Abstract

The notion of atherosclerosis as a chronic inflammatory disease has intensified research on the role of cytokines and the way these molecules act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are expressed by all types of cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects, and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leucocytes, and other vascular residing cells. It is now understood that widely used drugs such as statins, aspirin, methotrexate, and colchicine act in an immunomodulatory way that may beneficially affect atherogenesis and/or cardiovascular disease progression. Moreover, advancement in pharmaceutical design has enabled the production of highly specific antibodies against key molecules involved in the perpetuation of the inflammatory cascade, raising hope for advances in the treatment of atherosclerosis. This review describes the actions and effects of these agents, their potential clinical significance, and future prospects.

Introduction

Atherosclerosis is considered to be a chronic inflammatory disease1 and scientific interest has focussed on the role of cytokines as possible therapeutic agents for atherosclerosis, as cytokines are known to orchestrate the complex inflammatory response within the atherosclerotic plaque. Indeed, cytokines are produced by and act (often synergistically) on almost all cells involved in the pathogenesis of atherosclerosis, participating in all steps of the process, from the early endothelial dysfunction to the late formation and disruption of a vulnerable plaque.2

Throughout the years multiple therapeutic approaches in the cardiovascular field, i.e. statins and anti-hypertensive agents, have shown their ability to modify immunological and inflammatory responses in parallel to their principal effects as cholesterol-lowering agents or blood pressure reduction.3 Moreover, novel agents directed against specific targets in the inflammatory cascade are now also being applied in clinical settings.4 Interest in this novel therapeutic field is expanding rapidly, as demonstrated by the large number of ongoing clinical trials involving this kind of agents. As our knowledge regarding the role of cytokines in atherogenesis expands, newer approaches come to light and many show promising results in the fight against atherosclerosis. The goal of this review is to describe the actions and effects of anti-inflammatory agents, highlight available data on their clinical significance, and provide further insight regarding their future prospects.

Cytokines and atherosclerosis

In the context of atherosclerosis, cytokines can be classified broadly as pro- or anti-atherogenic, depending on their effects on the formation and progression of the atherosclerotic plaque (Figure 1).

Figure 1

Pro- and anti-atherogenic cytokines. Cytokines can be divided into two groups depending on whether they promote or suppress atherogenesis. Notably, there are also cytokines such as interleukin-2 and interleukin-17 whose exact role in atherogenesis has not been fully elucidated. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-α,β,γ, interferon-α, -β, and -γ; IL, interleukin (e.g. IL-1β, interleukin-1β); MCP-1, monocyte chemoattractant protein-1; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α.

Figure 1

Pro- and anti-atherogenic cytokines. Cytokines can be divided into two groups depending on whether they promote or suppress atherogenesis. Notably, there are also cytokines such as interleukin-2 and interleukin-17 whose exact role in atherogenesis has not been fully elucidated. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-α,β,γ, interferon-α, -β, and -γ; IL, interleukin (e.g. IL-1β, interleukin-1β); MCP-1, monocyte chemoattractant protein-1; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α.

Pro-atherogenic cytokines

Pro-atherogenic cytokines such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6 are secreted by macrophages, lymphocytes, natural killer cells, and vascular smooth muscle cells.2 Tumour necrosis factor-α and IL-1 signalling is mainly mediated by the p38 mitogen-activated protein kinase (p38MAPK)/nuclear factor kappa-light-chain-enhancer of the activated B-cell (NF-κΒ) pathway,5 and this affects almost all cells involved in atherogenesis by promoting the expression of cytokines, adhesion molecules, and the migration and mitogenesis of vascular smooth muscle and endothelial cells.2

The actions of pro-atherogenic cytokines can be better appreciated based on experimental studies with hyperlipidaemic mouse models. For example, TNF-α−/−, apolipoprotein E (ApoE)−/− double knockout mice showed decreased atherogenesis, endothelial adhesiveness, and inflammatory markers when compared with controls.6 Similar conclusions were drawn when ApoE−/− mice were treated with a recombinant soluble TNF-αp55 receptor that acted as decoy to inhibit TNF-α activity.7 In humans, TNF-α promotes the interaction between circulating leucocytes and the endothelium through up-regulation of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1).8

Interleukin-6 actions on the other hand are mediated by the IL-6 receptor and a signal transducing protein called gp130, which result in activation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 1 and 3.9 In studies with ApoE-deficient mice, recombinant IL-6 injections exacerbated the progression of atherosclerosis.10 Clinical studies have further revealed that IL-6 serum levels are increased in unstable angina patients and are considered an independent risk factor for coronary artery disease (CAD).2,11

Anti-atherogenic cytokines

Contrary to TNF-α, ΙL-1, and IL-6, several other cytokines appear to act in a protective manner against the formation of atherosclerotic plaques. For example, transforming growth factor-β (TGF-β) is closely associated with T-regulatory (Treg) cells, a distinct subset of T lymphocytes with known immunomodulatory activity. It is known that part of the immunomodulatory activity of Treg cells is mediated by the secretion of anti-inflammatory and atheroprotective cytokines including TGF-β, IL-10, and IL-35.12 As far as IL-10 is concerned, it appears to possess multiple anti-atherogenic activities including but not limited to down-regulation of TNF-α production13 and intercellular adhesion molecule 1 (ICAM-1) expression on endothelial cells.14

Even though a detailed presentation of the role of all cytokines goes beyond the scope of this review, it is crucial to keep in mind that cytokine actions are extremely complex. This issue represents an enormous challenge when developing and testing novel cytokine-related treatments, a problem that will become more evident as we discuss the potential risks and benefits of newer therapeutic approaches.

The emerging role of cytokine-related treatment

Established clinical approaches in humans

The first steps towards the development of anti-inflammatory treatments in atherosclerosis were accomplished while studying patients with chronic inflammatory and autoimmune diseases, such as psoriasis or rheumatoid arthritis. It has long been known that these conditions are associated with an increased risk of atherosclerosis similar to that of diabetes mellitus15 and a more severe presentation of adverse cardiovascular events.16,17 In addition, treatment with methotrexate or biological agents in rheumatoid arthritis protects against atherosclerosis,18 whereas anti-TNF-α therapy is also associated with a reduced risk for all cardiovascular events.19

In general, anti-inflammatory approaches in atherosclerosis can be divided into two major categories. The first includes conventional drugs with broad-based anti-inflammatory properties such as statins, aspirin, methotrexate, and colchicine, which can additionally affect the inflammatory cascade. The second group includes anti-inflammatory drugs designed to inhibit specific mediators and cytokines in the inflammatory pathway (Table 1 and Figure 2). Several ongoing and completed clinical trials testing the effects of these interventions in humans are summarized in Tables 2 and 3.

Table 1

Examples of cytokine-related therapeutic approaches in atherosclerosis

Intervention type Author Subjects Specific type of intervention Anti-atherogenic effects 
I. Clinical studies in humans 
Ia. Broad-based anti-inflammatory agents Bergh et al.20 Humans Simvastatin, rosuvastatin Suppression of VCAM-1, thrombomodulin, and eNOS expression in endothelial cells 
Tousoulis et al.21 Humans Atorvastatin ↓ The post-glucose loading levels of TNF-α 
Dahlman-Ghozlan et al.22 Human Methotrexate ↓ E-selectin, VCAM-1, and ICAM-1 
Elango et al.23 Human Methotrexate ↓ IL-6 levels 
Nidorf et al.24 Human Colchicine ↓CRP in patients with clinically stable CAD 
Ib. Blockade of inflammatory cytokines Tam et al.25 Humans Anti-TNF-α antagonists ↓ Progression of subclinical atherosclerosis 
Spinelli et al.26 Human Anti-TNF-α antagonists (etanercept or adalimumab) ↓ ADMA levels 
Avgerinou et al.27 Human Anti-TNF-α antagonists (adalimumab) ↓ ICAM and improves endothelial function 
Ridker et al.28 Human Inhibition of IL-1β (canakinumab) ↓ Glycated haemoglobin, glucose, CRP, IL-6, and fibrinogen levels 
Morton et al.29 Human Inhibition of IL-1 by IL-1 receptor antagonist (anakinra) ↓ CRP and IL-6 in patients after myocardial infraction 
Protogerou et al.30 Human Inhibition of IL-6 (tocilizumab) Improved endothelial function and decreased aortic stiffness 
II. Animal studies 
IIa. Delivery of anti-inflammatory cytokines Tian et al.31 Rats Adenovirus-mediated IL-19 delivery ↓ Neointimal proliferation in balloon angioplasty-injured rat carotid arteries 
Almer et al.32 Mice Liposomes coupled with IL-10 ↓ Atherosclerosis 
IIb. Targeting intracellular signalling Yoshimura et al.33 Rats In vivo transfection with an oligonucleotide that acts as decoy binding site for NF-κΒ ↓ Intimal hyperplasia after balloon angioplasty 
IIc. Inducing T-regulatory cells Steffens et al.34 Mice Anti-CD3 antibodies ↓ Atherogenesis
↑ TGF-β and Treg induction 
Dietrich et al.35 Mice Local IL-2 delivery ↓ Atherogenesis
↑ Treg expansion 
Intervention type Author Subjects Specific type of intervention Anti-atherogenic effects 
I. Clinical studies in humans 
Ia. Broad-based anti-inflammatory agents Bergh et al.20 Humans Simvastatin, rosuvastatin Suppression of VCAM-1, thrombomodulin, and eNOS expression in endothelial cells 
Tousoulis et al.21 Humans Atorvastatin ↓ The post-glucose loading levels of TNF-α 
Dahlman-Ghozlan et al.22 Human Methotrexate ↓ E-selectin, VCAM-1, and ICAM-1 
Elango et al.23 Human Methotrexate ↓ IL-6 levels 
Nidorf et al.24 Human Colchicine ↓CRP in patients with clinically stable CAD 
Ib. Blockade of inflammatory cytokines Tam et al.25 Humans Anti-TNF-α antagonists ↓ Progression of subclinical atherosclerosis 
Spinelli et al.26 Human Anti-TNF-α antagonists (etanercept or adalimumab) ↓ ADMA levels 
Avgerinou et al.27 Human Anti-TNF-α antagonists (adalimumab) ↓ ICAM and improves endothelial function 
Ridker et al.28 Human Inhibition of IL-1β (canakinumab) ↓ Glycated haemoglobin, glucose, CRP, IL-6, and fibrinogen levels 
Morton et al.29 Human Inhibition of IL-1 by IL-1 receptor antagonist (anakinra) ↓ CRP and IL-6 in patients after myocardial infraction 
Protogerou et al.30 Human Inhibition of IL-6 (tocilizumab) Improved endothelial function and decreased aortic stiffness 
II. Animal studies 
IIa. Delivery of anti-inflammatory cytokines Tian et al.31 Rats Adenovirus-mediated IL-19 delivery ↓ Neointimal proliferation in balloon angioplasty-injured rat carotid arteries 
Almer et al.32 Mice Liposomes coupled with IL-10 ↓ Atherosclerosis 
IIb. Targeting intracellular signalling Yoshimura et al.33 Rats In vivo transfection with an oligonucleotide that acts as decoy binding site for NF-κΒ ↓ Intimal hyperplasia after balloon angioplasty 
IIc. Inducing T-regulatory cells Steffens et al.34 Mice Anti-CD3 antibodies ↓ Atherogenesis
↑ TGF-β and Treg induction 
Dietrich et al.35 Mice Local IL-2 delivery ↓ Atherogenesis
↑ Treg expansion 

↑, increased; ↓, decreased; ADMA, asymmetric dimethyl arginine; CAD, coronary artery disease; CD3, cluster of differentiation 3; CRP, C-reactive protein; eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LDL, low-density lipoprotein; NF-κB, nuclear factor κB; NO, nitric oxide; TGF-β, transformation growth factor-β; TIMP, tissue inhibitor of matrix metalloproteinases; TNF-α, tumour necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1.

Table 2

Ongoing anti-inflammatory clinical trials in atherosclerosis

Drug Target NCT trial number and name Size Status Estimated completion date Study population Primary endpoint 
Canakinumab IL-1 NCT01327846 (CANTOS) 10 000 Not recruiting April 2017 Patients with MI and elevated hsCRP Time to first occurrence of MACE 
Anakinra IL-1Ra NCT01950299 (VCU-ART3) 99 Recruiting September 2017 STEMI patients CRP levels during the first 14 days period after STEMI (secondary: new heart failure after 12 months) 
Adalimumab TNF-α NCT01722214 106 Not recruiting February 2016 Psoriasis patients Change in ascending aorta inflammation as assessed with FDG-PET after 16 weeks of treatment 
NCT01954381 60 Completed, results not published July 2015 RA patients CF-PWV, central aortic pulse pressure and FMD after 24 weeks of treatment 
Etanercept NCT01522742 50 Recruiting January 2016 Psoriasis patients starting etanercept and matched controls Change in aortic-coronary inflammation status as assessed with FDG-PET after 3 months of treatment 
Tocilizumab IL-6 NCT01491074 120 Completed, results not published April 2014 Post-NSTEMI patients hsCRP levels during 56 h follow-up (secondary: infarct size, hsTrT, left ventricle size and function, endothelial function and coronary flow reserve) 
NCT02419937 125 Recruiting May 2017 NSTEMI, STEMI patients with drug or placebo given within 24 h MACE within 30 days 
NCT01331837 (Entracte) 3080 Not recruiting October 2016 Rheumatoid arthritis patients treated with tocilizumab vs. etanercept Time to occurrence of primary MACE 
Methotrexate Multiple NCT01594333 (CIRT) 7000 Recruiting December 2018 Stable CAD patients with T2DM or MetS MACE rate 
NCT02576067 (CIRT) 216 Not open yet May 2019 Patients with prior MI or angiographically demonstrated multi-vessel CAD Change in arterial inflammation as assessed with FDG-PET at 8 months 
NCT01741558 (TETHYS) 80 Unknown August 2014 STEMI patients Reduction of infarct size 
Methotrexate and colchicine Multiple NCT02366091 120 Recruiting November 2018 Stable CAD patients with hsCRP > 2 mg/L Coronary segment endothelial function at 8 weeks 
Colchicine Multiple NCT02551094 4500 Not open yet March 2019 Patients with recent (<30 days) acute MI MACE events 
NCT01709981 400 Recruiting April 2017 Patients referred for PCI Post-PCI IL-6 levels (secondary: 30 days MACE) 
NCT02162303 106 Not recruiting December 2015 Patients with atherosclerotic vascular disease Change in inflammation of the ascending aorta as assessed with FDG-PET at 6 months 
Drug Target NCT trial number and name Size Status Estimated completion date Study population Primary endpoint 
Canakinumab IL-1 NCT01327846 (CANTOS) 10 000 Not recruiting April 2017 Patients with MI and elevated hsCRP Time to first occurrence of MACE 
Anakinra IL-1Ra NCT01950299 (VCU-ART3) 99 Recruiting September 2017 STEMI patients CRP levels during the first 14 days period after STEMI (secondary: new heart failure after 12 months) 
Adalimumab TNF-α NCT01722214 106 Not recruiting February 2016 Psoriasis patients Change in ascending aorta inflammation as assessed with FDG-PET after 16 weeks of treatment 
NCT01954381 60 Completed, results not published July 2015 RA patients CF-PWV, central aortic pulse pressure and FMD after 24 weeks of treatment 
Etanercept NCT01522742 50 Recruiting January 2016 Psoriasis patients starting etanercept and matched controls Change in aortic-coronary inflammation status as assessed with FDG-PET after 3 months of treatment 
Tocilizumab IL-6 NCT01491074 120 Completed, results not published April 2014 Post-NSTEMI patients hsCRP levels during 56 h follow-up (secondary: infarct size, hsTrT, left ventricle size and function, endothelial function and coronary flow reserve) 
NCT02419937 125 Recruiting May 2017 NSTEMI, STEMI patients with drug or placebo given within 24 h MACE within 30 days 
NCT01331837 (Entracte) 3080 Not recruiting October 2016 Rheumatoid arthritis patients treated with tocilizumab vs. etanercept Time to occurrence of primary MACE 
Methotrexate Multiple NCT01594333 (CIRT) 7000 Recruiting December 2018 Stable CAD patients with T2DM or MetS MACE rate 
NCT02576067 (CIRT) 216 Not open yet May 2019 Patients with prior MI or angiographically demonstrated multi-vessel CAD Change in arterial inflammation as assessed with FDG-PET at 8 months 
NCT01741558 (TETHYS) 80 Unknown August 2014 STEMI patients Reduction of infarct size 
Methotrexate and colchicine Multiple NCT02366091 120 Recruiting November 2018 Stable CAD patients with hsCRP > 2 mg/L Coronary segment endothelial function at 8 weeks 
Colchicine Multiple NCT02551094 4500 Not open yet March 2019 Patients with recent (<30 days) acute MI MACE events 
NCT01709981 400 Recruiting April 2017 Patients referred for PCI Post-PCI IL-6 levels (secondary: 30 days MACE) 
NCT02162303 106 Not recruiting December 2015 Patients with atherosclerotic vascular disease Change in inflammation of the ascending aorta as assessed with FDG-PET at 6 months 

CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcomes Study; CAD, coronary artery disease; CF-PWV, carotid-femoral pulse wave velocity; CIRT, Cardiovascular Inflammation Reduction Trial; CK, creatinine kinase; FDG-PET, 18-fluorodeoxyglucose positron emission tomography; FMD, flow-mediated dilatation; hsCRP, high-sensitivity C-reactive protein; hsTrP, high-sensitivity troponin T; IL-1Ra, interleukin-1 receptor antagonist; MACE, major adverse cardiovascular event; MetS, metabolic syndrome; (N)STEMI, (non)-ST-segment elevation myocardial infarction; NCT, national clinical trial; PCI, percutaneous coronary intervention; T2DM, type 2 diabetes mellitus; TETHYS, The Effects of mETHotrexate Therapy on ST Segment Elevation Myocardial InfarctionS; TNF-α, tumour necrosis factor-α; VCU-ART3, Virginia Commonwealth University Anakinra Remodeling Trial.

Table 3

Completed anti-inflammatory clinical trials in atherosclerosis

Drug Target Author Size (treated/controls) Study population Results 
Golimumab TNF-α Tam et al.25 41 (20/21) Ankylosing spondylitis patients Placebo group showed an increase in arterial stiffness (PWV) over 6 months when compared with the group treated with golimumab 
Anakinra IL-1Ra Morton et al.36
MRC-ILA-HEART study 
182 (91/91) NSTEMI patients IL-1Ra treatment reduces inflammatory markers at 14 days post-NSTEMI. However, MACE at 30 days and 3 months were similar and at 1 year greater in the IL-1Ra than the control group 
Anakinra IL-1Ra Ikonomidis et al.37 80 (cross-over) Rheumatoid arthritis patients with and without CAD Anakinra leads to a greater improvement in endothelial, coronary, and aortic function in RA patients with CAD than non-CAD 
Anakinra IL-1Ra Abbate et al.38 VCU-ART2 (Virginia Commonwealth University Anakinra Remodeling Trial) 40 (20/20) STEMI patients Anakinra for 2 weeks post-STEMI has neutral effect on recurrent ischaemic events but may prevent new-onset heart failure or death in the long term after STEMI period 
Colchicine Multiple Nidorf et al.39 LoDoCo trial (low-dose colchicine trial) 532 (282/250) Patients with stable CAD Colchicine 0.5 mg/day in addition to standard therapy prevents CV events 
Methotrexate Multiple Choi et al.40 1240 (588/652) Rheumatoid arthritis patients Methotrexate use is associated with lower all-cause and CV mortality risk 
Corticosteroids Multiple Giugliano et al.41 2646 (meta-analysis) Acute MI patients Corticosteroid therapy in the acute setting after MI shows no significant mortality benefit in randomized control trials 
Ustekinumab/briakinumab IL-12/23 Tzellos et al.42 4653 (3179/1474) Psoriasis patients Patients on anti-IL-12/23 treatment had a significantly higher risk of MACEs compared with placebo 
Drug Target Author Size (treated/controls) Study population Results 
Golimumab TNF-α Tam et al.25 41 (20/21) Ankylosing spondylitis patients Placebo group showed an increase in arterial stiffness (PWV) over 6 months when compared with the group treated with golimumab 
Anakinra IL-1Ra Morton et al.36
MRC-ILA-HEART study 
182 (91/91) NSTEMI patients IL-1Ra treatment reduces inflammatory markers at 14 days post-NSTEMI. However, MACE at 30 days and 3 months were similar and at 1 year greater in the IL-1Ra than the control group 
Anakinra IL-1Ra Ikonomidis et al.37 80 (cross-over) Rheumatoid arthritis patients with and without CAD Anakinra leads to a greater improvement in endothelial, coronary, and aortic function in RA patients with CAD than non-CAD 
Anakinra IL-1Ra Abbate et al.38 VCU-ART2 (Virginia Commonwealth University Anakinra Remodeling Trial) 40 (20/20) STEMI patients Anakinra for 2 weeks post-STEMI has neutral effect on recurrent ischaemic events but may prevent new-onset heart failure or death in the long term after STEMI period 
Colchicine Multiple Nidorf et al.39 LoDoCo trial (low-dose colchicine trial) 532 (282/250) Patients with stable CAD Colchicine 0.5 mg/day in addition to standard therapy prevents CV events 
Methotrexate Multiple Choi et al.40 1240 (588/652) Rheumatoid arthritis patients Methotrexate use is associated with lower all-cause and CV mortality risk 
Corticosteroids Multiple Giugliano et al.41 2646 (meta-analysis) Acute MI patients Corticosteroid therapy in the acute setting after MI shows no significant mortality benefit in randomized control trials 
Ustekinumab/briakinumab IL-12/23 Tzellos et al.42 4653 (3179/1474) Psoriasis patients Patients on anti-IL-12/23 treatment had a significantly higher risk of MACEs compared with placebo 

CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; IL-1Ra, interleukin-1 receptor antagonist; MACE, major adverse cardiovascular event; MI, myocardial infarction; NNT, number needed to treat; OR, odds ratio; PWV, pulse wave velocity; RA, rheumatoid arthritis; (N)STEMI, (non-)ST-segment elevation myocardial infarction; TNF-α, tumour necrosis factor-α.

Figure 2

Cytokine-related therapeutic approaches in atherosclerosis. In the context of atherosclerosis, several methods have been studied to modify the inflammatory cascade. 1. Broad-based immunomodulatory agents. 2. Blockade of pro-inflammatory cytokines. 3. Delivery of anti-inflammatory cytokines with adenovirus vectors or liposomes. 4. Induction of regulatory T cells. 5. In vivo transfection with oligonucleotides. IL, interleukin; TNF-α, tumour necrosis factor-α; VSMC, vascular smooth muscle cell.

Figure 2

Cytokine-related therapeutic approaches in atherosclerosis. In the context of atherosclerosis, several methods have been studied to modify the inflammatory cascade. 1. Broad-based immunomodulatory agents. 2. Blockade of pro-inflammatory cytokines. 3. Delivery of anti-inflammatory cytokines with adenovirus vectors or liposomes. 4. Induction of regulatory T cells. 5. In vivo transfection with oligonucleotides. IL, interleukin; TNF-α, tumour necrosis factor-α; VSMC, vascular smooth muscle cell.

Statins

Statins are traditionally known for their hypolipidaemic effects but have also been shown to act in an immunomodulatory manner. This is believed to be due to decreased production of isoprenoid intermediates that are responsible for the post-translational modification of small GTPases. In other words, statins are able to modify intracellular inflammatory pathways.3

Indeed, several statins have been shown to antagonize the effects of inflammatory cytokines (Figure 3). For example, simvastatin appears to neutralize the pro-inflammatory and pro-atherogenic actions of TNF-α through inhibition of the TNF-α-induced expression of VCAM-1 and suppression of thrombomodulin and endothelial nitric oxide synthase.20 Atorvastatin improves vascular nitric oxide bioavailability and decreases the post-glucose loading levels of TNF-α.21 In addition, statins have been shown to affect the production of cytokines by leucocytes43 down-regulating the production of pro-inflammatory IL-1 and up-regulating the anti-inflammatory cytokine IL-10.44,45 Interestingly, recent studies have shown that the reduction of C-reactive protein (CRP) levels with statin treatment is independent from the reduction in LDL cholesterol levels.46

Figure 3

Examples of cytokine-related statin effects in the microenvironment of an atherosclerotic plaque. Statins have been shown to antagonize the effects of inflammatory cytokines. For example, simvastatin neutralizes the pro-atherogenic actions of tumour necrosis factor-α through inhibition of the tumour necrosis factor-α-induced expression of vascular cell adhesion molecule 1 and suppression of thrombomodulin, whereas atorvastatin improves vascular nitric oxide bioavailability. Simvastatin can potently down-regulate the production of known pro-inflammatory cytokines such as interleukin-1 while also up-regulating the expression of anti-inflammatory cytokines such as interleukin-10. Finally, simvastatin is also able to counteract the combined pro-proliferative effects of tumour necrosis factor-α and interleukin-18 on aortic smooth muscle cells. IL, interleukin; TNF-α, tumour necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1; VSMC, vascular smooth muscle cell.

Figure 3

Examples of cytokine-related statin effects in the microenvironment of an atherosclerotic plaque. Statins have been shown to antagonize the effects of inflammatory cytokines. For example, simvastatin neutralizes the pro-atherogenic actions of tumour necrosis factor-α through inhibition of the tumour necrosis factor-α-induced expression of vascular cell adhesion molecule 1 and suppression of thrombomodulin, whereas atorvastatin improves vascular nitric oxide bioavailability. Simvastatin can potently down-regulate the production of known pro-inflammatory cytokines such as interleukin-1 while also up-regulating the expression of anti-inflammatory cytokines such as interleukin-10. Finally, simvastatin is also able to counteract the combined pro-proliferative effects of tumour necrosis factor-α and interleukin-18 on aortic smooth muscle cells. IL, interleukin; TNF-α, tumour necrosis factor-α; VCAM-1, vascular cell adhesion molecule 1; VSMC, vascular smooth muscle cell.

It is therefore generally accepted that statins exert pleiotropic actions and affect a variety of parameters associated with atherosclerosis. Early administration of low-dose atorvastatin in patients with ST-elevation myocardial infarction (SEMI) can even improve the clinical outcome by down-regulating endothelial activation and inflammation.47 Recently, the PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in ACS Patients) has reported the beneficial effects of rosuvastatin in contrast-induced nephropathy caused in subjects with ST elevation myocardial infraction.48 Since inflammation promotes endothelial dysfunction and vulnerability of kidney vessels, this action may be mediated by anti-inflammatory effects of statins, as it was recently proposed.49

In regard to clinical applicability, several studies have revealed that an inflammatory-based treatment approach may be useful. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a 5-year randomized trial that included 5742 subjects without CAD, it was shown that lovastatin prevented ACS especially in the high CRP group despite a favourable lipid profile. Indeed, lovastatin reduced CRP levels by 15%, and it was effective to reduce cardiovascular events even in patients with favourable lipid profile at baseline but with increased CRP levels. Importantly, it was found that the number needed to treat to prevent one event in this category of patients with CRP levels >0.16 mg/dL was 48.50 In line with this evidence, the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)—one of the most important large-scale randomized control studies, which included 17 802 apparently healthy individuals randomized to either rosuvastatin 20 mg/day or placebo with follow-up for a median of 1.9 years—demonstrated that in subjects with CRP levels >2 mg/L, even with low LDL cholesterol levels, rosuvastatin treatment can decrease adverse cardiovascular events.51 Notably, the greatest benefit is observed in patients in whom rosuvastatin treatment decreases not only LDL levels <70 mg/dL but also CRP levels <1 mg/L (79% reduction in the event rate compared with subjects in the placebo arm or 0.24 events per 100 persons compared with 1.11 events per 100 persons, respectively).52 This is in accordance with several studies which show that the beneficial effects of statins cannot and should not be solely attributed to their lipid-lowering effects but are also related to their ability to dampen inflammation or improve endothelial53 and arterial wall function54 through lipid-independent mechanisms.3

Aspirin

Aspirin inhibits cyclooxygenase irreversibly and suppresses the production of prostaglandins and thromboxanes.55 Therefore, it acts not only as an antiplatelet agent but also as an anti-inflammatory one. In murine models of atherosclerosis, low-dose aspirin improves vascular inflammation and plaque stability.56 Recent data in ApoE-deficient mice support the hypothesis that aspirin can also reduce fractalkine levels (fractalkine acts both as a chemokine and as an adhesion molecule) and improve the severity of atherosclerotic lesions.57 Recently, it was also documented in humans that low-dose aspirin treatment reduces chemerin (a peptide chemoattractant for macrophages and an adipokine-regulating adipocyte differentiation and metabolism) secretion by adipocytes through reduction of pro-inflammatory cytokine secretion by macrophages.58 Aspirin further protects human endothelial function in the presence of inflammation59 and decreases the plasma levels of several inflammatory cytokines and markers such as IL-6, CRP, and monocyte colony-stimulating factor (M-CSF) in patients with stable angina.60 Interestingly, the use of aspirin as a primary prevention therapy is associated with a reduction in the development of myocardial infarction, which appears to be directly related to CRP levels, raising the possibility that the anti-inflammatory properties of aspirin may be as important as its anti-thrombotic effects.61 Moreover, in primary prevention, aspirin can improve arterial stiffness even after 2 weeks of low dose (160 mg/day).62 However, we have to notice that the exact anti-atherosclerotic effect of aspirin cannot be determined as reports support the notion that aspirin can reduce hypertriglyceridaemia, cholesterol, and free fatty acid production63 but also increases lipid peroxidation.64 Indeed, the exact benefit of aspirin in chronic CAD has recently been questioned by the results of the CONFIRM study (Coronary CT Angiography EvaluatioN for Clinical Outcomes study). In this multicentre international registry, 5712 individuals with normal coronary arteries and 4706 individuals with non-obstructive CAD were followed up for a median of 27.2 months, and aspirin use, contrary to statins, was not associated with mortality benefit in patients with non-obstructive CAD irrespective of the status of the plaque.65 Similarly, data from the prevention of progression of arterial disease and diabetes (POPADAD) trial have shown that even in patients with diabetes mellitus and asymptomatic peripheral arterial disease aspirin did not reduce the rate of cardiovascular events.66 Moreover, in 1884 recipients of low-dose aspirin with chronic kidney disease paired with 1884 non-recipients, the incidence of atherosclerotic events was significantly higher in the aspirin users.67 It would be interesting to study the effects of aspirin in groups with elevated vs. low levels of circulating inflammatory markers.

Methotrexate

Methotrexate is an antimetabolite drug that acts by inhibiting the metabolism of folic acid. Its anti-inflammatory actions, however, may also be attributed to an increase in adenosine levels.68 In fact, methotrexate treatment reduces the size of experimentally induced myocardial infarction probably via adenosine release which not only reduces inflammation but also improves coronary flow in the culprit lesion.69 In addition, previous studies have shown that methotrexate can further modulate the expression of ICAM-1, E-selectin, VCAM-1,22 and IL-6.23

Interestingly, studies have proved that low-dose methotrexate can decrease the cardiovascular risk of patients with chronic inflammatory disease. In patients with rheumatoid arthritis, methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality.40 Similar results were also described by van Halm et al. in a case–control study.70 However, some studies did not confirm the protective role of methotrexate in the incidence of cardiovascular events in rheumatoid arthritis patients.71 Therefore, further studies have now been designed to test this hypothesis. For example, the Cardiovascular Inflammation Reduction Trial (CIRT) aims to enrol 7000 individual to test the role of methotrexate in the medical management of stable CAD patients with persistent elevation of high-sensitivity CRP,72 while the TETHYS trial aims to evaluate its value in reducing infarct size when administered within the first 6 h of admission for ST-elevation myocardial infraction.73 Furthermore, a recently announced CIRT sub-study aims to evaluate the effects of methotrexate in arterial inflammation (as seen on PET-CT scanning) in patients with prior MI or multi-vessel CAD (NCT02576067). It is difficult, however, to definitely conclude that the beneficial effect of methotrexate in cardiovascular incidence is solely due to its anti-inflammatory properties. Studies have recently documented that methotrexate modifies lipid levels increasing both HDL and LDL cholesterol and affects macrophage cholesterol handling opposing foam cell formation.74

Colchicine

Evidence for the ability of colchicine to modify cytokine levels is based on patients with familiar Mediterranean fever. In this condition, modification of the inflammatory cascade with colchicine not only reduces symptoms of the disease but also decreases the risk for ischaemic heart disease.75 In addition, a retrospective cross-sectional study concluded that long-term treatment of gout with low-dose colchicine decreased not only CRP levels but also the incidence of myocardial infraction.76 Furthermore, Nidorf and Thompson showed that colchicine, in addition to aspirin and high-dose atorvastatin treatment, can significantly lower high-sensitivity CRP in patients with stable CAD.24 Finally, in the Low-Dose Colchicine (LoDoCo) trial—a prospective, randomized, observer blinded endpoint design study of 532 subject—addition of colchicine 0.5 mg/day to aspirin and/or clopidogrel and statins in CAD patients resulted in lower incidence (5.3%) of acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischaemic stroke vs. the placebo group (16%).39 Currently, several ongoing trials aim to evaluate the potential benefit of colchicine in improving cardiovascular indices and prognosis in patients with CAD as summarized in Tables 2 and 3.

Corticosteroids

A few reports that examined intermediate atherosclerotic markers such as arterial stiffness as assessed by pulse wave velocity have shown that the use of corticosteroids can act beneficially in some chronic inflammatory disorders such as polymyalgia rheumatic.77 However, corticosteroids in the setting of acute myocardial infarction have failed to demonstrate significant mortality benefit, as shown in one meta-analysis of randomized control trials.41 In addition, long-term use of corticosteroids in rheumatoid arthritis patients is associated with a significantly higher incidence of acute myocardial infarction.78

Specific target-based anti-inflammatory treatment

Blockade of pro-inflammatory and delivery of anti-inflammatory cytokines

As described in the previous section, the prophylactic effect of broad-based anti-inflammatory treatments is currently limited to statins and aspirin. Nevertheless, especially for aspirin, its value in primary prevention is equivocal while for methotrexate, colchicine, and corticosteroids results are not definitive. Therefore, several novel strategies have been developed to more specifically antagonize the actions of pro-inflammatory cytokines, the most important being the administration of soluble decoy receptors, direct receptor antagonists (e.g. endogenous IL-1Ra), and monoclonal antibodies (Table 4).

Table 4

Targeting pro-inflammatory cytokines for atherosclerosis treatment

Pro-inflammatory cytokines Role in atherosclerosis Possible treatments 
TNF-α Promotes atherosclerosis, adhesion of leucocytes to endothelium and impairs glucose tolerance Anti-TNF agents (etanercept, adalimumab, golimumab, and infliximab):
  • Improve endothelial function and arterial wall properties27

  • Restore asymmetric dimethyl arginine serum levels in patients with rheumatoid arthritis26

  • Increase circulating endothelial progenitor cells79

  • Improve insulin resistance80

  • Improve lipid profile81

  • Enhance plaquestability82

 
IL-1β Promotes atherosclerosis and is associated with the extent of atherosclerotic lesions Canakinumab (monoclonal human IL-1β antibody)
  • Reduces glycated haemoglobin, glucose, CRP, IL-6, and fibrinogen levels in stable diabetes mellitus patients28

  • CANTOS is in progress studying whether canakinumab can reduce heart attacks, strokes, and cardiovascular deaths in high-risk patients83

 
  Anakinra (a non-glycosylated version of human IL-1Ra)
  • Reduces IL-6 and endothelin-1 levels with a parallel increase in flow-mediated dilation, coronary flow reserve, and aortic distensibility84

  • But: MRC-ILA-HEART study in myocardial infraction patients: at the end of the 1-year follow-up rate of adverse events turns out to be higher in the treatment group29

 
IL-6 Exacerbates the progression of atherosclerosis, promotes inflammation Tocilizumab (a monoclonal antibody that blocks IL-6 receptor)
  • Improves endothelial function and decreases aortic stiffness30

  • The effect of tocilizumab in patients with non-ST elevation myocardial infraction is tested in phase II trials (e.g. NCT01491074)

 
Anti-inflammatory cytokines Role in atherosclerosis Possible treatments 
IL-19 Promotes T helper 2 cell response and dampens inflammation Adenovirus-mediated IL-19 delivery in rat models decreases neointimal proliferation after balloon angioplasty31 
IL-10 Suppresses immune and inflammatory responses Liposomes coupled with IL-10 in mice attenuate atherosclerosis32 
Pro-inflammatory cytokines Role in atherosclerosis Possible treatments 
TNF-α Promotes atherosclerosis, adhesion of leucocytes to endothelium and impairs glucose tolerance Anti-TNF agents (etanercept, adalimumab, golimumab, and infliximab):
  • Improve endothelial function and arterial wall properties27

  • Restore asymmetric dimethyl arginine serum levels in patients with rheumatoid arthritis26

  • Increase circulating endothelial progenitor cells79

  • Improve insulin resistance80

  • Improve lipid profile81

  • Enhance plaquestability82

 
IL-1β Promotes atherosclerosis and is associated with the extent of atherosclerotic lesions Canakinumab (monoclonal human IL-1β antibody)
  • Reduces glycated haemoglobin, glucose, CRP, IL-6, and fibrinogen levels in stable diabetes mellitus patients28

  • CANTOS is in progress studying whether canakinumab can reduce heart attacks, strokes, and cardiovascular deaths in high-risk patients83

 
  Anakinra (a non-glycosylated version of human IL-1Ra)
  • Reduces IL-6 and endothelin-1 levels with a parallel increase in flow-mediated dilation, coronary flow reserve, and aortic distensibility84

  • But: MRC-ILA-HEART study in myocardial infraction patients: at the end of the 1-year follow-up rate of adverse events turns out to be higher in the treatment group29

 
IL-6 Exacerbates the progression of atherosclerosis, promotes inflammation Tocilizumab (a monoclonal antibody that blocks IL-6 receptor)
  • Improves endothelial function and decreases aortic stiffness30

  • The effect of tocilizumab in patients with non-ST elevation myocardial infraction is tested in phase II trials (e.g. NCT01491074)

 
Anti-inflammatory cytokines Role in atherosclerosis Possible treatments 
IL-19 Promotes T helper 2 cell response and dampens inflammation Adenovirus-mediated IL-19 delivery in rat models decreases neointimal proliferation after balloon angioplasty31 
IL-10 Suppresses immune and inflammatory responses Liposomes coupled with IL-10 in mice attenuate atherosclerosis32 

TNF-α, tumour necrosis factor-α; IL-1β, interleukin-1β; CRP, C-reactive protein; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein; eNOS, endothelial nitric oxide synthase; IL-19, interleukin-19; IL-10, interleukin-10.

Anti-tumour necrosis factor-α treatment

Several anti-TNF agents (infliximab, etanercept, adalimumab, golimumab, and certolizumab) have been introduced recently against inflammatory and autoimmune diseases.85

Interestingly, spare pre-clinical data have shown that anti-TNF treatment can favourably affect atherosclerosis. Recently, in a model that reproduced in vivo interactions between leucocytes and endothelial cells, anti-TNF treatment diminished leucocyte-endothelial interactions induced by inflammatory stimuli.86 It is currently known that treatment with anti-TNF agents can improve endothelial function and arterial wall properties in patients with autoimmune diseases, such as psoriasis.27 Moreover, it has been reported that inhibition of TNF-α in rheumatoid arthritis can increase circulating endothelial progenitor cells concurrently with a proportional decrease of disease activity79 and decrease serum asymmetric dimethyl arginine levels.26

Clinical studies have revealed that anti-TNF-α therapies in patients with ankylosing spondylitis improve subclinical atherosclerosis and aortic stiffness when compared with placebo controls.87 A meta-analysis published in 2011 showed that anti-TNF-α treatment in rheumatoid arthritis is associated with a lower risk for all cardiovascular events.19 Nevertheless, we have to take into consideration that studies with these agents in patients with chronic heart failure have failed to improve patient outcome.88 Unfortunately, there are currently no ongoing trials evaluating the exact health or mortality benefit of anti-TNF-α agents in a large cohort of healthy or CAD patients and studies so far have been limited to rheumatological patients.

Interleukin-1β inhibition

Canakinumab is a monoclonal human antibody that binds to human IL-1β, blocking its interaction with its receptor. Interleukin-1β has so far been used in the treatment of rare hereditary IL-1β-driven disorders, such as Muckle–Wells syndrome. Treatment of such cryopyrin-associated periodic syndromes and rheumatoid arthritis with canakinumab produces a rapid and sustained inhibition of the acute phase response resulting in a substantial reduction in CRP levels.89,90

Previously, studies have shown that IL-1-deficient mice show decreased atherosclerosis.91 Moreover, in an atherosclerotic mouse model, inhibition of IL-1 orients tissue macrophages to an anti-inflammatory phenotype and atherosclerotic lesions are therefore reduced.92

Furthermore, canakinumab has been shown to effectively reduce glycated haemoglobin, glucose, CRP, IL-6, and fibrinogen levels in male patients with well-controlled diabetes mellitus and high cardiovascular risk.28 However, a definite cardiovascular event or survival benefit has not been demonstrated yet but is currently investigated by the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), which focusses on post-myocardial patients with persistent elevation of high-sensitivity CRP.83

Another approach used to modify IL-1 activity is by enhancing the activity of IL-1Ra, which in turn negatively regulates IL-1 signalling. For example, anakinra, a human IL-1Ra, can block the biological activity of IL-1 in rheumatoid arthritis patients by competitively inhibiting the binding of IL-1 to the IL-1-type receptor and also reduces IL-6 and endothelin-1 levels with a parallel increase in flow-mediated dilation, coronary flow reserve, and aortic dispensability.84 In the MRC-ILA-HEART study, subcutaneous IL-1Ra administration for 14 days in non-SEMI (NSTEMI) patients resulted in lower CRP and IL-6 levels at the end of the treatment; however, a higher rate of MACE was observed after the treatment (HR 3.39, 95% CI 1.10–10.4, P = 0.023).29 The VCU-ART 2 (Virginia Commonwealth University Anakinra Remodeling Trial) study showed that anakinra given for 2 weeks post-STEMI has a neutral effect on recurrent ischaemic events but may lower new heart failure incidence or mortality at 1 year (HR 0.16, 95% CI 0.03–0.76, P = 0.008),38 a finding that will be further evaluated by the more recent VCU-ART-3 trial (NCT01950299).

Intereleukin-6 inhibition

Potential strategies using anti-IL-6 therapies have not been as widely tested as in the case of TNF-α or IL-1. Tocilizumab is a monoclonal antibody that blocks both membrane-bound and circulating IL-6 receptor. Randomized trials in patients with rheumatoid arthritis have shown that tocilizumab increases total, HDL, and LDL cholesterol and triglyceride levels.93 Moreover, it results in improved endothelial function and decreased aortic stiffness.30 Currently, several ongoing studies investigate the role of tocilizumabin in NSEMI (NCT01491074, Phase 2 trial) and in comparison to etanercept in patients with rheumatoid arthritis and cardiovascular risk factors (NCT01331837, Phase 4 trial).

Anti-interleukin-12/23p40 and anti-interleukin-17 agents

Monoclonal antibodies that are targeted against the shared p40 subunit of IL-12 and IL-23 have recently been introduced in the treatment of psoriasis. These cytokines mediate the function of Th17 cells, a distinct subset of T cells that have been identified as a pro-atherogenic group of leucocytes within the atherosclerotic plaque.94 Despite these pro-atherogenic effects, a recent meta-analysis concluded that treatment with such agents (ustekinumab and briakinumab) may even increase the risk for major adverse cardiovascular events when compared with placebo.42 Brodalumab (an IL-17 receptor A antagonist), ixekizumab, and secukinumab (IL-17A antagonists), also used in psoriasis, are potential antagonists of atherosclerosis, given the pro-inflammatory nature of IL-17.95 Interleukin-17 inhibition attenuates atherosclerosis in animals,96 but clinical studies in humans are not available to date.

Anti-P-selectin agents

P-selectin, a cell adhesion molecule that organizes endothelial cell and platelet interactions, plays a role in leucocyte activation, formation of thrombi, and neointimal formation. The SELECT ACS study in 544 patients with NSTEMI showed that inclacumab—a recombinant monoclonal antibody against P-selectin—decreases the myocardial damage.97 However, the SELECT CABG study, a Phase 2 trial, which is planning to test the efficacy of inclacumab in saphenous vein graft disease, has not yet been published.

Targeting post-ischaemic reperfusion injury

Re-establishment of coronary perfusion after an acute ischaemic event causes the so-called reperfusion injury, which is attributed to oxidative stress, accumulation of reactive oxygen species, and ultimately diminished mitochondrial ability to produce energy in the form of ATP.98 Bendavia is an intravenously administered mitochondrial targeting peptide that has been shown to reduce myocardial infarct size and attenuate coronary no-reflow in experimental models when given before reperfusion.99 Therefore, the EMBRACE STEMI study enrolled 300 patients with first anterior STEMI to test whether Bendavia is superior to placebo for the reduction of myocardial infarction size.100 The first preliminary reports of this study have recently been announced and have shown that Bendavia infusion is safe although it did not achieve a significant reduction in the infarct size. However, future trials are planning to test if higher doses can be beneficial in patients with systolic heart failure (NCT02388464 and NCT02388529).

Experimental approaches in animal models

Future directions concerning the targeted modification of the inflammatory cascade can be derived from experimental models. However, the extrapolation of animal outcomes to human patients is not straightforward as significant differences exist in the pathophysiology of atherosclerosis between different species.101

Delivery of anti-inflammatory cytokines

Delivery of anti-inflammatory cytokines for therapeutic purposes has been attempted in experimental animal models with promising results. It is now possible to locally deliver anti-inflammatory cytokines to specific atherosclerosis sites via adenoviruses. Such is the case of IL-19 which is an anti-inflammatory cytokine that promotes the Th2 anti-inflammatory cell phenotype.31 Furthermore, a recently developed method exploits stealth liposomes that are coupled with IL-10 and act to specifically and reliably transfer the atheroprotective cytokine to the desired site in atherosclerotic plaques.32 It is obvious that these methods may have unknown risks, and studies on safety and efficacy are warranted before they can be applied in humans.

Targeting intracellular signalling

Certain studies have succeeded in limiting atherosclerosis by manipulating intracellular signalling in animal models. For example, an oligonucleotide that acted as a decoy binding site for NF-κB succeeded in preventing intimal hyperplasia following balloon angioplasty.33 An adenovirus-expressed suppressor of cytokine signalling 3 has also been successful in limiting inflammation though not in a model of atherosclerosis,102 and similar efforts have been done trying to block JAK3 signalling.103 However, given the ubiquitous nature of these molecules (especially NF-κΒ), it is important to guarantee that treatment does not interfere with normal processes in order to minimize adverse effects.

Promoting the actions of T-regulatory cells

Administration of anti-CD3 antibodies in mice with progressed atherosclerosis managed to suppress atherogenesis and was linked to up-regulated TGF-β and Foxp3 expression in lymphoid organs.34,104 In addition, oral calcitriol administration to hyperlipidaemic mice blocked atherosclerosis possibly by inducing the expansion of T-regulatory cells,105 whereas local delivery of IL-2 suppressed atherogenesis in already existing lesions through the same mechanism.35

Unanswered questions and future directions

The immune and inflammatory networks are complex and not fully understood at present, and even though our knowledge regarding the basic mechanisms of action of cytokines in humans is constantly expanding, there are still no absolute data on the benefit of targeted anti-inflammatory therapy in atherosclerosis. Notably, as demonstrated by the MRC-ILA-HEART study36 and other direct and indirect anti-inflammatory strategies such as with anti-IL-12/23 antibodies,42 corticosteroids,41 aspirin65 and COX-2 inhibitors,106 targeted and broad-based anti-inflammatory treatments may even lead to an increased rate of adverse cardiovascular events in some cases. Indeed, our experience shows that several drugs with promising results in animals fail to demonstrate similar efficacy in humans, such as Bendavia in the recent EMBRACE STEMI trial.100

Nevertheless, other studies have shown significant benefit for such anti-inflammatory strategies. Overall, there seems to be a significant gap between our detailed understanding of cytokine actions and the benefit of such targeted interventions. This could be explained by the complex actions of a huge number of cytokines that are involved in atherogenesis as well as by the lack of large-scale clinical trials that can provide reliable data on the efficacy of these strategies.

Therefore, modulation of cytokines poses a therapeutic dilemma and the risks and benefits of inflammation suppression must be weighed before treatment. Particularly in regard to the newer biological agents, observations are limited mostly to rheumatological patients, and small-scale clinical trials and evidence regarding health and survival benefit are lacking in some cases (e.g. TNF inhibitors). Interestingly, there are currently several such clinical trials that are taking place (most notably the CANTOS, CIRT, and Entracte trials) whose results are eagerly awaited and may shape the future of atherosclerosis management and treatment.

Conclusion

Atherosclerosis is considered an inflammatory disease, and the significant role of cytokines in the initiation and maintenance of a pro-inflammatory state is well established. In recent years, novel therapeutic approaches capable of modulating cytokine production or their actions have been tested or are under investigation. Indeed, broad-based immunomodulatory therapies or specific molecules against inflammatory cytokines are now under investigation for the treatment of high-risk atherosclerotic subjects generating new hopes for the future. However, so far, there are no definitive data on the benefit of targeted anti-inflammatory therapy in atherosclerosis and therefore further studies are needed. Hopefully, in the next few years, we are going to have new data that will provide answers and guidance for our next steps in the fight against atherosclerosis and coronary heart disease.

Authors' contributions

E.O. and E.K.E. contributed to the conception and design of the manuscript, drafted the manuscript, and approved the submitted manuscript. D.T., F.C., and J.C.K. contributed to the conception and design of the manuscript, revised the manuscript critically for important intellectual content, and approved the submitted manuscript.

Conflict of interest: none declared.

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