Effect of interleukin-6 inhibition on coronary microvascular and endothelial function in myocardial infarction

Holte, Espen; Kleveland, Ola; Ueland, Thor; Kunszt, Gabor; Bratlie, Marte; Broch, Kaspar; Michelsen, Annika E.; Bendz, Bjørn; Amundsen, Brage H.; Aakhus, Svend; Damås, Jan Kristian; Gullestad, Lars; Aukrust, Pål; Wiseth, Rune

doi:10.1136/heartjnl-2016-310875

Cited by 46 publications

(29 citation statements)

References 22 publications

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“…For example, Chen et al in 1994 showed that administration of PB1.3, a monoclonal antibody to P‐selectin, reduced oxidant stress, decreased leukocyte accumulation, and preserved cardiac function in dogs subjected to ischemia‐reperfusion . However, several other studies have failed to show a beneficial effect of inhibition of inflammation in improving myocardial infarct size or cardiac function …”

Section: Discussionmentioning

confidence: 99%

“…26 However, several other studies have failed to show a beneficial effect of inhibition of inflammation in improving myocardial infarct size or cardiac function. 4,27 Clinical trials investigating the use of anti-inflammatory drugs in chronic heart failure have been largely unsuccessful in mitigating the process of cardiac remodeling in chronic ischemia. Inhibition of TNF-a has also been studied in patients.…”

Section: Discussionmentioning

confidence: 99%

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Inflammation, Autophagy, and Apoptosis After Myocardial Infarction

Wang

Guo

Ding

et al. 2018

JAHA

184

129

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BackgroundThere is evidence for inflammation, autophagy, and apoptosis in the ischemic heart. Autophagy is a physiologic process for tissue survival. Apoptosis, on the other hand, is a mechanism that serves to clear the debris in the setting of tissue injury. The balance between autophagy and apoptosis may be important in cell survival and cardiac function.Methods and ResultsWe examined the interplay of inflammation and myocyte autophagy and apoptosis during the ischemic process. We subjected mice to total left coronary artery ligation and studied these animals for up to 4 weeks. The inflammatory (tumor necrosis factor [TNF]‐α, monocyte chemoattractant protein‐1, interleukin‐6, and interleukin‐1β) and autophagic signals (light chain‐3 and beclin‐1) were strongest during the first week and then began to decline. However, the apoptotic signals peaked at week 2 after left coronary artery ligation, and the elevated levels persisted until the end of the fourth week. To elucidate the role of inflammation in the regulation of myocyte autophagy and apoptosis, we administered TNF‐α inhibitor (CAS1049741‐03‐8, Millipore, Burlington, MA) to the mice daily during the first week of myocardial infarction. Anti‐TNF‐α therapy reduced the levels of inflammatory cytokines and the inflammatory cell infiltration in and around the infarct area. However, cardiac function measured by echocardiography (fractional shortening and ejection fraction) worsened with anti‐TNF‐α therapy. More importantly, application of TNF‐α inhibitor markedly inhibited autophagy and promoted myocyte apoptosis in the border zone.ConclusionsThese observations suggest that inflammatory response may be protective in the early stage of the myocardial infarction through stimulation of myocyte autophagy. Anti‐inflammatory treatment early after coronary occlusion may have an adverse effect.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inflammation, Autophagy, and Apoptosis After Myocardial Infarction

Wang

Guo

Ding

et al. 2018

JAHA

184

129

View full text Add to dashboard Cite

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“…In an ischemia/reperfusion mouse model of HF, IL-6 receptor blockade resulted in neither reduced cardiac remodeling nor smaller infarct size; however, treatment was started during the acute phase, which could explain why no effects were observed [113]. Also, in humans, inhibition of IL-6 has been tested, but it was not able to improve coronary flow reserve in patients post-myocardial infarction [114]. Nevertheless, because IL-6 has been shown to be involved in HF development, and because levels of this inflammatory marker are increased in HF and are able to predict HF outcome in various types of HF [5,[115][116][117][118][119], it could serve as an HF biomarker.…”

Section: Inflammation Marker Il-6mentioning

confidence: 99%

Novel heart failure biomarkers: why do we fail to exploit their potential?

Piek

Boer

et al. 2018

Critical Reviews in Clinical Laboratory Sciences

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“… Ridker et al 83 R, DB, PC 556 T2DM with high-MI risk Canakinumab 5 OR 15 OR 50 OR 150 mg 4 months CRP (+); fibrinogen (+); HbA1c (0); IL-6 (+); triglyceride (−). IL-6 inhibitors Holte et al 84 R, DB, PC 117 NSTEMI Tocilizumab 280 mg IV 6 months Coronary flow reserve (0); VCAM-1 (+) Kleveland et al 85 R, DB, PC 117 NSTEMI Tocilizumab 280 mg IV 6 months LVEF (0); SAE (0); nt-proBNP (0); Hb (0); hs-CRP (+); leukocytes (+); lipids (0); platelets (0); hs-TnT (+). Carroll et al .…”

Section: The Post-mi Immune Response As Therapeutic Target: From Fmentioning

confidence: 99%

Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition

Panahi

Papanikolaou

Torabi

et al. 2018

Cardiovascular Research

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Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies.

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Effect of interleukin-6 inhibition on coronary microvascular and endothelial function in myocardial infarction

Abstract: Tocilizumab did not affect CFR during hospitalisation or after 6 months. Tocilizumab increased VCAM-1 levels during hospitalisation, but this was not associated with reduced CFR in these patients.

Cited by 46 publications

References 22 publications

Inflammation, Autophagy, and Apoptosis After Myocardial Infarction

Inflammation, Autophagy, and Apoptosis After Myocardial Infarction

Novel heart failure biomarkers: why do we fail to exploit their potential?

Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition

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