hemodynamic and hemostatic function, adverse events, and follow-up assessment of cerebral function and mortality. Discussion We hypothesize that reducing the effect of circulating IL-6 by administering an IL-6 receptor antibody will mitigate the systemic inflammatory response and thereby modify the severity of PCAS, in turn leading to lessened vasopressor use, more normal hemodynamics, and better organ function. This will be assessed by primarily focusing on hemodynamics and biomarkers of organ damage during the initial 72 h. In addition, pro-inflammatory and anti-inflammatory cytokines will be measured to assess if cytokine patterns are modulated by IL-6 receptor blockage. Trial registration ClinicalTrials.gov Identifier: NCT03863015; submitted February 22, 2019, first posted March 5, 2019. EudraCT: 2018-002686-19; date study was authorized to proceed: November 7, 2018.

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Interleukin-6 receptor inhibition with tocilizumab induces a selective and substantial increase in plasma IP-10 and MIP-1β in non-ST-elevation myocardial infarction

Abstract: Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1β during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074.

Cited by 31 publications

References 25 publications

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure

Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus

Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial

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